Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Mg].[C:10]([P:14](Cl)[C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])([CH3:12])[CH3:11].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:10]([P:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: Cc1ccccc1Br
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccccc1P(C(C)(C)C)C(C)(C)C
Reaction time: 4 h
Yield: 91 %

Procedure:
In a 500 ml four-necked flask thoroughly purged with nitrogen, a Grignard reagent solution previously prepared from 20.5 g (0.12 mol) of 2-bromotoluene and 3.1 g (0.13 mol) of metallic magnesium in a mixed solvent of 100 ml of tetrahydrofuran and 40 ml of toluene, and 0.05 g (0.0005 mol (corresponding to 0.5% by mol)) of copper(I) chloride were placed. To the contents of the flask, a solution of 18.1 g (0.10 mol) of di-tert-butylphosphinous chloride in 30 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at 50° C. for 4 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 30 ml of a 5% sulfuric acid aqueous solution was added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 112° C. to 114° C. under reduced pressure of 3 Torr were collected. As a result, 21.5 g (purity: 99.0%) of the aimed di-tert-butyl(2-methylphenyl)phosphine was obtained. The yield was 91.0%.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2(O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:25])=[CH:11][C:10]=1[CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][C:9]1[C:10]([CH3:27])=[CH:11][C:12]([CH:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=3)[C:17]2=[O:25])=[CH:13][C:14]=1[CH3:15])([CH3:5])([CH3:7])[CH3:6]
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc(C2(O)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(N2C(=O)C(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)c3ccccc32)c1
Yield: 50.7 %

Procedure:
Combine 3-[4-(tert-Butyl-dimethylsilanyloxy)-3,5-dimethyl-phenyl]-3-hydroxy-1,3-dihydro-indol-2-one (15.34 g, 40 mmol), 3-methoxyphenylboronic acid (12.16 g, 80 mmol), copper (II) acetate (7.27 g, 40 mmol), triethyl amine (11.2 ml, 80 mmol) and 4A sieves (100 g) in dichloromethane (1 L) and heat at 32° C. for 1 day stirring mechanically. Add more 3-methoxyphenylboronic acid (6.0 g, 39 mmol), copper (II) acetate (7.27 g, 40 mmol), triethyl amine (5.6 ml, 40 mmol) and 4A sieves (50 g) and continue heating for 3 days. Filter the reaction through Celite washing liberally with dichloromethane. Add ethyl acetate to get more precipitate and refilter through Celite. Evaporate in vacuo to obtain an oil of about 30 g. Purify by preparative HPLC (gradient of 15% ethyl acetate/dichloromethane to 50% ethyl acetate/dichloromethane) to obtain 9.60 g of an orange foam. MS (ES): m/z=490 (M+1); 1H NMR (DMSO-d6); δ7.50 (t, 1H), 7.28-7.23 (m, 2H), 7.12-6.98 (m, 6H), 6.82 (d, 1H), 6.72 (s, 1H), 3.81 (s, 3H), 2.14 (s, 6H), 0.99 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: O.[OH-].[Na+:3].[NH2:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8].[C:11](Cl)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C1(C)C=CC=CC=1>[Na+:3].[C:11]([NH:4][CH2:5][CH2:6][S:7]([O-:10])(=[O:9])=[O:8])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NCCS(=O)(=O)[O-])OCc1ccccc1
Temperature: 25 °C

Procedure:
To 1000 ml of water in the RBF charge 192 gm of (3.0 eq) of sodium hydroxide under cooling followed by 200 gm of Taurine and dissolve it until clear solution is obtained. Cool to 0° C. to 5° C., and Charge 50% CBZ-Cl in toluene at 0° C. to 5° C. After completion of addition, maintain at room temperature for 14 h. Separate the toluene layer and wash the aqueous layer with 2×200 ml of ethyl acetate. Add slowly 27 gm of sodium hydroxide in 60 ml of water to the aqueous layer and adjust pH to 12-14. Cool to 0° C. to 5° C. and a white solid separates from the solution. Filter the solid and dry the solid at 60-70° C. Weight of the solid: 320 g
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[N:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:24](Cl)([Cl:26])=[O:25]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[N:11][C:9]=3[N:10]([C:24]([Cl:26])=[O:25])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: O=C1Nc2cccnc2Nc2cc(Cl)ccc21
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Temperature: 45 °C
Reaction time: 2 h

