Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:12][C:13]([CH2:19][N:27]2[CH2:32][CH2:31][O:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]2)=[C:14]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Product: COC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 40 %

Procedure:
Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.22 g, 2.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.5 g, 3 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.54 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH3:12].C([Li])CCC.CON(C)[C:21](=[O:24])[CH2:22][CH3:23]>C1COCC1>[CH3:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)N(C)OC
Reactant: Cc1cc(C(F)(F)F)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(C(F)(F)F)cc1C
Temperature: -71 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
Cool a solution of 1-bromo-2-methyl-4-(trifluoromethyl)benzene (2.00 g, 8.367 mmol) and THF (17 mL) to −71° C., and then add n-butyl lithium (2.5 M in hexanes, 9.204 mmol, 3.681 mL) over 5 minutes. Stir the mixture for 15 minutes at −71° C. Add N-methoxy-N-methylpropanamide (0.980 g, 8.367 mmol) to the mixture drop-wise over 3-4 minutes keeping temperature below −65° C. Continue to stir the solution at −71° C. for 15-20 minutes; then warm the solution to room temperature. Stir at room temperature for 40 minutes. Quench the reaction with a saturated ammonium chloride aqueous solution. Extract the aqueous layer with Et2O. Wash the combined organic extracts with water and brine. Dry the mixture over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the residue by flash chromatography (40 g RediSep® column) eluting with a gradient of 0-40% DCM/pentane to give the title compound as a colorless oil (1.490 g, 82% yield). 1H NMR (399.80 MHz, d6-DMSO) δ 7.84 (d, J=7.8 Hz, 1H), 7.64-7.61 (m, 2H), 2.93 (q, J=7.1 Hz, 2H), 2.39 (s, 3H), 1.03 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[CH2:22]([NH:24][CH2:25][CH2:26][OH:27])[CH3:23]>>[CH2:22]([N:24]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1)[CH2:25][CH2:26][OH:27])[CH3:23]
Reactant: CCNCCO
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Product: CCN(CCO)CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and 2-(ethylamino)ethanol were converted to yield 2-(Ethyl-{3-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-amino)-ethanol as colorless oil, MS: 374 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:10]12[O:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2>O>[C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[OH:16])(=[O:3])[CH3:2]
Reactant: C1CCC2OC2C1
Reactant: CC(=O)N1CCNCC1
Solvent: O
Product: CC(=O)N1CCNCC1[C@@H]1CCCC[C@@H]1O
Yield: 86.4 %

Procedure:
A mixture of 1-acetylpiperazine (5 g, 39 mmol) and cyclohexene oxide (3.95 mL, 39 mmol) in water (1.2 mL) was refluxed for 16 hours. The cooled reaction mixture was partitioned between 40% NaOH aqueous solution (20 mL) and diethyl ether (2×20 mL). The combined organic layers were dried over sodium sulfate and the solvent was evaporated in vacuo to yield 7.63 g of the title compound as white crystals (87% yield)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:28][CH:27]=2)[CH:10]([CH2:44][OH:45])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:46](Br)[CH:47]=[CH2:48]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:30][CH:31]=2)[CH:10]([CH2:44][O:45][CH2:48][CH:47]=[CH2:46])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: C=CCBr
Product: C=CCOCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 13 (g), by alkylating (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [WO 9709311, Example 148 (h)] with allylbromide there was obtained (3SR,4RS,5RS)-3-allyloxymethyl-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-( naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid; MS: 652 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5][C:6](=O)[CH:7]=1.O.C([O-])=O.[NH4+:18]>CO.[Pd]>[NH2:18][CH:6]1[CH2:5][CH2:4][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]([CH3:1])[CH2:7]1
Reactant: [NH4+]
Reactant: CCOC(=O)C1CCC(=O)C=C1C
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Solvent: O
Product: CCOC(=O)C1CCC(N)CC1C
Temperature: 25 °C

