Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCP(=O)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1.[CH2:30]([N:32]([CH2:40][CH3:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1)[CH3:31].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:40]([N:32]([CH2:30][CH3:31])[C:33]1[CH:34]=[C:35]([NH:39][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:8]([CH3:7])=[C:9]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=[CH:20][N:19]=3)[CH:10]=2)[CH:36]=[CH:37][CH:38]=1)[CH3:41]
Reactant: CCN(CC)c1cccc(N)c1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1cccc(NC(=O)c2ccc(C)c(Nc3nccc(-c4cccnc4)n3)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1.05 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4 mg, 0.7 mmol), N,N-diethyl-1,3-benzenediamine (115 mg, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is purified by chromatography on silica gel, eluent 2% methanol in dichloromethane and crystallised from acetone to give the title compound as a crystalline solid. 1H-NMR (400 MHz, DMSO-d6, δ): 1.07 (t, 6H); 2.31 (s, 3H); 3.29 (m, 4H); 6.38 (m, 1H); 7.06 (m, 2H); 7.11 (m, 1H); 7.36 (d, 1H); 7.43-7.50 (m, 2H); 7.67 (m, 1H); 8.21 (m, 1H); 8.43 (m, 1H); 8.51 (d, 1H); 8.66 (dd, 1H); 9.12 (s, 1H); 9.24 (m, 1H); 9.90 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:18])[C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=2[NH:8][C:9](=[O:13])[C:10]=1[O:11]C)[CH:2]=[CH2:3].B(Br)(Br)Br>ClCCl.O>[CH2:1]([C:4]1[C:5](=[O:18])[C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=2[NH:8][C:9](=[O:13])[C:10]=1[OH:11])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OC)c(=O)[nH]c2ccccc2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: C=CCc1c(O)c(=O)[nH]c2ccccc2c1=O
Yield: 74.3 %

Procedure:
To a solution of 4-allyl-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.2 g) in dichloromethane was added boron tribromide (1M in dichloromethane, 3 mL). The precipitate that formed was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated using toluene to azeotrope the water. The solid was recrystallized from hot toluene to give the title compound (0.14 g); mp 174°-175° C.; NMR: 5.80 (m,1); 5.03 (s,1); 4.98 (d,1); 3.38 (d,2); MS: m/z=229(M+1). Analysis for C13 H11NO3.0.1 H2O: Calculated: C, 67.58; H, 4.89; N, 6.06; Found: C, 67.63; H, 4.88; N, 5.95.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]1([C:50]2[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=2)[CH2:49][CH2:48]1.C(N(CC)CC)C>CN(C=O)C>[CH:47]1([C:50]2[S:51][CH:52]=[C:53]([C:55]([N:28]3[CH2:29][C:30]4([CH2:35][CH2:34][N:33]([CH2:36][C:37]5[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=5)[CH2:32][CH2:31]4)[O:25][CH2:26][CH2:27]3)=[O:56])[N:54]=2)[CH2:49][CH2:48]1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Reactant: O=C(O)c1csc(C2CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1csc(C2CC2)n1)N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1
Reaction time: 0.5 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.34 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.21 g), 2-cyclpropylthiazole-4-carboxylic acid (example 57, step c) (0.12 g) and triethylamine (0.38 mL) in DMF (7 mL) and the resulting yellow solution was stirred for 30 min. The mixture was partitioned between ethyl acetate and brine (100 mL), the organic layer was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.15 g.
Reaction SMILES: [H-].[Na+].[C:3]([C:11]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[N:13][NH:14][CH:15]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][O:24][CH2:25]Cl>CN(C)C=O>[C:3]([C:11]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[N:13][N:14]([CH2:23][O:24][CH3:25])[CH:15]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccccc1)c1c[nH]nc1-c1cccc(Cl)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1cc(C(=O)c2ccccc2)c(-c2cccc(Cl)c2)n1
Temperature: 0 °C

Procedure:
To 55% sodium hydride (1.9 g) was added N,N-dimethylformamide (3 ml) and stirred while cooled with ice. To this was then added dropwise a solution of 4-benzoyl-3-(3-chlorophenyl)pyrazole (1.24 g) in N,N-dimethylformamide. The reaction mixture was stirred for 20 minutes at room temperature after the vigorous foaming ceased. The reaction mixture was added with chloromethyl methyl ether (0.59 g) and stirred for 5 hours at room temperature, which was then poured into ice-water, extracted with ethyl acetate, washed with water and dried on anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The thus obtained residue was purified by column chromatography (silica gel; ethyl acetate/n-hexane=3/1) and recrystallized from acetonitrile to give the compound of interest (620 mg). M.P.: 105.5-107.9° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].Cl.[NH2:10][CH2:11][C:12]1[C:17]([Cl:18])=[N:16][CH:15]=[CH:14][N:13]=1>>[C:1]([O:4][CH2:5][C:6]([NH:10][CH2:11][C:12]1[C:17]([Cl:18])=[N:16][CH:15]=[CH:14][N:13]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: NCc1nccnc1Cl
Reactant: CC(=O)OCC(=O)O
Agent: Cl
Product: CC(=O)OCC(=O)NCc1nccnc1Cl
Yield: 90.3 %

