Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]([NH2:25])[CH3:24])=[CH:22][C:17]=2[NH:16][CH2:15][CH2:14]1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]([NH:25][C:6](=[O:8])[CH:5]=[CH:4][C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=3[F:1])[CH3:24])=[CH:22][C:17]=2[NH:16][CH2:15][CH2:14]1
Reactant: CC(N)c1ccc2c(c1)NCCO2
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1ccccc1F)c1ccc2c(c1)NCCO2
Reaction time: 72 h

Procedure:
A mixture of 2-fluorocinnamic acid (0.5 mmol), (±)-1-(3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethylamine, Preparation 13 (28.5 mg, 0.16 mmol), EDC hydrochloride (192 mg, 1 mmol), DMAP (61 mg, 0.5 mmol), and triethylamine (202 mg, 2 mmol) in CH2Cl2 was stirred for 3 days. The reaction mixture was directly subjected to purification by flash column chromatography on silica using EtOAc/Hexane (8:1) to provide the desired product (149 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1>CC(O)C>[CH:7]([O:12][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1)([CH3:8])[CH3:6]
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Solvent: CC(C)O
Product: COc1cccc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from propan-2-ol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-isopropoxy-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 313(MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(/C=C/c2cccs2)n1
Product: C(=C/c1cccs1)\c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 92 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-[(E)-2-(2-thienyl)ethenyl]oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-(2-thienyl)ethenyl]oxazole. The yield was 92%. Recrystallization from ethyl acetate-isopropyl ether gave colorless prisms, mp 131-132° C.
Reaction SMILES: [Cl-].[NH4+:2].C([O-])(=O)C.[Na+].[Cl:8][C:9]1[C:10]([CH2:27][CH:28]=O)=[C:11]([CH:25]=O)[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:13]([CH:15]([OH:17])[CH3:16])[CH:14]=1.O1CCCC1>O>[Cl:8][C:9]1[CH:14]=[C:13]([CH:15]([OH:17])[CH3:16])[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:11]2[C:10]=1[CH:27]=[CH:28][N:2]=[CH:25]2
Reactant: CC(O)c1cc(Cl)c(CC=O)c(C=O)c1-c1cccc(F)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ammonium chloride (28.5 mg, 0.533 mmol) and sodium acetate (43.7 mg, 0.533 mmol) in water (0.4 mL) was added to a solution of 4-chloro-3′-fluoro-6-(1-hydroxyethyl)-3-(2-oxoethyl)biphenyl-2-carbaldehyde (0.171 g, 0.533 mmol) in tetrahydrofuran (0.4 mL, 5 mmol). The reaction mixture was stirred at room temperature overnight and then extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, concentrated to dryness under reduced pressure. The crude product was used in the next step (0.16 g, 99%). LCMS calculated for C17H14ClFNO (M+H)+: m/z=302.1; Found: 302.1
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[F:14][C:15]([F:28])([F:27])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=O)=[CH:18][CH:17]=1>>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[O:11][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)=[N:12][N:13]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: FC(F)(F)c1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3-(4-trifluoromethylphenyl)propionic acid (218 mg; 1 mmol) as described in method 2; yield: 0.043 mg (12.0%); MS m/z: 359.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.21-3.25 (m, 2H); 3.31-3.35 (m, 2H); 7.54-7.56 (m, 2H); 7.64-7.67 (m, 2H); 7.86 (d, 1H, 3J=8.7 Hz); 7.92 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.24 (d, 1H, 4J=1.7 Hz); 8.87 (s, 1H); HPLC (METHOD [A]): rt 13.82 min (95.9%)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: N#Cc1ccc(F)cc1
Reactant: COCCCCCOC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCCCOC1CCN(c2ccc(C#N)cc2)CC1
Yield: 31.6 %

