Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reaction time: 1 h

Procedure:
A stirred suspension of 4-(4-(4-pyridyl)piperazin-1-yl)-phenol (1.34 g) in dry DMF (20 ml) was treated with sodium hydride (60% dispersion in mineral oil, 0.21 g) and the mixture stirred for 1 hour. To the resulting solution was added ethyl 4-bromobutyrate and the mixture was stirred for 16 hours. Solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, filtered through phase separating paper (Whatman 1PS) and evaporated. The residue was purified by flash chromatography on silica, eluting with 1.5/92.5/6 v/v/v methanol/ethyl acetate/aqueous ammonia (SG 0.89) and recrystallised from ethyl acetate/hexane to give the title compound (0.7 g) as a solid: m.p. 84°-85° C.; NMR (CDCl3) δ 8.3(2H,d); 6.86(4H,c); 6.72(2H,d); 4.12(2H,q); 4.0(2H,t); 3.47(4H,m); 3.20(4H,m); 2.5(2H,t); 2.1(2H,m); 1.26(3H,t); m/e 370(M+H)+ ; calculated for C21H27N3O3C, 68.3; H, 7.4; N, 11.4. Found: C, 68.1; H, 7.4; N, 11.1%.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:24])[CH2:6][C:7]1[O:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)[CH3:3].[CH:25](O)(C)C>>[CH3:3][CH:2]([O:4][C:5](=[O:24])[CH2:6][C:7]1[O:8][C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)[CH3:25]
Reactant: CCOC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)OC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 54 %

Procedure:
Sodium (80 mg, 3.5 mg atom) was dissolved in isopropanol (21 mL) and ethyl-4,5-diphenyl-2-oxazoleacetate (1.00 g, 3.2 mmol) added. The mixture was heated at reflux for about 1.5 hours, cooled and concentrated. The residue was diluted with water, acidified to pH=2 with 1N HCl solution and extracted with CH2Cl2. The combined extracts were dried over MgSO4, the solvent removed and the residue chromatographed or a column of silica gel. Elution with a mixture of hexanes and EtOAc (9:1) gave the title compound (0.57 g, 54%). IR (film) 1740 cm-1 ; 1H NMR (CDCl3) δ1.26 (6H, d, J=6Hz, CO2CH(CH3)2), 3.89 (2H, s, CH2CO2iPr), 5.08 (1H, septuplet, OCH(CH3)2), 7.25 to 7.40 (6H, m, aromatic H), 7.50 to 7.65 (4H, m, aromatic H); MS m/z 322 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([OH:22])=[N:10]2)=[CH:5][CH:4]=1.Cl.Cl[CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([O:22][CH2:25][C:26]3[N:27]=[CH:28][S:29][CH:30]=3)=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Reactant: ClCc1cscn1
Agent: Cl
Product: COc1ccc(-c2nc(OCc3cscn3)nn2-c2ccc(OC)cc2)cc1
Yield: 49.7 %

Procedure:
1,5-bis(4-methoxyphenyl)-3-(1,3-thiazol-4-ylmethoxy)-1H-1,2,4-triazole (132 mg, 49.7% yield) was prepared from 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol and 4-(chloromethyl)-1,3-thiazole hydrochloride by the similar manner described for Example 18.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:26])[C@@H:6]([NH2:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3].[Br:27][C:28]1[CH:36]=[C:35]([F:37])[C:31]([C:32](O)=[O:33])=[C:30]([F:38])[CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([O:4][C:5](=[O:26])[C@@H:6]([NH:25][C:32](=[O:33])[C:31]1[C:30]([F:38])=[CH:29][C:28]([Br:27])=[CH:36][C:35]=1[F:37])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCOC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(Br)cc1F