Procedure:
Ethyl 2-methyl-4-oxocyclohex-2-enecarboxylate (2.0 g, 10.98 mmol) is dissolved in MeOH (40 ml) and water (4.0 ml) to give a yellow solution. Ammonium formate (8.31 g, 132 mmol) is added and stirred at RT until the suspension dissolves to form a solution. Palladium on carbon (0.117 g, 1.098 mmol) is added and the reaction mixture is stirred at 70° C. for 1 hour. The mixture is filtered through Celite® (filter material) and washed with MeOH. The filtrate is concentrated in vacuo and the residue is partitioned between EtOAc and water. The aqueous portion is diluted with sat. sodium bicarbonate and washed with EtOAc. The pH is adjusted to pH14 using 1M NaOH and the aqueous is extracted with EtOAc. The combined organic extracts are dried MgSO4, filtered and concentrated in vacuo to afford the title compound; [MH]+186.24.
Reaction SMILES: [CH2:1]([C@@:8]12[CH2:21][C:20](=[O:22])[C@:19]([OH:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30](O)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=1.CN1C=CN=C1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@@:8]12[CH2:21][C:20](=[O:22])[C@:19]([OH:29])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30]([NH:33][C:34]3[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncccc1N
Reactant: O=C(O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)C(=O)C[C@@]21Cc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cn1ccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ncccc1NC(=O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)C(=O)C[C@@]21Cc1ccccc1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
(4bR,7R,8aR)-4b-benzyl-7-hydroxy-6-oxo-7-phenyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxylic acid (21 g, 49.2 mmol), 3-amino-2-picoline (5.8 g, 52.2 mmol) and 1-methylimidazole (20 mL, 246.2 mmol) were dissolved in anhydrous acetonitrile (105 mL). 1-Propanephosphonic acid cyclic anhydride (50 wt % in ethyl acetate) (47 mL, 78.8 mmol) was slowly added to control the mild exotherm. The mixture was stirred at 25° C. until the reaction was completed (less than an hour). Ethyl acetate (86 mL) was added to the mixture. The mixture was washed with water (4×100 mL). The organic phase was dried with MgSO4 and concentrated to dryness. The title product (22.3 g, 89% yield) was obtained as a light-yellow foam. 1H NMR (DMSO): δ 1.95 (m, 2H), 2.10 (m, 3H), 2.35 (s, 3H), 2.75 (m, 3H), 3.0 (d, 1H), 3.05 (m, 2H), 5.70 (s, 1H), 6.15 (d 1H), 6.60 (m, 2H), 7.10 (m, 3H), 7.25 (m, 2H), 7.30 (m, 5H), 7.65 (d, 1H), 7.70 (s, 1H), 8.15 (s, 1H), 9.85 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:21]([F:22])=[CH:20][C:5]2[N:6]=[C:7]([S:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15](C=O)[CH2:14][CH2:13]3)[NH:8][C:4]=2[CH:3]=1.Cl>CO>[F:1][C:2]1[C:21]([F:22])=[CH:20][C:5]2[N:6]=[C:7]([S:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[NH:8][C:4]=2[CH:3]=1
Reactant: O=CN1CCN(CCSc2nc3cc(F)c(F)cc3[nH]2)CC1
Agent: Cl
Solvent: CO
Product: Fc1cc2nc(SCCN3CCNCC3)[nH]c2cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.2 %

