Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:29](=O)([O:32]C)[O:30][CH3:31].[Cl-].[NH4+]>O1CCCC1>[CH3:31][O:30][C:29]([C:11]1[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=[C:17]([S:19][CH3:20])[CH:18]=[C:13]2[CH:12]=1)=[O:32]
Reactant: COC(=O)OC
Reactant: CSc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(SC)cnc2n1S(=O)(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 56.7 %

Procedure:
To a mixture of 1-benzenesulfonyl-5-methylthio-1H-pyrrolo[2,3-b]pyridine obtained in Example 33 (2) (0.80 g) and tetrahydrofuran (30 ml), a lithium diisopropylamide (5.81 mmol) solution in tetrahydrofuran was added dropwise at −78° C. under nitrogen atmosphere, and the mixture was heated to −30° C. and stirred for 20 minutes, followed by dropwise addition of a mixture of dimethyl carbonate (0.91 g) and tetrahydrofuran (2 ml) at −78° C., and the mixture was stirred at −78° C. for 6 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was subjected to silica gel column chromatography (hexane ethyl acetate=1:1) to obtain 0.54 g of the desired product.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(O)C>[CH2:13]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Oc1ccccc1
Reactant: CCCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCOc1ccccc1

Procedure:
Phenol (0.5 mole) was added to a solution of sodium ethoxide in ethanol (2 N; 250 ml) and 1-bromopentane (0.5 mole) was added dropwise while stirring. The mixture was heated under reflux for three hours and most of the solvent was then distilled off. Water was added to the residue and the organic layer was separated, washed twice with 10% aqueous NaOH, water, dilute H2SO4 and water, and was then dried over MgSO4. It was distilled in vacuo to give the title compound, b.p. 97°-101° C. at 14 mm Hg pressure. The identity and purity was confirmed by thin layer chromatography (TLC) and NMR and IR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#N)[C:3]=1[C:10]1[NH:11][C:12](=[O:30])[C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][CH:20]([O:22][CH3:23])[CH2:19]1)=[O:17].C(O)(=O)C>[Zn].O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:10]1=[C:15]([C:16]([N:18]3[CH2:21][CH:20]([O:22][CH3:23])[CH2:19]3)=[O:17])[CH:14]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12](=[O:30])[N:11]1[CH2:8]2
Reactant: COC1CN(C(=O)c2cc(-c3ccccc3)c(=O)[nH]c2-c2c(Cl)cccc2C#N)C1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COC1CN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2c(Cl)cccc2C3)C1
Yield: 29.1 %

