Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc2ncccc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc4ncccc4c3)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 173.8 mg (1.2 mmol) of 6-aminoquinoline and 115.6 mg (1 mmol) of pyridine hydrochloride in 15 mL of 2-ethoxyethanol was refluxed for 6 hr. The work up gave 212.5 mg (59.5%) of the product as a orange solid, m.p. 241-243° C., mass (electrospray, m/e): M+H 356.8. HRCIMS: calcd 356.127 for C20H17N5O2 (M+), obsd 356.1275.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][C:16]2=[O:24])[CH2:13][O:12]1.C([O-])(=O)C.[Na+].O>C(O)C>[Cl:1][C:2]1[N:3]([CH2:13][C:11]([OH:12])([CH3:10])[CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][C:16]2=[O:24])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC1(Cn2c(=O)oc3ccccc32)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)(Cn1cc([N+](=O)[O-])nc1Cl)Cn1c(=O)oc2ccccc21
Yield: 51.2 %

Procedure:
To a suspension of 2-chloro-4-nitro-1H-imidazole (503 mg, 3.41 mmol), 3-(2-methyloxiran-2-yl-methyl)-3H-benzoxazol-2-one (700 mg, 3.41 mmol) in ethanol (7 ml), sodium acetate (336 mg, 4.1 mmol) was added followed by stirring under reflux for 8 hours. The reaction mixture was allowed to return to room temperature. To a mixture, water was added, and the resulting solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1) to afford 3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-3H-benzoxazol-2-one (616 mg, yield 51%) as a light yellow powder.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:15])[CH2:7]1.[Br:16][CH2:17][C:18](Cl)=[O:19]>CN(C)C=O>[CH3:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:18](=[O:19])[CH2:17][Br:16])=[CH:14][C:9]=2[S:8](=[O:15])[CH2:7]1
Reactant: O=C(Cl)CBr
Reactant: CN1CS(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN1CS(=O)c2cc(C(=O)CBr)ccc21

