Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=1.[NH2:18][C:19]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][C:22]([Cl:32])=[CH:21][N:20]=1.O>CS(C)=O>[Cl:32][C:22]1[CH:23]=[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:8]3[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:29][CH:30]=2)[C:19]([NH2:18])=[N:20][CH:21]=1
Reactant: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Reactant: Fc1ncccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncc(Cl)cc1-c1ccc(Oc2ncccc2C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
A mixture of potassium carbonate (376 mg), 2-fluoro-3-(trifluoromethyl)pyridine (269 mg) and 4-(2-amino-5-chloropyridin-3-yl)phenol (300 mg) in DMSO (10 mL) was stirred at 120° C. for 3 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (470 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reaction time: 8 h
Yield: 103.4 %

Procedure:
A solution of 25.03 g (109.2 mmole) N-Boc isonipecotic acid was dissolved in 200 mL THF and treated with 200 mL 1 M borane-tetrahydrofuran complex in THF, and the mixture was stirred overnight. The mixture was concentrated under vacuum, diluted with 750 mL ethyl acetate, and washed with 150 mL 1 N HCl (6×) and then saturated brine. The organic layer was dried over sodium sulfate and concentrated to give 24.3 g of crude product as a white solid. This was used as is in the next step.
Reaction SMILES: Cl[CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]>O>[OH2:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:2][P:3]([OH:6])(=[O:5])[OH:4]
Reactant: NCCCCCCN
Reactant: O=P(O)(O)CCl
Solvent: O
Product: NCCCCCCNCP(=O)(O)O

Procedure:
Chloromethanephosphonic acid (6.5 g, 49.8 mmoles) and 1.6-diaminohexane (34.8 g, 300 mmoles) were dissolved in water (130 cm3) and heated under reflux for 20 hours. The water was removed and ethanol (250 cm3) was added to the solid residue. The phosphonic acid was filtered off and dried. The crude yield was 10.4 g (92%). A sample was purified by recrystallization from water/ethanol to give N-(6-aminohexyl)-aminomethanephosphonic acid monohydrate as a fine white crystalline solid having a melting point of 235° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:25])[N:16]2[CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)=[N:11][CH:10]=1.C(Cl)(Cl)Cl>CN(C)C=O.[Cu]=O.O>[O:24]1[CH2:23][CH2:22][O:21][CH:20]1[CH2:19][N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[CH:18]=2)[CH:13]=[CH:14][C:15]1=[O:25]
Reactant: c1c[nH]cn1
Reactant: O=c1ccc2ncc(Br)cc2n1CC1OCCO1
Agent: O=[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2ncc(-n3ccnc3)cc2n1CC1OCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
To a suspension of 77 mg of sodium hydride in 2 mL of N,N-dimethylformamide, 0.13 g of imidazole was added, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture, 0.20 g of 7-bromo-1-((1,3-dioxolan-2-yl)methyl)-1,5-naphthyridin-2(1H)-one was added dividedly, and then 18 mg of copper (II) oxide was added thereto. The reaction mixture was stirred at 135 to 140° C. for 30 minutes. The reaction mixture was cooled to room temperature, then chloroform and water were added thereto, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant residue, a mixed solvent of diethyl ether: ethyl acetate (3:1) was added, and the solid was filtered off to obtain 0.12 g of 1-((1,3-dioxolan-2-yl)methyl)-7-(1H-imidazol-1-yl)-1,5-naphthyridin-2(1H)-one as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@H:8]([N:11]=[N+]=[N-])[C@@H:7]1[C:14]([O:16][CH3:17])=[O:15].[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@H:8]([NH2:11])[C@@H:7]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1[C@@H](N=[N+]=[N-])C(=O)N1Cc1ccc(OC)cc1OC
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@H]1[C@@H](N)C(=O)N1Cc1ccc(OC)cc1OC

