Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].Cl[CH:12]([B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)[CH2:13][CH2:14][CH3:15].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>O1CCCC1>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH2:13]([CH:12]([B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)[NH2:5])[CH2:14][CH3:15]
Reactant: CCCC(Cl)B1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCCC(N)B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.2 %

Procedure:
1.7 ml (1.7 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise to a solution of 0.37 g (1.69 mmol) of 2-[1(RS)-chlorobutyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 20 ml of tetrahydrofuran under nitrogen at -78° C. The solution was then stirred overnight at room temperature. The solvent was removed by evaporation and the residue was taken up in diethyl ether. Insoluble material was removed by filtration and the filtrate was cooled to 0° C. 0.39 ml (5.1 mmol) of trifluoroacetic acid was added and the solution was stirred at 0° C. for 30 minutes. The solution was evaporated and the residue was co-evaporated with toluene to give 0.62 g of α-(RS)-propyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine trifluoroacetate as a brown oil which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([N:9]3[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]3)=[C:7]([N+:23]([O-])=O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[F:46][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:39]=1[C:37]1[S:38][C:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[C:35]([C:47](=[O:48])[NH:23][C:7]2[CH:6]=[N:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:8]=2[N:9]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]2)[N:36]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2C2CC2)CC1)C(F)(F)F
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(C2CC2)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 73 %

Procedure:
Following the procedure for Example 517 starting with (R)—N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid gave (R)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (142 mg, 73%). 1H-NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.76 (s, 1H), 7.87 (s, 1H), 7.41-7.34 (m, 1H), 7.10-7.00 (m, 2H), 6.39 (d, J=8 Hz, 1H), 4.25-4.15 (m, 1H), 3.45-3.36 (m, 3H), 3.35-3.15 (m, 2H), 2.25-2.12 (m, 1H), 2.10-1.70 (m, 5H), 1.55 (s, 9H), 1.35-1.15 (m, 2H), 1.10-1.00 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([CH2:9][NH:10][C:11]([C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:19][S:20]([C:23]1[CH:34]=[CH:33][C:26]([CH2:27]OS(C)(=O)=O)=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:12])#[N:8].[CH2:35]([SH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC(C)=O>[C:7]([CH2:9][NH:10][C:11]([C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:19][S:20]([C:23]1[CH:34]=[CH:33][C:26]([CH2:27][S:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:25][CH:24]=1)(=[O:21])=[O:22])=[O:12])#[N:8]
Reactant: SCc1ccccc1
Reactant: CS(=O)(=O)OCc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(CSCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (0.114 g, 0.35 mmol) was added to a solution of trans-methanesulfonic acid 4-[2-(cyanomethylcarbamoyl)-cyclohexylmethanesulfonyl]-benzyl ester (0.150 g, 0.35 mmol) and benzyl mercaptan (0.041 mL, 0.35 mmol) in acetone (4 mL). The reaction mixture was stirred overnight at 50° C. The solids were removed by filtration and washed with warm acetone. The combined filtrates were concentrated by rotary evaporation. Purification of the residue by silica gel chromatography using a gradient of 0%-20% ethyl acetate in dichloromethane yielded the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([F:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Si](C=[N+]=[N-])(C)C>CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:19])=[O:16])=[CH:13][C:12]([F:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(F)ncc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To 44 g of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid in 100 mL of methanol and 300 mL of chloroform at 0° C. was added 200 mL of 2 M (trimethylsilyl)diazomethane in hexanes. After allowing the reaction to warm to ambient temperature and stirring for 2 hours, the solvents were removed and the crude product purified by passing through a plug of silica gel with chloroform The product was then recrystallized from hexanes to give 32.6 g (73%) of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid, methyl ester: melting point 104 105° C. (decomposed); mass spectrum (m/e): M+H 270.9.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]O.[CH2:6]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].CS(C)=O>O>[CH2:6]([N:10]([CH2:4][CH2:3][CH2:2][Cl:1])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]
Reactant: OCCCCl
Reactant: CCCCNCCCC
Solvent: CS(C)=O
Solvent: O
Product: CCCCN(CCCC)CCCCl
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 9.5 g of 3-chloropropanol, 37 ml of dibutylamine and 50 ml of dimethylsulfoxide was stirred at 70°-80° C. for 8 hours. After cooling, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed from the mixture under reduced pressure. The residue was dissolved in 50 ml of chloroform, and under ice-cooling, 8 ml of thionyl chloride was added dropwise to the solution. After stirring at 50° C. for 3 hours, the solvent was removed from the reaction mixture under reduced pressure. Water was added to the residue and the mixture was washed with diethyl ether. The mixture was made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed from the extract under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform:ethanol=20:1) to give 12 g of N,N-dibutyl-3-chloropropylamine (yield: 58%, oily product).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:15]([O:17][CH2:18][CH2:19]O)[CH3:16].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:16][CH2:15][O:17][CH2:18][CH3:19])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: CCOCCO
Reactant: C=CCNc1ccc(CC(=O)O)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=CCNc1ccc(CC(=O)OCCOCC)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(allylamino)phenylacetic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 4-(allylamino)phenylacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C(O)(=O)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH:19]=O.C([BH3-])#N>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][NH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CNCc2ccc(F)c(F)c2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To (4-methoxyphenyl)methanamine (1.77 mL, 13.6 mmol) and acetic acid (2.7 mL, 45 mmol) in dichloromethane (15 mL) was added 3,4-difluorobenzaldehyde (1.0 m, 9.08 mmol). This mixture was heated in the microwave at 100° C. for 15 min. The reaction was cooled to room temperature and macroporous cyanoborohydride resin (9.8 g, 22.7 mmol) was added in portions. This mixture was stirred at room temperature for 16 hours. The resin was filtered off and rinsed with dichloromethane and the organics were washed with saturated sodium bicarbonate until bubbling ceased. The organics were dried over sodium sulfate and concentrated via rotovap. The resulting crude material was purified by silica gel chromatography using methanol dichloromethane gradient as eluent to afford N-(3,4-difluorobenzyl)(4-methoxyphenyl)methanamine as a yellowish oil (1.9 g, 80% yield). MS (M+H, 264); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.63 (br s, 1H), 3.56 (s, 2H), 3.61 (s, 2H), 3.71 (s, 3H), 6.84 (d, J=8.8 Hz, 2H), 7.14 (m, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.34 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:25]=[CH:24][C:20]2[S:21][CH2:22][CH2:23][C:19]=2[CH:18]=1.C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:49][CH:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=N2)C=1)(C)(C)C>O1CCCC1.[Cl-].[NH4+]>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:25]=[CH:24][C:20]2[S:21][CH2:22][CH2:23][C:19]=2[CH:18]=1)[CH2:49][CH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Reactant: COC(=O)Cc1ccc2c(c1)CCS2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc2c(c1)CCS2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69.2 %

