Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH3:25].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:25][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[CH2:19][O:18][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: CN1CCC[C@H]1CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CN1CCC[C@H]1COc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 79.5 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), (S)-(−)-2-hydroxymethyl-1-methylpyrrolidine (69 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 78 mg (0.31 mmol, 79%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 253 (M+1)+, calc. 253 (M+1)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][NH2:14].[C:25]([O:29][C:30]([NH:32][C:33](N1C=CC=N1)=[N:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:38]([O:37][C:35]([NH:34][C:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[N:14][CH2:13][CH2:12][N:11]([CH2:10][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)[CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][CH2:16]1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: NCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(=NCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)NC(=O)OC(C)(C)C
Yield: 74 %

Procedure:
Using General Procedure B: Reaction of N-(tert-butoxycarbonyl)-2-amino-acetaldehyde (0.204 g, 1.28 mmol) and (1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.284 g, 1.02 mmol) with NaBH(OAc)3 (0.430 g, 2.03 mmol) in CH2Cl2 (10 mL) provided 0.71 g of a yellow foam. The foam was dissolved in THF (10 mL) and treated with 6N hydrochloric acid (10 mL). The resultant solution was stirred at room temperature overnight. The solution was neutralized with solid K2CO3 (5 g), diluted with water (5 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.205 g (64%) of N1-(1H-Benzimidazol-2-ylmethyl)-1-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine as a yellow solid. To a solution of N1-(1H-Benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine (0.205 g, 0.64 mmol) in dry THF (6 mL) was added N.N′-bis-(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (Tetrahedron Lett. 1993, 34, 3389.) (0.201 g, 0.64 mmol) and the resultant mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the resultant oil was purified by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) and provided 0.267 g (74%) of N,N′-bis(tert-butoxycarbonyl)-N″-{2-[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-ethyl}-guanidine as a white foam.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([NH2:11])=[O:10])=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:24]([C:36]([F:39])([F:38])[F:37])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:8][N:7]1[C:3]([C:1]#[C:2][C:17]2[CH:16]=[C:15]([NH:20][C:21]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[C:24]([C:36]([F:39])([F:37])[F:38])[CH:23]=3)=[O:40])[CH:14]=[CH:13][C:18]=2[CH3:19])=[CH:4][N:5]=[C:6]1[C:9]([NH2:11])=[O:10]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc(C(N)=O)n1C
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc(C(N)=O)n1C

Procedure:
The title compound can be synthesized from 5-ethynyl-1-methyl-1H-imidazole-2-carboxylic acid amide and N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide in a manner similar to that described for Example 2. 5-ethynyl-1-methyl-1H-imidazole-2-carboxylic acid amide is prepared as in Example 2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:13][CH2:12][C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:14][CH2:15]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: COC(=O)CC12CCC(c3cccc(O)c3)(CC1)OC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 96 h
Yield: 76.7 %