Procedure:
A mixture containing 10.0 g (0.312 mol) of methyl cis-1-(2,4-dimethoxybenzyl)-3-azido-4-oxoazetidine-2-carboxylate, 1.0 g of 10% palladium on carbon, and 200 ml of ethanol is hydrogenated for 2 hrs at 40°-45° at 60 psi of hydrogen. The reaction mixture is allowed to cool to 25° and is filtered through filter-aid. After removing the solvents in vacuo a clear, yellow gum of the title product is obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([S:27]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH3:37][C@@H:38]1[CH2:43][NH:42][CH2:41][CH2:40][NH:39]1.C(N(CC)CC)C>C(O)CCCC.Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:42]4[CH2:41][CH2:40][NH:39][C@H:38]([CH3:37])[CH2:43]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=23)=[CH:12][CH:13]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(Cl)nn45)ccnc32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCN[C@H](C)C6)nn45)ccnc32)cc1
Yield: 68.8 %

Procedure:
A mixture of 0.330 g (0.58 mmol) of 6-chloro-2(4-fluorophenyl)-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine, 0.116 g (1.16 mmol) of (2R)-2-methylpiperazine and 0.08 ml (0.6 mmol) of triethylamine in 5 ml of pentanol is heated under reflux for 24 hours. The reaction medium is diluted with 100 ml of an aqueous solution of hydrochloric acid and the solution is washed with ethyl acetate. The aqueous phase is then basified by addition of aqueous ammonia and the product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The chestnut brown solid obtained is then purified by chromatography on a silica gel column (35 g) by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) in order to give 0.232 g of 2-(4-fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine in the form of a yellow powder after drying.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][C:15]4[CH:19]=[C:20]([CH:23]=C)[CH:21]=[CH:22][C:14]=4[C:13]=3[CH:12]=[N:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C[N+]1([O-])CC[O:29]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.[Os](=O)(=O)(=O)=O.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][C:15]4[CH:19]=[C:20]([CH:23]=[O:29])[CH:21]=[CH:22][C:14]=4[C:13]=3[CH:12]=[N:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2cnn1-c1ccc(CCC)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccc(-n2ncc3c2CCc2cc(C=O)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 3-(4-propylphenyl)-7-vinyl-4,5-dihydro-3H-benzo[e]indazole (Preparation 136E, 85 mg, 0.270 mmol) in THF (5 mL) were sequentially added NMO in water (0.090 mL, 0.433 mmol) and osmium tetroxide in water (0.066 mL, 10.81 μmol) at room temperature. The solution was vigorously stirred at room temperature overnight. Sodium periodate (116 mg, 0.541 mmol) in water (2 mL) was added. The mixture was stirred at room temperature under nitrogen for 2 hours. A white solid precipitated out. Water (2 mL) was then added and the solid was filtered, washed with water (2×2 mL) and dried to give 65 mg crude product which was used directly for the next step. LC/MS M+1=317.1. The product had an HPLC retention time=3.92 min. (condition A);
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17](Cl)[CH:18]=[CH:19][CH:20]=5)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.[CH2:25]([OH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+].O>CN(C)C=O.CCOCC>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([O:32][CH2:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[CH:18]=[CH:19][CH:20]=5)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1
Reactant: OCc1ccccc1
Reactant: Cn1c(=O)c2c(Cl)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(OCc3ccccc3)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Temperature: 110 °C
Reaction time: 5 h
Yield: 52.4 %

Procedure:
A mixture of (3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl5-oxo-6-chloro-4,5-dihydro-imidazo(1,5-a)quinazoline (0.4 g, 1.2 mmol), benzyl alcohol (0.32 g, 3 mmol), and sodium hydride (55% dispension in oil, 0.13 g, 3 mmol) in 20 ml of dry DMF (dimethylformamide) was stirred for 5 h at 110° C., then cooled to room temperature and was thereafter poured into 30 ml of water and 5 ml of ether. The mixture was then stirred for 1 h at 0° C. and the precipitate was filtered off, rinsed with water and dried giving 0.26 g (53%) of 3-(5-cyclopropyl-1.2.4-oxadiazol-3-yl)-4-methyl-5-oxo-6-benzyloxy-4,5-dihydro-imidazo (1,5-a)quinazoline, M.p. 221°-224° C.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:15]2[N:16]([C:20](=[O:22])[CH3:21])[C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH:23]([F:25])[F:24])[C@H:11]1[O:26]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[F:25][CH:23]([F:24])[C@@H:12]1[C@@H:11]([OH:26])[C@H:10]([OH:9])[C@H:15]2[NH:16][C:17](=[O:19])[O:18][C@H:14]2[CH2:13]1.[F:24][CH:23]([F:25])[C@H:12]1[CH2:13][C@H:14]([OH:18])[C@H:15]([NH:16][C:20](=[O:22])[CH3:21])[C@@H:10]([OH:9])[C@@H:11]1[OH:26]
Reactant: CC(=O)N1C(=O)O[C@H]2C[C@H](C(F)F)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]1O
Product: O=C1N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(F)F)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %
Yield: 31 %