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 8, starting from (S)-2-amino-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester (4.67 g, 13 mmol) , 4-bromo-2,6-difluorobenzoic acid (3.12 g, 13.16 mmol), HBTU (4.99 g, 13.16 mmol), and DIPEA (6.8 mL, 39 mmol), and after ISCO column chromatography purification, resulted in an amorphous off-white solid (6.71 g, 89%). ES-HRMS m/e calcd for C26H26BrF2N3O5 (M+H)+ 578.1097, found 578.1096.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>O1CCCC1>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]2[NH:1][C:24](=[O:25])[N:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(F)cc2N)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(F)c(Cl)cc32)CC1
Temperature: 50 °C

Procedure:
1,1-Dimethylethyl 4-[(2-amino-5-chloro-4-fluorophenyl)amino]-1-piperidinecarboxylate (D3) (0.87 mmol, 300 mg) was dissolved in 5 ml of tetrahydrofuran and carbonyldiimidazole (1,1′-(oxomethanediyl)bis-1H-imidazole) (3 eq., 2.6 mmol, 440 mg) was added at room temperature; the mixture was refluxed at 50° C. overnight. The mixture was cooled to room temperature, THF evaporated and it was diluted in ethyl acetate/H2O/NaHCO3 (saturated solution); the two layers were separated and the aqueous phase was extracted with ethyl acetate (2×); the organic phases were combined and washed with water and NaHCO3 (saturated solution), they were dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound that was purified by chromatography (methanol-NH3-dichloromethane) to yield the title compound, 170 mg 53%, M+−H=368.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@@H:34]([CH3:36])[CH2:33][C@H:32]1[C:37]([OH:39])=[O:38])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[CH3:36][C@@H:34]1[CH2:35][N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[C@H:32]([C:37]([O:39][CH2:2][C:3](=[O:4])[C:5]2[CH:6]=[CH:7][C:8]3[C:17]4[CH:16]=[C:15]5[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]5=[CH:13][C:12]=4[O:11][CH2:10][C:9]=3[CH:23]=2)=[O:38])[CH2:33]1
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a solution of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (647 mg, 1.74 mmol) in MeCN (20 mL) was added ((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (559 mg, 2.44 mmol) and DIPEA (0.36 mL, 2.09 mmol) and the solution was heated to 60° C. After stirring for 3 h, the solution was cooled to rt, and diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 50% EtOAc/hexanes) to afford (2S,4S)-1-tert-butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 4-methylpyrrolidine-1,2-dicarboxylate (621 mg, 69%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>CS(C)=O>[CH:31]1([NH:35][C:2]2[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=2)[C:5]([NH:7][C:8]2[CH:9]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]4[CH2:27][CH2:26]4)=[O:22])=[CH:17][CH:16]=3)[C:11]([CH3:14])=[CH:12][CH:13]=2)=[O:6])[CH2:34][CH2:33][CH2:32]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: NC1CCC1
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2ccnc(NC3CCC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) and cyclobutylamine (1 ml) in DMSO (1 ml) was heated at 140° C. for 72 h in a sealed tube. The reaction was concentrated under vacuum, the residue purified by preparative HPLC, to give, after evaporation of the solvents under vacuum 2-(cyclobutylamino)-N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide. NMR; δH [2H6]—DMSO 10.27,(1H, s), 8.62,(1H, t), 8.08,(1H, d), 7.93,(2H, d), 7.70-7.65,(2H, m), 7.43,(2H, d), 7.28,(1H, d), 7.06,(1H, d), 6.90,(1H, d), 6.81,(1H, s), 4.30,(1H, m), 3.16,(2H, t), 2.26,(2H, m), 2.20,(3H, s), 1.87,(2H, m), 1.67,(2H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.82 min, MH+455.
Reaction SMILES: NC1[C:3]([F:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.IC.[CH3:12][N:13]([CH:15]=O)[CH3:14]>[H-].[Na+].CCOC(C)=O>[Br:8][C:6]1[CH:7]=[C:15]([N:13]([CH3:14])[CH3:12])[C:3]([F:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(C)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-amino-5-bromo-2-fluoropyridine (Matrix Scientific, Columbia, S.C., USA, 1.571 mmol) in DMF (3 ml) and 55% NaH in oil (1.571 mmol) was stirred for 15 min at rt. Was added iodomethane (Aldrich, Buchs, Switzerland, 1.571 mmol) and the RM was stirred for 13 h at rt. The RM was diluted with EtOAc, washed with brine (4×), dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fraction containing the first eluting product were evaporated to give (5-bromo-2-fluoro-pyridin-3-yl)-dimethyl-amine as an orange oil (HPLC: tR 3.15 min (Method A); M+H=219, 221 MS-ES) and the fraction containing the second eluting product were evaporated to give the title compound as a red solid (HPLC: tR 2.90 min (Method A); M+H=205, 207 MS-ES).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[NH:9][C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].[CH2:18](I)[CH3:19].O>CN(C)C=O.C(OCC)(=O)C>[CH2:18]([N:9]1[C:8]2[CH:14]=[CH:15][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13])[CH3:19]
Reactant: CCI
Reactant: COC(=O)c1ccc2c(c1)OCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1C(=O)COc2cc(C(=O)OC)ccc21
Temperature: 25 °C
Yield: 26.4 %