Procedure:
A mixture of 1.17 g of 1-[[2-(2-chloro-6-cyanophenyl)-1, 6-dihydro-6-oxo-5-phenyl-3-pyridyl]carbonyl]-3-methoxyazetidine, 0.91 g of zinc powder and 25 ml of acetic acid was heated to boiling under reflux for 15 minutes under argon. The reaction mixture was then poured into 125 ml of water, whereupon the separated crystals were filtered off under suction and washed with water. The aqueous phase was exhaustively extracted with methylene chloride. The combined organic phases were evaporated and the residue was purified with the crystals obtained above. This material was chromatographed on silica gel with methylene chloride/acetone (9:1) and then recrystallized from toluene. There was obtained 0.33 g of 1-[(10-chloro-4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindol-1-yl)carbonyl]-3-methoxyazetidine as yellow crystals with a m.p. of 235°-238°.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[C:21]1[N:26]=[C:25]([CH3:27])[C:24]([CH2:28]O)=[CH:23][CH:22]=1>ClCCl>[Cl:3][CH2:28][C:24]1[C:25]([CH3:27])=[N:26][C:21]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[F:10])=[CH:22][CH:23]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CCl
Temperature: 0 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
1.67 g (1.017 ml, 14.02 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 2.0 g (70.1 mmol) [6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridin-3-yl]-methanol in 115 ml dichloromethane and stirred for 3 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate) and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:6) gave 1.79 g (83%) of 3-Chloromethyl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[C:30]([CH:36]=O)=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:36][C:30]2[C:29]([CH3:28])=[CH:34][C:33]([CH3:35])=[CH:32][N:31]=2)[CH2:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ncccc2-c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2-c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of the amine from above and 3,5-dimethyl-2-pyridinecarboxaldehyde in CH2Cl2 with NaBH(OAc)3 gave 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-phenyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) δ 1.20 (m, 3H), 1.40 (s, 9H), 1.84 (s, 3H), 2.20 (s, 3H), 2.34 (m, 2H), 2.75 (m, 4H), 3.69 (s, 2H), 3.79 (s, 2H), 7.04 (s, 1H), 7.22 (m, 6H), 7.46 (dd, 1H, J=7.27, 1.7 Hz), 8.01 (s, 1H), 8.49 (dd, 1H, J=4.8, 1.7 Hz) ppm. Deprotection with CH2Cl2/TFA using General Procedure F gave (3,5-dimethyl-pyridin-2-ylmethyl)-(3-phenyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine. 1H NMR (CDCl3) δ 1.72 (m, 2H), 1.92 (m, 2H), 2.34 (s, 3H), 2.44 (s, 3H), 2.70 (m, 3H), 3.25 (m, 2H), 4.16 (m, 4H), 7.28 (m, 2H), 7.45 (m, 3H), 7.58 (q, 1H, J=4.38 Hz), 7.86 (m, 2H), 8.49 (s, 1H), 8.80 (d, 1H, J=3.38 Hz) ppm.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH:30]1([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1>>[CH:30]1([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[CH2:35][CH2:34][CH:33]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:32][CH2:31]1
Reactant: O=C1CCC(C2CCCCC2)CC1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(C3CCCCC3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and bicyclohexyl-4-one using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10]([N:25]([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(C#N)cc1)C(=O)O
Reactant: CC(C)NC(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)C(Cc1ccc(C#N)cc1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
A mixture of 1 g of 2-(tert-butoxycarbonylamino)-3-(4-cyanophenyl)propionic acid and 0.540 g of diisopropylamine in 10 ml of DCM is cooled to 0° C., 0.960 ml of triethylamine is added, followed by addition of 1.76 g of bromotripyrrolidinophosphonium hexafluorophosphate, and the mixture is stirred for 2 hours and allowed to warm to RT. The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with water, with 5% KHSO4 solution, with water, with saturated NaHCO3 solution and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a heptane/EtOAc mixture (80/20; v/v). 0.4 g of the expected product is obtained; m.p.=172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][S:8][C:9]2[N:14]=[C:13](Cl)[CH:12]=[C:11]([Cl:16])[N:10]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[CH3:27]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[N:10]=[C:11]([Cl:16])[CH:12]=[C:13]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=3[CH3:27])[N:14]=2)=[CH:17][CH:18]=1
Reactant: Cc1cccc(N)c1C
Reactant: COc1ccc(CSc2nc(Cl)cc(Cl)n2)cc1
Solvent: CC#N
Product: COc1ccc(CSc2nc(Cl)cc(Nc3cccc(C)c3C)n2)cc1

Procedure:
To a solution of 2-p-methoxybenzylthio-4,6-dichloro-pyrimidine (19.8 g) in acetonitrile (100 l) is added 2,3-xylidine (16 ml) and the resulting mixture is refluxed for 36 hours. The solid is filtered, washed with a little amount of acetonitrile, then the filtrate is concentrated to dryness. The residue is purified by chromatography on silica-gel. 17 g of the desired product are obtained. M.p. 118°-119° C. (benzene/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:25])[N:15]([CH2:17][C:18]4[CH:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[CH3:32][NH:33][CH3:34]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:25])[N:15]([CH2:17][C:18]4[CH:19]=[N:20][C:21]([N:33]([CH3:34])[CH3:32])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=c1n(Cc2ccc(Cl)nc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Solvent: O
Product: CN(C)c1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)cnn3c2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 7-(4-chlorophenyl)-2-((6-(chloro)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (30 mg, 0.0667 mmol), prepared as described in Example 245, and N,N-dimethyl amine in water (1.0 mL) was heated to reflux. After 8 h, the solution was cooled to RT. The reaction mixture was concentrated under reduced pressure. The reside was purified by reverse phase HPLC to give the title compound, 7-(4-chlorophenyl)-2-((6-(dimethylamino)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (17.5 mg, 57%) as a yellow solid. HPLC: 1.41 min; M+H=458; 1H NMR (CDCl3) δ 8.63 (2H, d, J=5.0 hz), 8.23 (1H, d, J=5.0 Hz), 8.17 (1H, s), 7.58 (1H, d, J=10.0 Hz), 7.33 (2H, d, J=10.0 Hz), 7.23 (2H, d, J=5.0 Hz), 7.09 (2H, d, J=10.0 Hz), 6.47 (1H, d, J=10.0 Hz), 5.08 (2H, s), 3.07 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:22][C:23]1[N:28]2[CH:29]=[CH:30][N:31]=[C:27]2[CH:26]=[CH:25][CH:24]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]([Cl:38])([Cl:37])[C:34](Cl)=[O:35].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:32][C:33]([Cl:38])([Cl:37])[C:34]([C:29]1[N:28]2[C:23]([CH2:22][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]([F:20])([F:19])[F:21])(=[O:17])=[O:16])=[CH:24][CH:25]=[CH:26][C:27]2=[N:31][CH:30]=1)=[O:35]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N(CCCCCNS(=O)(=O)C(F)(F)F)Cc1cccc2nccn12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(CCCCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 57.9 %