Procedure:
To a suspension of (3aS,4R,5R,6S,7aS)-3-acetyl-6-(difluoromethyl)-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (892 mg, 1.89 mmol) in MeOH (20 mL) was added K2CO3 (781 mg, 5.66 mmol). The mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was purified by SiO2 column, eluted with 5%-10% MeOH in DCM to give (3aR,4R,5R,6S,7aS)-6-(difluoromethyl)-4,5-dihydroxyhexahydrobenzo[d]oxazol-2(3H)-one (256 mg, 69%) and N-((1S,2R,3R,4S,6S)-4-(difluoromethyl)-2,3,6-trihydroxycyclohexyl)acetamide (176 mg, 31%), both were as a white solid. (3aR,4R,5R,6S,7aS)-6-(difluoromethyl)-4,5-dihydroxyhexahydrobenzo[d]oxazol-2(3H)-one: MS m/z 246.1 (M+23, 100%); 1H NMR (400 MHz, MeOD) δ 6.18 (td, J=56.6 Hz, 1.3 Hz, 1H), 4.74-4.78 (m, 1H), 3.51 (t, J=6.9 Hz, 1H), 3.30-3.38 (m, 2H), 2.25 (dt, J=15.4 Hz, 3.2 Hz, 1H), 2.01-2.16 (m, 1H), 1.82-1.90 (m, 1H). N-((1S,2R,3R,4S,6S)-4-(difluoromethyl)-2,3,6-trihydroxycyclohexyl)acetamide: MS m/z 240.1 (M+1, 100%); 1H NMR (400 MHz, MeOD) δ 5.98 (t, J=55.1 Hz, 1H), 3.89 (br s, 1H), 3.46-3.57 (m, 2H), 3.14-3.23 (m, 1H), 2.05-2.20 (m, 1H), 2.00 (s, 3H), 1.76 (dt, J=14.2 Hz, 3.6 Hz, 1H), 1.34-1.42 (m, 1H)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[Br:13]Br>O1CCOCC1.N#N.ClC(Cl)C>[Br:13][C:6]1[N:2]([CH3:1])[C:3]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:5]=1
Reactant: BrBr
Reactant: Cn1ccnc1N1CCOCC1
Agent: N#N
Solvent: CC(Cl)Cl
Solvent: C1COCCO1
Product: Cn1c(Br)cnc1N1CCOCC1
Temperature: 60 °C
Yield: 31 %

Procedure:
4-(1-Methyl-1H-imidazol-2-yl)-morpholine (Nagarajan, K. et al. Indian J. Chem. Sect. B, 21, 10, 1982, 949–952) (1.02 g, 6.08 mmol) was dissolved in 35 mL of 1,4-dioxane under and N2 atmosphere. The mixture was heated to 60° C. and a solution of 0.34 mL (6.4 mmol) of Br2 in 10 mL of dichloroethane was added slowly. The mixture was heated for 1 h, then cooled. The mixture was concentrated and the residue was partitioned between 6.5 mL of 1 N NaOH and 25 mL of EtOAc. The NaOH solution was extracted twice more with EtOAc, and the extracts were washed with NaHCO3 and brine, dried with Na2SO4, filtered, concentrated, and chromatographed (0–4% MeOH (0.5% NH4OH) in CH2Cl2) to provide 464 mg of 4-(5-bromo-1-methyl-1H-imidazol-2-yl)-morpholine.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=1.[CH2:16](O)[CH3:17]>>[CH2:6]([O:5][C:3]([C:2]1[N:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]2=[N:8][C:16]=1[CH3:17])=[O:4])[CH3:7]
Reactant: CCOC(=O)CCl
Reactant: Cc1ccnc(N)c1
Reactant: CCO
Product: CCOC(=O)c1c(C)nc2cc(C)ccn12
Yield: 35 %

