Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]1=[O:9])[CH3:2].[N+](=[CH2:12])=[N-].CN(N=O)S(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1>[CH3:12][O:8][C:7]1[CH2:6][CH2:5][C:4](=[O:9])[C:3]=1[CH2:1][CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CCC1C(=O)CCC1=O
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: C1CCOC1
Product: CCC1=C(OC)CCC1=O

Procedure:
20 g of commercially available 2-ethyl-1,3-cyclopentanedione 2 partially dissolved in tetrahydrofuran (THF) was treated with etheral diazomethane generated from 50 g of N-methyl-N-nitroso-p-toluenesulfonamide, sold under the trademark Diazald (Aldrich Chemical Company). After standing several hours the solvent was removed under reduced pressure to give ca. 21 g of crude enol ether 3. Complete conversion to the enol ether 3 is obtained with a particularly clean reaction. But since the use of diazomethane is extremely hazardous, particularly when used in large scale reactions (greater than 20 grams), methanol with p-toluenesulfonic acid as the catalyst is preferred. The conversion to enol ether 3 is less complete, but the unreacted dione 2 can be recovered from the reaction mixture and recycled. The crude products of four reactions (84.1 g from 78.8 g of dione 2) were combined, dissolved in chloroform (CHCl3) and extracted with 5% NaHCO3. Removal of the CHCl3 under reduced pressure gave 69.5 g of the enol ether 3 (79% from dione 2) which was free of unreacted dione 2 as indicated by an nmr analysis. Distillation under reduced pressure (bp 82°-84° at 0.03 nm) gave a light colored oil: uv max (95% ethanol) 253 nm; ir (neat) 1685 cm-1 (cyclopentenone C=O) and 1620 cm-1 (enolic double bond), 1360 and 1270 cm-1 (enol ether); nmr (CDCl3) δ4.0 (s, 3, --OCH3), 2.17 (q,2, --CH2CH3 and 1.0 (t, 3, --CH2CH3).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:18][CH2:17]2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl>ClCCl.O>[CH:16]1([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]([N:5]=[C:1]=[S:2])=[CH:7][CH:8]=2)[CH2:18][CH2:17]1
Reactant: Nc1ccc(C2CC2)c2ccccc12
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: S=C=Nc1ccc(C2CC2)c2ccccc12
Temperature: 0 °C
Yield: 86 %

Procedure:
Thiophosgene (1.1 g, 9.7 mmol) was added to a solution of 1-amino-4-cyclopropyl-naphthalene (1.8 g, 9.7 mmol) and diisopropylethylamine (2 eq) in dichloromethane (50 mL) stirred at 0° C. The reaction mixture was stirred for 5 min at this temperature, then a 1% solution of HCl in water was added and the organic layer was separated, washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. Hexane was added, and the resulting precipitate was filtered. The solvent was evaporated to yield 1-cyclopropyl-4-isothiocyanatonaphthalene (1.88 g, 86%).
Reaction SMILES: [N:1]1([CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[Br:24]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:24][C:9]1[CH:10]=[CH:11][C:2]2[N:1]([CH:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCc3ccccc32)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCCc3cc(Br)ccc32)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A solution of compound 2 (3.15 g, 9.97 mmol) in DMF (15 mL) was cooled to 0° C. and treated drop wise with a solution of N-bromosuccinimide (1.77 g, 9.97 mmol) in DMF (15 mL). The reaction mixture was stirred at 0° C. for 3 hours then diluted with H2O (100 mL) and extracted into EtOAc (2×100 mL). The combined organic fractions were washed with brine (100 mL), dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (EtOAc:hexanes, 1:9) to obtain compound 3 (3.26 g, 83%) as a foam. 1H NMR (DMSO-d6) δ 1.38 (s, 9H), 1.41-1.52 (m, 5H), 1.80-1.87 (m, 1H), 2.12-2.17 (m, 1H), 2.65-2.69 (m, 2H), 2.79-2.92 (m, 2H), 3.00-3.08 (m, 1H), 3.15-3.25 (m, 1H), 3.53-3.59 (m, 1H), 3.96-4.04 (m, 1H), 6.93-6.96 (d, 1H, J=8.4 Hz), 7.23 (dd, 1H, J=2.4, 8.4 Hz), 7.29 (d, 1H, J=2.4 Hz); ESI-MS (m/z, %): 395 (MH+, 7), 341 (92), 339 (100).
