Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:14]([NH:22][NH2:23])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:23][N:22]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1nc[nH]c1C#N
Reactant: NNC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CCCCCNc1nc[nH]c1-c1nc(-c2ccccc2)n[nH]1
Temperature: 170 °C
Reaction time: 14 h
Yield: 15.1 %

Procedure:
The mixture of 4-(pentylamino)-1H-imidazole-5-carbonitrile (200 mg, 1.12 mmol), benzohydrazide (229 mg, 1.68 mmol) and potassium carbonate (100 mg, 0.72 mmol) in 1-butanol (6 ml) in a sealed tube was stirred at 170° C. for 14 hours. The reaction was diluted with water and extracted with EtOAc three times. The combined organic layers was dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative LCMS (method A) to yield the desired product (50 mg, 17% yield). LCMS calculated for C16H21N6 (M+H): 297.2; found 297.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:13])[C:9](=[O:12])[N:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.[C:14]([N:21](C)[C@H:22]([C:24](O)=[O:25])[CH3:23])(OC(C)(C)C)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[ClH:61]>>[ClH:61].[CH3:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([NH:1][C:24](=[O:25])[C@@H:22]([NH:21][CH3:14])[CH3:23])=[CH:3][CH:4]=2)[N:8]([CH3:13])[C:9]1=[O:12]
Reactant: Cn1c(=O)n(C)c2nc(N)ccc21
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Product: CN[C@@H](C)C(=O)Nc1ccc2c(n1)n(C)c(=O)n2C

Procedure:
5-Amino-1,3-dimethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (Russian Journal of Organic Chemistry, 2007, 43, 11, 1706-1709) was treated with Boc-N-methyl-L-alanine according to the General procedure 4 (PyBop coupling) and the product of the reaction deprotected according to the General procedure 3 (HCl deprotection) to afford the title compound. 1H NMR (400 MHz, Me-d3-OD): 7.93 (1H, d), 7.48 (1H, d), 4.04 (1H, d), 3.45 (6H, s), 2.77 (3H, s), 1.64 (3H, d). MS: [M+H]+=264.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[O:6][CH:7]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1/[CH:9]=[CH:8]/[C:5]1[O:6][CH:7]=[C:3]([CH2:2][O:38][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]3[CH:25]=[CH:26][N:27]=[C:23]3[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=2)[N:4]=1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)cc1
Yield: 55.5 %

Procedure:
Using 4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (274 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (300 mg) and 65% sodium hydride (39.5 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (285 mg) as a colorless crystal powder.
Reaction SMILES: F[C:2](F)(F)C1(F)OC1(F)F.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=O>>[F:11][C:12]([F:20])([F:19])[C:13](=[CH2:2])[C:15]([F:18])([F:17])[F:16]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: FC(F)(F)C1(F)OC1(F)F
Product: C=C(C(F)(F)F)C(F)(F)F

