Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:4].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.C(N(CC)CC)C>CC(O)C>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2ncnc3ccc(C(F)(F)F)cc23)C1

Procedure:
A mixture of tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (1.073 g, 4.682 mmol) as prepared in the previous step and commercially available 4-chloro-6-(trifluoromethyl)quinazoline (990 mg, 4.256 mmol) were stirred in anhydrous iPrOH and triethylamine at 90° C. under argon for 1 hour. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0%-5% MeOH/EtOAc) to give a yellow solid after drying under high vacuum.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[O:9]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10]1>CN(C=O)C.C1(C)C=CC=CC=1>[O:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:16])=[CH:10]1
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1ccoc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN1CC(=O)NC1=NC(=O)Nc1ccoc1
Reaction time: 3 h
Yield: 1.4 %

Procedure:
To a stirred mixture of 18.3 g (162 mM) of creatinine in 120 ml of anhydrous DMF was added a solution of 17.2 g (162 mM) of 3-furanyl isocyanate in 80 ml of toluene. After stirring the mixture for 3 hrs. at 65° C., the mixture was partially concentrated under vacuum and the residue poured into 1200 ml of water. The resulting precipitate was collected, washed with water and recrystallized from ethyl acetate. The solid was then chromatographed over silica gel using ethyl acetate as the eluant and the fractions containing the product were concentrated and the residue recrystallized from toluene to give 0.5 g of the above urea as a tan solid, m.p. 179°-181° C. (dec.).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[N:11]1)(C)(C)C.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[OH:25][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20].[N+:15]([C:13]1[CH:12]=[N:11][N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=1)([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NCCn1cc([N+](=O)[O-])cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCn1cc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of tert-butyl(2-(4-nitro-1H-pyrazol-1-yl)ethyl)carbamate (5.50 g, 21.49 mmol) in DCM (55 mL), TFA (20 mL, 261.16 mmol) was added dropwise. The resulting solution was stirred at 0° C. for 3 h, then the reaction mixture was concentrated in vacuo to obtain 2-(4-nitro-1H-pyrazol-1-yl)ethanamine-TFA salt as an off-white paste, which was used in the next step without further purification. LC-MS conditions A: tR=0.21 min, no ionization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[O:15][CH2:16][C:17](=[O:24])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][N:32]=2)[C:27]([CH:34]=O)=[CH:26]1.[OH-].[Na+]>C(O)C.Cl>[NH:25]1[C:33]2=[N:32][CH:31]=[CH:30][CH:29]=[C:28]2[C:27]([CH:34]=[C:16]2[O:15][C:14]([NH:13][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:7][C:2]=3[F:1])=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2=[O:24])=[CH:26]1
Reactant: CCOC(=O)C1=C(Nc2ccc(OCCOC)cc2F)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OCCOC)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 35.2 %

Procedure:
To a solution of ethyl 2-{[2-fluoro-4-(2-methoxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.011 g, 0.032 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0045 g, 0.031 mmol) in ethanol (0.2 mL), 2M hydrochloric acid in ethanol (0.016 mL, 0.032 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. Cooled with ice bath, 2M sodium hydroxide solution (0.015 mL, 0.029 mmol) was added dropwise to neutralize, and ethanol (1.5 mL) was added. The mixture was refluxed for further 30 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.0051 g, y. 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:33]1[CH:37]2[CH2:38][NH:39][CH2:40][CH:36]2[CH2:35][N:34]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:19])([F:20])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([N:39]4[CH2:38][CH:37]5[CH2:33][N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH:36]5[CH2:40]4)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)O)c4)cc3N2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)N5CC6CN(C(=O)OC(C)(C)C)CC6C5)c4)cc3N2)cc1OC
Yield: 54.9 %