Procedure:
210 g (1.60 mol) of aluminum chloride are introduced into a 500-cm3 ground-necked flask surmounted by a condenser, and 43 cm3 of dimethylformamide are then added dropwise and with magnetic stirring via a dropping funnel. 33 g (0.20 mol) of 3-methylbenzothiazolinone are then added and, while the reaction medium homogenizes, the temperature is stabilized at 70° C. using an oil bath. 19.8 cm3 (0.24 mol) of bromoacetyl chloride are then added gradually. After the addition, the mixture is left stirring for one hour at a temperature of 70° C. The reaction medium is hydrolyzed by pouring it onto crushed ice and the precipitate obtained is drained, washed with water until the filtrate is neutral and dried. The product is recrystallized in 95° strength alcohol.
Reaction SMILES: [CH:1]1([N:7]([CH:30]([CH3:32])[CH3:31])[C:8](=[O:29])[C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:28])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+]>C(Cl)Cl.C(OCC)C>[CH:1]1([N:7]([CH:30]([CH3:32])[CH3:31])[C:8](=[O:29])[C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:28])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(O)c2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OC)c1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(C(=O)c2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the compound prepared in Example 14 (500 mg, 1.1 mmol) in CH2Cl2 (5 ml) was added to a stirred slurry of pyridinium chlorochromate (500 mg, 2.3 mmol) and sodium acetate (180 mg, 2.2 mmol) in CH2Cl2 (10 ml). The reaction was stirred for 2 hrs at room temperature and diluted with ethyl ether (50 ml). After stirring the mixture for 15 min., the mixture was filtered through Florisil® activated magnesium silicate (available from Aldrich Chemical Co., Milwaukee, Wisconsin, and the Florisil® was washed thoroughly with ether. The filtrate was concentrated in vacuo and the residue chromatographed over silica gel using mixtures of ethyl acetate and hexane as the eluents. The title compound was obtained pure as a glass.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1.N1C=CC=CC=1>ClCCl.CN(C)C=O.O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[N:22][CH:23]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a stirring suspension of 5-methyl-2-nitrobenzoic acid (23.36 g, 129 mmol) in dichloromethane (100 mL) was added a couple of drops of N,N-dimethylformamide followed by oxalyl chloride (12.36 mL, 142 mmol). The reaction was stirred at room temperature overnight and the residue transferred slowly to an ice cold solution of 2-amino-5-chloropyridine (16 g, 126 mmol) and pyridine (30 mL) in dichloromethane (200 mL). The reaction was stirred overnight, treated with water (100 mL), and concentrated. The resulting mixture was treated with ethyl acetate (2 L), washed consecutively with aqueous citric acid, saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by recrystallization from toluene to give 26 g (69%) of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1.O>CN(C)C=O.C(OCC)(=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH:17]1[CH2:16][N:9]1[C:10]2[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:12]
Reactant: BrCC1OCCO1
Reactant: O=c1ccc2ncc(F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1ccc2ncc(F)cc2n1CC1OCCO1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.32 g of 7-fluoro-1,5-naphthyridin-2(1H)-one in 3 mL of N,N-dimethylformamide, 0.12 g of 60% sodium hydride was added at room temperature, and the mixture was stirred at 50 to 60° C. for 1 hour. Thereto was added 0.60 mL of 2-bromomethyl-1,3-dioxolan, the temperature was increased to 85 to 95° C., and the reaction mixture was stirred for 4 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were then added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. 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, chloroform was added, the solid was filtered off and purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=100:0 to 30:70 to obtain 0.23 g of 1-(1,3-dioxolan-2-ylmethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([N:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)=[O:5].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29](O)=[O:30])=[CH:23]2>>[CH2:12]([C@H:3]([NH:2][C:29]([C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([Cl:19])=[CH:28][CH:27]=2)=[O:30])[C:4](=[O:5])[N:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-3-phenyl-1-thiomorpholin-4-yl-propan-1-one hydrochloride (2.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (2.6 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, washed with acid first, then base). The crude product was then triturated with 1:1 ether-hexanes and dried. Yield 1.03 g, 94%; HPLC (60/40) 8.74 minutes (99%); PBMS 428/430 (MH+, 100%);
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[H-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]1[CH:27]=[CH:26][C:22]2[NH:23][CH:24]=[N:25][C:21]=2[C:20]=1[N+:28]([O-:30])=[O:29]>C(OCC)(=O)C.CN(C=O)C>[CH3:18][C:19]1[CH:27]=[CH:26][C:22]2[N:23]([CH2:8][C:5]3[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=3)[CH:24]=[N:25][C:21]=2[C:20]=1[N+:28]([O-:30])=[O:29]
Reactant: Cc1ccc2[nH]cnc2c1[N+](=O)[O-]
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2c(ncn2Cc2ccncc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 200-mL round-bottomed flask equipped with a magnetic stirrer was charged with 4-picolylchloride hydrochloride (1.20 g, 7.34 mmol) and DMF (30 mL) under argon. A 60% dispersion of sodium hydride in mineral oil (294 mg, 7.34 mmol) was added to the resulting solution and the reaction stirred at room temperature for 5 min. The reaction was then charged with potassium carbonate (3.55 g, 25.7 mmol), stirred at room temperature for 5 min and compound 2b (1.30 g, 7.34 mmol) was added. Once this addition was complete, the reaction was stirred at room temperature for 19 h. After this time the reaction was poured into ethyl acetate (1 L) and the resulting mixture washed with water (3×750 mL) followed by brine (750 mL). The resulting organic layer was dried over sodium sulfate, then filtered and the filtrate concentrated under reduced pressure providing a residue, which was purified by flash chromatography to afford compound 2c as a light-yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].C(=O)([O-])[O-].[NH4+:19].[NH4+]>[OH-].[NH4+].S([O-])([O-])(=O)=O.[Cu+2]>[NH2:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: [NH4+]
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Product: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 120 °C
Yield: 36.6 %

Procedure:
A mixture of 2-chloro-5-nitrobenzenesulfonamide (Example 17a, 0.88 g, 3.72 mmol), ammonium carbonate (0.88 g, 9.16 mmol), and copper(II)sulfate (0.175 g, 1.10 mmol) in concentrated aqueous ammonium hydroxide solution (4.4 mL) was heated for 4 h at 120° C. in a pressure reaction vessel. The mixture was allowed to cool to 25° C. and the resulting solid was collected by vacuum filtration, washed with water and dried to afford the desired product, 2-amino-5-nitrobenzenesulfonamide (0.295 g, 1.36 mmol, 36.5% yield) as a tan solid.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:21][C:22]1[C:37]([F:38])=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[C:24]([F:39])[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Pd+2].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1>[CH:13]1([N:10]2[CH2:9][CH2:8][C:7](=[O:19])[N:6]([CH3:20])[C:5]3[C:11]2=[N:12][C:2]([NH:21][C:22]2[C:37]([F:38])=[CH:36][C:25]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:27])=[C:24]([F:39])[CH:23]=2)=[N:3][CH:4]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1CCC(NC(=O)c2cc(F)c(N)cc2F)CC1
Reactant: CN1C(=O)CCN(C2CCCCC2)c2nc(Cl)ncc21
Agent: [Pd+2]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CN1CCC(NC(=O)c2cc(F)c(Nc3ncc4c(n3)N(C3CCCCC3)CCC(=O)N4C)cc2F)CC1
Temperature: 100 °C
Yield: 80.7 %