Procedure:
According to the procedure described in example 13 step 13a acetoxyacetic acid (0.667 g) and 2-aminomethyl-3-chloropyrazine hydrochloride (content 77%; 0.81 g) gave 2-((3-chloropyrazin-2-yl)methylamino)-2-oxoethyl acetate (0.99 g) after purification by column chromatography (silica gel; gradient of dichloromethane to dichloromethane/ethyl acetate 1/1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:18][C:19]([CH3:23])([CH3:22])[CH:20]=O)[CH2:15][CH:16]=[CH2:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:14]([S:18][C:19]([CH3:23])([CH3:22])[CH2:20][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:11])[CH3:12])[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCCSC(C)(C)C=O
Reactant: CC(C)(S)CNc1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Reaction time: 17 h
Yield: 83 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (3.5 g, 1.78×10-2 mol, 100 M %) and 2-(3-butenylthio)-2methylpropanal (4.23 g, 2.67×10-2 mol, 150 M %) were dissolved in 200 ml methanol. Glacial acetic acid (2.05 ml, 3.56×10-2 mol, 200 M %) and sodium cyanoborohydride (3.36 g, 5.35×10-2 mol, 300 M %) were then added. After 17 hours, the reaction was quenched by the addition of 100 ml 0.5N HCl. The acidic solution was then extracted with 2×100 ml diethyl ether. The combined organic extracts were washed with 100 ml saturated NaHCO3, followed by 100 ml saturated NaCl. The ether layer was then dried over anhydrous Na2SO4. The solvent was removed on the rotary evaporator, and the residue was purified by filtration through a 600 ml sintered-glass funnel silica bed, using 90% hexane/diethyl ether as the eluting solvent, to give 5 g (84% yield) 1-[2-(3-butenylthio)-2-methylpropylamino]-2-(2-mercapto-2-methylpropylamino)benzene as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[CH:17]=[N:16][NH:15][N:14]=2)[O:4]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26]>CC(C)=O>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[CH:17]=[N:16][N:15]([CH2:25][CH3:26])[N:14]=2)[O:4]1
Reactant: CCI
Reactant: CO[C@@H]1O[C@H](c2cn[nH]n2)[C@H]2OC(C)(C)O[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1ncc([C@H]2O[C@@H](OC)[C@@H]3OC(C)(C)O[C@@H]32)n1
Temperature: 25 °C
Yield: 46.1 %

Procedure:
A solution of 4-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2H-1,2,3-triazole (Preparation 23) (0.35 g, 1.45 mmol), potassium carbonate (0.2 g, 1.45 mmol) and iodoethane (0.12 ml, 1.45 mmol) in acetone (5 ml) was stirred at room temperature for 48 hours. The reaction mixture was allowed to cool to room temperature, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99.7:0.3 by volume) gradually changing to dichloromethane:methanol (99:1 by volume) to give initially 4-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-ethyl-2H-1,2,3-triazole (0.18 g) followed by the title compound (TLC data—Rf 0.25 in solvent system dichloromethane:methanol 98:2 by volume) contaminated with 25% of 5-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-1-ethyl-1H-1,2,3-triazole (0.16 g). This material was used in subsequent steps without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11]Br>O>[Br:11][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: O=[N+]([O-])c1cnccc1O
Reactant: BrBr
Solvent: O
Product: O=[N+]([O-])c1cncc(Br)c1O
Temperature: 50 °C
Yield: 79.8 %