Procedure:
A round bottom flask with a stir bar and argon inlet was charged with tetrahydrofuran (10 mL) and cooled to −78° C. Diisopropyl amine (155 μL, 1.10 mmol) was then added followed by the dropwise addition of a solution of n-butyl lithium (2.5M solution in hexanes, 422 μL, 1.06 mmol) and it was stirred at −78° C. for 15 min. After this time, a solution of (2,3-dihydro-benzo[b]thiophen-5-yl)-acetic acid methyl ester (200 mg, 0.96 mmol) in tetrahydrofuran (3 mL) and 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was added dropwise. It was then stirred for 1 h at −78° C. It was then treated with a solution of iodomethylcyclopentane (prepared in PCT WO2004/052869 A1 Example 1, 302 mg, 1.44 mmol) in 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) dropwise. The reaction was then stirred at −78° C. and gradually allowed to warm to 25° C. and stirred at 25° C. for 16 h. The reaction was then diluted with a saturated aqueous ammonium chloride solution (30 mL). The aqueous layer was and extracted with ethyl acetate (3×20 mL). The organics were then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 2% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid methyl ester (193 mg, 69).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.Cl[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[CH2:18][CH2:17]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)[CH:8]=2)[N:3]=1
Reactant: Oc1ccc2nc(Cl)cnc2c1
Reactant: Cc1ccc(N2CCC(CCCl)CC2)nn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCC(CCOc3ccc4nc(Cl)cnc4c3)CC2)nn1
Yield: 61.5 %

Procedure:
A mixture of 2-chloro-6-hydroxyquinoxaline (52 mg, 288 μmol), 3-[-4-(2-chloroethyl)-1-piperidinyl]-6-methyl pyridazine (76 mg, 317 μmol), potassium iodide (53 mg, 317 μmol) and potassium carbonate (199 mg, 1.44 mmol) in anhydrous dimethylformamide (2 ml) was heated at 90° under an Argon atmosphere for 2 days. Tlc (silica; ethyl acetate) showed new polar material. Removal of the solvent under high vacuum and then chromatography on silica (5 g; eluent: 30% hexane in ethyl acetate) gave the product as a white solid 68 mg (61%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]3[C@@H:15]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C@@H:16]4[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:27]1(O)CCCC1>>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]3[C:15]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:16]=4[NH:17][C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:27][CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)c(OC2CCCC2)c1
Reactant: OC1CCCC1
Product: c1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)c(OC2CCCCC2)c1