Procedure:
10-chloro-2-cyclohexyl-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 266; 33 mg, 0.113 mmol), 4-amino-2,5-difluoro-N-(1-methyl-4-piperidyl)benzamide (Intermediate 59; 29 mg, 0.108 mmol) and caesium carbonate were added to dioxane (3 mL) and the suspension bubbled with nitrogen for 10 minutes. tris(dibenzylideneacetone) palladium (II) (4 mg, 0.006 mmol) and XANTPHOS (6 mg, 0.1 mmol) were added and the mixture heated at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filter-cake was washed with DCM and the filtrate evaporated. The residue was dissolved in DCM and purified on a silica column eluting with a gradient of 0-5% 2M ammonia in MeOH/DCM over 30 column volumes. Fractions containing product were combined and evaporated to a solid, which was triturated with isohexane then filtered and dried to yield the title compound as a pale yellow solid (46 mg, 81%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][CH:5]=1.B1C2CCCC1CCC2.[O:22]1CCCC1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:22])=[CH:6][CH:5]=1
Reactant: C=Cc1ccc(C(=O)OC)cc1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: COC(=O)c1ccc(CCO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Methyl-4-vinylbenzoate 70 (2.270 g, 14.00 mmol) was dissolved in 50ml of tetrahydrofuran and cooled to 0° C. 9-BBN (0.5M in THF)(28.00 ml, 14.00 mmol) was added and the mixture was stirred for 2 hours. The solution was allowed to warm to room temperature and stirred for an additional 2 hours. The reaction was cooled to 0° C. and quenched with alkaline hydrogen peroxide. The mixture was then extracted with diethyl ether. The extracts were dried over anhydrous sodium sulfate and concentrated en vacuo. The residue was purified by flash chromatography on silica eluted with 4:1 hexane/acetone to give 1.632 g (64.7%) of 4-(2-hydroxyethyl)benzoic acid methyl ester 71 as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[OH:19][C:18]1[CH:22]=[CH:23][C:15]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[C:7]([CH:24]=[CH:3][CH:4]=3)[C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:1])[NH:13][C:12](=[O:14])[N:11]=2)=[CH:16][C:17]=1[CH3:21]
Reactant: Cc1cc(-c2cc(-c3cccc(C(=O)O)c3)[nH]c(=O)n2)ccc1O
Reactant: NCCCN1CCOCC1
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(-c3cccc(C(=O)NCCCN4CCOCC4)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.9 %

Procedure:
3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]benzoic acid (Compound 289, 15.5 mg, 48 umol) and commercially available 3-morpholinopropan-1-amine (5.8 mg, 40 umol) were dissolved in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL). To this solution was added commercially available 1-hydroxybenzotriazole (6.8 mg, 50 umol) followed by commercially available 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 umol). The reaction mixture was stirred at room temperature for 15 hours and was concentrated in vacuo. The reaction mixture was purified by reverse phase HPLC to give 5 mg of product. 1H NMR (400 MHz, d6-DMSO): δ 8.65 (t, 1H), 8.51 (s, 1H), 8.28-8.23 (m, 2H), 8.02-7.96 (m, 2H), 7.87 (dd, 1H), 7.63 (t, 1H), 7.46 (s, 1H), 6.92 (d, 1H), 3.56 (t, 4H), 3.36-3.32 (m, 2H), 2.40-2.33 (m, 6H), 2.20 (s, 3H), 1.78-1.68 (m, 2H). MS (EI): 450 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)=[CH:4][CH:3]=1.[N:25]([Sn](CCCC)(CCCC)CCCC)=[N+:26]=[N-:27].O1CCOCC1.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[N:18]=[N:25][NH:26][N:27]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)c(-c1ccc(Cl)cc1)nn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)cc1
Yield: 35 %

Procedure:
The title compound was prepared from 3-(4-chlorophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.35 1 g, 1.04 mmol), azidotributyl tin (0.351 g, 0.627 mL, 2.29 mmol) in toluene (10 mL) as described for the preparation of compound 35167. Deprotection was effected by treating a dioxane solution (5 mL) with 5 mL of 6.0N aqueous solution of hydrogen chloride. Half of the solid obtained upon completion of the reaction was purified by preparatory HPLC (0.054 g, 0.18 mmol, 35% yield over 2 steps) 1H NMR (DMSO-d6) 13.7 (s, 1H), 8.8 (s, 1H), 8.1 (t, 3H), 7.8 (d, 1H), 7.6 (t, 2H); ES-MS (m/z) 297 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[N:9]1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:22][CH2:21]2)=[O:19])=[N:9]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(Nc1noc2ccccc12)N1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
To a solution of N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) and triethylamine (0.309 ml, 2.22 mmol) in tetrahydrofuran (4 ml) was added benzoyl chloride (0.0970 ml, 0.833 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 134 mg (69.0%) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH2:21]([CH:23]([CH2:26][CH3:27])[CH:24]=[O:25])[CH3:22]>C1COCC1>[CH2:21]([CH:23]([CH2:26][CH3:27])[CH:24]([C:15]1[N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[N:12]=[CH:13][CH:14]=1)[OH:25])[CH3:22]
Reactant: CCC(C=O)CC
Reactant: Cc1ccc(S(=O)(=O)n2cccn2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ccnn1S(=O)(=O)c1ccc(C)cc1
Yield: 74.9 %