Procedure:
A mixture of methyl 2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (887 mg, 3.21 mmol), 3,4-dihydro-2H-pyran (0.5 ml, 5.47 mmol), and PPTS (81 mg, 0.321 mmol) in DCM (10 ml) was stirred at rt for 4 days. The reaction was concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford the title compound (887 mg, 77% yield) as a white solid. LCMS, [M+NH4]+=378.4. 1H NMR (500 MHz, CDCl3) δ 7.21 (t, J=8.0 Hz, 1H), 7.13-7.08 (m, 1H), 6.99 (ddd, J=7.8, 1.5, 1.0 Hz, 1H), 6.93 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 5.43 (t, J=3.2 Hz, 1H), 3.97-3.86 (m, 3H), 3.67 (s, 3H), 3.64-3.54 (m, 1H), 2.17 (s, 2H), 2.11-1.96 (m, 5H), 1.90-1.74 (m, 6H), 1.72-1.49 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]([CH2:32]O)=[C:29]([CH3:31])[N:30]=2)=[CH:22][CH:21]=1.ClC1C=CC(C(N)=S)=CC=1.ClC(C(C)=O)C(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:32][C:28]2[S:27][C:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[N:30][C:29]=2[CH3:31])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: NC(=S)c1ccc(Cl)cc1
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccc(Cl)cc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [2-(4-chloro-phenyl)-4-methyl-thiazol-5-yl]-methanol (prepared from 4-chloro-thiobenzamide and ethyl 2-chloro-acetoacetate in analogy to the procedures described in examples 33 a] and 33 b]) in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-3-{4-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=2[C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:17]#[N:18])=[O:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[CH:36]=[C:35]([F:37])[N:34]=[C:33]([F:38])[CH:32]=1.[I-].[Li+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[C:9](=[O:10])[NH:8][C:7](=[O:11])[N:6]([CH2:30][C:31]3[CH:36]=[C:35]([F:37])[N:34]=[C:33]([F:38])[CH:32]=3)[C:5]=2[C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:17]#[N:18])=[O:13])[CH2:3][CH2:2]1
Reactant: Fc1cc(CBr)cc(F)n1
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(C(=O)c2c(C3CC3)c(=O)[nH]c(=O)n2Cc2cc(F)nc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
3-(5-Cyclopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (10 mg, 0.034 mmol) was dissolved in 0.5 mL DMF. Potassium carbonate (4.7 mg, 1 eq.) and 4-bromomethyl-2,6-difluoro-pyridine (7 mg, 1 eq.) were added to the reaction, followed by lithium iodide (4.5 mg, 1 eq.) The reaction was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, followed by washing with brine. The organic layer was concentrated down and purified by reversed phase HPLC (MeCN/water) to give white powder (1.2 mg, 9%). LC-MS shows 420.9 (M−1). 1H NMR (300 MHz, CD3OD): δ 8.40 (s, 1H), 7.97 (s, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 6.58 (s, 2H), 4.85 (s, 2H), 2.44 (s, 3H), 1.01 (m, 1H), 0.72 (m, 3H), 0.43 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([C:11](=[O:21])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([F:20])[CH:13]=2)[CH:3]=1.[CH:22]([N:25](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[N:25]([CH3:22])[C:11]2([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([F:20])[CH:13]=1)[OH:21]
Reactant: COc1cc(F)cc(C(=O)c2cc(Br)ccc2C(=O)O)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(F)cc(C2(O)c3cc(Br)ccc3C(=O)N2C)c1

Procedure:
4-Bromo-2-(3-fluoro-5-methoxy-benzoyl)-benzoic acid (140 mg; 0.39 mmol) is dissolved in 1.4 ml N,N-dimethylformamide, treated with N,N-Diisopropylethylamine (154 μl; 1.19 mmol) and HATU (66 mg; 0.44 mmol). It is stirred at ambient temperature for 5 minutes before 2.0 mol/l methylamine (341 μl; 0.80 mmol) is added. After 16 hours the reaction mixture is purified via reversed phase chromatography under basic conditions.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11](OC)=[O:12])[N:5]=[C:4]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)[N:19]=2)[N:3]=1.[O:34]([CH2:36][CH2:37][CH2:38][NH2:39])[CH3:35].N1C=NC=N1.C1CCN2C(=NCCC2)CC1>>[O:34]([CH2:36][CH2:37][CH2:38][NH:39][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][CH:17]=[C:8]([CH2:7][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:25][CH:24]=4)[N:19]=3)=[N:5]2)[CH:9]=1)[CH3:35]
Reactant: COC(=O)c1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Reactant: COCCCN
Agent: c1nc[nH]n1
Solvent: C1CCC2=NCCCN2CC1
Product: COCCCNC(=O)c1cccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)c1
Temperature: 70 °C
Yield: 87.1 %

Procedure:
A mixture of methyl 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)benzoate (46 mg, 0.1 mmol) and 3-methoxylpropylamine (27 mg, 0.3 mmol) was treated with 1,2,4-triazole (7 mg, 0.1 mmol) and DBU (15 mg, 0.1 mmol), and heated to 70° C. overnight. The crude product was purified by a silica gel column with EtOAc to give N-(3-methoxylpropyl)-3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)benzamide as a white solid (45 mg, 87%). MS (ES+) C24H23F3N6O4 requires: 516. found: 517 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.28 (d, J=8.8 Hz, 2H), 7.77 (s, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 5.50 (s, 2H), 3.60-3.55 (m, 4H), 3.38 (s, 3H), 2.55 (s, 3H), 1.91-1.86 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([Br:13])[CH:15]=3)[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCN(C2CCCCC2)C1
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(C2CCCCC2)C1)c1cccc(Br)c1