Procedure:
To a solution of 7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine [prepared in Preparation 4(1)] (1.0 g) in dimethylformamide (80 ml) were added 60% sodium hydride (in oil) (0.25 g) and ethyl iodide (1.0 g) and the mixture was stirred at room temperature for a day. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was recrystallized from ethyl acetate/hexane to give 4-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.3 g).
Reaction SMILES: CN(C)[CH:3]=[O:4].[F:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[O:15])[CH:10]=[CH:11][CH:12]=1.[NH2:24][CH2:25][CH:26]([C:28]1[CH:33]=[C:32]([Cl:34])[C:31]([NH2:35])=[C:30]([Cl:36])[CH:29]=1)[OH:27]>C(OCC)(=O)C.CO.C(N(CC)CC)C>[NH2:35][C:31]1[C:30]([Cl:36])=[CH:29][C:28]([CH:26]([OH:27])[CH2:25][NH:24][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:14](=[O:15])[CH2:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=2)=[CH:33][C:32]=1[Cl:34].[C:3]([O-:4])(=[O:27])[C:14]([O-:16])=[O:15]
Reactant: CN(C)C=O
Reactant: O=C(Cc1cccc(F)c1)OCCCCCCBr
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOC(=O)Cc2cccc(F)c2)cc1Cl
Product: O=C([O-])C(=O)[O-]

Procedure:
According to method I (dimethylformamide, 3 hours at 90° C.) from (6-bromo-1-hexyl) 3-fluorophenylacetate and 2-amino-1-(4-amino-3,5-dichlorophenyl)ethanol. Working up by means of chromatography (ethyl acetate/methanol/triethylamine 16:2:1). Recrystallized as the oxalate from acetone. Melting point: 70°-71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl-].C[O:29][C:30](=[O:35])[CH2:31][C:32](O)=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:15]([C:32](=[O:33])[CH2:31][C:30]([OH:35])=[O:29])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CC(=O)O
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (103 mg, 0.26 mmol) was dissolved in absolute CH2Cl2 (13 ml) and malonic acid monomethyl ester chloride (42 mg, 0.31 mmol) was added dropwise. The mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was taken up in 20 ml and 2 N NaOH (2 ml) was added. The solution was stirred at room temperature overnight. Thereafter, the mixture was evaporated in vacuo and the residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 8:2:0.1, l=15 cm, V=5 ml). The crude product was taken up in CH2Cl2 again, the mixture was filtered with a glass filter crucible G4 and Celite® (kieselguhr from CELITE Corp., Lompoc, USA) and the filtrate was evaporated in vacuo. A colorless solid was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][CH2:8][C:9]([CH2:11][C:12](OC)=[O:13])=O>C(O)(=O)C>[CH2:8]([C:9]1[CH:11]=[C:12]([OH:13])[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=1)[CH3:7]
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1nc[nH]n1
Solvent: CC(=O)O
Product: CCc1cc(O)n2ncnc2n1