Procedure:
To 1-[(4-methylphenyl)sulfonyl]-1H-pyrazole (0.50 g, 2.26 mmol) [J Chem. Res., Synopses, 10, 327 (1979)] in THF (23 mL) at −78° C. was added a solution of t-butyllithium (1.7 M in pentane, 1.5 mL, 2.49 mmol) dropwise. After 10 min 2-ethylbutyraldehyde (0.31 mL, 2.49 mmol) was added. After 10 min the reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and then diluted with H2O (30 mL) and extracted with EtOAc (3×30 mL). The organic extract was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (EtOAc/hexane, 3:7) to give 0.546 g (75%) of 2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl}butan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10]([C:11]4[CH2:21][S:20][CH2:19][CH2:18][C:12]=4[NH:13][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:23].[Na+].Cl>[OH-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10]([C:11]4[CH2:21][S:20](=[O:23])[CH2:19][CH2:18][C:12]=4[NH:13][CH:14]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CSCC3
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CS(=O)CC3

Procedure:
To a solution of 0.29 g of 2-p-chlorophenyl-2,3,5,6,7,9-hexahydrothiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one in a mixture of 9.2 mL of 0.1N sodium hydroxide aqueous solution and 15 mL of water, 0.215 g of sodium metaperiodate is added under stirring and ice-cooling. The reaction mixture is stirred at room temperature overnight, the pH of the solution is adjusted to around 4 by adding dilute hydrochloric acid to precipitate a yellow solid. Solid is collected, washed with water, air-dried, triturated with hot ethyl acetate and dried in a vacuum oven at 80° overnight obtaining 2-p-chlorophenyl-2,3,5,6,7,9-hexahydro-8-oxo-thiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one, m.p. 298°-300° (dec).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5](=[CH2:7])[CH3:6])[CH3:2].[CH3:8][O:9][SiH:10]([O:13][CH3:14])[O:11][CH3:12]>[Pt]>[CH2:1]([NH:3][CH2:4][CH:5]([CH3:6])[CH2:7][Si:10]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:8])[CH3:2]
Reactant: CO[SiH](OC)OC
Reactant: C=C(C)CNCC
Agent: [Pt]
Product: CCNCC(C)C[Si](OC)(OC)OC
Temperature: 88 °C
Reaction time: 1 h
Yield: 150 %

Procedure:
To a 500 gallon reactor were added 489 kg (4.94 kmols) of N-ethylmethallylamine and 1425 g of platinum catalyst. The resulting solution was heated to 88° C. and 725 kg (5.94 kmols) of trimethoxysilane were added at such a rate to keep the temperature under 105° C. After addition was complete, the contents were heated to 110° C. for one hr. The low boiling byproducts were then removed by overhead stripping. The mixture was then cooled and approximately 60 L of methanol were added, and the reaction mixture was agitated at 50° C. for 1 hour before stripping the excess methanol. The resulting crude material (>97% purity) was then transferred from the reactor. The process was repeated without cleanup of the reactor to yield a combined total of 1638 kg (7.41 kmol) of N-ethyl-3-trimethoxysilyl-2-methylpropanamine.
Reaction SMILES: O=[C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH:15]=2)[O:10][C:4]2([CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[CH2:3]1.C[Si]([N:29]=[C:30]=[N:31][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:20]([C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:4]2([CH2:5][CH2:6][O:7][CH2:8][CH2:9]2)[CH2:3]/[C:2]/3=[N:29]/[C:30]#[N:31])[CH:24]=[CH:23][CH:22]=1)#[N:21]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC2(CCOCC2)O3)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1/CC2(CCOCC2)Oc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 0 °C
Yield: 80.8 %

Procedure:
A solution of 3-(4-oxo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-6-yl)benzonitrile (170 mg, 0.53 mmol) and TiCl4 (403 mg, 2.12 mmol) in anhydrous DCM (5 mL) was heated at 50 under microwave for 5 mins. Then bis-trimethylsilylcarbodiimide (198 mg, 1.06 mmol) was added and the mixture was heated at 60 for another 30 mins. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give (Z)—N-(6-(3-cyanophenyl)-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-ylidene)cyanamide (147 mg, crude), which was used in the next step without further purification.