Procedure:
Example ER-896386 was prepared in two steps from 3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoic acid (119 mg, 0.266 mmol) and commercially available tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (226 mg, 1.06 mmol) in a manner similar to that of example D-6 to afford intermediate tert-butyl 5-(3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (94 mg, 0.146 mmol, 55% yield). Then, this intermediate was resolved into its constituent enantiomers in a manner similar to that of ER-890044 (Section A) to afford tert-butyl 5-(3-((5S,7R)-5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (33 mg, 0.051 mmol) and tert-butyl 5-(3-((5R,7S)-5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (33 mg, 0.051 mmol). Then, intermediate tert-butyl 5-(3-((5S,7R)-5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (22 mg, 0.034 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-896386 (19 mg, 96% yield).
Reaction SMILES: [F:1][CH:2]([F:39])[O:3][C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:10]=[CH:11][C:12]=2[C:13]2[CH:14]=[C:15]([C:20]([NH:22][C@H:23]3[C:28]([F:30])([F:29])[CH2:27][CH2:26][CH2:25][C@H:24]3[NH:31]C(=O)OC(C)(C)C)=[O:21])[S:16][C:17]=2[CH2:18][CH3:19])[CH:9]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[NH2:31][C@H:24]1[C@@H:23]([NH:22][C:20]([C:15]2[S:16][C:17]([CH2:18][CH3:19])=[C:13]([C:12]3[CH:11]=[N:10][N:8]4[CH:9]=[C:4]([O:3][CH:2]([F:1])[F:39])[CH:5]=[N:6][C:7]=34)[CH:14]=2)=[O:21])[C:28]([F:29])([F:30])[CH2:27][CH2:26][CH2:25]1
Reactant: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(OC(F)F)cnc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1sc(C(=O)N[C@@H]2[C@H](N)CCCC2(F)F)cc1-c1cnn2cc(OC(F)F)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl {(1R,2R)-2-[({4-[6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-ethylthiophen-2-yl}carbonyl)amino]-3,3-difluorocyclohexyl}carbamate (0.037 g, 0.064 mmol) was dissolved in dichloromethane (0.639 mL) and trifluoroacetic acid (0.250 mL, 3.24 mmol) was added. The reaction was stirred at room temperature for 2 h. 5N NaOH (aq) was added and extracted 3× with dichloromethane. The organic layers were combined, dried with sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (0-5% MeOH/DCM) to give the title compound. LRMS (APCI) calc'd for (C20H21F4N5O2S) [M+H]+, 472.1; found 472.1. 1H NMR (CD3OD, 500 MHz) δ 9.04 (d, J=2.4, 1H), 8.59 (d, J=2.4, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 6.97 (t, J=72.5, 1H), 3.24 (s, 1H), 3.02 (q, J=7.5, 2H), 2.15 (s, 1H), 1.48-1.99 (m, 4H), 1.32 (t, 3H), 1.00-1.18 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[NH:19])[NH2:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].C([O-])([O-])=O.[K+].[K+].[CH:30]([CH:32]([CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[N:42][CH:43]=1)[C:33](OC)=O)=[O:31]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]3[NH:18][CH:33]=[C:32]([CH2:37][C:38]4[CH:43]=[N:42][CH:41]=[N:40][CH:39]=4)[C:30](=[O:31])[N:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: N=C(N)CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COC(=O)C(C=O)Cc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=c1nc(CCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 120 °C

Procedure:
A mixture of 3-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)propanimidamide (150 mg, 0.316 mmol), K2CO3 (131 mg, 0.949 mmol) and methyl 2-formyl-3-(5-pyrimidinyl)propanoate (188 mg, 0.633 mmol) in NMP (1.5 mL) was heated with a microwave reactor at 120° C. for 2 h. Purification via a reverse phase Biotage then afforded the title compound as a white solid. LCMS: rt=3.13 min, [M+H+]=487
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.CN(C)C=O.[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCCCC(=O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(O)CCCN/C=C1\C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (212 mg, 0.75 mmole), dimethylformamide (5 mL), and 4-aminobutanoic acid (78 mg, 0.75 mmole) is stirred at room temperature for 1 hour. The reaction mixture is diluted with ether, filtered, washed with fresh ether and dried to give a salmon solid, 164 mg, (61%), mp 260-2° C. dec; MS (ES+): m/z 353.0 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:9]>>[C:8](=[O:9])([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)[O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1
Reactant: OC1CCOC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 1 starting from 3-hydroxytetrahydrofuran (Aldrich, Cat. #H59109) and p-nitrophenyl chloroformate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH:28]=[CH:27]1>C(O)C.[OH-].[Na+]>[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:32])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30])([OH:25])=[O:24]
Reactant: O=C1C=CC(=O)O1
Reactant: NCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C\C(=O)NCCCCCCCCCCCCCCCCCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 105.9 %

