Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:38])[CH2:9][N:10]([CH2:26][C@H:27]([OH:37])[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][OH:36])[CH:29]=2)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:17][CH:16]=2)=[CH:4][C:3]=1[CH2:39][OH:40].I.[NH2:42][C:43]1[C:44]([C:51]([NH:53][C:54](=[NH:57])SC)=[O:52])=[N:45][C:46]([Cl:50])=[C:47]([NH2:49])[N:48]=1.C(N(C(C)C)CC)(C)C>C(O)C>[OH:37][C@H:27]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][OH:36])[CH:29]=1)[CH2:26][N:10]([CH2:9][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([CH2:39][OH:40])[CH:4]=1)[OH:38])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:54]([NH:53][C:51]([C:44]2[C:43]([NH2:42])=[N:48][C:47]([NH2:49])=[C:46]([Cl:50])[N:45]=2)=[O:52])=[NH:57])=[CH:19][CH:20]=1
Reactant: NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(O)c(CO)c2)C[C@H](O)c2ccc(O)c(CO)c2)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(O)c(CO)c2)C[C@H](O)c2ccc(O)c(CO)c2)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 65 °C
Reaction time: 5 h
Yield: 29.4 %

Procedure:
A solution containing 66 (45 mg, 0.08 mmol) dissolved in ethanol (4 mL) was heated to 65° C. The reaction mixture was treated with 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (32 mg, 0.12 mmol) and diisopropylethylamine (0.40 μL). The reaction mixture was stirred at that temperature for 5 h under N2 atmosphere. The solution was concentrated in vacuo. The resulting residue was first purified by column chromatography eluting with a mixture of 0-20% (10% concentrated ammonium hydroxide in methanol) and dichloromethane and then further purified by preparative TLC using the same solvent system to afford the desired product 67 (18 mg, 30%) as a pale yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 7.26 (s, 1H), 7.10 (s, 2H), 6.97 (s, 1H), 6.68 (s, 1H), 6.58 (s, 1H), 4.88 (br, 1H), 4.46 (s, 3H), 3.16 (s, 2H), 1.58-1.23 (m, 6H); m/z (ESI) 766 [C39H53ClN8O7+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[S:15])=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[S:15])[NH:1][CH2:2][C:3]([NH2:5])=[O:4])=[CH:9][CH:8]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: NCC(N)=O
Product: NC(=O)CNC(=S)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
Glycinamide (5.0 g) and 4-fluorophenyl-isothiocyanate (9.18 g) were stirred in (200 mL). The mixture was heated at reflux for 5 minutes then stirred at ambient temperature for 20 minutes. The precipitated solid was collected by filtration, washed with chloroform and air dried to give 2-[3-(4-fluorophenyl)-thioureido]-acetamide (10.7 g) as a light pink solid, m.p. 168°-170° C. (dec.). Mass spectrum (EI, M.+) m/z 277. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.97 (broad s, 1 H), 7.82 (broad s, 1 H), 7.45-7.52 (m, 3 H), 7.10-7.17 (m, 3 H), and 4.06 ppm (s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[CH2:20]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:10]=2[CH3:12])[C:6]([CH:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)=[CH:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C)c2[nH]cc(C3CCN(C)CC3)c2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(C)c2c(c1)c(C1CCN(C)CC1)cn2Cc1ccccc1
Yield: 80.5 %