Procedure:
To a solution of 3.55 g (7.64 mmol) of 5-[N-tert-butoxycarbonyl-N-[5-(trifluoromethanesulfonamido)pentan-1-yl]aminomethyl]imidazo[1,2-a]pyridine and 2.80 g (22.92 mmol) of 4-dimethylaminopyridine in 35 ml of chloroform was added dropwise 2.6 ml (22.92 mmol) of trichloroacetyl chloride, while stirring at room temperature for 3 minutes. The reaction mixture was heated for 15 hours under reflux. The reaction mixture was poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, which was extracted with 150 ml of chloroform. The organic layer was washed with 250 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=100:1) to give 2.70 g of the desired compound (58.2%, pale yellow liquid).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: CS(=O)(=O)Nc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CS(=O)(=O)Nc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with N-(3-formylphenyl)methanesulfonamide was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N-[3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]methanesulfonamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH:28]([OH:30])[CH3:29])[CH2:24][CH2:23]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][CH:25]([CH:28]([OH:30])[CH3:29])[CH2:24][CH2:23]3)=[O:15])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Reactant: CC(O)[C@H]1CC[C@H](CN)CC1
Product: CC(O)C1CCC(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)CC1

Procedure:
Prepared from 2-(Benzo[1,3]dioxol-5-yloxy)-nicotinic acid and (+)-trans-1-(4-Aminomethyl-cyclohexyl)-ethanol. 1HNMR (CDCl3) δ0.97 (1,m), 1.10 (3, m), 1.17 (4, m), 1.19 (4,m), 3.23 (1,t), 3.44(2,q), 6.00(2,s), 6.58 (1, dd), 6.64 (1,s), 6.8 (1, d), 7.10 (1,m), 7.9 (1,m), 8.18 (1,m), 8.53 (1, d); MS: m/e 399 (M++1).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][CH2:9][CH2:10][N:11]1[C:18]2[N:14]([N:15]=[CH:16][CH:17]=2)[CH:13]=[CH:12]1>C(O)=O>[CH:5]([NH:8][CH2:9][CH2:10][N:11]1[C:18]2[N:14]([N:15]=[CH:16][CH:17]=2)[CH:13]=[CH:12]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: NCCn1ccn2nccc12
Solvent: O=CO
Product: O=CNCCn1ccn2nccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of acetic anhydride {19.5 ml) and formic acid [15.7 ml) was stirred at room temperature for 45 minutes. The mixture was cooled at 5° C and -(2-aminoethyl)-1H-imidazo[1,2-b]pyrazole was added thereto. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was evaporated and the residue was subjected to column chromatography on silica gel using a mixture of ethyl acetate and methanol (9:1) as eluent. Fractions containing the object compound were combined and evaporated to give 1-(2-formylaminoethyl)-1H-imidazo[1,2-b]pyrazole (7 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[F:11][C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1.Cl[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38]>C(Cl)Cl>[F:11][C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:31]2)=[CH:26][CH:27]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)c(F)c1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
Diisopropylethylamine (0.14 mL, 0.75 mmol) was added to a suspension of 4-({[2′-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (0.10 g, 0.25 mmol) in CH2Cl2 (7 mL). The mixture was cooled to 0° C. in an ice bath, and isopropyl chloroformate (1.0M in toluene, 0.28 mL, 0.28 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature, and stirred overnight. The mixture was then concentrated to give the crude product as a colorless oil. The crude product was purified by chromatography on a silica gel column eluted with 5:6 EtOAc/hexane to give 0.11 g (98%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.80-7.70 (m, 2H), 7.65-7.55 (m, 1H), 7.50 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.6 Hz), 4.92 (septet, 1H, J=6.1 Hz), 4.25-4.15 (m, 2H), 3.86 (d, 2H, J=6.3 Hz), 3.09 (s, 3H), 2.85-2.75 (m, 2H), 2.10-1.90 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.10 (m, 8H); LRMS (ESI), m/z 450 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[C:17]([CH2:20][OH:21])[S:18][CH:19]=1>CN(C=O)C>[OH:21][CH2:20][C:17]1[S:18][CH:19]=[C:15]([CH2:14][S:13][CH2:12][CH2:11][NH:10][C:3]([NH:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])[N:16]=1
Reactant: NCCSCc1csc(CO)n1
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: CN(C)C=O
Product: CNC(=C[N+](=O)[O-])NCCSCc1csc(CO)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 54.3 %

