Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)N.O=[C:21]([CH2:28][CH3:29])[CH2:22][CH2:23][C:24]([O:26]C)=[O:25]>C(O)(C)(C)C>[Cl:19][C:14]1[CH:15]=[C:16]([Cl:18])[CH:17]=[C:12]2[C:13]=1[C:28]([CH3:29])=[C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[N:10]2[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:1])=[CH:8][CH:3]=1
Reactant: NN(Cc1ccccc1Cl)c1cc(Cl)cc(Cl)c1
Reactant: Cl
Reactant: CCC(=O)CCC(=O)OC
Solvent: CC(C)(C)O
Product: Cc1c(CCC(=O)O)n(Cc2ccc(Cl)cc2)c2cc(Cl)cc(Cl)c12

Procedure:
Following the method of Example 2, but using 1-[1-(chlorophenyl)methyl-1-(3,5-dichlorophenyl) hydrazine hydrochloride and methyl 4-oxohexanoate as the starting materials, in t-butanol as solvent, the title compound was prepared.
Reaction SMILES: NN.O=[C:4]1[C:12]2C(=CC=CC=2)C(=O)[N:5]1[O:14][CH2:15][C:16]1[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:18]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]3[N:26]=[N:27][N:28]=[C:20]3[C:19]=2[N:29]=1.[CH2:43](O)C>>[CH3:25][C:22]1[N:21]2[N:26]=[N:27][N:28]=[C:20]2[C:19]2[N:29]=[C:16]([CH2:15][O:14][N:5]=[C:4]([CH3:43])[CH3:12])[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:18]=2[C:23]=1[CH3:24]
Reactant: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNC(=O)c3ccccc3)c12
Reactant: CCO
Agent: NN
Product: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Anhydrous hydrazine (0.47 mL, 15 mmol) was added to a stirred suspension of N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]benzamide (2.8 g, 5.0 mmol) in ethanol (50 mL). After two hours, a solid was isolated by filtration and the filter cake was washed with ethanol. Acetone (25 mL) and methanol (25 mL) were added to the solid and the mixture was stirred overnight. The volatiles were removed under reduced pressure to afford a solid that was triturated with 1 M aqueous sodium hydroxide (10 mL) and 1:1 methanol/acetone (4 mL). The solid was isolated by filtration, washed with water, and dissolved in chloroform (100 mL). The solution was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to afford 1.9 g of a N-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}benzamide as a white solid.
Reaction SMILES: [NH2:1][C@@:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([Br:18])[N:12]=1)([CH3:10])[CH2:3][C@H:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[N+:19]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]=[C:29]=S)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C>CC#N>[Br:18][C:13]1[N:12]=[C:11]([C@:2]2([CH3:10])[CH2:3][C@H:4]([C:5]([F:6])([F:7])[F:8])[O:9][C:29]([NH:28][C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:32][CH:31]=3)=[N:1]2)[C:16]([F:17])=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@](N)(C[C@H](O)C(F)(F)F)c1nc(Br)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@]1(c2nc(Br)ccc2F)C[C@H](C(F)(F)F)OC(NC(=O)c2ccc([N+](=O)[O-])cc2)=N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4S)-4-amino-4-(6-bromo-3-fluoropyridin-2-yl)-1,1,1-trifluoropentan-2-ol (7f, 0.183 g, 0.553 mmol) in MeCN (3 mL) was added 4-nitrobenzoyl isothiocyanate (Matrix, 0.150 g, 0.719 mmol). The mixture was stirred at room temperature for 30 min. Additional 4-nitrobenzoyl isothiocyanate (30 mg) was added and the reaction was allowed to stir for additional 20 min. N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (Aldrich, 0.170 g, 0.884 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.241 mL, 1.382 mmol) was added and the reaction mixture was heated to 70° C. for 1 h. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated washed with brine, and dried over sodium sulfate. The filtrate was concentrated under reduced pressure and the crude material was purified by silica gel chromatography (0-60% EtOAc/hexanes) to obtain the title compound as an off-white solid. MS m/z=505/507 [M]+/[M+2]+. Calculated: 505.2
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl[C:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.Cl.Cl[CH2:32]CCl>>[C:20]12([C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[C:1]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:32])=[O:13])=[O:8])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2
Reactant: O=C(O)CCCC(=O)c1ccccc1
Reactant: ClC12CC3CC(CC(C3)C1)C2
Reactant: ClCCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)CCCC(=O)c1cccc(C23CC4CC(CC(C4)C2)C3)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 24 %