Procedure:
A solution of 4-fluorobenzonitrile (0.38 g), 4-(5-methoxypentyloxy)piperidine (0.62 g) and potassium carbonate (0.87 g) in DMF (8 ml) was stirred at 90-95° C. for 6 hours. The reaction mixture was poured into water (50 ml) and extracted twice with a mixture of ethyl acetate and n-hexane (50 ml: 20 ml). The extracts were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v-2:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(5-methoxypentyloxy)-N-(4-cyanophenyl)piperidine (294 mg).
Reaction SMILES: CC(S([NH:7][C@@H:8]([C:10]1[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][CH:15]=1)[CH3:9])=O)(C)C.Cl>CO>[F:19][C:16]([F:17])([F:18])[C:13]1[N:12]=[CH:11][C:10]([C@H:8]([NH2:7])[CH3:9])=[CH:15][N:14]=1
Reactant: C[C@@H](NS(=O)C(C)(C)C)c1cnc(C(F)(F)F)nc1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)c1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of 2-methyl-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}propane-2-sulfinamide (7.23 g, 24.5 mmol) in methanol (100 mL) was added hydrogen chloride (4.0 Min dioxane; 18.5 mL, 74.0 mmol). The mixture was stirred at ambient temperature. After 1 h, the mixture was concentrated to give the title compound (4.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=O)[CH:5]=[C:4](N[C@@H](C)C(OC)=O)[N:3]=1.CO.[NH3:21]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:21])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc(N[C@@H](C)C(=O)OC)nc(Cl)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccnc(Cl)n1
Yield: 89 %

Procedure:
A solution of the (S)-methyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate (3.719 g, 13.59 mmol) in 7M ammonia in methanol (20 mL, 140 mmol) was heated in a sealed tube for 3 days at 50° C. After cooling, the precipitated solid was filtered off and rinsed with MeOH (2×5 mL) then dried under vacuum at 40° C. to give (S)-6-(1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide as a pale yellow powder (2.946 g, 12.09 mmol, 89% yield). LC/MS: m/z=244.2 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-]>CO.O>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2
Reactant: CCOC(=O)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
144 (440 mg, 1.47 mmol) is dissolved in 10 ml of methanol and treated with a solution of LiOH (70 mg, 1.47 mmol) in 5 ml of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([CH2:10][CH2:11][C:12](O)=[O:13])=O)=[CH:6][CH:5]=1>CCO>[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]2[CH:10]=[CH:11][C:12](=[O:13])[NH:1][N:2]=2)=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Solvent: CCO
Product: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrazine (8.9 mL, 0.28 mol) was added to a suspension of 3-(4-chlorobenzoyl)propionic acid (30.0 g, 0.14 mol) in EtOH. The resulting mixture was heated to reflux for 1 hour, stirred at room temperature overnight and chilled with an ice bath. The title compound precipitated out of this mixture (23.85 g, 81%) as a yellow solid: mp 175°-176° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH:11]=O)=[CH:5][CH:4]=1)#[N:2].[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.C([BH3-])#N.[Na+]>>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:11][CH:10]=[CH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: N#Cc1ccc(C=CC=O)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc(C=CCN2CCc3nc(N)sc3CC2)cc1
Yield: 8 %

Procedure:
Prepared from 3-(4-cyano-phenyl)acrolein and 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine by reductive amination with sodium cyanoborohydride. Yield: 8% of theory, Melting point: 199°-205° C. (decomp).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:19]=[C:18]([CH:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[F:29])[NH:21]2)[C:17](O)=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CC#N.C(O)(C(F)(F)F)=O>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[N:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([F:29])[C:27]=3[CH2:28][CH:20]2[C:18]2[N:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=2[O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1C1Cc2c(F)cccc2N1
Reactant: O=CCCOCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Fc1cccc2c1CC1c3nc(Cl)ccc3OC(CCOCc3ccccc3)N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of 3-(benzyloxy)propanal (465 mg, 2.83 mmol) and 6-chloro-2-(4-fluoroindolin-2-yl)pyridin-3-ol (500 mg, 1.89 mmol) in MeCN (15 mL) was added TFA (10 mg, 0.09 mmol). The mixture was stirred at room temperature for 3 hours. The it was basified by NaHCO3 (aq.), and then it was concentrated in vacuo, the resulting residue was purified using column chromatography (petroleum ether:EtOAc=10:1) to provide 6-(2-(benzyloxy)ethyl)-2-chloro-11-fluoro-12,12a-dihydro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (540 mg, yield: 69%). 1H-NMR (CDCl3, 400 MHz) δ 7.28˜7.38 (m, 5H), 7.04˜7.10 (m, 2H), 6.95 (d, J=8.8 Hz, 1H), 6.60 (d, J=8.0 Hz, 1H), 6.50 (t, J=8.0 Hz, 1H), 5.93 (t, J=7.2 Hz, 1H), 5.02 (d, J=8.8 Hz, 1H), 4.55 (d, J=2.4 Hz, 1H), 3.62˜3.71 (m, 3H), 3.40˜3.48 (m, 1H), 2.19˜2.27 (m, 2H). MS (M+H)+: 411.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([CH:15]([O:19][CH2:20][CH3:21])[C:16]([OH:18])=O)=[C:10]([F:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26]1[C:33]([F:34])=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[F:35]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:22])[C:11]([CH:15]([O:19][CH2:20][CH3:21])[C:16]([NH:24][CH2:25][C:26]3[C:27]([F:35])=[CH:28][C:29]([C:30]#[N:31])=[CH:32][C:33]=3[F:34])=[O:18])=[C:12]([F:14])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C(=O)O)c1c(F)cc(-c2ccc(N)nc2)cc1F
Reactant: N#Cc1cc(F)c(CN)c(F)c1
Agent: Cl
Product: CCOC(C(=O)NCc1c(F)cc(C#N)cc1F)c1c(F)cc(-c2ccc(N)nc2)cc1F