Procedure:
1-[2-(5,6-Difluorobenzimidazol-2-ylthio)ethyl]-4-formylpiperazine (1.70 g, 5.2 mmol) was dissolved in methanol (20 mL), and 12N hydrochloric acid (2 mL) was added to the solution, followed by stirring for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and saturated ammonia-methanol was added thereto, followed by stirring for five minutes at room temperature. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform: saturated ammonia-methanol=100:3), to thereby yield 1-[2-(5,6-difluorobenzimidazol-2-ylthio)ethyl]piperazine (1.40 g, yield 90%) as a brown oil.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][S:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][S:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: COc1ccc(SCCN)nc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(SCCNC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)nc1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
4-geranyloxybenzoic acid(1.92 g) was dissolved in chloroform(40 ml) and triethylamine(1.95 ml), and then diphenylphosphinic chloride(1.34 ml) was added thereto while being cooled with ice. After being stirred for 1 hour, the mixture, with 2-(2-aminoethylthio)-5-methoxypyridine(1.29 g) added thereto, was stirred for 17 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.84 g of the aimed compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17](N(OC)C)=[O:18])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[Mg]Br.O1CCCC1.[Cl-].[NH4+].O>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)=[O:18])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CON(C)C(=O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: Br[Mg]c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCc1nnc(-c2ccc3c(c2)CCO3)o1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a solution of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]-N-methoxy-N-methylpropionamide (2.50 g, 8.24 mmol) in tetrahydrofuran (50 mL) was added 1 M (2-thienyl)magnesium bromide-tetrahydrofuran solution (9.9 mL, 9.9 mmol), and the resulting mixture was stirred at room temperature for 1 hr. A saturated aqueous ammonium chloride solution (50 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (1.10 g, yield 41%) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C1(C)C=CC=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]Cl)=[CH:16][CH:15]=1>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:16][CH:15]=1
Reactant: CC(O)CN
Reactant: ClCCc1ccc(Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
In a separate 250-mL round-bottom flask equipped with a magnetic stir bar, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, was charged 1-aminopropan-2-ol (60.1 g, 800 mmol), which was then heated to 85° C. To this was slowly added the toluene solution of 1-chloro-4-(2-chloroethyl)benzene from Step A while maintaining the reaction temperature at <99° C. On completion of the addition, stirring was continued at 90 to 95° C. for 2 h. Toluene (50 mL) and water (25 mL) were added and the mixture was stirred at 70 to 75° C. for 15 minutes before the phases were separated at room temperature. The upper aqueous phase was extracted with toluene (2×25 mL) at 70 to 75° C. Then, the combined organic phases were washed with water (2×25 mL) at 70 to 75° C., and concentrated by distillation under reduced pressure at 60° C. (bath). The residue was diluted with toluene to a total volume of 112.5 mL and the yellow solution was stirred under nitrogen overnight at 50° C. (bath). Karl Fischer titration showed 0.091% water.
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[F:8][CH:9]([F:18])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)(OCC)OCC>>[CH2:1]([O:4][CH:5]=[C:11]([C:10](=[O:17])[CH:9]([F:18])[F:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)C(F)F
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)C(F)F
Temperature: 65 °C
Reaction time: 6 h

Procedure:
Acetic anhydride (3.6 moles) is heated to 100 to 105° C., to which a mixture of crude ethyl difluoroacetoacetate (˜0.96 moles) and triethyl orthoformate (1.8 moles) is added drop-wise. The reaction mixture is kept at 100 to 105° C. for 6 hours. The reaction mixture is cooled to 60 to 70° C. and then concentrated under vacuum to remove excessive acetic anhydride, triethyl orthoformate, and generated ethyl acetate. A pale brown liquid is obtained.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][S:29]([CH2:32][C:33](O)=[O:34])(=[O:31])=[O:30]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (106 mg, 78%), MS (ISP) m/z=451.3 [(M+H)+], mp 260.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and 2-methylsulfonyl-acetic acid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:11][N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3].C(N(CC)CC)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]([C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a cooled (0° C.) solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (100 mg, 0.278 mmol) in DCM (5 mL) was added triethylamine (50.4 μL, 0.362 mmol) followed by pivaloyl chloride (45 μL, 0.362 mmol). After warming slowly to room temperature and stirring for 16 hours, the mixture was partitioned between DCM (10 mL) and saturated NaHCO3 (10 mL). The aqueous layer was extracted with DCM (10 mL) and the combined organics were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was chromatographed (19:1 hexanes/ethyl acetate) to provide the product as a pale yellow oil (114 mg, 92%).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][C:11]([C:15]1[NH:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]=1)([CH3:14])[C:12]#[N:13]>C1COCC1>[CH3:14][C:11]([C:15]1[NH:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]=1)([CH3:10])[CH2:12][NH2:13]
Reactant: CC(C)(C#N)c1nc(-c2ccccc2)n[nH]1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)(CN)c1nc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
DIBAL-H (0.75 mL, 0.75 mmol, 1M in THF) was added to a solution of 2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propanenitrile (80 mg, 0.37 mmol) in dry THF (5 mL) at 0° C. The reaction mixture was allowed to warm up to room temperature and further stirred for 2 h. The reaction mixture was then quenched carefully with water and diluted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propan-1-amine (70 mg, crude), which was carried through without further purification. MS (ESI) m/z: Calculated for C12H16N4: 216.14. found: 217.2 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])C.[C:25]([CH2:27][C:28]([NH2:30])=[O:29])#[N:26].N1CCCCC1>CO>[C:25]([C:27]1[C:28]([OH:29])=[N:30][C:4]([OH:24])=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])#[N:26]
Reactant: CCCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Reactant: N#CCC(N)=O
Solvent: C1CCNCC1
Solvent: CO
Product: CCCCCCCCCCCCCCCCc1cc(O)nc(O)c1C#N
Yield: 40 %