Procedure:
33.6 g (0.4 mmol) of 3-amino-1H-1,2,4-triazole and 52 g (0.4 mol) of methyl 3-oxo-n-valerate were heated in 130 ml acetic acid for 70 min. After cooling crystals precipitated, which were filtered by suction and dissolved in 1 l water. After several extractions with dichloromethane the combined organic layers were dried over sodium sulfate, and the solvent distilled off in vacuo. The title compound crystallized during the evaporation in colorless crystals,
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH:10]([C:14]1[S:15][CH:16]=[C:17]([CH2:19][S:20][CH2:21][CH2:22][NH2:23])[N:18]=1)[C:11]([NH2:13])=[NH:12].[CH3:24][O:25][C:26](OC)=[N:27][C:28]#[N:29]>CO>[NH:10]([C:14]1[S:15][CH:16]=[C:17]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:26](=[N:27][C:28]#[N:29])[O:25][CH3:24])[N:18]=1)[C:11]([NH2:13])=[NH:12]
Reactant: COC(=NC#N)OC
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Yield: 69 %

Procedure:
Triethylamine (2.02 g.) was added to a suspension of 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole dihydrochloride (3.04 g.) in methanol (30 ml.) stirred at room temperature. Dimethyl (N-cyanoimido)carbonate (1.14 g.) was added and the mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was extracted with ethyl acetate (35 ml.) and the solution was washed with water (25 ml., 10 ml.) then dried (magnesium sulphate) and evaporated under reduced pressure to give 2-guanidino-4-[2-(3-cyano-2-methylisoureido)ethylthiomethyl]thiazole (2.16 g.). The n.m.r. spectrum in CDCl3 /d6 dimethyl sulphoxide using tetramethylsilane as internal standard had the following resonances (δ): 7.7 (1H, very broad); 6.7 (4H, broad); 6.4 (1H, singlet); 3.8 (3H, singlet); 3.6 (2H, singlet); 3.4 (obscured by H2O); 2.7 (2H, broad triplet).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH:16](OS(C)(=O)=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:14][Cl:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CS(=O)(=O)OC(CCCl)c1ccccc1
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: ClCCC(c1ccccc1)n1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a RT solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (424 mg, 2.76 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 121 mg, 3.03 mmol). The reaction mixture was stirred for 30 min at RT and then a solution of methanesulfonic acid 3-chloro-1-phenyl-propyl ester in DMF (2 mL) was added at 0° C. The resulting mixture was stirred overnight at RT and then diluted with H2O and EtOAc. The organic layer was separated, washed 3 times with water, dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc), affording 4-Chloro-7-(3-chloro-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine as a colorless oil (480 mg, 56% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@@H:12]1[CH2:16][C@@H:15]([C:17]([OH:19])=O)[C@H:14]([C:20]([N:22]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23]2)=[O:21])[CH2:13]1)(=[O:11])=[O:10].[CH2:29]1[C:31]([NH2:34])([C:32]#[N:33])[CH2:30]1.Cl>>[C:32]([C:31]1([NH:34][C:17]([C@@H:15]2[CH2:16][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=3[Cl:1])(=[O:10])=[O:11])[CH2:13][C@H:14]2[C:20]([N:22]2[CH2:26][CH2:25][C:24]([F:27])([F:28])[CH2:23]2)=[O:21])=[O:19])[CH2:29][CH2:30]1)#[N:33]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2Cl)C[C@H]1C(=O)N1CCC(F)(F)C1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 117 step 7 using (1R,2R,4S)-4-(2-chloro-4-bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (example 187 step 3) and 1-amino-cyclopropyl cyanic hydrochloride. Light yellow foam (93%). MS (EI): 566.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([NH:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)C>[C:21]([O:11][CH2:10][CH2:9][NH:8][C:7]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:23])[CH3:22]
Reactant: O=[N+]([O-])c1ccc(NCCO)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OCCNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a flask containing 2-(4-nitroanilino)-1-ethanol (0.91 g) in dichloromethane (25 mL) at 0° C. is added triethylamine (1.8 mL), acetyl chloride (0.85 mL) and 4-dimethylaminopyridine (0.06 g). The reaction mixture is allowed to warm to room temperature over 3 hours. The reaction mixture is diluted with diethyl ether, washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica eluting with 50% ethyl acetate in heptane. The product-containing fractions are evaporated to give 0.61 g of 2-(4-Nitroanilino)ethyl acetate as a yellow solid To a Parr bottle containing 2-(4-nitroanilino)ethyl acetate (0.61 g) and ethyl acetate (10 mL) is added 10% palladium on carbon (0.05 g). The reaction mixture is shaken for 2 hours under 50 psi of hydrogen gas. The reaction mixture is filtered through Celite with ethyl acetate washes. The filtrate is concentrated under reduced pressure. The residue is treated with diethyl ethoxymethylenemalonate (0.60 mL) and heated to 135° C. under a flow of argon gas. After 1 hour the reaction is cooled to room temperature, adsorbed onto silica gel, and chromatographed on silica eluting with 60% to 80% ethyl acetate in heptane. The product-containing fractions are evaporated to give 0.45 g diethyl 2-[(4-{[2-(acetyloxy)ethyl]amino}-anilino)methylene]malonate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH2:11])[N:10]=[C:4]2[CH:3]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>C1COCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH:11][C:15]([NH:14][CH2:12][CH3:13])=[O:16])[N:10]=[C:4]2[CH:3]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(Br)ccn2n1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(Br)ccn2n1
Temperature: 100 °C

