Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].CC(C)=O.C(Cl)Cl.Cl.[S:11]1[CH:15]=[CH:14][C:13]2[CH:16]=[C:17]([CH:20]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:21](OC)=[O:22])[CH:18]=[CH:19][C:12]1=2>C(O)C.O>[S:11]1[CH:15]=[CH:14][C:13]2[CH:16]=[C:17]([CH:20]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[CH2:21][OH:22])[CH:18]=[CH:19][C:12]1=2
Reactant: COC(=O)C(OC1CCCCO1)c1ccc2sccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: OCC(OC1CCCCO1)c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
In 41.3 ml of ethanol was dissolved the methyl (-)-2-(benzo[b]thiophen-5-yl)-2-(tetrahydropyranyloxy)acetate, and to this solution was added 2.90 g of sodium borohydride, and the resulting mixture was stirred at 25° C. for 8 hours. Subsequently, 13.23 ml of acetone was 1 dropwise added with ice-cooling to decompose the excessive sodium borohydride, and thereafter, 138 ml of methylene chloride and 138 ml of water were added thereto, and the pH was adjusted to 8.5 with 2N hydrochloric acid. The organic layer formed was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue thus obtained was washed with petroleum ether to obtain 12.0 g (yield: 96%) of colorless (-)-2-(benzo[b]thiophen-5-yl)-2-(tetrahydropyranyloxy)ethanol as a diastereomer mixture.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C(N(CC)C(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:16][C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 500 mL round-bottomed flask was added 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (4.2 g, 17.31 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (6.37 g, 19.04 mmol) [prepared according to the procedure of Preparation 6], N,N-diisopropyl ethylamine (4.53 ml, 26.0 mmol) and Pybrop (12.05 g, 26.0 mmol) in dichloromethane (DCM) (150 ml). After stirring at RT for 12 h, the reaction solution was washed with H2O (2×100 mL) and the organic layer was dried Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with [EtOAc/hexanes, 1:1] to give the product [7.8 g, 86%] as a white solid: LCMS (ES) m/z 524 (M+H)+.
Reaction SMILES: N1C2C=CC=CC=2N=N1.[CH3:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.[C:20]([NH:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][SH:26])(=[O:22])[CH3:21].CN1CCOCC1.Cl>O1CCCC1>[C:20]([NH:23][CH:24]([CH2:25][S:26][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([CH3:10])=[CH:12][CH:13]=1)[C:27]([OH:29])=[O:28])(=[O:22])[CH3:21]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: Cl
Agent: c1ccc2[nH]nnc2c1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)NC(CSC(=O)c1ccc(C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of benzotriazole (9.91 g, 83.2 mmol) in tetrahydrofuran (80 mL) was added 4-methylbenzoyl chloride (5.0 mL, 37.8 mmol) (5 g, 95%). After 2 hours, the resulting slurry was filtered and the solid was rinsed with tetrahydrofuran (25 mL). The filtrates were combined and added to a solution of N-acetyl-L-cysteine (5.55 g, 34.0 mmol) and N-methylmorpholine (3.74 mL, 34.0 mmol) in tetrahydrofuran (50 mL) at 0° C. The resulting mixture was allowed to warm to ambient temperature over 16 hours. Aqueous hydrochloric acid (1 M, 100 mL) was added to the mixture and the resulting mixture was concentrated at reduced pressure to a volume of approximately 125 mL. Additional aqueous hydrochloric acid (80 mL) was added and the mixture was extracted with dichloromethane (180 mL then 80 mL). The combined organic extracts were combined, dried over sodium sulfate, filtered and concentrated at reduced pressure. Ethyl acetate (100 mL) was added and the resulting slurry was stirred for 2 hours. The resulting slurry was filtered and dried to give a white solid (5.7 g, 60%). 1H NMR (300 MHz, DMSO) δ=12.94 (s, 1H), 8.34 (d, J=7.9 Hz, 1H), 7.86-7.74 (m, 2H), 7.35 (d, J=8.5 Hz, 2H), 4.43 (dt, J=5.0, 8.4 Hz, 1H), 3.53 (dd, J=5.0, 13.8 Hz, 1H), 3.21 (dd, J=8.5, 13.8 Hz, 1H), 2.37 (s, 3H), 1.83 (s, 3H). MS (ESI) m/z 282 (M+1)+.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1F)[CH:10]=[O:11].C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>C(OCC)(=O)C.O>[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)[CH:10]=[O:11]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2ccnc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a DMF (20 mL) solution of 3-chloro-4-fluorobenzaldehyde (500 mg), potassium carbonate (1.20 g) and imidazole (275 mg) were added one by one, and the reaction solution was agitated at 80° C. overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=10:1), and 548 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9].[ClH:14].[CH3:15][C:16]1([CH3:31])[O:21][C:20]2[CH:22]=[C:23]([CH:26]=[CH:27][C:28]([OH:30])=O)[CH:24]=[N:25][C:19]=2[NH:18][CH2:17]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[ClH:14].[CH3:31][C:16]1([CH3:15])[O:21][C:20]2[CH:22]=[C:23](/[CH:26]=[CH:27]/[C:28]([N:2]([CH3:1])[CH2:3][C:4]3[O:5][C:6]4[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=4[C:8]=3[CH3:9])=[O:30])[CH:24]=[N:25][C:19]=2[NH:18][CH2:17]1