Reaction SMILES: C([O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6])C.[CH3:11][N:12]([CH3:16])[C:13](Cl)=[S:14]>C(#N)C>[CH3:11][N:12]([CH3:16])[C:13]([NH:6][C@H:5]([C:4]([OH:3])=[O:10])[CH:7]([CH3:9])[CH3:8])=[S:14]
Reactant: CCOC(=O)[C@@H](N)C(C)C
Reactant: CN(C)C(=S)Cl
Solvent: CC#N
Product: CC(C)[C@H](NC(=S)N(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Valine ethyl ester (0.0028 mol) in 10 ml acetonitrile was reacted with dimethylthiocarbamoyl chloride (0.0056 mol) at 50° C. for 2 hours. Solvent acetonitrile was removed by rotary evaporation. Trifluoroacetic acid (10 ml) was added and the mixture stirred at room temperature for 15 min. The trifluoroacetic acid was removed by rotary evaporation. The residue was dissolved in water and analyzed by FAB/MS. The expected product, dimethylthiocarbamoyl valine (MH+=205), was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.Cl.[CH2:11]([N:18]([CH2:22][CH2:23]Cl)[CH2:19][CH2:20][Cl:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].Cl.O1CCOCC1>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC>[ClH:21].[CH2:11]([N:18]1[CH2:22][CH2:23][C:7]([C:8]#[N:9])([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: N#CCc1ccncc1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: C1COCCO1
Product: N#CC1(c2ccncc2)CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Combine 4-pyridylacetonitrile (19.4 g, 125 mmol), N-benzyl-N,N-bis-(2-chloroethyl)amine hydrochloride (33.6 g, 125 mmol), and hexadecyltributylphosphonium bromide (3 g, 6 mmol) and a 50% aqueous sodium hydroxide solution. Heat to 100° C. After 1 hour, cool the reaction mixture to ambient temperature and repeatedly extract with diethyl ether. Extract the combined organic layers twice with an aqueous 10% hydrochloric acid solution (350 mL). Combine the aqueous layers and neutralize with an aqueous 50% sodium hydroxide solution. Again extract three times with diethyl ether, combine the organic layers, dry over MgSO4, and filter. Add a solution of hydrochloric acid in dioxane (60 mL 4M, 240 mmol) and evaporate in vacuo to give 1-benzyl-4-cyano-4-(pyridin-4-yl)-piperidine hydrochloride.
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9]CC)=[O:8])=[O:5])C.[OH-].[Na+]>CO>[C:7]([CH:6]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]([OH:5])=[O:3])([OH:9])=[O:8]
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(C(=O)O)C(=O)O
Yield: 100.2 %

Procedure:
A solution of 91.1 g of 2-(ethyloxycarbonyl)-4-methylpentanoic acid, ethyl ester in 300 ml of methanol is treated for 6 hours at 80° C. with 400 ml of 10% sodium hydroxide. The solution is concentrated in vacuo to 400 ml and acidified with 10% hydrochloric acid. The product is extracted with ethyl acetate to yield 67.6 g of the title compound, which crystallizes on standing. Recrystallization from ethyl acetate-hexane yields the title compound, melting point 102°-105° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[C:19]=1Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1([S-])C=CC=CC=1.[Na+]>C(O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[C:19]=1[S:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(SCc2ccccc2)c(Cl)c(S(N)(=O)=O)c1
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [S-]c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(SCc2ccccc2)c(Sc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
A mixture of ethyl 3-benzylthio-4-chloro-5-sulfamylbenzoate (0.77 g), thiophenol (0.36 ml), and dry ethanol (15 ml) containing 3 millimoles of sodium thiophenolate is refluxed for 20 hours. After cooling the precipitate is collected by filtration to yield ethyl 3-benzylthio-4-phenylthio-5-sulfamylbenzoate with a melting point of 151°- 152° C.
