Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4](O)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:27](C(OC(C)(C)C)=O)=[N:28]C(OC(C)(C)C)=O.[ClH:43]>O1CCCC1.O>[ClH:43].[ClH:43].[NH:27]([C@H:4]1[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]1)[NH2:28]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CN1CC[C@@H](O)C1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CN1CC[C@H](NN)C1
Reaction time: 1 h

Procedure:
To a mixture of (3R)-1-methylpyrrolidin-3-ol and 35 mL of tetrahydrofuran was added 18.2 g of triphenylphosphine, and a solution of 13.2 g of di-tert-butyl azodicarboxylate in 10 mL of a tetrahydrofuran was added dropwise thereto under ice-cooling, followed by stirring for 1 hour, and further stirring at room temperature for 1 hour. To the reaction mixture was added 40 mL of a 6 M hydrochloric acid, followed by stirring at room temperature overnight. To the reaction mixture was added 40 mL of water, tetrahydrofuran was evaporated under reduced pressure, and then 20 mL of dichloromethane was added thereto and the organic layer was separated. The obtained aqueous layer was washed with 20 mL of dichloromethane twice, and the aqueous layer was evaporated under reduced pressure, and then coevaporated with isopropanol. After forming a precipitate, the obtained solid was collected by filtration and dried under reduced pressure to obtain 7.92 g of (3S)-3-hydrazino-1-methylpyrrolidine dihydrochloride.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15].C(N(CC)CC)C>ClCCl>[S:2]([O:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)CCCCC=CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CCCCC=CCOS(C)(=O)=O
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
Methane sulphonylchloride (8.07 g; 1.1 eq) was added dropwise over 30 minutes to a stirred solution of 9-hydroxy-non-7-en-2-one (10 g) in dry dichloromethane (60 ml) containing an excess of triethylamine (9.71 g; 1.5 eq), at -10° C. The solution was stirred for a further 20 minutes. The reaction mixture was washed with cold water, cold 5 N hydrochloric acid, cold 5% sodium bicarbonate solution and cold brine then was dried and evaporated in vacuo at <30° to give 9-mesyloxy-non-7-en-2-one (12.7 g) as a deep red oil.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (560 mg, 88%).
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[C:10]([NH2:24])[O:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]N.CO>O>[C:2]1([CH:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)=[C:10]([NH:24][CH3:25])[O:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Reaction time: 48 h
Yield: 93 %

Procedure:
In this example, 2.5 ml of aqueous 2N hydrochloric acid was added at room temperature to a stirred slurry containing 10 g of 2-phenyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran in 60 ml of aqueous 40 wt % methyl amine followed by the addition of 50 ml of methanol. The resulting suspension was heated to reflux and refluxed for about 24 hours and then allowed to cool and stand at room temperature for about 2 days. The mixture was then added to a dilute acid solution containing 58 ml of aqueous 12N hydrochloric acid in 300 ml of water and then extracted twice with methylene chloride. The methylene chloride extracts were combined and successively washed once with water, once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The washed solution was dried over magnesium sulfate and evaporated under vacuum affording 9.7 g of the title compound as a pale yellow foam (yield=93%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.[Li]C(CC)C.C1CCCCC1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[C@@H:30]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[C:32](=[O:38])[CH2:31]1)[C:25]#[N:26]>C1COCC1>[CH3:9][C:4]1[CH:3]=[C:2]([C@:32]2([OH:38])[C:33]3[N:34]([CH:35]=[N:36][CH:37]=3)[C@@H:30]([C:29]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[F:21])[CH2:31]2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Cc1ccc(Br)cc1C
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc([C@@]2(O)C[C@H](c3ccc(C#N)cc3F)n3cncc32)cc1C
Temperature: -40 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
To a solution of 4-bromo-1,2-dimethylbenzene (77 mg, 0.42 mmol) in THF (1 mL) at −78° C. was added a solution of 1.4 M s-BuLi in cyclohexane (0.33 ml, 0.46 mmol). The crude was warmed to −40° C. and stirred between −40° C. and −30° C. for 1 hr. The crude was cooled to −60° C. A solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (50 mg, 0.21 mmol) in THF (1 mL) was added. The crude was stirred at −60° C. for 1 hr. The crude was warmed to room temperature in 4 hrs. The crude was quenched with NH4Cl and diluted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was purified via preparation plate using 7% (2M NH3 in MeOH)/CH2Cl2 to give 7.8 mg of the entitled product as the major diastereomer. MS 348.1 (M+H); LCMS condition A, retention time 1.31 min. 1H NMR (400 MHz, CDCl3) δ ppm 2.20 (s, 3H), 2.20 (s, 3H), 2.91 (dd, 1H), 3.29 (dd, 1H), 5.71 (d, 1H), 6.87 (s, 1H), 7.07 (d, 1H), 7.10-7.20 (m, 2H), 7.21 (s, 1H), 7.34 (d, 1H), 7.36 (s, 1H), 7.39-7.43 (m, 1H).