Reactant: CC1(C)CNc2ncc(C=CC(=O)O)cc2O1
Reactant: CNCc1oc2ccccc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OC(C)(C)CN3)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl-(3-methyl-benzofuran-2-ylmethyl)-amine (88 mg, 0.5 mmol) in DMF (5 mL) were added in sequential order 3-(2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid hydrochloride (107 mg, 0.46 mmol), 1-hydroxybenzotriazole (68 mg, 0.5 mmol), diisopropylethylamine (240 uL, 1.38 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (100 mg, 0.5 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product was extracted with ethyl acetate (3×10 mL), dried with sodium sulfate, filtered and concentrated. The free base was re-solvated in methylene chloride (5 mL) and a solution of 4M HCl in dioxane (1 mL) was added to precipitate the hydrogen chloride salt as a pale yellow solid (84 mg, 43%): 1H NMR (400 MHz, DMSO-d6) δ 8.94 (1s, 1H), 8.01-8.06 (m, 2H), 7.47-7.58 (m, 3H), 7.16-7.25 (m, 3H), 4.73-4.94 (rotamers, 2s, 2H), 3.42 (s, 2H), 3.04 (s, 3H), 2.42 (s, 3H), 1.34 (s, 6H); MS (ESI) m/e 392 (C23H25N3O3+H)+.
Reaction SMILES: [CH3:1][CH:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10]Br)[C:5](=[O:12])[CH2:4][S:3]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:10][CH2:9][CH2:8][CH2:7][N:6]2[C:5](=[O:12])[CH2:4][S:3][CH:2]2[CH3:1])[CH2:23][CH2:22]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC1SCC(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCCN2C(=O)CSC2C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 2-methyl-3-(4-bromobutyl)-4-thiazolidinone (3.0 g), 1-(2-methoxyphenyl)piperazine (2.3 g), anhydrous K2CO3 (3.5 g) and NaI (200 mg) in 100 ml of anhydrous CH3CN was heated to 80° under N2. After 4 hours no starting material remained as judged by TLC. The mixture was cooled to room temperature, filtered and concentrated in vauco. The residue was chromatographed on silica, using EtOAc as the eluent. This provided 2.18 g of product as a clear oil which solidified in vacuo (0.1 mmHg) overnight.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=O)=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=[C:10]3[C:3]4[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=4[NH:8][C:9]3=[O:11])=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=O
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Yield: 25.5 %

Procedure:
4-Chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (80 mg, 0.47 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (124 mg, 0.47 mmol) at room temperature to give 50 mg (26%) of 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:3]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:25][CH3:26]>CN(C=O)C>[CH2:25]([N:5]1[C:6](=[O:9])[CH2:7][CH2:8][C:2]([CH3:17])([CH3:1])[C:3]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]1=2)[CH3:26]
Reactant: CCI
Reactant: CC1(C)CCC(=O)Nc2ccc([N+](=O)[O-])cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 2.5 h
Yield: 95 %

Procedure:
Combined 5,5-Dimethyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (520 mg, 2.22 mmol), cesium carbonate (1.52 g, 4.7 mmol), iodoethane (355 uL, 4.44 mmol) and DMF (12 mL). Stirred at room temp. for 2.5 hours. Evaporated off solvent, added water and extracted into methylene chloride. Dried organic layer over sodium sulfate, filtered and concentrated under reduced pressure to yield a brown solid, 1-Ethyl-5,5-dimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (553 mg, 95%). mp 67° C.; LCMS: m/z=263.08 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.31 (d, 1H, J=2.5 Hz), 8.17 (dd, 1H, J=8.7, 2.6 Hz), 7.38 (d, 1H, J=8.8 Hz), 3.89 (m, 2H), 2.31 (m, 2H), 2.12 (m, 2H), 1.42 (s, 6H), 1.33 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16]Br)[C:8]=2[C:9]([Cl:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH3:18][N:19]1[N:23]=[N:22][C:21]([C:24]2[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=2)=[N:20]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([C:21]4[N:22]=[N:23][N:19]([CH3:18])[N:20]=4)[CH:25]=3)[C:8]=2[C:9]([Cl:12])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: Cn1nnc(-c2cccc(O)c2)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cccc(-c4nnn(C)n4)c3)csc12
