Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (460 mg, 1.23 mmol) from Step 2 of this Example in DCM (25 mL) at 0° C. was added 70% meta-chloroperbenzoic acid (333 mg, 1.35 mmol), and the mixture was allowed to warm to rt and stirred for a further 30 min. To the mixture was added saturated aq NaHCO3 and the organic layer was separated. The aqueous layer was re-extracted with DCM and the combined organic layers were washed with saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (481 mg, 100%) as a cream solid which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.40-8.50 (m, 2H), 7.84-7.95 (m, 2H), 7.50 (d, J=8.3 Hz, 1H), 5.68 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 391 and 393 (M+H)+.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[Cl:23][C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2cccc(Cl)c2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (3-chlorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.03 (s, 3H), 2.20 (s, 3H), 4.51 (d, J=3.0 Hz, 2H), 6.91 (d, J=6.8 Hz, 1H), 7.02-7.15 (m, 2H), 7.20 (t, J=6.4 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 7.55 (bs, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.78 (s, 1H), 8.10 (s, 1H), 8.49 (d, J=3.8 Hz, 1H); MS (ESI) m/z 340.1 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH2:24][CH2:23][CH2:22]2>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:25]2[C:26]3[C:21](=[CH:20][C:19]([CH3:18])=[CH:28][CH:27]=3)[CH2:22][CH2:23][CH2:24]2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Cc1ccc2c(c1)CCCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)CCCN2c1ncnc(Cl)n1
Temperature: 0 °C

Procedure:
2,4-Dichloro-1,3,5-triazine (1.95 g, 13 mmol) was dissolved in DMF (50 mL) under N2 and cooled to 0° C. DIEA (1.68 g, 13 mmol) was added, followed by the addition of 6-methyl-1,2,3,4-tetrahydroquinoline (1.91 g, 13 mmol). The reaction was stirred with gradual warming to RT. The reaction was quenched after 3 h with water, which causes a sticky precipitate to form. The mixture was extracted 3× with EtOAc. The EtOAc extracts were washed brine, combined, dried over Na2SO4, filtered, and concentrated, then dried under high vacuum to remove residual traces of DMF. The recovered material was purified by elution through a 17×2.5 cm column of silica gel (5%, 10%, 20% and 40% EtOAc/Hexane step gradient) giving 1-(4-chloro-[1,3,5]triazin-2-yl)-6-methyl-1,2,3,4-tetrahydro-quinoline as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7](O)[N:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:16][C:7]1[N:8]=[C:9]([CH3:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[CH3:1]
Reactant: Cc1cc2c(C)ccnc2c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2c(C)ccnc2c(Cl)n1
Temperature: 104 °C
Yield: 66.1 %