Procedure:
4-hydroxy-3-nitropyridine (40 g, 0.285 mol) was added to 200 ml of water and then bromine (18.44 ml, 0.36 mol) was slowly added thereto at room temperature. The reaction mixture was stirred under heating for 2 hours at 50° C. and then cooled to room temperature. The resulting precipitate was filtered, washed with water, and then dried to give the titled compound as a pale yellow solid (49.8 g, 87.8%). The product was used in the subsequent step without further purification.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:21]2(=[O:36])=[O:35])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])(=[O:3])[CH3:2].[C:44]([O:48][C:49](=[O:60])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][NH2:59])=[CH:53][CH:52]=1)([CH3:47])([CH3:46])[CH3:45].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(Cl)Cl.CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[C:44]([O:48][C:49](=[O:60])[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([CH2:57][CH2:58][NH:59][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[S:21]3(=[O:36])=[O:35])=[CH:16][CH:15]=2)=[CH:55][CH:56]=1)([CH3:45])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)Cc1ccc(CCN)cc1
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)[C@H](Cc4ccccc4)NC(C)=O)C(=O)O)cc3)S2(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)[C@H](Cc4ccccc4)NC(C)=O)C(=O)NCCc4ccc(CC(=O)OC(C)(C)C)cc4)cc3)S2(=O)=O)cc1
Reaction time: 3 h

Procedure:
The title C compound, (S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid (83.4 mg, 0.137 mmol) is dissolved in DMF (2 mL) and a solution of [4-(2-amino-ethyl)phenyl]-acetic acid t-butyl ester (32.2 mg, 0.137 mmol) in CH2Cl2 (0.5 mL) is added followed by a solution of HOBt (21.9 mg, 0.143 mmol) in DMF:CH2Cl2 (50:50, 0.5 mL), and finally EDCl (27.6 mg, 0.143 mmol) and TEA (0.020 mL, 0.143 mmol) as a slurry in CH2Cl2 (0.5 mL). The reaction is mixed well to give a homogeneous solution. After 3 h, EtOAc (100 mL) is added and the reaction is washed three times with 2N aqueous HCl (50 mL) and saturated aqueous NaHCO3 (50 mL). EtOAc layer is dried over anhydrous Na2SO4 and concentrated to yield {4-[2-((S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionylamino)-ethyl]-phenyl}-acetic acid t-butyl ester as an oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][NH:18][CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.[C:39]([O:43][C:44]([N:46]1[CH:50]([C:51](O)=[O:52])[CH2:49][O:48][C:47]1([CH3:55])[CH3:54])=[O:45])([CH3:42])([CH3:41])[CH3:40].C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][N:18]([C:51]([CH:50]3[CH2:49][O:48][C:47]([CH3:55])([CH3:54])[N:46]3[C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])=[O:52])[CH2:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CNC[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)COC1(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@@H](O[C@H]1CN(C(=O)C2COC(C)(C)N2C(=O)OC(C)(C)C)C[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 38 mg (0.094 mmol) (3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidine (Example 1. Step E) in 7.5 mL methylene chloride was added 12.7 mg (0.094 mmol) HOBT, 34.7 mg (0.14 mmol) 3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidine-4-carboxylic acid, 0.04 mL (0.28 mmol) triethylamine and 54 mg (0.28 mmol) EDC. The resulting mixture was stirred at RT for 16 hr. The reaction mixture was partitioned between 5 mL brine and extracted with EtOAc (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvent removed under vacuum. The yellow oil was purified by prep TLC eluting with methylene chloride/methanol (95/5) to give the title compound. 1H-NMR (CDCl3) rotamers: δ: 1.4-1.8 (m, 18H), 3.20-3.70 (m, 2H), 3.88-4.3 (m, 3H), 4.43-4.70 (m, 1H), 6.97-7.10 (m, 2H), 7.20-7.35 (m, 3H), 7.53. 7.55, 7.62 (3s, 2H), 7.75, 7.78 (2s, 1H)ppm. MS: 631.3 (MH+) observed.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH3:15])[CH:22]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: COc1cc(N)ccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccc(C(F)(F)F)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (25.0 g, 110.3 mmol) in dichloromethane (125.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (13.7 g, 110.3 mmol), pyridine (26.8 mL, 330.9 mmol) and dichloromethane (500.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexane, the hexane was decanted and the product was dried under reduced pressure to yield 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (25.7 g, 74%) as a cream solid. ESI-MS m/z calc. 314.07. found 315.3 (M+1)+; Retention time: 1.49 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.15-8.04 (m, 1H), 8.00-7.85 (m, 2H), 7.76 (d, J=8.1 Hz, 1H), 7.26-7.15 (m, 2H), 3.85 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.CCN(CC)CC.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.CC(OC)(C)C>[Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[C:6]([CH2:8][O:9][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ncc(CO)cc1Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(CO[Si](C)(C)C(C)(C)C)cc1Cl
Yield: 93.6 %