Reaction SMILES: Br[C@@H:2]1[C@@H:29]([OH:30])[C@@:28]2([CH3:31])[C@@H:13]([CH2:14][C@@H:15]3[O:20][C@@:19]4([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH:21]4[Br:27])[C@@H:17]([CH3:18])[C@@H:16]32)[C@H:12]2[C@H:3]1[C@:4]1([CH3:33])[C@@H:9]([CH2:10][CH2:11]2)[CH2:8][C@@H:7]([OH:32])[CH2:6][CH2:5]1.BrC1C[C@@H](C)CO[C@@]21[C@@H](C)[C@@H]1[C@]3(C)[C@@H](C[C@@H]1O2)[C@H]1[C@@H]([C@]2(C)[C@@H](CC1)C[C@@H](O)CC2)CC3=O>N1C=CC=CC=1.[Ag]=O>[Br:27][CH:21]1[CH2:22][C@@H:23]([CH3:24])[CH2:25][O:26][C@@:19]21[C@@H:17]([CH3:18])[C@@H:16]1[C@:28]3([CH3:31])[C@@H:13]([CH2:14][C@@H:15]1[O:20]2)[C@H:12]1[C@@H:3]([C@:4]2([CH3:33])[C@@H:9]([CH2:10][CH2:11]1)[CH2:8][C@@H:7]([OH:32])[CH2:6][CH2:5]2)[C@H:2]1[O:30][C@@H:29]31
Reactant: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@H](Br)[C@@H](O)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Agent: O=[Ag]
Agent: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5CC(=O)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Solvent: c1ccncc1
Product: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@H]5O[C@H]5[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Reaction time: 71 h

Procedure:
The following procedure is a variation of that described in Helv. Chim. Act., 1953, 36, 1241. (3β,5α,11α,12β,25R)-11,23-dibromospirostan-3,12-diol (18.08 g) was dissolved in pyridine (500 mL) at room temperature and treated with silver oxide (70.0 g). The resulting mixture was stirred in the dark for 71 hours. The mixture was filtered and the solid washed with ether and then chloroform. These washes were combined with the filtrate and concentrated. The resulting solid was purified by flash chromatography (1:1 hexane:ethyl acetate) to give 12.2 g of a 1:1 mixture of the title compound and (3β,5α,25R)-23-bromospirostan-3-ol-12-one. Further chromatography (7:3 hexane:ethyl acetate) provides pure title compound. (3β,5α,11β,12α,25R)-23-bromo-12-(trichloroacetoxy)spirostan-3,11 -diol: Using the procedure described in J. Chem. Soc., 1956, 4330, (3β,5α, 11β,12β,25R)-23-bromo-11,12-epoxyspirostan-3-ol was treated with trichloroacetic acid in toluene at room temperature for 3 days to give the title compound. (3β,5α, 11β,12α,25R)-23-bromo-spirostan-3,11,12-triol: Using the procedure described in J. Chem. Soc., 1956, 4330, (3β,5α,11β,12α,25R)-23-bromo-12-(trichloroacetoxy)spirostan-3,11-diol was saponified with sodium hydroxide in water and ethanol to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([O-:21])=[O:20])([O-])=O.[Na+:22]>[Ni]>[NH2:1][C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([O-:21])=[O:20].[Na+:22]
Reactant: O=C([O-])Cc1cccc(Oc2ccccc2Cl)c1[N+](=O)[O-]
Agent: [Ni]
Agent: [Na+]
Product: Nc1c(CC(=O)[O-])cccc1Oc1ccccc1Cl

Procedure:
Thus obtained sodium 2-[2-nitro-3-(2-chlorophenoxy)phenyl]acetate was subjected successively to catalytic reduction using Raney nickel to give sodium 2-[2-amino-3-(2-chlorophenoxy)phenyl]acetate. This product was identified with crop obtained in Example 5-(2) by I.R. and N.M.R. spectra.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)C(Cl)=O.[CH3:22][NH:23][O:24][CH3:25].Cl.C(OC1C=CC(C(Cl)=O)=CC=1)CCCC>C1(C)C=CC=CC=1.O1CCCC1.N1C=CC=CC=1.CN(C)C=O>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:23]([CH3:22])[O:24][CH3:25])=[O:13])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CNOC
Reactant: CCCCCOc1ccc(C(=O)O)cc1
Agent: CCCCCOc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCOc1ccc(C(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-n-pentyloxybenzoic acid (5.0 g) in toluene was added oxalyl chloride (15 ml) and N,N-dimethylformamide (0.1 ml) and the mixture was stirred for 2 hours at room temperature. The solvents were evaporated under reduced pressure to give crude 4-n-pentyloxybenzoyl chloride. To a suspension of N,O-dimethylhydroxylamine a hydrochloride (3.51 g) and pyridine (5.82 ml) in tetrahydrofuran (25 ml) was added the solution of crude 4-n-pentyloxybenzoyl chloride in tetrahydrofuran (25 ml) dropwise at 0° C. and the mixture was stirred for 3 hours at room temperature. To the reaction mixture 1N HCl was added and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give N-(4-n-pentyloxybenzoyl)-N,O-dimethylhydroxylamine (4.63 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=1>CN(C)C=O>[F:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([F:22])[CH:18]=1)[CH2:14][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2ccn(Cc3cc(F)cc(F)c3)c2c1