Procedure:
By a method similar to Preparation 26, using 5-methoxy-7-methyl-3-(1-methylpiperidin-4-yl)-1H-indole (5.81 mmol, 1.50 g) and benzyl bromide (5.81 mmol, 0.993 g), THF (100 mL), 35% potassium hydride (5.81 mmol, 0.665 g), and 18-crown-6 (0.58 mmol, 0.153 g) afforded 1.63 g (81%) of the title compound: mass spectrum (ion spray): m/z=349 (M+1): Calculated for C23H28N2O-0.3H2O: C, 78.06; H, 8.15; N, 7.92. Found: C, 78.13; H, 7.84; N, 8.03.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[H-].[Na+].[CH2:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-chloro-2-nitrophenyl methyl ether (5 g, 26.596 mmol) in dry DMF (150 mL) was cooled to 0° C. by ice water and NaH (3.51 g, 87.750 mmol, 60% purity) was added portionwise, and then the reaction was warmed to ambient temperature and stirred for 1.5 hours. The reaction was cooled to 0° C. and CH2(COOEt)2 (14.04 g, 87.768 mmol) was added. The result mixture was warmed to ambient temperature and heated to 80° C. for 13 hours. The reaction was cooled to ambient temperature and poured into ice water and added 2N HCl to adjust pH to 3. Extracted with EtOAc and the organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified via column chromatograph to afford diethyl (3-methoxy-4-nitrophenyl)propanedioate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.86 (d, J=8.3 Hz, 1H), 7.25 (s, 1H), 7.07 (d, J=8.3 Hz, 1H), 4.67 (s, 1H), 4.23˜4.29 (m, 4H), 4.00 (s, 3H), 1.31 (t, J=7.0 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Br:12])[C:9](=[O:13])[NH:8][C:7]=1[C:14]([F:17])([F:16])[F:15])=[O:5])[CH3:2].[CH2:18](O)[C:19]([F:22])([F:21])[F:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:8][C:7]=1[C:14]([F:17])([F:15])[F:16])[CH3:2]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5-Bromo-1,6-dihydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (CAS Registry No. 862111-61-3) (5.0 g, 16 mmol) was dissolved in tetrahydrofuran (80 mL). To the solution were added trifluoroethanol (1.37 mL, 19 mmol), triphenylphosphine (5.0 g, 19 mmol) and diethyl azodicarboxylate (3.7 mL, 19 mmol) at 0° C. The mixture was stirred for 30 min at 0° C. and for 6 h at room temperature. The solvent was removed in vacuo and the residue dissolved in dichloromethane and washed with water. Organic phases were pooled, dried with MgSO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel with dichloromethane:heptane 1:2 to yield the product as white solid, MS (ISP) 397 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>O1CCCC1>[Br:7][C:4]1[S:3][C:2]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1cnc(N2CCNCC2)s1
Temperature: 160 °C
Yield: 94 %

Procedure:
A mixture of 2.06 mmol 2,5-dibromothiazole, 6.17 mmol piperazine and 6.17 mmol triethylamine in 6 ml tetrahydrofuran in a sealed tube was heated at 160° C. for 10 min under microwave irradiation. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to afford the title compound as a white crystalline solid (yield 94%). MS (m/e): 250.0 ({81Br}M+H+, 100%), 248.0 ({79Br}M+H+, 76%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1)=O.[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:20]([N:19]([CH2:1][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1)[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNCc1ccccc1
Reactant: COC(=O)c1sc(C=O)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1sc(CN(C)Cc2ccccc2)cc1-c1ccccc1
Reaction time: 18 h
Yield: 94.3 %

Procedure:
To a solution of 172 (0.706 g, 2.87 mmol) in DCE (15 mL) was added N-Methylbenzylamine (0.388 mL, 3.01 mmol) and sodium triacetoxyborohydride (0.851 g, 4.01 mmol) and stirred for 18 hours. The reaction mixture was diluted in DCM and washed with a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude residue was purified by ISCO (40 g column, 0-30% ethyl acetate in hexanes) to yield compound 173 (951 mg, 94%) a colorless oil.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1>C1COCC1.CO>[OH:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
Sodium borohydride (5.7 g, 0.15 mol) was added in portions to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (15 g, 75 mmol) in THF/MeOH (150 mL/30 mL) at −10° C. The reaction mixture was stirred for 30 min at −10° C. and then poured into ice-water (300 mL). The resulting mixture was extracted with EtOAc (300 mL×3) and the combined extracts were dried over anhydrous sodium sulfate and concentrated to afford tert-butyl 4-hydroxypiperidine-1-carboxylate (13.2 g, 87% yield).
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:45]([NH:47][C@H:48]([C:53](O)=[O:54])[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:46].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]([O:24][C:53]([C@@H:48]([NH:47][CH:45]=[O:46])[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:54])[CH2:11][C@@H:10]1[O:9][C:8](=[O:25])[C@H:7]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Reactant: CC(C)C[C@H](NC=O)C(=O)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(C)C)NC=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
166 g of (3S,4S)-3-hexyl-4-((R)-2-hydroxy tridecyl)-2-oxetanone obtained from Reference Example 1 was dissolved in 830 mL of tetrahydrofuran. After the addition of 160 g of triphenylphosphine (PPh3) and 86 g of N-formyl-L-leucine, the reaction mixture was cooled to 0° C. A mixed solution where 120 mL of diisopropylazodicarboxylate (DIAD) was diluted in 332 mL of tetrahydrofuran, was continuously added thereto over 1.5 hours. After stirring for further 30 minutes, the reaction mixture was stirred for 4 hours while slowly raising its temperature. After removing the solvent, 832 mL of hexane was added thereto, and the reaction mixture was stirred for 5 hours. The formed solid was removed therefrom by filtration, and the hexane layer thereof was washed with 499 mL of 55% methanol/distilled water three times. The remaining organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was removed under a reduced pressure. Then, 2.5 L of hexane was added thereto, and the reaction mixture was cooled to 10° C. and stirred for 1 hour, followed by addition of a seed of orlistat solid. The reaction mixture was slowly cooled to 0° C. again, and stirred overnight. The obtained solid was filtered, washed with 500 mL of cold hexane, and dried, to obtain 192.5 g of the title compound (yield: 83%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5](OC2C=CC=CC=2)=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[C:5]([NH:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:25])([F:35])[F:36])[CH:28]=2)=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccccc2)cc1Oc1ccccc1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccccc2)cc1NCc1cccc(C(F)(F)F)c1