Procedure:
To 16.2 g. (0.1 mole) of 3-amino-1-cyclohexylpyrrolidine in 100 ml. of chloroform was added with stirring 15.1 g. (0.07 mole) of 3-bromobenzoyl chloride. After stirring for 1 hour, the solution was extracted with dilute sodium hydroxide. The chloroform layer was dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized twice from ethyl acetate-isopropyl ether. The impure crystalline material was then partitioned between ethyl acetate and dilute hydrochloric acid. The acid layer was made basic with sodium hydroxide and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, concentrated, and the residue recrystallized from ethyl acetate-isopropyl ether solvent. The yield was 9.1 g. (36.6%); m.p. 128°-130°C.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:15]1[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1)[CH2:6][NH:7]C(=O)OC(C)(C)C)(=[O:3])[CH3:2].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH2:7][CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:23])([F:24])[F:25])=[CH:17][N:16]=1
Reactant: CC(=O)NC(CNC(=O)OC(C)(C)C)c1ncc(C(F)(F)F)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC(CN)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.30 g of tert-butyl 2-(acetylamino)-2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethylcarbamate (0.034 mol) are diluted in a mixture of dichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL). After stirring overnight at room temperature, the reaction mixture is concentrated to dryness to yield to 1.34 g of desired product N-{2-amino-1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}acetamide trifluoroacetate (99%).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([O:27][C:28]([O:30][CH3:31])=[O:29])[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.CN(C=O)C.[Cl:39]C(Cl)Cl>[Pd].CO>[ClH:39].[F:33][C:22]1[CH:23]=[C:24]([CH3:32])[C:25]([O:27][C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[CH:19][C:10]([OH:9])=[CH:11][CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: ClC(Cl)Cl
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)ccc23)c(F)cc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(O)ccc23)c(F)cc1C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
7-Benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (1.53 g, 3.25 mmol) and 10% palladium-on-charcoal catalyst (180 mg) in a mixture of methanol (75 ml), DMF (6 ml) and trichloromethane (30 ml) was stirred under hydrogen at 1.5 atmospheres pressure for 45 minutes. The catalyst was removed by filtration through diatomaceous earth and the solvent removed from the filtrate by evaporation. The residue was triturated with ether, the resulting solid was collected by filtration and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxyquinazoline hydrochloride (1.23 g, 84%) as an orange solid.
Reaction SMILES: [NH:1]([C:8]1[C:13](I)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:1]([C:8]1[C:13](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: Clc1ncc(I)c(Nc2ccccc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1ncc(/C=C/c2ccccc2)c(Nc2ccccc2)n1
Yield: 13 %

Procedure:
A solution of 4-anilino-2-chloro-5-iodopyrimidine (Method 59, 331 mg, 1 mmol), styrene (130 mg, 1.2 mmol), triethylamine (0.5 ml) and palladium acetate (20 mg) in acetonitrile (10 ml) was heated at 80° C. for 20 hours. The solution was poured into water (100 ml) and the mixture was extracted with ethyl acetate (2×50 ml). The extracts were washed with water (2×50 ml) and saturated sodium chloride (50 ml) and dried. Volatile material was removed by evaporation and the residue was purified by bond elute chromatography, eluting with 10% ethyl acetate in isohexane, to give the product (40 mg). NMR (CDCl3): 6.8 (d, 1H), 7.0 (d, 2H), 7.15 (t, 1H), 7.3-7.45 (m, 5H), 7.5 (d, 2H), 7.6 (d, 2H), 8.2 (s, 1H); MS (MH+): 308, 310.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:21]3[S:22][C:23]4[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[CH:26][C:24]=4[CH:25]=3)[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:37]O.C[O-].[Na+]>ClCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:21]3[S:22][C:23]4[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[CH:26][C:24]=4[CH:25]=3)[C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[C:10]([CH2:11][O:12][CH3:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(C)cc2cc(-c3c(CN4CCNC(=O)C4)c(CO)n4ncnc(N)c34)sc12
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COCc1c(CN2CCNC(=O)C2)c(-c2cc3cc(C)cc(OC)c3s2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 21 %