Procedure:
In the form of the present invention starting from hexafluoropropylene oxide, a vapor stream of hexafluoropropylene oxide is fed at any convenient flow rate, e.g., in the range of about 0.04 to about 0.06 g-mole/hr to a reactor maintained at a temperature in the range of about 400° to about 650° C. and containing a fluorinated catalyst (hereinafter described) for a residence time sufficient to for a vapor stream comprising hexafluoroacetone which is not isolated but forwarded directly to a heating zone of the reactor for conversion to hexafluoroisobutylene.
Reaction SMILES: [CH3:1][NH2:2].CO.[CH2:5]([S:7]([C:10]1[CH:37]=[CH:36][C:13]([O:14][C:15]2[C:16]([CH:30]([OH:35])[C:31](OC)=[O:32])=[CH:17][C:18]3[N:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[NH:20][C:19]=3[CH:29]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:6].C[C:39](C)([O-:41])C.[K+]>>[CH2:5]([S:7]([C:10]1[CH:11]=[CH:12][C:13]([O:14][C:15]2[C:16]([CH:30]3[O:35][C:39](=[O:41])[N:2]([CH3:1])[C:31]3=[O:32])=[CH:17][C:18]3[N:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[NH:20][C:19]=3[CH:29]=2)=[CH:36][CH:37]=1)(=[O:8])=[O:9])[CH3:6]
Reactant: CN
Reactant: CC(C)(C)[O-]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(O)C(=O)OC)cc1
Agent: [K+]
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C2OC(=O)N(C)C2=O)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
1 N methylamine/methanol solution (2 ml) was added to methyl (6-(4-(ethylsulfonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazol-5-yl)(hydroxy)acetate (14 mg) obtained in (step 2), and the reaction liquid was stirred at 50° C. for 3 hours. The solvent was evaporated away under reduced pressure, and to a tetrahydrofuran (2 ml) solution of the resulting residue, added were 1,1′-carbonyldiimidazole (2.5 mg) and triethylamine (0.01 ml), and the reaction liquid was stirred at 70° C. for 2 hours. then, potassium t-butoxide (3 mg) was added to it, and the reaction liquid was stirred at 70° C. for 5 minutes. The reaction mixture was purified through reversed-phase middle-pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water/acetonitrile/0.1% trifluoroacetic acid), and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline water in that order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([NH2:31])[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1C=CC=C[CH:10]=1.C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C=C>>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([NH2:31])[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:24])([CH3:25])[CH3:26])=[O:20])[CH:9]=[CH2:10]
Reactant: CNC(=O)[C@@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(C)(C)C
Agent: C=CCOC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)C[C@@H](N)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Reaction time: 2 h
Yield: 87 %

Procedure:
As described in Example 1(b) for the preparation of 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester trifluoroacetate salt, crude 3(R)-(t-butoxycarbonylamino)-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester was deprotected after 2 hours. Flash column chromatography with 0.5% TFA/7% MeOH/CHCl3 gave 2.46 g (87%) of 3(R)-arnino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester trifluoroacetate salt as a colorless foam. 1H NMR(CD3OD): δ 5.96(ddt, 1H, J=5.6, 10.6, 17.1 Hz), 5.35 (ddd, 1H, J=1.6,3.1, 17.1 Hz), 5.25 (ddd, 1H, J=1.2, 2.5, 10.3 Hz), 4.66 (ddd, 2H, J=1.2, 1.3, 5.9 Hz), 4.34 (dd, 1H J=5.6, 7.8 Hz), 4.21 (s, 1H), 3.03 (dd, 1H, J=5.6, 17.4 Hz), 2.94 (dd, 1H, J=7.5, 17.4 Hz), 2.71 (d, 3H, J=5.0 Hz), 1.46 (s, 9H), 0.99 (s, 9H). IR (KBr): 3413, 2966, 1672, 1656, 1207, 1143 cm-1. HRFABMS: Calculated for C14H25N3O4Na (M+Na+): 322.1743. Found: 322.1747. Anal. Calculated for C14H25N3O4.2.5 F3COOH.0.5 CHCl3 : C, 36.36; H, 4.38; N, 6.52. Found: C, 36.34; H, 4.25; N, 6.51.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(O[CH2:21][CH:22]1[CH:26]([CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][O:24][CH2:23]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>COCCOCCOCCOC>[CH2:1]([N:9]1[CH2:21][CH:22]2[CH2:23][O:24][CH2:25][CH:26]2[CH2:27]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2COCC2COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOCCOC
Product: c1ccc(CCN2CC3COCC3C2)cc1