Procedure:
Using a procedure analogous to that described in Example 12, 3 gm (71.2% of theory) of the title compound, m.p. 140°-142° C. (recrystallized from ethanol), were obtained by stirring a mixture of 3.51 gm of 6-chloro-4-nitro-1,3-diphenoxy-benzene, 4 gm of 3-trifluoromethyl-benzylamine and 5 ml of dioxane for 20 hours at 100° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]1[C@H:46]([CH:47]=[CH2:48])[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].CCN(CC)CC.C(C1C=CC(C2C=CC=CC=2)=C(P)C=1C(C)(C)C)(C)(C)C>C(#N)C.Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:30]([O:34][C:35]([N:37]1[C@H:46](/[CH:47]=[CH:48]/[C:13]2[CH:12]=[CH:11][C:10]([N:16]3[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]3(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=2)[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: C=C[C@@H]1Cc2ccccc2CN1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc(-c2ccccc2)c(P)c1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 80 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (0.77 g, 1.4 mmol) and (S)-3-vinyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.44 g, 1.7 mmol) in acetonitrile (5 mL) in a pressure vessel is added Et3N (0.32 mL, 2.3 mmol) followed by di-t-butyl-phosphinobiphenyl (0.017 g, 0.057 mmol). The solution is degassed by nitrogen sparging for 10 min, and then Pd(OAc)2 (0.006 g, 0.028 mmol) is added and the mixture is heated to 80° C. for 18 h. The mixture is cooled to RT and is diluted with 1N HCl and extracted with EtOAc (2×30 mL). The organic layer is washed with brine (3×30 mL) and dried over Na2SO4. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 5 to 30% EtOAc in hexanes to give the title compound.
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24](CC4(C)OCCO4)[CH2:23][CH2:22][C:21]([C:32](O)=[O:33])=[CH:20][C:19]=3[CH:35]=2)=CC=1)CCC.S(Cl)(Cl)=O.C[N:41](C=O)C.CN(CC1C=CC(N)=CC=1)C1CCOCC1>C1COCC1.O.C(N(CC)CC)C>[NH:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:35][C:19]=2[CH:20]=[C:21]([C:32]([NH2:41])=[O:33])[CH2:22][CH2:23]1
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC2(C)OCCO2)cc1
Agent: CN(Cc1ccc(N)cc1)C1CCOCC1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)C1=Cc2ccccc2NCC1
Reaction time: 1 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-[(2-methyl-1,3-dioxolan-2-yl)methyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (300 mg) in THF (10 ml) were added thionyl chloride (0.068 ml) and DMF (one droplet) at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (151 mg) and triethylamine (0.7 ml) in THF (3 ml) at 0° C. The mixture was stirred at room temperature for 20 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethanol:ethyl acetate=1:19→1:10), and the resulting crystals were purified by recrystallization (ethyl acetate-diisopropyl ether) to give 7-[4-(2-butoxyethoxy)phenyl]-1-[(2-methyl-1,3-dioxolan-2-yl)methyl]-N-[4-[[N-methyl-N-tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 107) (144 mg) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:7][C:4]2([CH2:6][CH2:5]2)[CH2:3]1.[OH-].[Na+]>C1COCC1.O>[CH3:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][C:4]2([CH2:6][CH2:5]2)[CH2:3]1
Reactant: CC1(C(=O)OCc2ccccc2)CC2(CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(=O)O)CC2(CC2)C1
Temperature: 50 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
To a stirred solution of Intermediate 317A (200 mg, 0.868 mmol) in THF (2 mL) and water (1 mL) was added NaOH (104 mg, 2.61 mmol) at RT and the reaction mixture was warmed to 50° C. and stirred for 12 h. The reaction mixture was concentrated under a reduced pressure, the residue was to pH 2 with a 1.5 N aq. solution of HCl and extracted with Et2O (3×15 mL) The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 317B as a colorless liquid (0.12 g, 99%). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.38-11.71 (m, 1H), 2.68-2.50 (m, 2H), 1.86-1.66 (m, 2H), 1.43 (s, 3H), 0.62-0.19 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.[CH3:28][C:29]1[S:33][C:32]([C:34]([OH:36])=[O:35])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:27][O:26][C:17]1[CH:18]=[C:19]([O:22][CH2:23][O:24][CH3:25])[CH:20]=[CH:21][C:16]=1[C:4]1[C:3]([CH2:2][O:36][C:34]([C:32]2[S:33][C:29]([CH3:28])=[CH:30][CH:31]=2)=[O:35])=[C:12]2[C:7]([NH:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[NH:11]2)=[CH:6][CH:5]=1
Reactant: COCOc1ccc(-c2ccc3c(c2CCl)NC(=O)C(C)(C)N3)c(OC)c1
Reactant: Cc1ccc(C(=O)O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)s2)NC(=O)C(C)(C)N3)c(OC)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A mixture of 8-chloromethyl-7-(2-methoxy-4-methoxymethoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 10, 238 mg, 0.609 mmol), 5-methyl-2-thiophenecarboxylic acid (133 mg, 0.936 mmol), and potassium carbonate (261 mg, 1.89 mmol) was suspended in anhydrous N,N-dimethylformamide (5 mL) and stirred at 80° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL). It was washed with water (100 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (264 mg) as a yellow amorphous product. (Yield 87%)
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([O-:9])=[O:8].Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[N+:7]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([O-:9])=[O:8]
Reactant: CCOC(=O)CCl
Reactant: O=[N+]([O-])c1cccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccsc1[N+](=O)[O-]
Temperature: -50 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
Potassium tertiary-butoxide (652 mg, 5.81 mmol) was dissolved in tetrahydrofuran (150 ml) and the solution cooled to −50° C. A solution of 2-nitrothiophene (250 mg, 1.94 mmol) (Avocado) and ethyl chloroacetate (0.22 ml, 1.94 mmol) (Aldrich) was added dropwise in dry tetrahydrofuran (4 ml) over 5 minutes. The reaction mixture was stirred at −50° C. for 1 hour then quenched with acetic acid (0.5 ml), then washed with water (20 ml). The aqueous phase was extracted with ethyl acetate and the combined organic fractions were washed with saturated brine solution. The organic phase was dried over magnesium sulfate, evaporated to dryness and the residue chromatographed on silica gel using hexane/ethyl acetate (4:1) as eluent to give 261 mg of ethyl 2-nitrothiophene-3-acetate as a red/brown viscous oil. MS(ES): mn/e 216 [M+H].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([O:17][C:16]([F:15])([F:25])[F:26])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A mixture of compound 4,6-dichloro-2-phenyl-pyrimidine (27 g, 112 mmol), 4-trifluoromethoxy aniline (21 g, 119 mmol) and triethylamine (33 mL, 225 mmol) in n-butanol (300 mL) was refluxed for 20 hours under nitrogen atmosphere. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The crude compound was passed through the silica gel by using 5-6% ethylacetate in petroleum ether to afford the compound (6-chloro-2-phenyl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (20 g, 46%) as off-white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].C(O)C>[Ni].O>[CH2:20]([OH:21])[CH2:19][CH:17]([CH2:16][CH2:15][CH2:14][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:8])[CH3:13])[CH3:18]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Reaction time: 120 h