Procedure:
15.2 g ethyl 2-chloroacetate were added to a solution of 10 g 2-amino-4-methylpyridine in 200 ml ethanol, the mixture was stirred under reflux for 8 hours and the reaction solution was stirred overnight at room temperature. After removal of the solvent, the residue was taken up with aqueous 10% strength HCl, and the mixture was washed with methylene chloride, rendered basic with sodium bicarbonate and extracted with methylene chloride. The combined organic phases were washed with water and dried over sodium sulfate. After removal of the solvent and purification by column chromatography, the product was obtained in a yield of 35%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[N:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClN1C(=O)CCC1=O.N1C=CC=CC=1.[CH2:28]([OH:33])[CH2:29][CH2:30][CH:31]=[CH2:32].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:32][CH:31]([CH2:30][CH2:29][CH2:28][OH:33])[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=NO)cc1OC
Reactant: C=CCCCO
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C2=NOC(CCCO)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
(3,4-dimethoxyphenyl)(hydroxyimino)methane (1.05 g, 5.801 mmol) was dissolved in 30 mL of tetrahydrofuran under N2. After adding N-chlorosuccinimide (0.93 g, 6.96 mmol) and pyridine (46.9 L, 0.580 mmol) at room temperature, the reaction was continued for 30 min at 60. After cooling to room temperature, 4-pentene-1-ol (0.90 mL, 8.701 mmol) dissolved in 2 mL of tetrahydrofuran was added. Then, after adding triethylamine (0.97 mL, 6.961 mmol) dissolved in 2 mL of tetrahydrofuran, the reaction was continued for 1 hr at 50. When the reaction was completed, saturated NaHCO3 solution was added, and then the same was extracted with ethyl acetate. After drying over anhydrous MgSO4, the crude product was purified by column chromatography on silica gel (hexane/ethyl acetate=1/2, v/v) to obtain 1.38 g (90.6%) of the target compound.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[N:16]1([C:21]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[N:17]1>>[CH3:7][N:6]1[C:2]([C:24]2[CH:23]=[CH:22][C:21]([N:16]3[CH:20]=[CH:19][CH:18]=[N:17]3)=[CH:26][CH:25]=2)=[C:3]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[N:4]=[CH:5]1
Reactant: OB(O)c1ccc(-n2cccn2)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-pyrazol-1-yl-phenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C19H14N6, 327. Found, 327.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][S-:14].[Na+]>CN(C=O)C.O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([S:14][CH3:13])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(SC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (1.38 g, 8.06 mmol) and sodium methyl mercaptide (0.622 g, 8.87 mmol) in DMF (25 mL) was stirred at room temperature for 18 hours. The reaction was the diluted with water and extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give (3-methoxy-4-nitrophenyl)(methyl)sulfane (0.95 g, 59%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:25]([N:16]1[CH2:17][CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH2:15]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccccc3)CC2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1cccnc1)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
A solution of 20 mg (0.06 mmol) of 3-(RS)-((4-phenyl)-piperidin-1-yl)methyl-4-(SR)-phenylpyrrolidine (from Example 30, Step A), 19 mg (0.19 mmol) of TEA and 6 mg (0.05 mmol) of 4-DMAP in 2 mL of CH2Cl2 (2 mL) was treated with 28 mg (0.16 mmol) of nicotinoyl chloride·HCl and was stirred at rt for 2 h. The reaction was concentrated in Vacuo. Preparative thin layer chromatography (silica gel GF, 20×20 cm, 1000 microns) using 92:8 v/v MeOH/CH2Cl2 +0.5% NH4OH as the eluant afforded 20 mg (71%) of the title compound as a yellow foam. 1H NMR (500 MHz, CDCl3): δ7.17-8.88 (9H), 1.27-4.24 (22H). Mass Spectrum (NH3 -CI): 426 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=2)[CH:10](OS(C)(=O)=O)[CH3:11])=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O.C(OC(C)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=2)[CH:10]([N:25]=[N+:26]=[N-:27])[CH3:11])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)C(Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])C(Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Temperature: 70 °C