Reaction time: 0.5 h
Yield: 123.6 %

Procedure:
—Sodium hydride (50% dispersion in oil, 4.8 g, 100 mmol) was added to a solution of 6-nitroindole (15.0 g, 92.6 mmol) in dry dimethylformamide (750 ml). After 30 min. stirring, 1-bromomethyl-3,5-difluoro-benzene (19.5 g, 94 mmol) was added. Stirring was continued for 1 h and the reaction mixture was quenched with water. The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was stirred with heptane to produce a white solid which was collected by filtration to give 1-(3,5-difluoro-benzyl)-6-nitro-1H-indole (33 g). The product was used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:41])[N:27]3[C:30]([O:32][CH:33](Cl)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:42]([OH:47])(=[O:46])[CH2:43][CH2:44][CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:41])[N:27]3[C:30]([O:32][CH:33]([O:47][C:42](=[O:46])[CH2:43][CH2:44][CH3:45])[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OC(Cl)c1ccccc1
Reactant: CCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(=O)OC(OC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of chloro(phenyl)methyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (4.11 g, 6.66 mmol) in dimethyl formamide (40 mL) was added butyric acid (0.91 mL, 9.99 mmol) and cesium carbonate (1.63 g, 4.99 mmol). The reaction was stirred at room temperature for 20 hours then diluted with ethyl acetate (40 mL) and washed with 1:1 water/brine (3×50 mL). The organics were dried (MgSO4) and concentrated. The crude product was purified by column chromatography on silica eluting with 0.5% Et3N/ethyl acetate to give butyryloxy(phenyl)methyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-91 (1.12 g). The material was determined to be 67% pure by LCMS.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>O1CCCC1>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([B:21]([OH:22])[OH:20])=[CH:3][N:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cncc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cncc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
A solution of 2.0 gm (9.6 mMol) 4-bromoisoquinoline in 30 mL tetrahydrofuran was cooled to −100° C. To this solution were added dropwise 6.3 mL (10.1 mMol) n-butyl-lithium (1.6 M in hexane) dropwise, and the resultant solution was stirred for 30 minutes. To this solution was then added dropwise a solution of 4.4 mL (19.2 mMol) triisopropylborate and the reaction mixture was then stirred for 18 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium chloride. The phases were separated and the aqueous phase extracted well with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was sonicated in a mixture of hexane:ethyl acetate. The resulting suspension was filtered to provide 0.57 gm (34%) isoquinolin-4-ylboronic acid as a light orange solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[C:23]([C:24]3[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([S:31][CH3:32])[N:25]=3)=[CH:22][C:19]([CH:20]=O)=[CH:18][N:17]=2)=[CH:11][CH:10]=1.CCO.C([BH3-])#N.[Na+]>CC(O)=O.O.CCOC(C)=O>[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[C:23]([C:24]3[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([S:31][CH3:32])[N:25]=3)=[CH:22][C:19]([CH2:20][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:18][N:17]=2)=[CH:11][CH:10]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc(SC)n2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Nc2ncc(CN3CCOCC3)cc2-c2nc(C)nc(SC)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
Morpholine (0.018 mL, 0.204 mmol) and a few drops of AcOH (3.88 μL, 0.068 mmol) were added to a stirred suspension of 6-(6-methoxypyridin-3-ylamino)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)nicotinaldehyde (25 mg, 0.068 mmol) in EtOH (3.00 mL, 51.4 mmol), the mixture was stirred at room temperature for 1 h, then treated with sodium cyanoborohydride (4.26 mg, 0.068 mmol) and stirred at room temperature overnight. The mixture was diluted with water and EtOAc (10 mL each). The separated aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude product which was purified by flash column chromatography (ISCO CombiFlash®, Teledyne ISCO, Lincoln, Nebr., DCM to 10% DCM in MeOH) to give N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-5-(morpholinomethyl)pyridin-2-amine (19 mg, 0.043 mmol, 63.7% yield) as a yellow solid. LCMS (API-ES) m/z 440 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]2[C:9](=[O:18])[C:10]3[C:15]([C:16](=[O:17])[C:7]=2[CH:6]=[C:5]([C:19]([O:21]C)=[O:20])[S:4]1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[OH-].