Procedure:
Phenethylamine (0.15 mole, 18.2 grams) was reacted with a mixture of the cis and trans isomers of 3,4-bis(tosyloxymethyl)tetrahydrofuran, represented by formulas (XIX), (0.05 mole, 22.0 grams) in 60 ml triethylene glycol dimethyl ether at 185°C. for 3 hours. The reaction mixture was cooled to room temperature and neutralized with 75 ml methanolic sodium hydroxide solution (0.10 mole, 4.0 grams). After the reaction mixture was concentrated under aspirator pressure, 150 ml diethyl ether was added and sodium tosylate (18.5 grams) was filtered. Vacuum distillation of the filtrate gave 5-phenethyl-hexahydro-1H-furo(3,4-c)pyrrole (6.9 grams, b.p. 111° to 112°C./0.12 mm Hg). 5-Phenethyl-hexahydro-1H-furo(3,4-c)pyrrole was dissolved in 700 ml anhydrous diethyl ether and anhydrous hydrogen chloride was bubbled through the solution. The resulting 5-phenethyl-hexahydro-1H-furo(3,4-c)pyrrole hydrochloride was filtered, washed with ether, and dried. The product obtained had a melting point of 176° to 177°C.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:6][N:7]([CH3:29])[CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[N:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:9]1>>[CH3:6][N:7]([CH3:29])[CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH:3]([CH3:5])[CH3:4])=[N:23][CH:22]=3)=[CH:17][CH:18]=2)[CH2:9]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(O)nc3)cc2)C1
Reactant: CC(C)CBr
Product: CC(C)COc1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)cc2)cn1

Procedure:
1-Bromo-2-methylpropane was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide by method H-a. This resulted in the product with the molecular weight of 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: C(O[C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)C.[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.OS(O)(=O)=O>C1COCC1>[CH2:10]([C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC1=CC(=O)CC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1C=C(Cc2ccccc2)CC1
Reaction time: 6 h
Yield: 35 %

Procedure:
A solution of 3-ethoxy-2-cyclopenten-1-one (5 g, 0.89 mol) in THF (70 mL) was added at room temperature to a solution of 2M benzyl magnesium chloride (800 mL) under N2 and stirred for 6 h. The resulting mixture was poured into a solution of 30% H2SO4 and stirred for 5 h. The resulting organic layer was separated, and the aqueous layer was extracted with several portions of ether. The combined organic layer was dried (MgSO4), and concentrated in vacuo to give the title compound (3.1 g, 35%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:12][N:13]([CH3:31])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[CH3:21])=[CH:16][CH:15]=1>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]([C:17]2[CH:16]=[CH:15][C:14]([N:13]([CH3:31])[CH3:12])=[CH:19][CH:18]=2)=[CH:21][CH:20]([CH:21]=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([N:13]([CH3:12])[CH3:31])=[CH:19][CH:18]=2)[C:22]2[CH:23]=[CH:24][C:25]([N:28]([CH3:29])[CH3:30])=[CH:26][CH:27]=2)[C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:29])[CH3:30])=[CH:24][CH:23]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Solvent: CCO
Product: CN(C)c1ccc(C(=CC(C=C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
Proceeding in a manner similar to that described in Example 1 above, a mixture 1.5 g of 4-dimethylaminobenzaldehyde, 5.4 g of 1,1-bis(4-dimethylaminophenyl)ethane, 100.0 ml of ethyl alcohol and 2.0 ml of glacial aacetic acid was maintained at reflux approximately forty-two hours. After cooling to ambient temperature, the reaction mixture was poured into one liter of ice water, and the resulting solid was collected by filtration and recrystallized from isopropyl alcohol to obtain 2.5 g of bis{[1,1-bis(4-dimethylaminophenyl)ethenyl]}(4-dimethylaminophenyl)methane, a white solid which melted at 215°-220° C. Significant infrared maxima appeared at 1620 cm-1 (v.s.) and 1355 cm-1. The nuclear magnetic resonance spectrum was in accord with the assigned structure. An acetone solution of the product spotted onto clay, phenolic resin and organic acid coated papers slowly developed blue-colored images. Exposure of a paper coated with the product to bromine vapor developed a dark blue image. An acetone solution of the product, chloranil and a phenolic resin was coated onto a glass plate and dried. The transmission spectrum of the coating had a significant adsorption at 715 nonometers.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([Cl:20])[C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:8]2=[O:17])=[C:4]([Cl:21])[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:19]=[C:18]([Cl:20])[C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]1=[O:17]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1N(Cc2c(Cl)cc(Br)cc2Cl)CCC12CCCCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1N(Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCC12CCCCC2
Temperature: 90 °C
Yield: 102.7 %