Procedure:
A solution of methyl 3-chloro-5-(hydroxymethyl)-2-pyridinecarboxylate (332.6 mg, 1.650 mmol), Et3N (0.345 ml, 2.475 mmol), and tert-butyldimethylsilyl chloride (261 mg, 1.732 mmol) in DMF (4 ml) was stirred at room temperature for 3 h. The crude was diluted with TBME (40 ml) and organic phase was washed with water and brine. Combined organic phases were washed with sat NH4Cl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (488 mg, 84% yield) as yellow oil pure enough to be used in the next step.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:24])[CH:7]([CH3:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:9].C1COCC1.O>CO>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[CH:7]([CH3:23])[C:6]([OH:24])=[O:5])=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)C(=O)Nc1ccc(-c2ccccc2)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
LiOH.H2O (73 mg, 1.7 mmol) was added to a solution of N-biphenyl-4-yl-2-methyl-malonamic acid methyl ester (330 mg, 1.16 mmol) in a mixture of methanol (1.75 mL), THF (10 mL) and H2O (1 mL). The resulting mixture was stirred for 2 hours at ambient temperature then concentrated. The residue was diluted with water, acidified with conc. HCl. The resulting precipitate was isolated by filtration and dried to afford 260 mg (83%) of N-biphenyl-4-yl-2-methyl-malonamic acid.
Reaction SMILES: [CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:7]=[C:6]1[CH3:19])([CH3:3])[CH3:2].[NH4+:20].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)(Cl)Cl>C(Cl)Cl.O>[CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:20])[C:8]=2[N:7]=[C:6]1[CH3:19])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: Cc1nc2c[n+]([O-])c3ccccc3c2n1NC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc2c(N)nc3ccccc3c2n1NC(C)C
Reaction time: 0.5 h

Procedure:
A solution of N-isopropyl(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.95 g, 7.61 mmol) in 75 mL of CH2Cl2 was treated with 35 mL of concentrated NH4OH solution. To the rapidly stirred solution was added p-toluenesulfonyl chloride (1.52 g, 7.99 mmol). After stirring for 30 min, the reaction mixture was treated with CHCl3 (25 mL) and H2O (35 mL). The layers were separated and the organic portion was washed with 2% Na2CO3 solution (2×), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give a light-yellow solid. Crystallization from propyl acetate gave N1-isopropyl-2-methyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (747 mg) as off-white crystals. mp 227–229° C.; 1H NMR (300 MHz, CDCl3) δ 8.19 (dd, J=8.2, 1.1 Hz, 1H), 7.79 (dd, J=8.4, 0.7 Hz, 1H), 7.53–7.45 (m, 1H), 7.33–7.26 (m, 1H), 5.42 (s, 2H), 4.91 (d, J=1.4 Hz, 1H), 3.73–3.62 (m, 1H), 2.64 (s, 3H), 1.15 (d, J=6.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 151.4, 151.3, 144.9, 133.3, 127.6, 127.3, 124.6, 122.4, 120.2, 115.4, 52.3, 20.9, 13.8; MS m/z 256 (M+H)+; Anal. Calcd for C14H17N5: C, 65.86; H, 6.71; N, 27.43; Found: C, 65.59; H, 6.56; N, 27.09.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:29])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4,4-difluoropiperidin-1-yl)quinolin-7-yl]ethanone (20 mg, 0.06 mmol) and ammonium acetate (47.5 mg, 0.616 mmol) in methanol (0.35 mL) and acetonitrile (0.35 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (7.7 mg, 0.12 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude amine was used directly in the next step. LCMS calculated for C16H19ClF2N3 (M+H)+: m/z=326.1; Found: 326.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24]CC3C=CC(OC)=CC=3)=[O:23])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:8])(=[O:9])[N:7]=1
Reactant: COc1ccc(CNC(=O)NCCCCCCOc2cccc3c2C(N)=NS(=O)(=O)N3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)NCCCCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.5 %

Procedure:
A solution of 1-(6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexyl)-3-(4-methoxybenzyl)urea (122 μmol, 58 mg) (Example 279) in DCM (2.5 mL) was treated with TFA (2.5 mL). The reaction mixture was stirred at room temperature for 4 hours, then the volatiles were removed under a stream of nitrogen. The oily residue was triturated with ether, the precipitate collected, washed with ether, then dissolved in MeOH and evaporated to gives the desired product (44 mg, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.364 (m, 6H), 1.812 (pentet, J=7 Hz, 2H), 2.943 (br t, 2H), 4.154 (d, J=7 Hz, 2H), 4.131 (t, J=7 Hz, 2H), 5.349 (br. s, 2H), 5.894 (br. s, 1H), 6.607 (d, J=8 Hz, 1H), 6.752 (d, J=8 Hz, 1H), 7.456 (t, J=8 Hz, 1H), 7.824 (br. s, 1H), 8.351 (br. s, 1H), 10.945 (s, 1H). MS 356 (MH+).