Temperature: 65 °C

Procedure:
A mixture of 3-bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (042 g, 1.24 mmol) (from Example 1 supra), 3-(2-methyl-2H-tetrazol-5-yl)-phenol (0.23 g, 1.31 mmol) (from Example 30 supra), potassium iodide (0.21 g, 1.24 mmol), potassium carbonate (0.38 g, 2.78 mmol) and 18-crown-6 (16.0 mg, 0.06 mmol) in N,N-dimethylformamide (15 mL) was heated at 65° C. for 1 day. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give 4-chloro-3-[3-(2-methyl-2H-tetrazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.15 g, 28%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[CH:10]=[C:9]([C:12](Cl)=[O:13])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[OH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][Si](C)(C)C)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[OH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][C:12](=[O:13])[C:9]2[CH:8]=[CH:7][C:6]3[CH2:5][CH2:4][CH2:3][C:2]([CH3:15])([CH3:1])[C:11]=3[CH:10]=2)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Reactant: CC1(C)CCCc2ccc(C(=O)Cl)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C(C)(C)CCC3)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12 g (54 mmol) of 8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthoyl chloride, 14.7 g (59 mmol) of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate (prepared in Example 5(a) of patent EP 0,661,258) and 200 ml of dichloromethane are introduced into a round-bottomed flask. 21.6 g (162 mmol) of AlCl3 are added portionwise at 0° C. and the mixture is stirred at room temperature for 8 hours. The reaction medium is poured into ice and extracted with dichloromethane, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (50/50). 12.5 g (64%) of the expected product are collected, with a melting point of 114-6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][C:12]=1[O:21][CH3:22].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[O:34][C@@H:35]1[CH2:39][NH:38][C@H:37]([CH2:40][O:41][C:42]2[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=2)[CH2:36]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:38]2[CH2:39][C@@H:35]([O:34][C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:24]=3)[CH2:36][C@H:37]2[CH2:40][O:41][C:42]2[CH:43]=[CH:44][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:50][CH:51]=2)=[O:20])=[CH:13][C:12]=1[O:21][CH3:22]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.7 %

Procedure:
A mixture of 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (310 mg, 0.93 mmol), methyl 4-[(2S,4S)-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (350 mg, 0.93 mmol), EDC.HCl (267 mg, 1.40 mmol) and DMAP (171 mg, 1.40 mmol) in DMF (10 ml) was stirred at room temperature for 3 days. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [100 g, n-hexane/EtOAc(1/1)CHCl3/MeOH(50/1)], to give methyl 4-[(2S,4S)-1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (450 mg, 68%) as a pale brown amorphous. 1H-NMR (CDCl3) δ2.32 (m, 1H), 2.58 (d, J=14.5 Hz, 1H), 3.63 (d, J=2.7 Hz, 1H), 3.70 (s, 3H), 3.86 (s, 3H), 3.84-3.95 (m, 2H), 4.15-4.64 (m, 4H), 5.11 (br, 1H), 6.79-7.06 (m, 7H), 7.21-7.46 (m, 7H), 7.66-7.77 (m, 3H), 7.92 (d, J=8.8 Hz, 1H), 7.97 (m, 1H), 8.17 (d, J=8.4 Hz, 1H); MS (ESI) m/z 694 (M++1), 696 (M++3).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([O:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:5]1[OH:30])=[N+:2]=[N-:3].N1C=CC=CC=1.[C:37](Cl)([CH3:39])=[O:38]>C(Cl)Cl>[C:37]([O:30][C@H:5]1[C@H:6]([O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:7][CH2:8][CH2:9][C@@H:4]1[N:1]=[N+:2]=[N-:3])(=[O:38])[CH3:39]
Reactant: CC(=O)Cl
Reactant: [N-]=[N+]=N[C@H]1CCC[C@@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](N=[N+]=[N-])CCC[C@H]1OC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