Procedure:
Purged with N2 a mixture of 2-(4-bromo-2,6-dichloro-benzyl)-2-aza-spiro[4.5]decan-1-one (0.091 g, 0.23 mmol) and 4-fluorophenylboronic acid (0.097 g, 0.69 mmol) in toluene (6 mL) and 2M sodium carbonate (0.8 mL). Treat the reaction with Pd(PPh3)4 (0.013 g, 0.011 mmol) and heat to 90° C. for 2 hours under N2. Cool the reaction and dilute with ethyl acetate, and then wash with 1N HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 0.096 g (100%) of the titled product. Rf=0.25 (3/1 hexanes/ethyl acetate). MS (m/z): 406 (M+).
Reaction SMILES: [CH2:1]([C:4]1[Se:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].[Li]CCCC.[Br:14]Br.S([O-])(O)=O.[Na+]>C(OCC)C>[Br:14][C:6]1[Se:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:8][CH:7]=1
Reactant: CCCc1ccc[se]1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CCCc1ccc(Br)[se]1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
24.3 g (about 0.97 mol) of crude 2-propylselenophene are initially introduced in 100 ml of diethyl ether, and 64.5 ml (0.10 mol, 15% soln. in hexane) of n-BuLi are rapidly metered. The mixture is heated under reflux for 1 h and subsequently cooled to −70° C. 16.5 g (0.10 mol) of bromine are added, and the batch is stirred for 1 h at 0° C. and for 3 h at RT. The mixture is added to semi-conc. sodium hydrogensulfite soln., and the organic phase is separated off. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:14](C)[C:13](=O)[C:12]([CH:28]([OH:30])[CH3:29])=[C:11]3[NH:31]C(=O)C)=[CH:4][CH:3]=1.[CH3:35]S(Cl)(=O)=O.C(N(CC)CC)C.[CH3:47][OH:48]>C1COCC1.CCOC(C)=O>[NH2:31][C:11]1[C:10]2[C:15](=[N:16][C:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)[N:14]([CH3:13])[C:47](=[O:48])[C:12]=1[CH:28]([O:30][CH3:35])[CH3:29]
Reactant: CC(=O)Nc1c(C(C)O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reactant: CO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(C)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reaction time: 4.5 h

Procedure:
The product of Example 3 (50 mg) in THF (1 mL) was combined with methansulfonyl chloride (15 μL) and triethylamine (27 μL) at 0° C. The reaction stirred 15 minutes at which point methanol (2 mL) was added. The reaction stirred 4.5 hours before it was diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluted with 0-20% EtOAc in hexane afforded the title compound. HPLC/MS: 488.0 (M+1), 490.0 (M+3); Rt=4.45 min.
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]2[C:21]=1[C:20](=[O:22])[CH2:19][CH2:18]2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:23][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[C:21]2[C:17]=1[CH2:18][CH2:19][C:20]2=[O:22])([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COc1ccc(O)c2c1C(=O)CC2
Reactant: CCCSP(=O)(Cl)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCSP(=O)(OCC)Oc1ccc(OC)c2c1CCC2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Ethyl S-propyl chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 7-methoxy-4-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product, O-ethyl S-propyl O-(7-methoxyindan-1-on-4-yl) thiophosphate.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:6]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:1]1([NH:4][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:7]3[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=3)[CH2:12][CH2:13]2)[CH2:3][CH2:2]1
Reactant: O=C1CCC(c2cccnc2)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1cncc([C@H]2CC[C@H](NC3CC3)CC2)c1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
Cyclopropyl amine (11.4 mL, 165 mmol) was added to a solution of 4-(3-pyridyl)cyclohexanone (19.2 g, 110 mmol) in DCE (360 mL) and acetic acid (12.6 mL, 220 mmol). The reaction mixture was cooled to 0° C. and NaBH(OAc)3 (46 g, 220 mmol) was added protionwise. After being stirred for 21 h at 23° C., the reaction was re-cooled to 0° C. and quenched with 1 M NaOH (200 mL). The aqueous layer was extracted with CH2Cl2 (2×200 mL) and the combined organic layers were washed with brine (300 mL), dried with MgSO4, filtered, and concentrated in vacuo. The crude mixture of cis and trans amines was purified by flash column chromatography (gradient elution, 40% EtOAc/hexanes (2.5% TEA)→70% EtOAc/hexanes (2.5% TEA)) to provide trans-N-cyclopropyl-4-(pyridine-3-yl)cyclohexylamine.
Reaction SMILES: [C:1]([N:5]1[CH:17]=[C:16]2[C:7]([C:8](=[O:18])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C)[CH2:21][CH2:22]N(C)C.C([Li])CCC.C(I)C>C(OCC)(=O)C.C1COCC1>[C:1]([N:5]1[C:17]([CH2:21][CH3:22])=[C:16]2[C:7]([C:8](=[O:18])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)n1cc2c(n1)c(=O)[nH]c1ccccc12
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1c2c(nn1C(C)(C)C)c(=O)[nH]c1ccccc12
Temperature: 0 °C
Yield: 91.3 %