Procedure:
4,6-Dimethyl-[1,7]naphthyridin-8-ol (1.26 g, 7.23 mmol) and phosphorus oxychloride (6.7 mL, 72 mmol) in toluene (18 mL) are heated at 100° C. overnight. Phosphorus oxychloride (20 mL, 215 mmol) is added and the reaction mixture is heated at 104° C. for 1 d. The reaction mixture is cooled to RT and poured in a mixture of ice and water under stirring. After 30 min 20% NaOH is added until pH 6-7. The aqueous layer is extracted with DCM and the combined organic layers are washed with brine, dried and evaporated under reduce pressure to give a residue that is purified by flash chromatography (eluent 0-50% EtOAc/cyclohexane) to furnish 8-chloro-4,6-dimethyl-[1,7]naphthyridine (920 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][CH:12]([OH:21])[CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:5][CH:4]=1.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31].O>O1CCCC1>[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([O:21][CH:12]2[CH2:11][O:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:14][CH:13]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: COc1ccc(C2=NC(c3ccccc3)C(O)CO2)cc1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2=NC(c3ccccc3)C(OC(=O)Nc3ccc(Cl)c(Cl)c3)CO2)cc1
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
A solution of (4RS, 5RS)-2-(4-methoxyphenyl)-4-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.42 g) in anhydrous tetrahydrofuran (15 cc) is added at a temperature in the region of 20° C. to an oily suspension (50% by weight; 0.27 g), maintained under an argon atmosphere, of sodium hydride in anhydrous tetrahydrofuran (15 cc), and the solution obtained is stirred for 30 minutes at this same temperature. A solution of 3,4-dichlorophenyl isocyanate (1.05 g) in anhydrous tetrahydrofuran (10 cc) is then added dropwise and stirring is continued for 4 hours at a temperature in the region of 20° C. Distilled water (20 cc) is then added and the mixture is extracted with dichloromethane (3×80 cc). The organic phases are combined, washed with distilled water (3×20 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is purified by chromatography on silica (0.063-0.2 mm; 300 g) contained in a column 3.5 cm in diameter (eluent: dichloromethane), collecting 30 cc fractions. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is again purified by chromatography on silica (0.063-0.2 mm; 125 g) contained in a column 2 cm in diameter [eluent: cyclohexane/ethyl acetate (6:4 by volume)], collecting 20-cc fractions. The fractions 5 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (4RS, 5RS)-5-(3,4-dichlorophenylcarbamoyloxy)-2-(4-methoxyphenyl)-4-phenyl-5,6-dihydro-4H-1,3-oxazine (1.1 g), m.p. 130° C., is obtained.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([NH:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[O:21])[C:11]([NH:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(NC)nc1C
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)c(NC)nc1C
Yield: 82 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-methylaminopyridin-3-yl)carbamate and 1-(3,5-dimetoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[C:13]2[N:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=2[N:15]=[CH:16][N:17]=1>CN(C=O)C.O>[Cl:22][C:20]1[CH:19]=[CH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:13]=2[N:21]=1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a solution of 1-methylpiperidin-4-ol (0.095 g, 0.825 mmol) in DMF (2.500 ml) was added NaH (0.041 g, 55% dispersion in mineral oil, 0.945 mmol) at 0° C. After stirring for 30 min at room temperature, the reaction mixture was cooled to 0° C., followed by the addition of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.15 g, 0.750 mmol). After stirring for 2 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine (0.09 g, 43%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.03-2.12 (2H, m), 2.17-2.21 (2H, m), 2.22-2.32 (2H, m), 2.34 (3H, s), 2.84-2.89 (2H, m), 5.38-5.45 (1H, m), 7.73 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.81 (1H, s).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[N+:58]([O-:60])=[O:59])[C:47]1=[O:61])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[N+:58]([O-:60])=[O:59])[C:47]1=[O:61])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2[N+](=O)[O-])C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2[N+](=O)[O-])C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
A solution containing the product from Example 2C (0.082 g, 0.154 mmol) in THF (1.5 mL) was treated with the product from Example 123A (0.057 g, 0.17 mmol), DEPBT (0.069 g, 0.231 mmol), and N,N-diisopropylethylamine (0.135 mL, 0.77 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% acetate/dichloromethane, followed by 0-5% methanol in ethyl acetate to give the title compound (0.080 g, 61% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([CH:13]=O)[C@@H:10]([OH:15])[C@H:9]([OH:16])[C@H:7]2[N:8]=1)[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH2:17]([NH:24][CH2:13][C@H:11]1[O:12][C@H:6]2[C@H:7]([N:8]=[C:4]([NH:3][CH2:1][CH3:2])[S:5]2)[C@@H:9]([OH:16])[C@@H:10]1[OH:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C=O)O[C@@H]2S1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CNCc3ccccc3)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carbaldehyde (76.00 mg; 0.31 mmol; 1.00 eq.) in methanol (1.00 ml) was added benzylamine (0.05 ml; 0.46 mmol; 1.50 eq.), and sodium cyanoborohydride (9.70 mg; 0.15 mmol; 0.50 eq.) in 0.5 mL MeOH. The reaction was stirred at room temperature for 2 h. The desired product was isolated by prep HPLC (0% B for 10 min, then 0 to 30% B over 10 min, 0.1% TFA, 220 nm) to afford (3aR,5R,6S,7R,7aR)-5-[(benzylamino)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (12.2 mg, 12%) as a white solid (once lyophilized).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][CH:21]1[C:25](=[O:26])[N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[CH2:23][CH:22]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:24]1[C:25](=[O:26])[C@H:21]([NH:20][C:11]([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[O:13])[C@H:22]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:23]1
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)C1CN(c2ccccc2F)C(=O)C1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H]1CN(c2ccccc2F)C(=O)[C@@H]1NC(=O)c1cnc2ccccc2c1
Reaction time: 2.5 h
Yield: 73 %