Procedure:
5.0 g (26.0 mmol) of 4-benzoylbutyric acid was dissolved in 100 ml of 1,2-dichloroethane, and 8.70 g (65.03 mmol) of aluminum trichloride and 5.30 (31.21 mmol) of 1-chloroadamantane were added thereto, followed by stirring the mixture at 60° C. for 6 hours. The reaction mixture was poured into hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue were added 100 ml of methanol and 5 ml of conc. sulfuric acid, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was poured into water, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica-gel column chromatography (eluent: a mixture of 1% ethyl acetate and hexane) to obtain 2.13 g of the above-mentioned compound (yield 24%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:3]=1[C:16]([O:18]C)=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[NH2:24]>>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([S:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:8])=[O:9])[C:3]=1[C:16]([NH:24][C:23]1[CH:22]=[C:21]([Cl:20])[CH:27]=[C:26]([Cl:28])[CH:25]=1)=[O:18]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)c1c(Br)ccn1S(=O)(=O)c1ccccc1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1c(Br)ccn1S(=O)(=O)c1ccccc1
Yield: 95.8 %

Procedure:
Prepared from 2.00 g (5.81 mmol) of methyl 3-bromo-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate and 2.82 g (17.41 mmol) of 3,5-dichloroaniline following the experimental procedure described in Preparation 44a. The product was purified by flash chromatography (0% to 40% hexane/AcOEt) to give 2.64 g (96% yield) of the title compound as a beige solid.
Reaction SMILES: C(CC[CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]1C=O)#N.[C:14]1([CH3:24])[CH:19]=CC(S(O)(=O)=O)=CC=1.[CH2:25]([NH2:28])[CH2:26][NH2:27].[O-]CC.[Na+]>C(O)C>[NH:27]1[CH2:26][CH2:25][N:28]=[C:19]1[CH2:14][CH2:24][CH:9]1[CH2:10][CH2:11][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: NCCN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#CCCC1CCCCCN1C=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C1CNCCC(CCC2=NCCN2)C1
Temperature: 200 °C
Yield: 79 %