Procedure:
Following the procedure for the preparation of (5aS*,10bS*)-10-[2-(cyclopentyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole and substituting cyclohexanol for cyclopentanol while making non-critical variations the title compound was obtained as 278 mg (32%) of a white foam: 1H NMR (400 MHz, CDCl3) δ 7.84 (br s, 1H), 7.35-7.26 (m, 3 H), 7.15-7.11 (m, 1H), 7.04-7.01 (m, 2H), 6.95 (d, J=7.2 Hz, 1H), 4.08-4.06 (m, 1H), 3.09-3.07 (m, 2H), 2.97-2.96 (m, 2H), 2.85-2.83 (m, 2H), 2.47-2.37 (m, 2H), 1.90 (m, 2H) 1.71 (m, 2H), 1.51 (m, 2H), 1.41 (m, 2H), 1.15 (m, 3 H); HRMS (FAB) calcd for C24H28N2O+H1: 361.2280 found 361.2270.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.CC(C)([O-])C.[K+].[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[CH:44]1[CH2:46][O:45]1.C(OCC)(=O)C>CS(C)=O>[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[CH:44]([OH:45])[CH2:46][O:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4]1
Reactant: c1ccc2cc(C3CO3)ccc2c1
Reactant: OCC1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OC(COCC1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1)c1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
A mixture of 6.0g of 2-hydroxymethyl-4-tritylmorpholine, 1.0 g of potassium tert-butoxide and 6 ml of dimethyl sulfoxide was heated to 80° C. Thereto was dropwise added, at 80°-85° C. in 2 hours, a solution of 2.8 g of 2-(2-naphthyl)oxirane dissolved in 6 ml of dimethyl sulfoxide. The resulting mixture was stirred at the same temperature for 3 hours. The reaction mixture was cooled and added to a mixture of 60 ml of ice water and 60 ml of ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 9.0 g of oily 1-(2-naphthyl)-2-[(4-tritylmorpholin-2-yl)methoxy]ethanol (compound No. 254).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[NH2:43][C@@H:44]([CH2:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)[CH2:45][OH:46]>C(Cl)Cl>[CH:48]1([CH2:47][C@H:44]([NH:43][C:23]([C:22]2[CH:26]=[CH:27][C:19]([C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:6]4[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=4)[CH2:12][CH2:13]3)=[O:18])=[CH:20][CH:21]=2)=[O:25])[CH2:45][OH:46])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: N[C@H](CO)CC1CCCCC1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@H](CO)CC3CCCCC3)cc2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid (1.5 g) was dissolved in methylene chloride (60 ml) and then, triethylamine (0.7 ml) was added and cooled. Pivaloyl chloride (0.58 ml) was added slowly to the solution at 0~5° C. and the mixture was stirred at SoC for 2 hours. And then triethylamine (1.7 ml) and (S)-(+)-2-amino-3-cyclohexyl-1-propanol hydrochloride (0.87 g) were added in order, the solution was stirred at 0° C. for 3 hours and heated slowly to 20° C. and stirred for 1 hour. The reaction mixture was washed with water twice and the solvent was concentrated under reduced pressure. The concentrated residue was recrystallized using isopropanol and ether. The recrystallized product was filtered and dried to give 2.07 g (yield: 80%) of the desired compound. m.p.: 139~140° C.; 1H-NMR(CDCl3), ppm: δ 0.89~1.01(m, 2H), 1.22(m, 9H), 1.34(m, 1H), 1.45(m, 2H), 1.71(m, 4H), 1.81(m, 1H), 3.10(m, 4H), 3.51(m, 3H), 3.61(m, 1H), 3.76(m, 1H), 3.89(m, 2H), 4.13(m, 1H), 4.26(m, 1H), 6.59(m, 1H), 6.83(m, 1H), 6.95(m, 1H), 7.40(m, 2H), 7.67(m, 1H), 7.77(m, 2H)
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:15])OC(C)(C)C)=O.C(OCC)(=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1CCCCC1>CCO>[O:15]=[C:9]1[NH:8][C:4]2[S:5][CH:6]=[CH:7][C:3]=2[CH:1]=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)Nc1sccc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2ccsc2[nH]c1=O