Procedure:
11.6 g (0.0472 mol) of 9-chloro-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, suspended in a mixture of 450 ml of anhydrous dioxane and 6.4 ml (0.08 mol) of pyridine, were combined at 45° C., within 20 minutes, with 47.1 ml (0.094 mol) of a 20% solution of phosgene in toluene. The reaction mixture was stirred for 2 hours at 45° C. and then for 4 hours at 60° C. The mixture was filtered while hot, the filtrate was evaporated down in vacuo, the crystallising residue remaining was resuspended in 100 ml of dioxane, refluxed for 2 hours, evaporated down once more, mixed with copious amounts of water and suction filtered. After drying in a circulating air dryer the product had an m.p. of 265°-267° C., RF 0.70 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/ethyl acetate 1/1 v/v).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.B(O)(O)[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:20][CH:19]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:28][N:27]([CH3:29])[S:24]([C:21]1[CH:20]=[CH:19][C:18]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:23][CH:22]=1)(=[O:25])=[O:26]
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: CN(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccc(-c2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Compound 83 (100 mg, 0.43 mmol), 4-(N,N-dimethylsulfonamidophenyl)boronic acid (198 mg, 0.87 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), S-Phos (18 mg, 0.04 mmol), and K2CO3 (299 mg, 2.17 mmol) were dissolved in dioxane/H2O (2.2 mL, 10/1, v/v), and stirred overnight at 100° C. The reaction mixture was diluted with H2O/EtOAc. The resulting precipitate was filtered, washed with H2O/EtOAc, and dried under vacuum to provide 171 (120 mg, 73% yield) as a grey solid. LC-MS (M+H=380, obsd.=380).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO.CCOC(C)=O>[NH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C#N)ccc1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.3 mmol) in 100 mL of EtOH is added SnCl2 (13.9 g, 61.7 mmol). The resulting solution is heated at reflux. After 2 hours, the solution is cooled to ambient temperatures. The solution is poured into 150 mL of ice water. The pH of the solution is adjusted to >7 with a solution of saturated NaHCO3. The solution is diluted with EtOAc and the resulting mixture is filtered through Celite. The filtered solution is separated. The organic layer is dried over MgSO4, filtered and concentrated to give the title compound (1.57 g, 8.7 mmol) as an off-white solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:32]=3)[CH:25]=2)[CH:21]=[CH:22][CH:23]=1>[Cu].C1(C)C=CC=CC=1>[O:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[O:30][C:26]1[CH:25]=[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=2)[CH:29]=[CH:28][CH:27]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Clc1cccc(-c2cccc(Oc3cccc(Oc4ccccc4)c3)c2)c1
Reactant: Oc1ccccc1Oc1ccccc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(Oc2cccc(Oc3cccc(-c4cccc(Oc5ccccc5Oc5ccccc5)c4)c3)c2)cc1
Yield: 61 %