Reaction SMILES: [Br:1]Br.[CH:3]1([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C:17]([O:19]CC)=[O:18])[CH:8]=2)[CH2:6][CH2:5][CH2:4]1.O.[OH-].[Li+].Cl>C(O)(=O)C.O>[Br:1][C:3]1([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C:17]([OH:19])=[O:18])[CH:8]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: BrBr
Reactant: CCOC(=O)c1cc(C2CCC2)nc(C(F)(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(C2(Br)CCC2)nc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
Bromine (0.13 mL, 2.6 mmol) was added to a solution of ethyl 6-cyclobutyl-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.65 g, 2.4 mmol, from Step B) in acetic acid (2.0 mL) and the reaction was heated to 80° C. for one hour. The mixture was concentrated and the resulting oil was dissolved in THF (8.0 mL) and cooled to 0° C. A solution of lithium hydroxide, monohydrate (0.20 g, 4.7 mmol) in water (2.0 mL) was added. After stirring for 20 minutes, 1N HCl was added to achieve pH 4. Additional water was introduced and the product was extracted with six portions of 10% isopropanol in chloroform. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford product which was used without further purification (0.64 g, 80%). H NMR (400 MHz, dmso) δ 8.27 (s, 1H), 3.17-2.97 (m, 2H), 2.92-2.71 (m, 2H), 2.34 (dtt, J=10.9, 9.1, 6.9 Hz, 1H), 1.84 (dtt, J=11.0, 8.6, 5.6 Hz, 1H); LCMS (M+H)+: 324.9, 326.7.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:11][CH2:10]2>C(Cl)Cl>[Cl:3][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:11][CH2:10]2
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(CO)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCc2cc(CCl)ccc21
Reaction time: 1 h
Yield: 51.1 %

Procedure:
Thionyl chloride (0.355 mL, 4.90 mmol) was added to a solution of N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (660 mg, 2.450 mmol) in DCM (10 mL). The whole was stirred for 1 h before the reaction mixture was evaporated to dryness and the crude material was purified by silica flash column chromatography (EtOAc/heptane: from 0% to 60% of EtOAc) to afford the title compound as a white solid (360 mg, 51%). MS (ESI): m/z [M−H]− 286.0
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CS(=O)(=O)CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCCS(C)(=O)=O)cc1)n2C)c1ccccc1
Yield: 66 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and 2-(methylsulfonyl)ethyl chloroformate. Yield: 66% of theory, C32H36N6O7S (648.8); Rf value: 0.44 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=649; (M+H+Na)++=336(M+2H)++=325.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:15]([NH2:16])=[C:14]([NH2:17])[C:12](=[O:13])[N:11]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NC1N(CC2CCCCC2)C(=O)N(CC2CCCCC2)C(=O)C=1N=O.O.[CH:51]([C:53]1[CH:63]=[CH:62][C:56]([CH:57]=[CH:58][C:59]([OH:61])=[O:60])=[CH:55][CH:54]=1)=O>CO.[Pd]>[CH:19]1([CH2:18][N:11]2[C:12](=[O:13])[C:14]3[N:17]=[C:51]([C:53]4[CH:63]=[CH:62][C:56](/[CH:57]=[CH:58]/[C:59]([OH:61])=[O:60])=[CH:55][CH:54]=4)[NH:16][C:15]=3[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]2=[O:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Agent: [Pd]