Procedure:
According to general procedure C, (RS)-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-ethoxy-acetic acid (intermediate from example 334.4, contains 2 equivalent of NaCl) was reacted with 4-aminomethyl-3,5-difluoro-benzonitrile hydrochloride (example 318.1) to give (RS)-2-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-N-(4-cyano-2,6-difluoro-benzyl)-2-ethoxy-acetamide as off-white solid. MS 459.6 ([M+H]+)
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25](O)(=[O:34])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:28]1([CH:27]=[CH:26][C:25]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1
Yield: 67.6 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (4.8 mL), cinnamic acid (2.6 g), WSC.HCl (3.3 g), and methylene chloride (150 mL), to give the captioned compound (3.7 g, 67%) as an oily product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1.[CH2:22]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:32])=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH3:25]
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC
Reactant: CCCCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)NC2CCC(OC(C)=O)CC2c2ccc(OC)c(OC)c2)cc1

Procedure:
790 mg of (±)-acetic acid (1RS,3RS,4RS)-4-amino-3-3,4-dimethoxyphenyl)cyclohexyl ester (compound B1), 620 mg of 4-butoxybenzoic acid, 614 mg of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride and 2 mg of 4-dimethylaminopyridine are stirred in 7 ml of dichloromethane for 18 h. 5 ml of water are added, the phases are separated and once the organic layer is extracted with 3 ml of dichloromethane. Then the organic layer is washed with 2.5 ml of saturated aqueous potassium bicarbonate solution and the aqueous solution is once extracted with 5 ml of dichloromethane. The combined organic layers are dried over magnesium sulfate, then the solvent is removed to give 1172 mg of the title compound as a colorless foam.
Reaction SMILES: CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:43]([C:45]1[N:50]=[CH:49][NH:48][C:47](=O)[CH:46]=1)[CH3:44].[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:54])[CH3:53]>CN(C=O)C>[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][N:62]([C:47]2[CH:46]=[C:45]([CH2:43][CH3:44])[N:50]=[CH:49][N:48]=2)[CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1cc(=O)[nH]cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.9 %

Procedure:
4 mL DIPEA and 3 g PYBOP was added to 2.9 g 6-ethyl-3H-pyrimidin-4-one in 10 mL DMF. The reaction was stirred 5 min at ambient temperature and 1.1 g piperazine-1-carboxylic acid tert-butyl ester was added. The reaction was stirred overnight at RT. The solvent was removed and the residue was purified by HPLC to give 1 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11](O)([CH3:13])[CH3:12].S(=O)(=O)(O)O>ClCCl>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[C:6]([C:11]([CH3:13])([CH3:12])[CH3:10])[CH:7]=1
Reactant: CC(C)(C)O
Reactant: Cc1cc(O)ccc1Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1cc(O)c(C(C)(C)C)cc1Br
Temperature: 25 °C
Yield: 51 %