Procedure:
A solution of tert-butyl 3-formyl-2-thienylcarbamate (11-3, 1.90, 8.36 mmol, 1 equiv), diethyl malonate (2.54 mL, 16.7 mmol, 2.00 equiv), and piperidine (0.413 mL, 4.18 mmol, 0.500 equiv) in EtOH (100 mL) was heated at reflux for 6 h. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (EtOAc, initally, then 10% MeOH in EtOAc) to give ethyl 6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (10-4). 1H NMR (400 MHz, CDCl3) δ 11.57 (brs, 1H), 8.60 (s, 1H), 7.33 (d, 1H, J=6.0 Hz), 7.21 (d, 1H, J=6.0 Hz), 4.49 (q, 2H, J=7.1 Hz), 1.46 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:12].[Br:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>ClCCCl.ClCCl>[Br:13][CH2:14][CH2:15][CH2:16][C:17]([NH:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: O=C(Cl)CCCBr
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCCBr)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A solution of 4-chloroquinolin-3-amine (3.70 g, 20.74 mmol) and 4-bromobutyryl chloride (11.54 g, 62.22 mmol) dissolved in 100 mL of 1,2-dichloroethane was heated to reflux. After 17 hours the reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous K2CO3, H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to give a brown solid. The solid was triturated with a mixture of hexane and ether, filtered and dried to give 4-bromo-N-(4-chloroquinolin-3-yl)butanamide (3.65 g) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[N:8]=C[N:6]3[CH:11]=[N:12][N:13]=[C:5]3[C:4]=2[CH:3]=1>CO.C(Cl)Cl>[Cl:1][C:2]1[S:10][C:9]([NH2:8])=[C:4]([C:5]2[NH:6][CH:11]=[N:12][N:13]=2)[CH:3]=1
Reactant: Clc1cc2c(ncn3cnnc23)s1
Solvent: ClCCl
Solvent: CO
Product: Nc1sc(Cl)cc1-c1nnc[nH]1
Temperature: 60 °C

Procedure:
To a stirring mixture of 8-chlorothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (60 mg, 0.285 mmol) in MeOH (10 mL) was added N-methylethyl 1,2-diamine (106 mg, 1.4 mmol). The resulting mixture was warmed to 60° C. for 1 hr. The reaction mixture was cooled to rt and then diluted with DCM. This mixture was then washed several times with a saturated NH4Cl solution. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give 5-chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine. This amine was taken directly to the next coupling reaction without further purification. Retention time (min)=1.227, method [1], MS(ESI) 201.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][C:4]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(N)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methoxy-3-trifluoromethyl aniline (500 mg, 2.62 mmol) in 20 mL of tetrahydrofuran was added potassium carbonate (470 mg, 3.4 mmol), followed by phenyl chloroformate (532 mg, 3.4 mmol). This solution was stirred overnight at room temperature, then concentrated and purified by silica gel chromatography using a gradient of ethyl acetate/hexanes 0-20% to afford phenyl 4-methoxy-3-(trifluoromethyl)phenylcarbamate as a white solid. 1H NMR (300 MHz, CDCl3) 7.75-7.65 (m, 2H), 7.60-7.40 (m, 2H), 7.27-7.19 (m, 3H), 7.00-6.93 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[C:17](=[O:19])[CH2:16][CH2:15]2>CCOC(C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:18]=2[C:17](=[O:19])[CH2:16][CH2:15]3)[N:3]=1
Reactant: O=C1CCc2cccc(O)c21
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Product: O=C1CCc2cccc(Oc3cncc(Cl)n3)c21
Yield: 100 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 7-hydroxyindanone (219 mg, 1.49 mmol), and crystallisation in AcOEt, the title compound was obtained (348 mg). Yield: 100%. 1H NMR (250 MHz, DMSO-d6) δ 2.56-2.61 (m, 2H, H3), 3.16 (t, 2H, H3, J=5.6 Hz), 7.25 (d, 1H, Harom 4, J=7.9 Hz), 7.54 (d, 1H, Harom 6, J=7.6 Hz), 7.78 (t, 1H, Harom 5, J=8.3 Hz), 8.49 (s, 1H, HPz 5), 8.62 (s, 1H, HPz 3). m/z: 261.0 [(M+H)+, calcd for C13H9ClN2O2 260.0].
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].[CH2:17]([Mg]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:15]=[C:4]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccc1

Procedure:
Prepared as described in Example 6 from (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (600 mg, 2.58 mmol) and benzylmagnesium chloride (2.0 M in THF, 3.87 mL, 7.75 mmol). Yield 653 mg (96%).