Procedure:
To a solution of 3-quinolinecarboxylic acid (118 mg, 0.68 mmol) in CH2Cl2 (3 ml) was added oxalyl chloride (0.12 ml, 1.36 mmol) and the solution was stirred for 2.5 h. Removal of the solvent in vacuo gave a colorless solid which was redissolved in CH2Cl2 (3 ml). To this solution was added a solution of aminopyrrolidinone of Example W (200 mg, 0.68 mmol) and triethylamine (344 mg, 3.4 mmol) in CH2Cl2 (3 ml) and the resulting solution was stirred for 18 h. Removal of the solvent in vacuo and purification of the resulting solid via radial chromatography (4 mm plate) eluting with 2% EtOH/CH2Cl2 gave the title compound (223 mg, 73%) as a solid. 1H NMR (300 MHz, CDCl3) δ9.35 (1H, d), 8.68 (1H, d), 8.19 (1H, d), 7.94 (1H, d), 7.84 (1H t), 7.64 (1H, t), 7.54 (1H, t), 7.32 (1H, m), 7.19 (2H, m), 5.28 (1H, t), 4.21 (1H, m), 3.91 (1H, d), 3.78 (1H, q), 3.49 (1H, s), 1.41 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24]>>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: COc1ccc(CCCC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-(4-methoxyphenyl)butanamide was prepared as described in Example 5, Step 1 using 4-(4-methoxyphenyl)butyric acid and 4-chloro-3-(trifluoromethyl)aniline. LCMS, AA: Rt=2.17 min, [MH− 370.1].
Reaction SMILES: [CH2:1]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:1]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1ccc(CN2CCOC(Cc3ccccc3)C2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCOC(Cc3ccccc3)C2)cc1
Temperature: 120 °C

Procedure:
The above compound could be made in the following manner: 1 eq. of 2-Benzyl-4-(4-bromo-benzyl)-morpholine could be combined with 1.5 eq. of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 6.7 eq. of 2M sodium carbonate solution, toluene and ethanol. The reaction mixture could be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture could be filtered through Celite and concentrated in vacuo. The residue could be diluted with water and extracted with ethyl acetate. The combined organic phases could be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material could be purified by flash chromatography to afford product.
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.[CH3:12][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])=[C:18]([CH3:26])[CH:17]=1)[CH3:14].CN(CC1OC(CSC[CH2:39][NH:40][C:41]2[C:45](OC)=[N:44][S:43](=[O:49])(=[O:48])[N:42]=2)=C(C)C=1)C.CN>CO>[CH3:14][N:13]([CH2:15][C:16]1[O:20][C:19]([CH2:21][S:22][CH2:23][CH2:24][NH:25][C:45]2[C:41]([NH:40][CH3:39])=[N:42][S:43](=[O:49])(=[O:48])[N:44]=2)=[C:18]([CH3:26])[CH:17]=1)[CH3:12]
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1oc(CN(C)C)cc1C
Reactant: Cc1cc(CN(C)C)oc1CSCCN
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Solvent: CO
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1oc(CN(C)C)cc1C

