Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:14]=2)[C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:12]=1.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C:26]1=O.C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>CO.C(O)(=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH:19]3[CH2:24][CH2:23][N:22]([CH:26]4[CH2:25][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27]4)[CH2:21][CH2:20]3)[N:14]=2)[C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:12]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: O=c1oc(-c2cc(Cl)cc3c2OCCC3)nn1C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1oc(-c2cc(Cl)cc3c2OCCC3)nn1C1CCN(C2Cc3ccccc3C2)CC1
Reaction time: 18 h

Procedure:
1.0 g (2.68 mmol) of 5-(6-chloro-3,4-dihydro-2H-benzopyran-8-yl) -3-(piperidin-4-yl) -1,3,4-oxadiazol-2(3H)-one hydrochloride is added to a solution of 1.13 g (8.60 mmol) of indan-2-one in 15 ml of methanol containing 0.169 ml of acetic acid, 0.709 g (1.13 mmol) of sodium cyanoborohydride is added at a temperature of 5° C. and the mixture is stirred for 18 h. 15 ml of aqueous hydrochloric acid are added and, after stirring for 30 min, the mixture is neutralized with 2M aqueous sodium hydroxide. The mixture is extracted with dichloromethane, the organic phase is separated and dried and the solvent is evaporated under reduced pressure. The residue is purified by preparative thin layer chromatography, elution being carried out with a 98/2 mixture of dichloromethane and methanol. A white solid is obtained, the hydrochloride of which is prepared in the usual way. 0.8 g of salt is isolated. Melting point: 283-284° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:20]3[C:19]([O:21][CH3:22])=[CH:18][CH:17]=[C:16]([C:23](OC4C=CC([N+]([O-])=O)=CC=4)=[O:24])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[C:12]([Cl:35])[CH:13]=3)=[CH:5][CH:4]=1.[Cl:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43]([Cl:46])[C:44]=1[NH2:45].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43]([Cl:46])[C:44]=1[NH:45][C:23]([C:16]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:35])[CH:13]=3)[N:8]([CH2:7][C:6]3[CH:36]=[CH:37][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:20]=2[C:19]([O:21][CH3:22])=[CH:18][CH:17]=1)=[O:24]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(Cn2c3ccc(Cl)cc3c3c(C(=O)Oc4ccc([N+](=O)[O-])cc4)ccc(OC)c32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c3ccc(Cl)cc3c3c(C(=O)Nc4c(Cl)cncc4Cl)ccc(OC)c32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
To a solution of 4-Nitrophenyl 9-(4-methoxy benzyl)-6-chloro-1-methoxy-4-carbazole carboxylate (95 mg, 0.232 mmoles) in dry DMF (5 ml) under nitrogen atmosphere, 3,5-dichloro-4-amino pyridine (37.8 mg, 0.232 mmoles) was added followed by sodium hydride (60% suspension, 20.0 mg, 0.464 mmoles) and the reaction mixture was stirred at room temperature for two hours. Ice pieces were added to the reaction mixture, diluted with water (15 ml) and neutralized with 1N HCl. The precipitated product was filtered, washed with water and dried under vacuum to give 60 mg of the title compound as an off white solid, m. p: 257-258° C.
Reaction SMILES: C(OC([N:8]([C:24]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[C:26]([CH2:36][S:37][C:38]2[S:39][C:40]([CH2:43][CH3:44])=[N:41][N:42]=2)[N:25]=1)[CH2:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH:13]=[C:12]([CH3:23])[CH:11]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[CH2:43]([C:40]1[S:39][C:38]([S:37][CH2:36][C:26]2[N:25]=[C:24]([NH:8][CH2:9][C:10]3[CH:15]=[C:14]([NH:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH:13]=[C:12]([CH3:23])[CH:11]=3)[CH:29]=[C:28]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[CH:27]=2)=[N:42][N:41]=1)[CH3:44]
Reactant: C=CCOC(=O)Nc1cc(C)cc(CN(C(=O)OC(C)(C)C)c2cc(N3CCOCC3)cc(CSc3nnc(CC)s3)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)Nc1cc(C)cc(CNc2cc(N3CCOCC3)cc(CSc3nnc(CC)s3)n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-{N-tert-butoxycarbonyl-N-[3-methyl-5-(2-propenyloxycarbonylamino)benzyl]amino}-6-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-4-morpholinopyridine (92 mg) was dissolved in trifluoroacetic acid (1 ml), followed by stirring at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to liquid separation with ethyl acetate-a saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to obtain the above identified compound (55 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[CH:13][N:14]=[N:15][C:16](O)=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:20].C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:20][C:16]1[N:15]=[N:14][CH:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nncc2c1cnn2-c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Fc1ccc(-n2ncc3c(Cl)nncc32)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyridazin-4-ol (1.30 g, 5.65 mmol), and POCl3 (25 mL) is warmed at 100° C. After 4 hours, the reaction mixture is cooled to room temperature and added dropwise to ice cold water, followed by periodic addition of crushed ice to control the exotherm. To the aqueous solution is added EtOAc and the mixture is neutralized with sodium bicarbonate. The organic layer is separated and the aqueous layer is extracted with EtOAc (3×50 mL). The combined organic layers are washed with saturated aqueous sodium bicarbonate (2×30 mL) and brine (2×30 mL), dried over magnesium sulfate, filtered and concentrated to afford 4-chloro-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyridazine, which is used without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.CN1CCOCC1.Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]>C1COCC1>[CH2:27]([O:26][C:24]([O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1)=[O:25])[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)COC(=O)Cl
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)COC(=O)OC(=O)c1ccc(-c2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
With the exclusion of air, 6.0 g (30 mmol) of 4-(pyridin-2-yl)-benzoic acid are suspended at −20° C. in 90 ml of THF, and 9.90 ml (90 mmol) of N-methyl-morpholine and 4.32 ml (33 mmol) of isobutyl chloroformate are added. After 30 min, the mixture is filtered, washed with a small amount of cold THF, and the filtrate is partially concentrated by evaporation; the residue is diluted with methylene chloride, washed with ice-water and cold brine, dried (Na2SO4) and concentrated by evaporation to form the title compound: 1H-NMR (CDCl3) i.a. 8.75 (m, 1H), 8.16 (AB, J=8, 4H), 7.81 (m, 2H), 7.32 (4-line system, J=5, 1H), 4.16 (d, J=7, 2H), 2.10 (9-line system, J=7, 1H), 1.02 (d, J=7, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[CH3:16][S+](C)(C)=O.[OH-].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([O:14][CH2:16]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.6 %