Agent: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Yield: 91 %

Procedure:
The title compound was prepared from 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil by the method of J. Perutmattam, Syn. Commun. 1989, 19:3367-3370. 1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was freshly prepared by shaking a mixture of 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (from step (c), 5.00 g) in methanol (250 ml)-water (25 ml) with 10% palladium on carbon (0.50 g) under hydrogen (50 psi) on a Parr shaker for 2 h. The catalyst was filtered off (Celite) and the colorless filtrate was concentrated to 25 ml. 4-Formylcinnamic acid (Aldrich, 2.53 g, 14.35 mmol) was added to this solution of 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil and the resulting yellow mixture was concentrated and the residual yellow solid dried by evaporation of several portions of absolute ethanol. The resulting yellow powder (Schiff base intermediate) was stirred in dimethoxyethane (115 ml) with iodine (4.0 g) at 60° C. (oil bath) for 20 h. A saturated aqueous solution of sodium thiosulfate was added to the warm reaction mixture until complete decolorization of iodine resulted. The pale yellow precipitate was filtered off, washed with water, and dried at 0.5 Torr to give (E)-4-[1,3 bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid as a pale yellow powder (6.73 g, 91%), m.p. >300° C. Such samples were further purified by dissolving them in 1N aqueous sodium hydroxide, filtering the resulting hazy solution through Celite, and acidifying the clear filtrate with hydrochloric acid. The resulting precipitate was filtered and washed with water to give title compound as a pale yellow powder, m.p. >300° C.; 1H-NMR (DMSO-d6) δ: 13.80 and 12.40 (both br m, 1 each, CO2H and NH), 8.12 (d, J=8.3 Hz, 2, 2 phenyl CH), 7.84 (d, J=8.4 Hz, 2, 2 phenyl CH), 7.64 (d, J=16.0 Hz, 1, CH═), 6.64 (d, J=16.0 Hz, 1, CH═), 3.93 (d, J=7.0 Hz, 2, CH2N), 3.79 (d, J=6.8 Hz, 2, CH2N), 2.0-1.4 and 1.3-0.85 (both br m, 22 total, 2 cyclohexyl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]=[CH:35][CH2:36][NH2:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:15])[NH:37][CH2:36][CH:35]=[CH:34][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Reactant: COc1ccccc1C=CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccccc1C=CCNC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
150 mg (0.416 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 81.4 mg (0.499 mmol) of 3-(2-methoxyphenyl)-allylamine were dissolved in 10 ml of dichloromethane. 120 mg (0.624 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 63.7 mg (0.416 mmol) of 1-hydroxybenzotriazole were added to the obtained solution under cooling with ice, and they were stirred at room temperature for 2 hours. Dichloromethane was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the product was washed with 1 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1) to obtain the title compound.