Procedure:
A mixture containing 2-cyanoethyl hexahydro-1H-azepine-1-carboxaldehyde (1.94 g, 0.01M) and ethylenediamine p-toluenesulfonate (5.4 g, 0.023M) was heated at 200° C. under nitrogen for 41/2 hrs. The mixture was dissolved in ethanol (30 ml), basified with sodium ethoxide (0.024M), filtered and stripped to dryness. The residue was distilled at 180° to about 190° C., 0.05 mmHg to give rac-4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepine (79% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18](=[O:32])[C@@H:19]([NH2:31])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:16][O:17][C:18](=[O:32])[C@@H:19]([NH:31][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH:14]=[CH2:15])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)OC
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of 2-(S)-tert-butoxycarbonylamino-pent-4-enoic acid (3.8 g, 18.0 mmol) and 2-(S)-amino-3-naphthalen-2-yl-propionic acid methyl ester (4.1 g, 18.0 mmol) in DMF (40 mL) are added 1-hydroxybenzotriazole (3.1 g, 23.4 mmol), N-methylmorpholine (9.1 g, 90.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (4.5 g, 23.4 mmol) consecutively and the reaction mixture is stirred for 3 hours. The reaction is quenched with aqueous NH4Cl and extracted with ethyl acetate. The extract is dried over Na2SO4, filtered and concentrated in vacuo and the residue purified over silica gel (hexanes/ethyl acetate, 1:1) to afford 6.4 g (84% yield) of the desired product.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[C@@H:22]12[CH2:30][NH:29][CH2:28][C@@H:27]1[CH2:26][CH2:25][CH2:24][NH:23]2.N12CCN(CC1)CC2>CN(C)C=O.C(#N)C>[C:12]([C:11]1[C:2]([N:29]2[CH2:30][C@@H:22]3[C@@H:27]([CH2:26][CH2:25][CH2:24][NH:23]3)[CH2:28]2)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
690 mg (2.25 mmol) of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are stirred with 312 mg (2.47 mmol) of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane and 504 mg (4.50 mmol) of 1,4-diazabicyclo[2.2.2]-octane (DABCO) in a mixture of 6.6 ml of dimethylformamide and 6.6 ml of acetonitrile at room temperature overnight. All the volatile components are removed in vacuo, the residue is taken up in water and the resulting solution is brought to pH 7 with dilute hydrochloric acid. The precipitate formed is filtered off with suction, the filtrate is extracted with methylene chloride and the combined organic phases are dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:16]=1[C:17]([N:19]([CH3:30])[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:18])C.C(=O)(O)[O-].[Na+].[S:44]([O-:48])([O-])(=[O:46])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:44]([C:15]1[CH:34]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:32]=[CH:31][C:16]=1[C:17]([N:19]([CH3:30])[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:18])(=[O:48])=[O:46])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cc(C(F)(F)F)ccc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(C(F)(F)F)ccc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.53 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.36 g of 2-ethylsulfanyl-N-methyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide and 3 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.37 g of 2-ethylsulfonyl-N-methyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide (hereinafter, referred to as Compound of Present Invention 3).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH2:5][CH:6]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])[CH2:7][OH:8].[OH-].[Na+]>C1COCC1.CO>[C:15]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][C:12]([C:10]([NH:9][CH:6]([CH2:7][OH:8])[CH2:5][CH2:4][C:3]([OH:24])=[O:2])=[O:11])=[CH:17][CH:16]=1
Reactant: COC(=O)CCC(CO)NC(=O)c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC(CO)NC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A solution of 4-[(Biphenyl-4-carbonyl)-amino]-5-hydroxy-pentanoic acid methyl ester (333 mg, 1.06 mmol) in THF (10 mL) and MeOH (1.27 mL) was added to 1N NaOH (1.27 mL, 1.27 mmol, 1.2 equiv) at room temperature. The mixture was stirred for 2 hours and TLC indicated the reaction was complete. Solvent was removed and the residue was dissolved in water. After adjusting the pH to 4 with 1N HCl, solid precipitated from the solution. The solid was then collected by filtration, washed with water, and dried under vacuum overnight to afford 240 mg of 4-[(Biphenyl-4-carbonyl)-amino]-5-hydroxy-pentanoic acid in 76.7% yield. MS (ESI) m/z 314.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[CH:17][C:18]=3F)[N:13]=[CH:12][N:11]=2)=[C:7]2[O:22][CH2:23][O:24][C:6]2=[CH:5][CH:4]=1.CCC([O-])(C)C.[Na+].CN1CCCC1=O.[OH:39][CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>O>[Cl:2][C:3]1[C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[CH:17][C:18]=3[O:39][CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:13]=[CH:12][N:11]=2)=[C:7]2[O:22][CH2:23][O:24][C:6]2=[CH:5][CH:4]=1
Reactant: OC1CCOCC1
Reactant: Fc1cc(F)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1cc(OC2CCOCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 60 °C

Procedure:
4-(6-Chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline hydrochloride salt (80 g) was added portionwise to a stirred mixture of sodium tert-pentoxide (90.2 g) and N-methylpyrrolidin-2-one (500 ml) under an atmosphere of nitrogen gas. 4-Hydroxytetrahydropyran (23.5 ml) and N-methylpyrrolidin-2-one (35 ml) were added and the resultant mixture was heated to 60° C. for 3 hours. Water (764 ml) was added to the heated reaction mixture during 3 hours and the mixture was stirred and heated to 60° C. for a further 3 hours. The warm reaction mixture was filtered and the isolated solid was washed with water (2×230 ml) and dried in vacuo to constant weight. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (68.6 g, 95% HPLC purity using Method A, retention time 4.6 minutes); m.p. 209-212° C.; NMR Spectrum: (DMSOd6) 1.9-2.0 (m, 2H), 2.1-2.2 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.95 (m, 2H), 5.05 (m, 1H), 6.1 (s, 2H), 6.95 (d, 1H), 7.05 (d, 1H), 7.1 (d, 1H), 7.3 (d, 1H), 8.4 (s, 1H), 9.3 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[O:17]=[C:15]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2nccs2)CC1
Reaction time: 20 h