Procedure:
To a solution of 44.9 g (0.225 mol) of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (31) in 500 ml acetonitrile was added successively 59.5 g (0.27 mol) trimethyl sulphoxonium iodide and 18.9 g (0.338 mol) fine crushed potassium hydroxide. The reaction mixture was vigorously stirred for two days under a nitrogen atmosphere at room temperature. After complete conversion the solvent was evaporated in vacuo and the residue was taken up in dichloromethane. The organic layer was washed with aqueous citric acid solution (6×), dried over sodium sulphate and concentrated in vacuo. This crude product was used without further purification for the next step (43.5 g, 0.204 mol, 90.6% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>N1C=CC=CC=1.C(OCC)(=O)C>[C:19]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:31])=[O:30])=[CH:27][CH:28]=1)(=[O:21])[CH3:20]
Reactant: COC(=O)c1ccccc1Sc1ccccc1N
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1Sc1ccccc1NS(=O)(=O)c1ccc(NC(C)=O)cc1

Procedure:
A solution of methyl 2-[(2-aminophenyl)thio]benzoate (0.444 g, 1.71 mmol) and 4-(acetylamino)benzenesulfonyl chloride (0.440 g, 1.88 mmol) in pyridine (1.6 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and washed with 0.5 N HCl (×2), water (×2), half brine and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with 1-5% MeOH in DCM to provide the title compound. MS (ES, M+H+): 457.2. 1H NMR (400 MHz, CD3OD) δ 7.92 (bd, J=8 Hz, 1H), 7.75 (bd, J=8 Hz, 1H), 7.55 (bd, J=9.2 Hz, 2H), 7.50-7.44 (m, 3H), 7.42 (bd, J=8 Hz, 1H), 7.18 (bt, J=7.6 Hz, 1H), 7.14 (bt, J=7.6 Hz, 1H), 7.05 (bt, J=8 Hz, 1H), 6.23 (bd, J=8 Hz, 1H), 3.95 (s, 3H), 2.14 (s, 3).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:18])[O:7]2.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>ClCCl.CS(C)=O>[CH:2]([C@H:3]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:18])[O:7]2)=[O:1]
Reactant: O=C1C[C@@H]2[C@H](CO)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1

Procedure:
A solution of Corey lactone, (1S,5R,6R,7R)-6-(hydroxymethyl)-7-(tetrahydropyranyioxy)-2-oxabicyclo[3.3.0]octan-3-one (1), (6.800 g) in dichloromethane (40 ml) was oxidized by means of Swern oxidetion with using a solution of oxalyl chloride (2M dichloromethan solution, 30 ml) in dichloromethane (100 ml), DMSO (8.45 ml), and triethylamine (16.9 ml). After the usual work up, Corey aldehyde, (1S,5R,6R,7R)-6-formyl-7-(tetrahydropyranyloxy)-2-oxabicyclo [3.3.0]octan-3-one (2) was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([OH:25])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.N1(C(N2C=CN=C2)=O)C=CN=C1.O>CN(C)C=O>[N:26]1([CH2:32][CH2:33][NH:34][C:23](=[O:25])[CH2:22][CH2:21][C:20]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:11]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Reactant: NCCN1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2)NCCN1CCOCC1
Temperature: 25 °C

Procedure:
3-[2-(2-Oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (Compound VI) (1 g), 630 L of 2-morpholin-4-yl-ethylamine, and 530 mg of di-imidazol-1-yl-methanone, in 10 mL of N,N-dimethyl-formamide, were stirred at room temperature for 1 hr. The reaction mixture was poured into water. The precipitate was filtered and was suspended in hot ethanol. After the suspension was cooled to room temperature, the precipitate was filtered, was washed with ethanol, and was dried in an oven overnight to give N-(2-morpholin-4-yl-ethyl)-3-[2-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionamide (Compound VII).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.Cl[Si](CC)(CC)CC.CS([N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33](=[O:41])[C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[CH:30][CH:31]=2)[C:26]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=2)=[CH:25]1)(=O)=O>C1COCC1.CCCCCC.O.CO>[Cl:48][C:44]1[CH:43]=[C:42]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[C:29]([C:33]([C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)([OH:41])[C:6]4[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=4)[CH:28]=3)[NH:24][CH:25]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: Cn1ccnc1
Reactant: CS(=O)(=O)n1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2[nH]cc(-c3cccc(Cl)c3)c2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of 1-methylimidazole (53 mg) in anhydrous THF (3 mL) was added dropwise a solution of butyllithium in hexane (1.6 M, 430 μL) at about −78° C. The mixture was stirred at about −78° C. for about 15 minutes. To the solution was added dropwise a solution of chlorotriethylsilane in THF (1.0M, 660 μL). The mixture was warmed to room temperature and stirred at room temperature for 1 hour. The mixture was cooled to about −78° C. and to it was added dropwise a solution of butyllithium in hexane (1.6M, 430 μL). The solution was stirred at about −78° C. for about 1 hour and in the following 15 minutes, it was warmed to about −15° C. The solution was cooled to about −78° C. To it was added dropwise a solution of 1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indole (95 mg) (see preparation #7) in THF (2 mL). The mixture was warmed to room temperature and stirred for about 2 hours. The solution was cooled to about 0° C. and to it was added methanol and water. The mixture was stirred for about 2 hours. The solution was concentrated in vacuo. The residue was dissolved in dichloromethane (DCM) and washed with water once. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, on silica, eluting with DCM/MeOH 95:5. Affording the title compound Rf=0.20 (silica, DCM/MeOH 9:1), MS (ES) 447.2; Calc. MW=447.4. 60 mg, yield: 63%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[CH2:8][CH3:9].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl>CS(C)=O.O>[CH2:7]([NH:10][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)[CH2:8][CH3:9]
Reactant: CCCN
Reactant: ClCCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCNCCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-propyl amine (0.26 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to oily compound which was later crystallized by benzene hexane to get N-(n-propyl)-(4-(naphthalen-2-yloxy)butyl)amine, solid, m.p. 118° C., (yield 0.51 gm, 93.2%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:8][C:7](S(CC3C=CC=CC=3)(=O)=O)=[N:6][C:5]=2[N:32]=1.[Cl:33][C:34]1[C:35]([F:42])=[C:36]([CH2:40][SH:41])[CH:37]=[CH:38][CH:39]=1.C(O)C.[BH4-].[Na+]>CS(C)=O>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:8][C:7]([S:41][CH2:40][C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[C:35]=3[F:42])=[N:6][C:5]=2[N:32]=1
Reactant: C[C@H](CNC(=O)OC(C)(C)C)Nc1nc(S(=O)(=O)Cc2ccccc2)nc2nc(N)sc12
Reactant: Fc1c(Cl)cccc1CS
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: C[C@H](CNC(=O)OC(C)(C)C)Nc1nc(SCc2cccc(Cl)c2F)nc2nc(N)sc12
Temperature: 50 °C