[Na+].O.Cl>C1COCC1>[CH3:1][O:2][CH:3]1[C:8]2[C:9](=[O:18])[C:10]3[C:15]([C:16](=[O:17])[C:7]=2[CH:6]=[C:5]([C:19]([OH:21])=[O:20])[S:4]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: COC(=O)C1=CC2=C(C(=O)c3ccccc3C2=O)C(OC)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC1SC(C(=O)O)=CC2=C1C(=O)c1ccccc1C2=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho [2,3-c] thiine-3-carboxylate (106 mg, 0.33 mmol) was dissolved in THF (2 ml). 1.75M solution of sodium hydroxide (0.32 mg, 0.55 mmol) was added dropwise at 0° C. followed by water (0.5 ml). The reaction mixture was stirred at 0° C. for 3 hours, then water (10 ml) was added, and the reaction mixture was acidified to pH=3 with 5% hydrochloric acid. After that, the reaction mixture was extracted with dichloromethane (5×5 ml). Organic fractions were evaporated to dryness. The residue 98 mg (crude) was used in the next step.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][C:7](=[O:13])[C:8]([O:10]CC)=O)[CH3:2].[CH2:17]([NH2:19])[CH3:18]>C(O)C>[CH2:17]([NH:19][C:8]([C:7]([NH:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])=[O:13])=[O:10])[CH3:18]
Reactant: CCOC(=O)C(=O)NCC(OCC)OCC
Reactant: CCN
Solvent: CCO
Product: CCNC(=O)C(=O)NCC(OCC)OCC
Yield: 85.1 %

Procedure:
To a solution of 20.0 g of ethyl N-(2,2-diethoxyethyl)oxamate in 60 ml of ethanol was added 6.1 ml of 70% by weight aqueous ethylamine solution, and the mixture was subjected to reaction at room temperature for 1 hour. After the completion of the reaction, the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 17.0 g (yield: 85.1%) of N-ethyl-N'-(2,2-diethoxyethyl)oxamide having a melting point of 131°-132° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][C:8]1[C:9]([CH3:28])=[C:10]([C:15]2[C:24]3[N:23]=[CH:22][CH:21]=[N:20][C:19]=3[C:18]([C:25]([OH:27])=[O:26])=[CH:17][CH:16]=2)[CH:11]=[C:12]([CH3:14])[CH:13]=1>CC#N>[Cl:4][C:11]1[C:12]([CH3:14])=[CH:13][C:8]([O:7][CH3:6])=[C:9]([CH3:28])[C:10]=1[C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([C:25]([OH:27])=[O:26])=[CH:17][CH:16]=1
Reactant: COc1cc(C)cc(-c2ccc(C(=O)O)c3nccnc23)c1C
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: COc1cc(C)c(Cl)c(-c2ccc(C(=O)O)c3nccnc23)c1C
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 33.1 %

Procedure:
Sulfuryl chloride (29 μL, 0.37 mmol) in CH3CN (1 mL) was added dropwise to a cold (−5° C.) suspension of 8-(3-methoxy-2,5-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Step 97.1) (113 mg, 0.37 mmol) in CH3CN (4 mL). The reaction mixture was stirred for 10 min at −5° C., quenched by addition of H2O (1 mL) and filtered to afford 42 mg of the title compound as a yellow solid. Title compound: ESI-MS: 343.0 [M+H]+; tR=4.90 min (System 1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:24])[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.C(=O)(O)[O-].[Na+].[CH2:30]([O:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>O1CCCC1.O>[Cl:24][C:4]1[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:14])([CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=[C:2]([NH:1][C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])[CH:3]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N)cc(Cl)c21
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(NC(=O)OCc3ccccc3)cc(Cl)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 g (0.035 mol) of 7-amino-9-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one are dissolved in 360 ml of dry tetrahydrofuran, treated with 10 g of ground sodium bicarbonate and 8 ml of chloroformic acid benzyl ester and stirred at room temperature for 31/2 hours. The mixture is treated with ethyl acetate and water, and separated aqueous phase is extracted twice with ethyl acetate and the combined organic extracts are dried and evaporated. The residue is chromatographed on 600 g of silica gel with methylene chloride/ethyl acetate (20:1 ) as the elution agent. From ether there is obtained benzyl 9-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepine-7-carbamate of melting point 212°.