Procedure:
To a round-bottomed flask containing 2-(1-tert-butoxycarbonyl-piperazin-4-yl)-acetic acid×2HCl (0.150 g, 0.54 mmol) was added 2-aminothiazole (0.059 g, 0.59 mmol) and anhydrous dichloromethane (7 ml). The reaction mixture was cooled into an ice-bath under argon, and then diisopropylethylamine (0.29 ml, 1.66 mmol) was added followed by PyBOP (0.280 g, 0.54 mmol). The ice-bath was removed, and the reaction mixture was allowed to stir for 20 h under argon. The solvent was removed in vacuo, the residue was absorbed on silica gel and the free running powder was placed on a 20 g isolute silica column which was eluted with 30 to 50% ethyl acetate in dichloromethane. The title compound was obtained as a colourless oil that solidified on standing at room temperature (0.123 g, 70%); 1H-NMR (500 MHz, DMSO-d6) 1.40 (s, 9H, C(CH3)3), 2.47 (br t obscured by solvent peak, piperazine NCH2), 3.31 (s, 2H, NCH2CO), 3.34 (br t, 4H, piperazine N(CH2)2), 7.22 (d, J=3.5 Hz, 1H, thiazole H), 7.47 (d, J=3.5 Hz, 1H, thiazole H), 11.84 (s, 1H, CONH);
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]([CH2:10][C:11]1[N:12]=[C:13]([NH:16][C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)=[O:18])[S:14][CH:15]=1)[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>>[ClH:27].[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][NH:19][C:17](=[O:18])[NH:16][C:13]1[S:14][CH:15]=[C:11]([CH2:10][N:8]([CH2:7][C:6]([OH:29])=[O:5])[CH3:9])[N:12]=1
Reactant: CN(CC(=O)OC(C)(C)C)Cc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)O)Cc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Product: Cl

Procedure:
({2-[3-(3,4-Dichloro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amino)-acetic acid tert-butyl ester (Example 109) was treated with trifluoroacetic acid overnight. The TFA was removed by evaporation the residue was triturated with 2N HCl in diethyl ether to afford the title compound. 1H-NMR (300 MHz, CD3OD): δ 7.48 (d, 2H), 7.25 (d, 2H), 7.18 (s, 1H), 4.40 (s, 2H), 4.33 (s, 2H), 3.89 (s, 2H), 2.91 (s, 3H). M/z (pos. ESI)=402 (M+H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=O)[NH:2]2.[N:9]1[O:10][N:11]=[C:12]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[CH:15]=[CH:14][C:13]=12.O.S(=O)(=O)(O)O>C1COCC1.ClCCl.[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][N:2]2[C:18]([C:16]1[CH:15]=[CH:14][C:13]2=[N:9][O:10][N:11]=[C:12]2[CH:17]=1)=[O:19]
Reactant: O=C1NC2C=CC1C2
Reactant: O=C(Cl)c1ccc2nonc2c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc2nonc2c1)N1CC2CCC1C2
Reaction time: 18 h