Procedure:
A suspension of Example 125 (88 mg, 194 μmol) in dichloromethane (5 ml) was treated with thionyl chloride (29 μl, 389 μmol), and the mixture was stirred at rt for 65 min. Another portion of thionyl chloride (29 μl, 389 μmol) was added, and stirring was continued for 1.5 h. An excess of methanol was then added, followed by dropwise addition of a 5.4 M solution of sodium methylate in methanol (84 mg, 1.56 mmol) until pH 8 was reached. After stirring for 3 days, the volatiles were evaporated under reduced pressure, and the residue was separated by preparative RP-HPLC (Reprosil C18, gradient 20-40% acetonitrile/0.2% aq. trifluoroacetic acid). The product fractions were evaporated to yield 19 mg of the title compound (21% of th.).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([CH2:16][CH2:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][C:20]=2[F:29])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[SH:35].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:29][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:19]=1[CH2:18][CH2:17][CH2:16][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][S:35][C:31]3[S:30][CH:34]=[CH:33][CH:32]=3)[CH2:6][CH2:7]1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccccc23)CCN(CCCl)CC1
Reactant: Sc1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccccc23)CCN(CCSc2cccs2)CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of 1.8 g of ethyl 1-(2-chloroethyl)-4-[3-(3-fluoroquinolin-4-yl)propyl]piperidine-4-carboxylate monohydrochloride, 0.48 cm3 of thiophene-2-thiol, 2.8 g of potassium carbonate and 0.75 g of potassium iodide in 200 cm3 of anhydrous acetonitrile was stirred under an inert atmosphere for 18 hours at a temperature in the region of 70° C. After cooling to about 20° C., the suspension was filtered, washed with 3 times 30 cm3 of acetonitrile and the filtrate was then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. The evaporation residue was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 6 cm; height 30 cm), eluting with ethyl acetate and collecting 50-cm3 fractions. Fractions 25 to 52 were combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.3 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]-1-[2-(thiophen-2-ylthio)ethyl]piperidine-4-carboxylate were obtained in the form of a viscous orange-colored oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])(=O)=O>CS(C)=O>[Cl:30][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: CS(=O)(=O)CCOS(C)(=O)=O
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)CCN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 120 °C

Procedure:
To a scintillation vial containing N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine (10 mg, 0.023 mmol) and K2CO3 (8 mg, 0.058 mmol) was added DMSO (0.5 ml) and 2-(methylsulfonyl)ethyl methanesulfonate (30 mg). The reaction mixture was capped and heated to 120° C. in an oil bath for 4 hr. The resulting solution was purified by reverse phase preparative HPLC to yield 5′-chloro-N6-(3-fluorobenzyl)-N2′-(trans-4-(2-(methylsulfonyl)ethylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine (3.7 mg, 24%). LCMS (m/z): 532.2 (MH+), retention time=0.62 min as a TFA salt after lypholyzing.
Reaction SMILES: C([O:8][P:9]([CH2:19][C:20]1([C:25]([NH:27][C@H:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([O:42]CC3C=CC=CC=3)=[O:41])[C:29]2=[O:50])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1)([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[P:9]([CH2:19][C:20]1([C:25]([NH:27][C@H:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([OH:42])=[O:41])[C:29]2=[O:50])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1)([OH:10])([OH:11])=[O:8]
Reactant: O=C(CN1C(=O)[C@@H](NC(=O)C2(CP(=O)(OCc3ccccc3)OCc3ccccc3)CCCC2)CCc2ccccc21)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)C2(CP(=O)(O)O)CCCC2)CCc2ccccc21
Yield: 77.5 %

Procedure:
1.9 g of benzyl (3S)-3-(1-dibenzylphosphonomethylcyclopentane-1-carbonylamino)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation see Example 1G) were dissolved in 100 ml of ethanol. 1.2 g of a 5% strength palladium catalyst on active carbon were added to the solution and it was hydrogenated for 3 hours at a hydrogen pressure of 5.5 bar. For workup, the catalyst was filtered out, the filtrate was evaporated in vacuo and the residue was dried. 0.9 g of the title compound was obtained as a foamy product, IR: 3400, 1720, 1630 cm-1 (KBr); [α]D20 =-140.8° (c=0.5 in methanol).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[N:11]=[C:10]([CH2:12]Br)[CH:9]=[CH:8][C:6]=2[N:7]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[K].CO>CC(N(C)C)=O.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([NH2:14])[C:5]2[N:11]=[C:10]([CH2:12][S:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Sc1ccccc1
Reactant: Nc1nc(N)c2nc(CBr)ccc2n1
Agent: [K]
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc(N)c2nc(CSc3ccccc3)ccc2n1
Reaction time: 72 h
Yield: 0.7 %

Procedure:
To a suspension of 7 (~2.5 mmol) in anhydrous dimethylacetamide was added 1 mL thiophenol (5 mmol) and 690 mg anhydrous potassium (5 mmol). After the suspension was stirred for 3 days, the spot of 7 disappeared from TLC. The Rf value of one of new spots which is assigned as 9 is 0.35 (in 2:8 methanol:chloroform). The solvent DMAC was removed under diminished pressure. The solid residue was washed with methanol three times and filtered. The combined liquid was added silica gel and then the methanol was evaporated to dryness. A small amount of product was separated through a dry column. 1HNMR, the product. After crystallization, 5 mg of pure product was obtained.