Procedure:
In a mixture of 100 ml of ethanol and 50 ml of 1N aqueous sodium hydroxide solution, 22-aminodocosanoic acid (400 mg, 1.12 mmoles) was dissolved at 40° C. To the obtained solution, the temperature being maintained at 40° C., maleic anhydride (4.39 g, 44.8 mmoles) was gradually added over a period of 5 hours. The reaction mixture was kept at a pH of 8-10 during the addition, and the mixture was stirred for additional 30 minutes and then treated in the same manner as in Reference Example 4, to give N-(21-caboxyheneicosyl)maleamic acid (538 mg, 83%) having the following properties.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:23](=O)([O:27]CC)[O:24][CH2:25][CH3:26]>C1COCC1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:23]([O:24][CH2:25][CH3:26])=[O:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Temperature: 30 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
To a suspension of NaH (54 gm, 1.11 moles) in dry THF (500 ml) a solution of ethyl 2-(4-(benzyloxy)phenyl)acetate (100 gm, 0.37 moles) in dry THF (100 ml) was added at 0° C. To this was added diethyl carbonate (180 ml, 1.48 mole) dropwise over a period of one hour maintaining the reaction temperature at below 5° C. The reaction mixture was then stirred for 18 hours at 30° C. The contents of the reaction mixture were poured into ice cold water and extracted with ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and evaporated under reduced pressure to yield 100 gm of product as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]([C:13]([O:15][CH2:16]C)=[O:14])[CH2:6][CH2:5]2.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([O:12][C:11]1[CH:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH:7]([C:13]([O:15][CH3:16])=[O:14])[O:8]2)=[CH:3][C:2]=1[Cl:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1CCc2cc(Cl)c(O)cc2O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCc2cc(Cl)c(OCc3ccccc3)cc2O1
Reaction time: 0.33 h
Yield: 6.9 %

Procedure:
A solution of ethyl 6-chloro-7-hydroxychroman-2-carboxylate (3.0 g, 11.7 mmol) in THF is treated with NaH (3.0 equiv, 35 mmol) at 0° C., stirred for 20 minutes, treated with benzylbromide (3.0 g, 17.5 mmol), stirred for 16 hr, concentrated and diluted with water and EtOAc. The aqueous phase is separated, acidified to pH 1-2 with 2N HCl and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is dissolved in methanol, treated with a catalytic amount of p-toluenesulfonic acid, heated at reflux temperature for 18 hr, cooled and concentrated in vacuo. This resultant residue is triturated under EtOAc/hexanes and filtered. The filtercake is further purified by short-column chromatography (silica gel, 5:1 hexane:EtOAc as eluent) to afford the title product as a light yellow solid, 2.7 g (6.9% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]([F:6])([CH3:5])[CH2:3][OH:4].[CH3:7][S:8](Cl)(=[O:10])=[O:9].O>C(Cl)Cl>[CH3:7][S:8]([O:4][CH2:3][C:2]([F:6])([F:1])[CH3:5])(=[O:10])=[O:9]
Reactant: CC(F)(F)CO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(F)(F)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.6 %

Procedure:
To a mixture of 2,2-difluoropropan-1-ol (2.00 g, 20.8 mmol) and TEA (3.16 g, 31.25 mmol) in dry DCM (20 mL) was added methanesulfonyl chloride (2.84 g, 24.96 mmol) at 0° C. The resulting reaction mixture was stirred at rt for 1.5 h. Water was added and the mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to give the title product (2.70 g, 15.52 mmol, 75% yield), which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[O:8]([CH2:15][CH2:16][OH:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:5][C:6](=[O:7])[O:17][CH2:16][CH2:15][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: O=C=NC(=O)CCl
Reactant: OCCOc1ccccc1
Solvent: c1ccccc1
Product: O=C(CCl)NC(=O)OCCOc1ccccc1