Procedure:
To a mixture of the product from example 25 step f) (1.2 g), the product from example 25 step g) (1.6 g) in a mixed solvent of ethanol (30 ml) and DMSO (5 ml) was added sodium borohydride (100 mg) and the mixture heated at 50° C. for 2 hours. The ethanol was removed by rotary evaporation and the crude product extracted into ethyl acetate and washed with water. The subtitle compound was obtained by purification (SiO2, 1:1)dichloromethane:ethyl acetate as eluant) to give (1.95 g).
Reaction SMILES: C([O:4][P:5](=[S:11])([O:7][CH:8]([CH3:10])[CH3:9])[SH:6])(C)C.[O-2].[Zn+2:13].[Zn].[P].[C:16]1(C)[CH:21]=CC=C[CH:17]=1>>[P:5]([O-:4])([O:7][CH:8]([CH3:9])[CH3:10])([S:6][CH:16]([CH3:21])[CH3:17])=[S:11].[Zn+2:13].[CH:16]([S:6][P:5]([O-:4])([O:7][CH:8]([CH3:9])[CH3:10])=[S:11])([CH3:21])[CH3:17]
Reactant: CC(C)OP(=S)(S)OC(C)C
Reactant: Cc1ccccc1
Agent: [O-2]
Agent: [P]
Agent: [Zn+2]
Product: CC(C)OP([O-])(=S)SC(C)C