Compound 2 (625 mg, 1.57 mmol), pyridine (363 μL, 4.69 mmol) and AcCl (272 μL, 3.13 mmol) were dissolved in CH2Cl2 (15 mL) under nitrogen atmosphere at room temperature. After 2 h the mixture was diluted with CH2Cl2. The organic layer was washed (HCl(aq) 5%, sat NaHCO3, brine), dried (MgSO4), filtered and concentrated. No further purification was needed. The reaction yielded 100% of 3. 1H-NMR (CDCl3) 7.45 (m, 6 H), 7.20-7.35 (m, 9 H), 5.14 (t, J=9.49 Hz, 1 H), 2.99-3.10 (m, 2 H), 1.93 (s, 3 H), 1.86 (m, 1 H), 1.50 (m, 2 H), 1.25-1.40 (m, 2 H), 0.80 (m, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Br:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:22][C:13]1[S:12][C:11]([CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])=[CH:15][C:14]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(Cc1cc(-c2ccccc2)cs1)C(=O)OC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc(-c2ccccc2)c(Br)s1)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
To a solution of tert-butyl methyl[(4-phenyl-2-thienyl)methyl]carbamate (4.77 g) in N,N-dimethylformamide (30 mL) was added N-bromosuccinimide (2.83 g) at room temperature and the mixture was stirred for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=99:1→19:1) to give the title compound as a pale-yellow oil (yield 4.1 g, yield of 2 steps 67%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Br.[NH2:28][C:29]1[S:30][C:31]([Br:34])=[CH:32][N:33]=1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[Br:34][C:31]1[S:30][C:29]([NH:28][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:33][CH:32]=1
Reactant: Nc1ncc(Br)s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc(Br)s2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (prepared in Example 130, 300 mg, 1.01 mmol) and dry N,N-dimethylformamide (2 drops) in methylene chloride (3 mL) was cooled to 0° C. and then treated dropwise with oxalyl chloride (115 μL, 1.32 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo. The resulting yellow oil was dissolved in a small amount of methylene chloride and then slowly added to a solution of 2-amino-5-bromothiazole monohydrobromide (395 mg, 1.52 mmol) and triethylamine (424 μL, 3.04 mmol) in N,N-dimethylformamide (3 mL). The resulting reaction mixture was then stirred at 25° C. for 15 h. The resulting reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (50 mL). The combined organic layers were then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded the N-(5-bromo-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide (160 mg, 35%) as a tan foam: mp 73-75° C. (foam to gel); EI-HRMS m/e calcd for C18H21BrN2O3S2 (M+) 456.0177, found 456.0176.
Reaction SMILES: [CH:1]([C@:4]1([C:18]([N:20]2[CH2:25][CH:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:8][CH2:7][C@@H:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][O:13][CH2:12][CH:11]2[O:16][CH3:17])[CH2:5]1)([CH3:3])[CH3:2]>CO>[CH:1]([C@:4]1([C:18]([N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:8][CH2:7][C@@H:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][O:13][CH2:12][CH:11]2[O:16][CH3:17])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC1COCC[C@H]1N[C@@H]1CC[C@@](C(=O)N2CC=C(c3cccc(C(F)(F)F)c3)CC2)(C(C)C)C1
Solvent: CO
Product: COC1COCC[C@H]1N[C@@H]1CC[C@@](C(=O)N2CCC(c3cccc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
(4R)-N-((1 R,3S)-3-Isopropyl-3-[4-[3-(trifluoromethyl)phenyl] -3,6-dihydropyridin-1(2H)-yl]carbonylcyclopentyl)-3-methoxytetrahydro-2H-pyran-4-amine (8.0 mg, 0.016 mmol) was dissolved in methanol (0.63 mL), degassed-purged with N2, followed by the addition of Palladium (3.44 mg) (10% dry weight on wet activated carbon). The reaction flask was degassed-purged with N2 three times, then stirred at room temperature under H2 (1 atm) overnight. The mixture was filtered through celite pad, washed with methylene chloride and concentrated to provide the desired product as a white solid (5.7 mg, 71%). LC-MS calculated for C27H40F3N2O3:(M+H) 497.2; found 497.2.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])=[O:40])=[CH:35][CH:34]=1>>[CH:1]1([CH:7]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:40])=[CH:37][CH:38]=2)[C:9]2[C:10]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: OC(c1cn(-c2ccc(C(F)(F)F)cn2)nc1CCc1ccccc1)C1CCCCC1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2cn(-c3ccc(C(F)(F)F)cn3)nc2CCc2ccccc2)C2CCCCC2)cc1
Yield: 27.7 %

Procedure:
Using cyclohexyl{3-(2-phenylethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.28 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.20 g, 28%) was obtained as a white solid.