Procedure:
Phytol (21.0 g, 70.8 mmol), ethanol (180 mL) and a stir bar were added to a 500 mL round bottom flask. Raney Nickel 2800 (as purchased, a 50% by weight solution in water if used as purchased, Nickel >89% metal present) (6.8 g, 51.5 mmol) was added, and the flask sealed and flushed with hydrogen. A 12″ needle was used to bubble hydrogen through the solution for 10 minutes. The reaction was stirred for 5 days, using a balloon as a hydrogen reservoir. Hydrogen was also bubbled through the reaction mixture at 24 h and 48 h, 5 minutes each time. The metal catalyst was then removed by filtering through Celite. The ethanolic solution was concentrated, and 200 mL of DCM added to the resulting oil. The solution was washed with water (2×100 mL), dried over MgSO4, and concentrated. TLC indicated formation of the phytanol product, yield 20.0 g.
Reaction SMILES: [F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]([N:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[C:12]#[N:13])=[CH:7][N:6]=1)([F:4])[CH3:3].N>[Ni]>[F:4][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]([N:14]2[CH2:19][CH2:18][C:17]([F:20])([F:21])[CH2:16][CH2:15]2)[CH2:12][NH2:13])=[CH:7][N:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ncc(C(C#N)N2CCC(F)(F)CC2)cn1
Agent: [Ni]
Agent: N
Product: CC(F)(F)c1ncc(C(CN)N2CCC(F)(F)CC2)cn1

Procedure:
2-(2-(1,1-difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)acetonitrile (39 mg, 0.065 mmol, 50%) was dissolved in ammonia (2034 μl, 4.07 mmol, 2 molar in MeOH) and hydrogenated on H-Cube, by passing the solution over the Ra-Ni catcart 3 times at 60° C. and 60 bar. The solution was concentrated to afford 2-(2-(1,1-difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamine, which was used crude in the next reaction.