Procedure:
A 500 ml. reaction flask equipped with stirrer, condenser, and Dean Stark trap was charged with 191 g. (1.03 moles) of o-phenoxyphenol, 50 ml. of toluene and 39.5 g. (0.70 mole) of potassium hydroxide. The mixture was heated to reflux and water azeotroped from the system. Diglyme (100 ml.) was then added followed by 20 g. (0.053 mole) of 3-chloro-3'-(m-phenoxyphenoxy)biphenyl over a 30 minute period. To this mixture 2.5 g. of cuprous chloride and 0.5 g. of copper powder was added and after removing the diglyme be distillation, the reaction mixture was heated at 230°-240° for 18 hours. The mixture was cooled, diluted with 500 ml. of ether and centrifuged to remove copper and potassium salts. The salts were washed with additional ether, and the ether fractions combined and washed with 25% potassium hydroxide solution followed by water washing to neutrality. After drying the ethereal solution over magnesium sulfate, and removing ether in vacuo, the resulting oil was distilled to give 16.9 g of the desired product, bp 255°-260°/0.02 mm.; nD25 1.6480.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[N:10]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][CH:11]1[C:14]([O:16][CH3:17])=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:14]([C:11]1([C:5]2[C:4]([F:9])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:12][CH2:13][N:10]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15]
Reactant: COC(=O)C1CCN1C(=O)OC(C)(C)C
Reactant: Fc1cc(Cl)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ncc(Cl)cc2F)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5-chloro-2,3-difluoropyridine (1.39 g, 9.29 mmol, Eq: 1.00) and 1-tert-butyl 2-methyl azetidine-1,2-dicarboxylate (2 g, 9.29 mmol, Eq: 1.00) in toluene (15 ml) was added dropwise at 0° C. over 15 min a 0.5 M solution of KHMDS (18.6 ml, 9.29 mmol, Eq: 1.00) in toluene. The colorless solution turned into light brown. After stirring at 0° C. for 45 min, the reaction mixture was allowed to warm up to 25° C. The reaction mixture was stirred for 2.5 h. Saturated aqueous NH4Cl solution (100 ml) was added and the aqueous phase was extracted with AcOEt (2×150 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 60% AcOEt in heptane) to yield a colorless viscous oil as a racemate (1.746 g; 55%). m/z=345.2 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.C(N(CC)CC)C.[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17].[Cl:20][C:21]1[N:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27]([N:31]3[CH:39]([OH:40])[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:41])=[N:28]2)=[CH:23][CH:22]=1>C(Cl)Cl.O>[Cl:20][C:21]1[N:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27]([N:31]3[CH:39]([O:40][C:16]([N:15]([CH3:19])[CH3:14])=[O:17])[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:41])=[N:28]2)=[CH:23][CH:22]=1
Reactant: CN(C)C(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 73.3 %

Procedure:
Pyridine (10 cc.), triethylamine (5 cc.) and dimethylcarbamoyl chloride (1.61 g.) are added successively to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (3.11 g.) in methylene chloride (50 cc.). The reaction mixture is stirred for 16 hours at a temperature of about 20° C. and water (50 cc.) and methylene chloride (25 cc.) are then added. The aqueous layer is decanted off and washed with methylene chloride (2 × 25 cc.). The organic layers are combined, washed with water (2 × 25 cc.), dried over sodium sulphate and evaporated to dryness under reduced pressure. Recrystallisation of the residue obtained from acetonitrile (45 cc.) gives 2-(7-chloro-1,8-naphthyridin-2-yl)-3-dimethylaminocarbonyloxy-isoindolin-1-one (2.8 g.) melting at 218° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH:13]([CH:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:14])[CH:9]=[C:8]2[C:3]=1[CH:4]1[CH2:26][C:25](=O)[CH2:24][CH2:23][CH:5]1[CH:6]([CH3:22])[NH:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:34].[Na+].Cl>CO>[NH2:34][CH:25]1[CH2:24][CH2:23][CH:5]2[CH:6]([CH3:22])[NH:7][C:8]3[C:3]([CH:4]2[CH2:26]1)=[C:2]([OH:1])[CH:11]=[C:10]([S:12][CH:13]([CH:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:14])[CH:9]=3
Reactant: CCCCCC(C)C(C)Sc1cc(O)c2c(c1)NC(C)C1CCC(=O)CC21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CCCCCC(C)C(C)Sc1cc(O)c2c(c1)NC(C)C1CCC(N)CC21