Procedure:
To a solution of 4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-methylsulfonyloxybutane (1.1 kg, 2.9 mol) in N,N-dimethylformamide (4.1 L) was added sodium azide (378 g, 5.8 mol), and the reaction was heated at 70° C. for 7 h. After cooling to room temperature, the reaction mixture was diluted with isopropyl acetate (11 L) and was washed with sodium bicarbonate (50% saturated aqueous solution) and water (5.5 L). The organic layer was separated and treated with Darco KB (254 g) overnight. The mixture was filtered over solka floc, washed with toluene and concentrated. The residue was diluted with toluene (1 L) and was loaded onto a silica gel pad, which was eluted with 90:10 hexane/ethyl acetate to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[OH:21][CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH2:23][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:18][CH2:17][C:5]1=2
Reactant: CN1CCc2[nH]c3ccc(C(C)(C)O)cc3c2C1
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(C(C)(C)O)ccc3n2CC(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
To a stirred solution of 2-(2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-8-yl) propan-2-ol (942 mg, 3.86 mmol) in DMF (5 mL) was added sodium hydride (60%, 464 mg, 11.58 mmol). After stirring for 10 min, the reaction mixture was cooled to 0° C. and a solution of 4-(oxiran-2-yl)pyridine (700 mg, 5.8 mmol) in DMF (2 mL) was added. The reaction mixture was allowed to warm to RT and stirring was continued for 16 h. The progress of reaction was monitored by LCMS and NMR. The reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was crystallized from ether to yield 2-(2,3,4,5-tetrahydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-2-methyl-1H-pyrido[4,3-b]indol-8-yl) propan-2-ol (500 mg) as yellow solid. 1H NMR (CDCl3, freebase) δ (ppm): 8.37 (d, 2H), 7.36 (s, 1H), 7.20 (d, 1H), 7.11 (d, 2H), 7.04 (d, 1H), 4.82 (t, 1H), 4.05 (d, 2H), 3.49 (d, 1H), 3.4 (d, 1H), 2.9 (m, 1H), 2.85 (m, 1H), 2.64 (m, 2H), 2.40 (s, 3H), 1.65 (s, 6H). Separation by chiral HPLC provided enantiomers 23a and 23b. Optical rotations: Compound 23a, (−)52.54 (c 0.55, Chloroform, 95.4% HPLC purity); Compound 23b, (+)29.08 (c 0.56, Chloroform, 98.94% HPLC purity).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([O:17]COC)[CH:5]=1)(=[O:3])[CH3:2].C1CNC(=O)C1.[Br:27][Br-]Br.O>O1CCCC1>[Br:27][CH2:2][C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([OH:17])[CH:5]=1)=[O:3]
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1OCOC
Agent: O=C1CCCN1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COc1ccc(C(=O)CBr)cc1O
Temperature: 25 °C
Reaction time: 21 h
Yield: 46 %

Procedure:
To a solution of ethyl 2-(4-acetyl-2-methoxymethoxyphenoxy)acetate (1.51 g) in tetrahydrofuran (30 ml) was added pyrrolidone hydrotribromide (2.92 g), and the mixture was stirred for 21 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/diethyl ether/dichloromethane=3/2/2) and subsequent crystallization from hexane and diethyl ether (1/1) gave ethyl 2-[4-(2-bromoacetyl)-2-hydroxyphenoxy]acetate (780 mg).
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[CH:7]1([N:13]=[C:14]=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.NC(N)=N>>[CH2:1]([N:5]([CH3:6])[C:14]([NH:13][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[N:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N=C(N)N
Product: CCCCN(C)C(=NC1CCCCC1)NC1CCCCC1

Procedure:
A mixture of 17.78 g of N-butyl-N-methylamine (0.204 mol) and 21.05 g of dicyclohexylcarbodiimide (0.102 mol) is refluxed for 3 h. GC analysis then shows a conversion of greater than 99.50 of the dicyclohexylcarbodiimide. The colorless final mixture is concentrated at 60° C. under 1 mbar for 2 h so as to give 29.9 g of a colorless and virtually odorless liquid of medium viscosity, corresponding to the expected guanidine (yield 99.70).