Procedure:
A solution of 4-bromo-3-methylphenol (Aldrich, 5.1 g, 27.3 mmol) in anhydrous dichloromethane (50 mL) was treated with 2-methyl-2-propanol (15 mL) and concentrated sulfuric acid (3 mL) and stirred at ambient temperature for 3 months. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography using 3-5% ethyl acetate in hexane as the eluent afforded the title compound as a deep yellow oil (3.42 g, 51%). It was used as such for the next step.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCN(c1cc(CO)cc(C(=O)OC)c1)S(C)(=O)=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCN(c1cc(CBr)cc(C(=O)OC)c1)S(C)(=O)=O
Reaction time: 15 h

Procedure:
To a solution of methyl 3-(hydroxymethyl)-5-[(methylsulfonyl)(propyl)amino]benzoate (2.99 g, 9.92 mmol) in dichloromethane (90 mL) were added carbon tetrabromide (4.28 g, 12.9 mmol) and triphenylphosphine (3.12 g, 11.9 mmol). After 15 h, the reaction mixture was concentrated in vacuo and purified by flash chromatography (silica, 0-40% EtOAc/hexanes) to provide methyl 3-(bromomethyl)-5-[(methylsulfonyl)(propyl)amino]benzoate as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 4.50 (s, 2H), 3.94 (s, 3H), 3.67 (t, J=7.2 Hz, 2H), 2.90 (s, 3H), 1.56-1.46 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([NH:37][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=1[F:45])=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[O:18])[CH:13]=2)[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:17]([C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=4[F:45])=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)[NH:16][CH:15]=1)=[O:18]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of tert-butyl (3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)carbamate (450 mg, 0.72 mmol) in 10 ml of methylene chloride was added 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 20 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-aminopropyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as grey solid. Yield: 320 mg, 85%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([Cl:12])=[CH:5][C:4]=1[NH2:13].[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[NH2:13][C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][NH:1][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: NCc1cc([N+](=O)[O-])c(Cl)cc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc([N+](=O)[O-])c(Cl)cc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(aminomethyl)-5-chloro-4-nitrobenzenamine (2.5 g, 12.25 mmol) in THF (35 mL), TEA (3.0 mL) and pivaloyl chloride (1.96 mL, 14.7 mmol) were added and the reaction mass was stirred at RT for 5 h. The reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was washed with dilute HCl and dilute sodium bicarbonate solution, separated, dried over anhydrous sodium sulphate and concentrated to afford 2.0 of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.30 (d, J=5.4 Hz, 2H), 7.81 (d, J=9.9 Hz, 1H), 7.96 (d, J=6.3 Hz, 1H), 8.21 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21]([CH2:29][CH2:30][O:31][CH3:32])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1)[CH3:20]>>[CH2:19]([N:21]([CH2:29][CH2:30][O:31][CH3:32])[C:22]1[N:23]=[CH:24][C:25]([NH:28][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:26][CH:27]=1)[CH3:20]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCN(CCOC)c1ccc(N)cn1
Product: CCN(CCOC)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[ethyl-(2-methoxy-ethyl)-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-ethyl-N2-(2-methoxy-ethyl)-pyridine-2,5-diamine. LCMS calcd for C21H21F3N4O3 (m/e) 434, obsd 435 (M+H).
Reaction SMILES: CS(C)=O.[F-].[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C-:22]#[N:23].[Na+]>O>[C:6]([C:16]1[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=1)(=[O:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCC(=O)c1ccccc1
Reactant: [C-]#N
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCC(=O)c1ccc(C#N)cc1
Yield: 100 %

Procedure:
To 1350 ml of dimethylsulfoxide were added 292.2 g (1.238 mol) of the above 4-nonanoyl-benzene fluoride and 67.4 g (1.374 mol) of sodium cyanide, which were reacted at 110°-125° C. for 12 hours. After the cooling up to room temperature, the reaction solution was poured into 2.7 l of water and extracted with 2 l of chloroform. The extract was washed with a saturated saline solution and dried on anhydrous magnesium sulfate. The solvent was distilled off to obtain 317.9 g (yield: 100%) of brown oily substance of 4-nonanoyl benzonitrile having an infrared absorption spectrum of 1680 cm-1.