Procedure:
To 10 ml. of dry methanol is added 1.51 g. (3.1 mmole) of dl-1-hydroxy-6-methyl-3-(3-methyl-2-octylthio)-5,6,6a,7,10,10a-hexahydrobenzo[c]quinoline-9(8H)one, 2.39 g. (31 mmole) ammonium acetate and 0.272 g. (4.34 mmole) sodium cyanoborohydride, and the resulting mixture is heated at reflux for two days. The resulting mixture is acidified to pH 2 with hydrochloric acid and evaporated to dryness in vacuo. The residue is taken up in water, washed with ethyl ether, the aqueous phase adjusted to pH 12 with sodium hydroxide solution and extracted with ethyl ether. The extracts are washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness to provide the title compound as a mixture of diastereomers which are separated, if desired, by fractional crystallization followed by column chromatography on silica gel.
Reaction SMILES: [N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[C:12]([O:31][CH3:32])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([CH:22]([C:24]3[N:28]([CH3:29])[C:27]([CH3:30])=[N:26][CH:25]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.ClCCl>O1CCOCC1.[O-2].[O-2].[Mn+4]>[N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[C:12]([O:31][CH3:32])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[N:28]([CH3:29])[C:27]([CH3:30])=[N:26][CH:25]=3)=[O:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 2.25 h

Procedure:
A heterogeneous mixture of (3-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol (625 mg, 1.32 mmol, Intermediate 21: step a) and manganese dioxide (809 mg, 7.91 mmol) in dioxane (13 mL) was heated to 100° C. After 135 minutes, the flask was allowed to cool to 23° C. Dichloromethane (40 mL) was added and the mixture was filtered through Celite®, rinsing with dichloromethane. Silica gel (3 g) was added to the filtrate and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with 30% ethyl acetate-hexanes initially, grading to 100% ethyl acetate provided the title compound as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[O:42][CH3:43])=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:54].C(=O)([O-])O.[Na+].Cl[C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62]>C(OCC)(=O)C>[CH2:64]([O:63][C:61]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[O:42][CH3:43])=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)=[O:45])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:54])=[O:62])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCCN)C(=O)CO3)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCCNC(=O)OCc2ccccc2)C(=O)CO3)cc1
Reaction time: 1 h