Procedure:
When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with an equimolar amount of 2-[(5-dimethylaminomethyl-3-methyl-2-furyl)methylthio]ethylamine [prepared in Step B] and the resultant 3-{2-[(5-dimethylaminomethyl-3-methyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with an excess of methylamine, the title compound is thereby produced.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(OCC)(=O)C>[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)(=[O:17])[CH3:16]
Reactant: CCOC(=O)C(C)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)c1ccc(NC(C)=O)cc1
Yield: 84.7 %

Procedure:
To 10 g (0.0517 mole) of ethyl 2-(4-aminophenyl)propionate was added 50 ml of ethyl acetate with stirring, and to this solution, a mixed solution of 5.81 g of acetic anhydride and 10 ml of ethyl acetate was added dropwise and was stirred for 3 hours. After completion of the reaction, the reaction mixture was washed with a saturated solution of sodium bicarbonate and with a saturated solution of sodium chloride. After the ethyl acetate layer was dried over anhydrous magnesium sulfate, the ethyl acetate was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give 10.3 g of ethyl 2-(4-acetylaminophenyl)propionate (Yield: 85%). M.P. 94.5°-95.5° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18])=[O:8])[CH2:2][CH3:3]
Reactant: NC(=O)c1ccncc1N
Reactant: CCCOc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccccc1C(=O)Nc1cnccc1C(N)=O

Procedure:
In a similar manner to Example 68 a) reaction of 2-propoxybenzoyl chloride (0.99 g), 3-aminoisonicotinamide (0.69 g) and triethylamine (0.51 g) in acetonitrile (15 ml) afforded a crude product (1.45 g) which was recrystallized from methanol to afford 3-(2-propoxybenzamido)isonicotinamide, 0.73 g, m.p. 214-7° C.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[SH:16][CH2:17][C:18]([OH:20])=[O:19].CN(C=O)C.[OH-].[Na+]>O>[C:18]([CH2:17][S:16][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)([OH:20])=[O:19]
Reactant: O=C(O)CS
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CSc1ccc(C(=O)c2ccccc2)cc1
Temperature: 107.5 °C
Yield: 75.2 %

Procedure:
55 g 4-chloro benzophenone and 24 g mercaptoacetic acid are added into a 500 ml three-neck flask, and are dissolved with 350 ml DMF to obtain a solution, and then 23 g solid sodium hydroxide is added into the solution. Heating the solution to reflux (105-110° C.), and starting to cool the solution when the content of 4-chloro benzophenone detected by HPLC is less than 1%. The reaction solution is added into 500 ml water, and then water insoluble substances are extracted with 100 ml methylbenzene. Concentrated hydrochloric acid is used to regulate the pH value of the aqueous phase to 3-4, then some solid substances precipitates, filtering to obtain crude products, and the weight after drying is 58 g; the dried crude products are recrystallized in dichloroethane to obtain 52 g white crystal, with a yield of 75% and a melting point of 130-132° C. 1H-NMR data (solvent DMSO-d6): δ3.796 ppm, s, 2H; δ7.402, 7.429 ppm, d, 2H, δ7.451, 7.476, 7.501 ppm, t, 2H, δ7.567, 7.590, 7.614 ppm, t, 1H, δ7.740, 7.767 ppm, d, 2H, δ7.753, 7.775 ppm, d, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[CH2:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([N+:35]([O-:37])=[O:36])[CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([N+:35]([O-:37])=[O:36])[CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:18]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([N+:35]([O-:37])=[O:36])[CH:22]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cc(CCNCc2ccccc2)ccc1OCc1ccccc1
Reactant: BrCCCCCCCCBr
Product: O=[N+]([O-])c1cc(CCN(CCCCCCCCN(CCc2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1

Procedure:
Similarly, by employing 1,8-dibromooctane in the above condensation with N-benzyl-4-benzyloxy-3-nitrophenethyl-amine as described above there is obtained the corresponding N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-nitrophenyl)-ethyl]-octamethylenediamine which is carried through the same sequence of reactions, namely reduction with Raney nickel and hydrogenation with palladium-on-carbon, to yield N,N'-bis[2-(3-amino-4-hydroxyphenyl)-ethyl]-octamethylenediamine.