Procedure:
To a round-bottomed flask containing 2-tert-butyl-2,5-dihydropyrazolo[3,4-c]quinolin-4-one (20.0 g, 82.99 mmol) was added THF (500 mL) followed by N,N,N′,N′-tetramethylethylenediamine (48.13 g, 414.94 mmol). The reaction was stirred under a nitrogen atmosphere in an ice bath. To this suspension n-butyl lithium (2.5 M in hexanes, 130.0 mL, 324.91 mmol) was added dropwise. The reaction mixture was stirred in the ice bath for 2 minutes and then ethyl iodide (258.38 g, 1.66 mol) was added to the reaction. The reaction was stirred in the ice bath for 10 minutes and then the ice bath was removed. The reaction was stirred at ambient temperature overnight. Methanol (60 mL) was carefully added to quench the reaction and the solvent was evaporated to afford a dark oil. The oil was taken up in ethyl acetate (800 mL) and the organic layer was washed with water (3×600 mL). The organic layer was separated, dried (MgSO4), filtered, and evaporated to afford 2-tert-butyl-1-ethyl-2,5-dihydro-pyrazolo[3,4-c]quinolin-4-one (20.4 g) as a brown solid. A portion of this solid (15.2 g) was transferred to a round-bottomed flask and concentrated hydrochloric acid (410 mL) was added. The reaction was heated to 120° C. for 1 hour and then stirred at ambient temperature overnight. The solids in the reaction mixture were separated by filtration and washed with water. The solids were transferred to a round-bottomed flask and stirred in diethyl ether (100 mL) for 15 minutes. The product was isolated by filtration to afford 1-ethyl-2,5-dihydro-pyrazolo[3,4-c]quinolin-4-one as the hydrochloride salt. The product was stirred in 2N sodium hydroxide (60 mL) for 1.5 hours, filtered, washed with diethyl ether (600 mL), and dried under reduced pressure to afford 1-ethyl-2,5-dihydro-pyrazolo[3,4-c]quinolin-4-one as a tan brown solid (4.23 g).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH2:21][OH:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])(C)(C)C.N1C=CC=CC=1.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>ClC(Cl)C.ClCCl>[O:7]=[C:6]1[NH:8][C@@H:9]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:21][O:22]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(C[C@H]1COC(=O)N1)OCc1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of the alcohol (95.7 g) from Step 1 in dichloroethane (925 mL) was added pyridine (625 mL) and the mixture was cooled to 0-5° C. Anhydrous p-toluenesulfonic anhydride (105.7 g) was added and the mixture was warmed to room temperature and stirred for 1 hour and then heated to 90° C. for 2 hours. The mixture was cooled, diluted with dichloromethane (1000 mL) and washed with 1N HCl (3×600 mL). The organic layer was washed with brine, dried with sodium sulfate and the solvents were removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes in a 1:1 ratio followed by ethyl acetate to yield benzyl [(4S)-2-oxo-1,3-oxazolidin-4-yl]acetate.