Procedure:
14.11 g of 2-methylamino-2-methylthio-1-nitroethylene was added to a solution of 15.81 g of 4-[[(2-aminoethyl)thio]-methyl]-2-hydroxymethylthiazole in 190 ml of DMF. The solution was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure to give a residue which was chromatographed on silica gel eluting with 5-10% methanol in acetonitrile to give 12.8 g (61%) of N-[2-[[[2-(hydroxymethyl)-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:31]#[N:32])[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1)C(F)(F)F
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Temperature: 85 °C
Yield: 54 %

Procedure:
Trifluoro-methanesulfonic acid 3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl ester (5.00 g, 11.4 mmol) and zinc cyanide (1.47 g, 12.5 mmol) were combined in DMF (110 ml), degassed (evac./N2 purge 3×) then charged with tetrakis(triphenylphosphine) palladium (0) (1.8 g, 1.60 mmol). The resulting reaction mixture was heated to 85° C. in an oil bath for 6 h. Upon cooling to room temperature, the reaction mixture was filtered through a Celite pad and rinsed with EtOAc (200 ml). The filtrate was washed with water and saturated aqueous NaCl solution (1×200 ml each), dried over Na2SO4, filtered, and concentrated and chromatographed on silica gel eluting with 50% EtOAc/hexanes to provide an oil (1.95 g, 54%). (TLC 50% EtOAc/hexanes Rf 0.28); 1H NMR (400 MHz, CDCl3) δ 7.49–7.52 (m, 2H), 7.45–7.48 (m, 3H), 7.35–7.39 (m, 2H), 7.10–7.14 (m, 1H), 7.00–7.02 (m, 1H), 3.98 (ABq, □AB=48.9 Hz, J=13.0 Hz, 2H), 3.31–3.33 (m, 1H), 3.16–3.21 (m, 2H), 2.21–2.25 (m, 2H), 1.95–2.07 (m, 4H), 1.76–1.80 (m, 2H), 1.41–1.59 (m, 2H); APCI MS m/z 317.2 (M+1)+.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=O)=O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10](S)=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:1][Cl:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(S)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccccc1SCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
A solution of 27.2 g of sulfuryl chloride in 50 ml of dry carbon tetrachloride was added dropwise to a cold (ice-salt bath) solution of 25 g of 4-methylbenzenethiol in 50 ml of carbon tetrachloride containing a few drops of pyridine. The solution was stirred for 0.5 hour at ice-salt bath temperature, allowed to warm to room temperature, then heated under gentle reflux for 0.5 hour. The solution was filtered through a layer of anhydrous sodium sulfate and the filtrate concentrated under reduced pressure. The red liquid residue was distilled to give 24.1 g of 2-methylbenzenesulfenyl chloride, b.p. 67°-69° at 2 mm, nD25 1.6015.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C(OC(N1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])=O)C>C1COCC1>[NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[N:2]1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1c1cc[nH]n1

Procedure:
1H-Pyrazol-3-ylamine (2 g, 24 mmol) and 1,3-dioxo-1,3-dihydro-isoindole-2-carboxylic acid ethyl ester (5.3 g, 24 mmol) are stirred in THF (70 ml) at room temperature for 18 hours. The reaction mixture is then concentrated to half volume and filtered to remove the titled compound which is washed with methanol followed by diethyl ether.
Reaction SMILES: [SH2:1].[CH3:2][C:3]([C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])[O:9][CH2:10][C:11]#[N:12])([CH3:5])[CH3:4].C(N(CC)CC)C>N1C=CC=CC=1.CCOCC>[CH3:18][C:17]([C:14]1[CH:13]=[C:8]([CH:7]=[C:6]([C:3]([CH3:2])([CH3:4])[CH3:5])[C:15]=1[OH:16])[O:9][CH2:10][C:11](=[S:1])[NH2:12])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cc(OCC#N)cc(C(C)(C)C)c1O
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)c1cc(OCC(N)=S)cc(C(C)(C)C)c1O

Procedure:
Hydrogen sulfide gas is bubbled for 30 minutes into a solution of [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy] acetonitrile (1.16 g, 4.44 mmol) and triethylamine (0.68 mL, 4.88 mmol) in pyridine (4.5 mL). The reaction mixture is diluted with ether and washed once with dilute aqueous hydrochloric acid, three times with water, and once with brine. The organic phase is dried over magnesium sulfate and filtered. Argon is bubbled through the organic solution to remove residual hydrogen sulfide. The organic phase is concentrated in vacuo and the solid residue is crystallized from ether/hexane yielding 1.1 g (82%) of white crystals of 2-[3,5-bis((1,1-dimethylethyl)-4-hydroxyphenoxy]-ethanethioamide; mp 163.0°-164.0° C.