Procedure:
To a two liter three-necked flask equipped with a stirrer, nitrogen inlet, and a Dean-Stark trap/condenser was added under nitrogen, 526.5 g (2.25 eq.) of diisopropyl dithiophosphoric acid and about 600 ml toluene. To this solution was added 146.5 g zinc oxide (60% eq. excess) at which point the temperature rose to about 74° C. The reaction mixture was heated to reflux and maintained at reflux for about four hours. A total of about 20 ml of water was collected, after which the reaction mixture was further diluted with 200 ml toluene and filtered hot, two times through Celite. The clear filtrate was stripped in a Rotary-Evaporator under full pump vacuum and a water-bath temperature up to 72° C. The product obtained weighed 592.3 g and was a soft, white, crystalline solid--% zinc=14.00, % phosphorus=13.83.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][C:18]=1[NH2:27]>>[CH:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][C:18]=1[NH:27][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: Nc1ccc2c(c1)CCCC2
Product: O=c1[nH]c2ncccc2c2cc(Nc3ccc4c(c3)CCCC4)ccc12
Yield: 65.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 5,6,7,8-tetrahydro-2-naphthylamine (96 mg; 0.65 mmol) to provide 248 (49 mg, 27% yield) as a brown solid. LC-MS (M+H (parent)=343, obsd.=343).
Reaction SMILES: Br[C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C([Li])C(C)C.[B:19](OCCCC)([O:25]CCCC)[O:20]CCCC>CCOCC>[CH:11]([C:10]1[CH:9]=[CH:8][C:7]2[NH:6][N:5]=[CH:4][C:3]=2[C:2]=1[B:19]([OH:25])[OH:20])([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc2[nH]ncc2c1Br
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]CC(C)C
Solvent: CCOCC
Product: CC(C)c1ccc2[nH]ncc2c1B(O)O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-bromo-5-isopropyl-1H-indazole (1.6 g, 6.9 mmol) in Et2O (4 mL) is added slowly to a suspension of KH (1.0 g of 30% dispersion in mineral oil, 7.7 mmol) in Et2O (20 mL) at 0° C. and the mixture is stirred for 20 min. After cooling to −78° C., i-BuLi (8.9 mL of 1.7 M in Hex, 15 mmol) is added and the resulting mixture is stirred for 40 min at −78° C. To this is added B(On-Bu)3 (5.6 mL, 21 mmol) and the mixture is stirred for 24 h at room temperature. The reaction mixture is quenched with 1N H3PO4 and extracted with Et2O. The combined Et2O layers are back-extracted with 1N NaOH (3×10 mL). The combined NaOH extracts are acidified with 1N H3PO4 and extracted with EtOAc. The EtOAc extracts are washed with saturated brine, dried (MgSO4), and concentrated to yield 5-isopropyl-1H-indazole-4-boronic acid. 1H NMR (CDCl3) 7.85 (s, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 3.6 (br s, 2H), 2.88 (m, 1H), 1.32 (d, 6H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=2)[N:4]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:3]=1.[CH:27]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[N:32]=1)([CH3:29])[CH3:28].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:27]([O:30][C:31]1[N:32]=[C:33]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:12][C:13]([CH3:16])=[N:14][N:15]=4)[CH:9]=3)[N:4]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:18])=[O:19])[CH:3]=2)[CH:34]=[CH:35][CH:36]=1)([CH3:29])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(C)o4)ccc32)cc1
Reactant: CC(C)Oc1cccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(C)o4)ccc32)cc1
Temperature: 120 °C

Procedure:
2-(3-Iodo-1-tosyl-1H-indol-5-yl)-5-methyl-1,3,4-oxadiazole (113 mg, 0.236 mmol), 2-isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (74.4 mg, 0.283 mmol) (Combiphos Catalysts Inc.), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (6.74 mg, 0.014 mmol) (Strem), Pd2(dba)3 (6.48 mg, 7.07 μmol) (Strem), and potassium phosphate (150 mg, 0.707 mmol) (Reidel-de Haen) were weighed into a 20 mL glass microwave vial, which was then purged with argon. The solids were treated with dioxane (2.5 mL) and H2O (0.25 mL), the tube was sealed, and the contents were heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 15 min. The mixture was treated with 1N NaOH and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated to give the crude product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH:26]([CH3:28])[CH3:27])[CH:20]=4)[CH2:14][CH2:13]3)[C:11](=S)[NH:10][C:9]2=[O:30])[CH:5]=[CH:6][CH:7]=1.[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH:26]([CH3:28])[CH3:27])[CH:20]=4)[CH2:14][CH2:13]3)[C:11]([NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])=[N:10][C:9]2=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cccc(CN2CCC3(CC2)C(=S)NC(=O)N3c2cccc(F)c2)c1
Reactant: CC(C)CN
Solvent: CS(C)=O
Product: CC(C)CNC1=NC(=O)N(c2cccc(F)c2)C12CCN(Cc1cccc(OC(C)C)c1)CC2
Temperature: 110 °C

Procedure:
To a solution of 1-(3-Fluoro-phenyl)-8-(3-isopropoxy-benzyl)-4-thioxo-1,3,8-triaza-spiro[4.5]decan-2-one SNS-1 (21.4 mg, 0.05 mmol) in DMSO (1 mL) was added isobutyl amine (36.5 mg, 0.5 mmol). The reaction mixture was heated at 110° C. for 12 hr. The crude was purified by preparative HPLC to provide (14-8).