Procedure:
7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (compound 3, 1.22 g, 5.73 mmol) was dissolved in THF/toluene (1:1, 60 mL), then ethyl isocyanate (4.07 g, 57.3 mmol) and a catalytic quantity of dibutyltindiacetate (6 drops) were added to the mixture. The reaction was then heated in a sealed tube at 100° C. for 24 h. This mixture was allowed to cool, then the solvents removed under reduced pressure to afford an oily solid, which was triturated with Et2O, giving a solid which was collected by filtration. Further material was isolated by flash chromatography of the resulting filtrate on silica (2% MeOH/CH2Cl2 as eluant) to give compound 1-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-ethyl-urea (4) LCMS (APCI+) 284, 286.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1
Reactant: CCNCC
Reactant: CCOC(=O)c1c(CCl)nc2ccc(Cl)cc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)c1c(CN(CC)CC)nc2ccc(Cl)cc2c1-c1ccc(Cl)cc1

Procedure:
According to the same manner as that described in Example 33, ethyl 6-chloro-2-chloromethyl-4-(4-chlorophenyl)quinoline-3-carboxylate was reacted with diethylamine to give ethyl 6-chloro-4-(4-chlorophenyl)-2-(N,N-diethylaminomethyl)quinoline-3-carboxylate. This compound was recrystallized from ethanol. Colorless prisms, mp. 132°-133° C.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:30]([Cl:41])[CH:29]=2)=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[N:16][CH:17]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:42]C1C=CC(C2C=CC(N)=CC=2)=C(C)C=1>>[Cl:42][C:7]1[C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[N:16][CH:17]=2)=[C:3]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:30]([Cl:41])[CH:29]=2)[CH:2]=1
Reactant: Cc1cc(Cl)ccc1-c1ccc(N)cc1
Reactant: O=C(O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cn1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)c(Cl)cc2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cn1

Procedure:
The title compound was prepared as described in Example 77 substituting 2,4′-dichloro-[1,1′-biphenyl]-4-amine (see Example 74) for 4′-chloro-2′-methyl-[1,1′-biphenyl]-4-amine.