Procedure:
Chloroacetylisocyanate (12g) was added slowly to the solution of β-phenoxyethylalcohol (13.8g) and benzene (100ml) at room temperature.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:26][C:27]3[O:28][C:29]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:30]=4[CH:31]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.C=O.C(Cl)(Cl)Cl.N>C(O)=O>[C:36]([C:33]1[CH:34]=[CH:35][C:29]2[O:28][C:27]([CH2:26][CH:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][C@H:10]4[CH2:11][CH2:12][N:8]([CH3:6])[CH2:9]4)=[CH:15][CH:16]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:31][C:30]=2[CH:32]=1)#[N:37]
Reactant: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: C=O
Agent: N
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C)C2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1.8 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)-propionate was dissolved in 28 ml of formic acid, and the solution was stirred at 70° C. for 1 hour. The resulting reaction solution was concentrated to dryness, and the residue thus obtained was dissolved in 8 ml of formic acid. 0.29 ml of 37% formaldehyde was added thereto, and then refluxed under heating for 4 hours. After cooling, the reaction solution was mixed with chloroform, and then adjusted to pH 10-11 with aqueous ammonia, and the resulting organic layer was collected and dried.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C1COCC1>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: NCc1cccnc1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NCc3cccnc3)c(Br)c2)c(SC)s1

Procedure:
The reaction was conducted following the procedure for Example 162: step a, using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.226 mmol), (Example 2: step c), 3-aminomethyl pyridine (0.046 g, 0.430 mmol), THF [4.0 mL]. Chromatography of the residue (25%–50% EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. for C18H16BrN3O4S3: 515.44 (M+H); found 514.1, 516.0.
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH:3]([NH:15]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>[OH-].[Na+]>[NH2:15][CH:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][CH:6]=1)[CH:2]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[OH:1]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To 1,1-dimethylethyl (1RS,2SR)-2-hydroxy-2-(4-pyridyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate (300 mg, 0.76 mmol) was added trifluoroacetic acid (3 ml), and the mixture was stirred at room temperature for 10 min. To the reaction solution was added 1N aqueous sodium hydroxide solution (10 ml) and the mixture was extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give (1RS,2SR)-2-amino-1-(4-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (135 mg, 60%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH3:13])[CH2:9][CH2:8][CH2:7]2.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32](Cl)=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>C1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][C:12]=2[CH3:13])[CH2:9][CH2:8][CH2:7]3)=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: Cc1cc2c(cc1CCN)CCC2
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)NCCc2cc3c(cc2C)CCC3)cc1OC

Procedure:
5-Aminoethyl-6-methylindan (4.0 g, 0.029 mole) was dissolved in 100 ml of dry benzene, 4 ml of triethylamine was added and a solution of the previously prepared 3,4-dimethoxyphenylacetyl chloride in dry benzene was added to the substituted indan mixture. The reaction mixture was refluxed for several hours and then gently heated overnight at a temperature below reflux. The reaction was then cooled, washed with 3×100 ml of 20% HCl solution, 3×100 ml of 8% NaHCO3 solution and 2×125 ml of water. The benzene layer was then reduced in volume on a rotary evaporator to yield a solid precipitate. The solid was filtered, washed with benzene, air dried to yield a slightly pink powder (3.5 g, mp 144°-145° C.). The crude product was then recrystallized from benzene (large volume), mp 144°-144.5° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:35][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: NC1CCCCCC1
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)NC3CCCCCC3)c(=O)n12
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, 9.96 g (0.088 mol) of cycloheptylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -12° C. and -15° C. during 40 minutes. The reaction mixture is stirred for 1 hour below -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to obtain 20.4 g (85.2%) of the named compound as yellow crystals, m.p.: 172°-174° C.