Procedure:
3-Oxo-nonadecanoic acid ethyl ester (11.3 mmol), cyanoacetamide (0.95 g, 11.3 mmol) and piperidine (0.95 g, 11.3 mmol) in MeOH (3 mL) were heated under reflux for 24 h. The solvent was evaporated, and the residue was dissolved in hot water. The product was precipitated by addition of concentrated HCl, filtered, washed with ice water and CHCl3 and dried in vaccum to give 3-cyano-2,6-dihydroxy-4-hexadecyl-pyridine as a white powder. Yield: 40%. Anal. C22H36N2O2: Calcd: C, 73.29; H, 10.06; N, 7.77; O, 8.88. Found: C, 73.35; H, 10.12; N, 7.85; O, 8.97. MS (ESIMS): m/z: 360.3.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:33])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:34](O)=O>>[C:1]1([S:7]([NH:10][C:11]([C:12]2[CH:17]=[CH:16][C:15]3[N:18]=[CH:34][N:19]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)[C:14]=3[CH:13]=2)=[O:33])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Reactant: O=CO
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc2ncn(Cc3ccc(-c4ccccc4)cc3)c2c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 0.400 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide and 2 ml of formic acid was stirred at 90° C. for 3 hours. The reaction solution was concentrated, and was precipitated with methanol. The crystals precipitated were separated through filtration, and were dried to give 0.243 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)benzimidazole (241).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:49]=[C:50]1[C:59]2[C:54](=[CH:55][CH:56]=[C:57]([C:60]3[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=3)[CH:58]=2)[O:53][CH:52]=[CH:51]1>CN(C=O)C>[O:49]=[C:50]1[C:59]2[C:54](=[CH:55][CH:56]=[C:57]([C:60]3[CH:61]=[C:62]([NH:66][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:63]=[CH:64][CH:65]=3)[CH:58]=2)[O:53][CH:52]=[CH:51]1
Reactant: Nc1cccc(-c2ccc3occc(=O)c3c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3occc(=O)c3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 25.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(4-oxo-4H-chromen-6-yl)-phenylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.007 g of product in 27% yield: LCMS (ESI) m/z 426 (MH+).
Reaction SMILES: [Br-:1].[CH3:2][N+:3]1([CH3:25])[C:12]2[C:7](=[C:8]([N:17]=NC3C=CC=CC=3)[CH:9]=[C:10]([CH2:14][CH2:15][CH3:16])[C:11]=2[OH:13])[CH2:6][CH2:5][CH2:4]1.O.[H][H]>[Pd].CO>[Br-:1].[CH3:25][N+:3]1([CH3:2])[C:12]2[C:7](=[C:8]([NH2:17])[CH:9]=[C:10]([CH2:14][CH2:15][CH3:16])[C:11]=2[OH:13])[CH2:6][CH2:5][CH2:4]1
Reactant: CCCc1cc(N=Nc2ccccc2)c2c(c1O)[N+](C)(C)CCC2
Reactant: [H][H]
Agent: [Pd]
Agent: [Br-]
Solvent: O
Solvent: CO
Product: CCCc1cc(N)c2c(c1O)[N+](C)(C)CCC2

Procedure:
One introduces into a stainless steel autoclave 15.75 g of N,N-dimethyl-1,2,3,4-tetrahydro-5-phenylazo-7-propyl-8-hydroxyquinolinium bromide (i.e. 0.05 mole) with 170 ml of water and 17 ml of methanol, and one adds 3 g of 5% palladium on charcoal. One hydrogenates under a 3 kg/cm2 to 5 kg/cm2 hydrogen pressure. After cooling, one filters off the catalyst, evaporates the filtrate, and redissolves the residue in ether so as to remove the aniline. One recrystallizes in acetonitrile and one washes again with ether.