Procedure:
The stirred solution of 0.300 g of benzyl 3-[4-(4-aminobutyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 316b) and 3 ml of ethyl acetate is admixed at 0° C. with 3 ml of aqueous 1M sodium hydrogencarbonate solution and 0.072 ml of benzyl chloroformate. After 1 hour, the reaction mixture is poured onto water (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases are washed with brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (1:1 EtOAc-heptane); Rt=5.90.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:23])[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:24][O:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].O>N1C=CC=CC=1>[CH2:16]([N:11]1[CH2:10][CH:9]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:28]([CH2:27][CH2:26][O:25][CH3:24])(=[O:30])=[O:29])[CH:7]=[CH:6][CH:5]=3)([OH:23])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(C2(O)C3CCC2CN(Cc2ccccc2)C3)c1
Reactant: COCCS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COCCS(=O)(=O)Nc1cccc(C2(O)C3CCC2CN(Cc2ccccc2)C3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-(3-Amino-phenyl)-3-benzyl-3-aza-bicyclo[3.2.1]octan-8-ol (1.63 g, 5.28 mmol) stirred in pyridine (20 ml) at 0° C. was charged with 2-methoxy-ethanesulfonyl chloride (1.26 g, 7.93 mmol) dropwise causing a color change from yellow to bright orange. The reaction was warmed to room temperature and judged complete by TLC after 1 h. Following addition of water (20 ml), the product was extracted with EtOAc (4×30 ml), washed with saturated aqueous NaCl solution (6×30 ml), dried over Na2SO4, filtered and concentrated to a crude red oil (2.37 g, >100%). 1H NMR (400 MHz, CDCl3) δ 7.35–7.10 (m, 4H), 3.78 (ddd, J=7.5, 3.3, 2.1 Hz, 2H), 3.59 (s, 2H), 3.36 (d, J=2.5 Hz, 3H), 3.17, (m, 2H), 2.85 (d, J=16.3 Hz, 3H), 2.61 (d, J=8.3 Hz, 2H), 2.36 (s, 2H), 1.79 (d, J=7.0 Hz, 2H), 1.37 (d, J=10.0 Hz, 2H); APCI MS m/z 431.2 (M+1)+.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:29][CH3:30])[CH2:5][CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[C:11]3[S:19][C:20]4[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([OH:28])[C:21]=4[C:9]([C:10]=23)=[N:8]1)[CH3:3].Cl[C:32]1C2C(=O)C3C(=C(OC)C=CC=3O)SC=2C([N+]([O-])=O)=CC=1.ClC1C=CC([N+]([O-])=O)=C(SC2C(OC)=CC=C(OC)C=2C(O)=O)C=1.S(Cl)(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[CH2:29]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[C:11]3[S:19][C:20]4[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([O:28][CH3:32])[C:21]=4[C:9]([C:10]=23)=[N:8]1)[CH3:30]
Reactant: COc1ccc(O)c2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3sc12
Reactant: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Sc1c(OC)ccc(O)c1-2
Agent: COc1ccc(OC)c(C(=O)O)c1Sc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Sc1c(OC)ccc(OC)c1-2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Other 10-hydroxy-7-methoxy-, 10-methoxy-7-hydroxy-, and 7,10-dimethoxy-5-nitro-2-(substituted)-2H[1]benzothiopyrano[4,3,2-cd]indazoles can be prepared in the manner of Examples 33 through 35 and 54. One such compound is 2-[2-(diethylamino)-ethyl]-7-methoxy-5-nitro-2H[1]benzothiopyrano[4,3,2-cd]indazol-10-ol, hydrochloride salt, mp 267°-270° C. The latter compound is prepared from 1-chloro-5-methoxy-8-hydroxy-4-nitro-9H-thioxanthen-9-one which in turn is prepared as follows: A suspension of 5.8 g (0.016 mol) of 2-[(5-chloro-2-nitrophenyl)thio]-3,6-dimethoxybenzoic acid, 50 ml of toluene, and 3.8 g (0.032 mol) of thionyl chloride was heated under reflux for two hours, concentrated to dryness in vacuo, and dissolved in 50 ml of nitrobenzene. The solution was treated portionwise with 3.6 g (0.026 mol) of AlCl3, keeping the temperature below 35° C. during the addition. The mixture was stirred for two hours at 70° C., chilled in a refrigerator overnight, and poured into 400 ml of ice-cold H2O. The mixture was extracted four times with CH2Cl2 and the extracts were combined, dried (MgSO4), and concentrated in vacuo to dryness. The residue was triturated successively in petroleum ether and hot MeOH, and recrystallized from DMF to give 1.2 g of product, 272°-273° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[Cl:22][C:23]1[CH:33]=[CH:32][C:26](/[CH:27]=[CH:28]/B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:22][C:23]1[CH:33]=[CH:32][C:26](/[CH:27]=[CH:28]/[C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([CH3:20])=[C:15]([CH:17]5[CH2:19][CH2:18]5)[N:16]=4)[CH:13]=3)[C:4](=[O:21])[CH:3]=2)=[CH:25][CH:24]=1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(/C=C/c4ccc(Cl)cc4)cc3=O)cn12
Temperature: 70 °C
Yield: 38.5 %

Procedure:
A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (178 mg), (E)-(4-chlorostyryl)boronic acid (189 mg), potassium carbonate (214 mg), PdCl2(dppf) (18.9 mg), THF (3 ml) and water (1 ml) was heated at 70° C. under N2 atmosphere overnight. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (80 mg) as a solid.