Procedure:
10% Pd/C (0.25 g) was added to a solution of 2-azabicyclo[2.2.1]hept-5-en-3-one in THF (30 ml) and dichloromethane (30 ml) and the mixture hydrogenated at room temperature for 18 h. The solids were filtered off, the solvent evaporated under vacuum, the residue dissolved in THF (60 ml) and lithium aluminum hydride (2 g) added slowly. The mixture was refluxed for 1 h and cooled to +5° C. before adding hexane (60 ml) and concentrated sodium hydroxide solution (4 ml). Celite (2 g) was added and the mixture stirred for 1 h before filtering off the solids and washing with THF (10 ml). To the mixture was added triethylamine (3 ml) and a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (2 g, 11.0 mmol) in dichloromethane (10 ml) and the mixture stirred overnight. Water (100 ml) was added, acidified to pH 2 with sulfuric acid and extracted with ethyl acetate (2×100 ml). The combined organics were washed with saturated sodium bicarbonate solution (100 ml), dried (NaSO4) and evaporated onto silica gel (5 g) and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane (1:1)→(3:1)→(1:0) to give the desired product as white crystals (0.28 g) after crystallization from MTBE/hexane: mp=92-93° C., LC-MS, MH+=244; 1H NMR (300 MHz, CDCl3, rotamers) δ 7.93-7.87 (m, 2H), 7.59-7.54 (m, 1H), 4.79 and 4.17 (s, total 1H), 3.61 and 3.48 (m, total 1H), 3.28 and 3.08 (dd, J=9.3 and 1.5 Hz, total 1H), 2.74 and 2.64 (s, total 1H), 1.90-1.47 ppm (m, 6H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[P:6]([O:15]C(C)C)([O:11][CH:12]([CH3:14])[CH3:13])[O:7][CH:8]([CH3:10])[CH3:9]>C(OCC)(=O)C>[CH:8]([O:7][P:6]([CH2:2][CH:3]1[CH2:5][CH2:4]1)(=[O:15])[O:11][CH:12]([CH3:14])[CH3:13])([CH3:10])[CH3:9]
Reactant: BrCC1CC1
Reactant: CC(C)OP(OC(C)C)OC(C)C
Solvent: CCOC(C)=O
Product: CC(C)OP(=O)(CC1CC1)OC(C)C
Temperature: 144 °C
Yield: 94.3 %

Procedure:
Bromomethyl-cyclopropane (26.00 g, 0.193 mol) was added to triisopropyl phosphite (35.9 mL, 0.30 mol) at ambient temperature, under a nitrogen atmosphere. The resulting solution was stirred and heated at reflux (144° C. bath temperature) overnight. The reaction mixture was allowed to cool to ambient temperature and then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) and then with saturated brine (2×350 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated by rotary evaporation and then under high vacuum to yield 39.96 g of cyclopropylmethyl-phosphonic acid diisopropyl ester (0.182 mol, 94% yield) as a colorless oil. 1H NMR (400 MHz, DMSO) δ 4.63-4.54 (m, 2H); 1.67-1.60 (d of d, 2H) 1.27-1.24 (d of d, 12H); 0.85-0.75 (m, 1H); 0.52-0.46 (m, 2H); 0.21-0.16 (m, 2H); ESMS (m/z): (M+1)+ found, 221; (M+23)+ found, 243.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11]Br)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[C@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:31])[CH2:21]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C@H:20]2[C@@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:11][C:7]4[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][CH:8]=4)[C:23]3=[O:31])[CH2:21]2)=[CH:18][CH:19]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(CBr)n1
Product: O=C(O)c1cccc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)n1

Procedure:
The title compound was prepared in analogy to Example 1 starting from 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C23H17ClN2O3: 404, observed (M+H)+: 405.2 1H NMR (400 MHz, DMSO-d6) δppm 2.12 (dd, J=9.09, 4.80 Hz, 1 H) 2.39 (dd, J=8.08, 4.80 Hz, 1 H) 3.22 (t, J=8.59 Hz, 1 H) 5.14 (s, 2 H) 6.15 (d, J=7.33 Hz, 1 H) 6.73 (t, J=7.45 Hz, 1 H) 6.88 (d, J=7.58 Hz, 1 H) 7.00-7.10 (m, 1 H) 7.26 (d, J=1.01 Hz, 1 H) 7.38 (s, 4 H) 7.84-7.98 (m, 2 H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2ON=[C:29]([CH3:32])[N:28]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1)[CH3:2].Cl.C(C1[C:38](N[C@H]2CCC[C@@H]2N)=[N:39]C=C(C(F)(F)F)N=1)C.N1C=CC=NC=1C1C=CC=CC=1C(O)=O>>[CH2:1]([C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:39]=[CH:38][CH:32]=[CH:29][N:28]=2)=[N:5][CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Reactant: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-c1nc(C)no1
Agent: Cl
Agent: O=C(O)c1ccccc1-c1ncccn1
Product: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-c1ncccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzamide (Example 149) from (1S,2S)-1-N-[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 41; 450 mg 1.64 mmol) and 2-(pyrimidin-2-yl)benzoic acid (CAS number 400892-62-8; 328 mg, 1.64 mmol) to afford the title compound.