Reaction SMILES: C(#N)C.[I-].[Na+].C[Si](Cl)(C)C.[O:11]1CCO[CH:12]1[C:16]1[CH:17]=[C:18]([CH:22]([C:24]2[S:25][C:26]([CH3:29])=[CH:27][CH:28]=2)O)[CH:19]=[CH:20][CH:21]=1>O>[CH3:29][C:26]1[S:25][C:24]([CH2:22][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[CH:12]=[O:11])=[CH:28][CH:27]=1
Reactant: Cc1ccc(C(O)c2cccc(C3OCCO3)c2)s1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(Cc2cccc(C=O)c2)s1
Temperature: -20 °C
Yield: 41.8 %

Procedure:
To a solution of acetonitrile (20 mL) and sodium iodide (2.9 g) was added trimethylsilyl chloride (2.1 g) at room temperature under stirring. The reaction solution thus obtained was cooled to −20° C., and (3-[1,3]dioxolan-2-yl-phenyl)-(5-methyl-thiophen-2-yl)-methanol (1.1 g) described in Manufacturing Example 52-1 and acetonitrile (5 mL) were added thereto under stirring. The reaction solution was returned to room temperature and stirred for 10 minutes. Water was added to the reaction solution, which was then extracted with ethyl acetate. The solvent was evaporated from the organic layer under a reduced pressure, and the residue was purified by silica gel chromatography (heptane:ethyl acetate=2:1) to obtain the titled compound (360 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)=[CH2:2].[Li]CCCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:22](=[O:24])[CH3:23])=[N:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)=[CH2:2]
Reactant: CON(C)C(C)=O
Reactant: C=Cc1ccc(-n2cncn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(-n2ncnc2C(C)=O)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]-triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min. To this N-methoxy-N-methyl acetamide in THF (0.66 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×50 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (280 mg, 23%): mp 97-98° C.; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.50 (d, 2H), 7.38 (d, 2H), 6.68 (dd, 1H), 5.85 (d, 1H), 5.38 (d, 1H), 2.75 (s, 3H); ESIMS m/z 214.14 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([CH2:34][CH:35]=[CH2:36])[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH2:38].C[N+]1([O-])CCOCC1.[OH2:47]>CC(C)=O.C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([CH2:34][CH:35]([OH:47])[CH2:36][OH:38])[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: C=CCC1(NC(=O)OC(C)(C)C)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1(CC(O)CO)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Temperature: 25 °C

Procedure:
A solution of 100 mg (0.19 mmol) of [1-allyl-4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (52) in a mixture of 250 μL of water and 500 μL of acetone was treated with 36.2 mg (0.27 mmol) N-methylmorpholine oxide monohydrate and 24.0 μL (1.91 μmol) of a 2.5% solution of osmium tetroxide in tert-butanol. The mixture was stirred at room temperature until complete conversion was indicated by LCMS. The reaction was then quenched by addition of saturated aqueous sodium bisulfite, extracted with ethyl acetate, dried over magnesium sulfate and concentrated. 68 mg of crude [4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(2,3-dihydroxy-propyl)-cyclohexyl]-carbamic acid tert-butyl ester (56) could be isolated as mixture of stereoisomers. Rt=1.92 min (Method C). Detected mass: 557.3 (M+H+).
Reaction SMILES: C[Zn]C.I[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:14]([O-:16])=[O:15])[NH:7][N:6]=1.[CH3:17]O.Cl>O1CCOCC1.C(Cl)Cl>[CH3:17][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:14]([O-:16])=[O:15])[NH:7][N:6]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: CO
Agent: C[Zn]C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1n[nH]c2cccc([N+](=O)[O-])c12
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A solution of dimethyl zinc (1.73 ml, 3.46 mmol) was added dropwise to a mixture of 3-iodo-4-nitro-1H-indazole (0.500 g, 1.73 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (0.427 g, 0.519 mmol) in dioxane (0.2M, 9 mL) under argon. The mixture was heated under reflux for 2 hours. After cooling, MeOH (<1 mL) was added, followed by 2N HCl (1 mL) and DCM (5 mL). After stirring mixture for 30 minutes, the organic layer was separated, washed with saturated aqueous sodium bicarbonate, water, and brine. The combined organic extracts were dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (1-10% EtOAc in DCM to provide 3-methyl-4-nitro-1H-indazole (0.082 g, 27% yield) as a brown residue.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1)(=O)=O.O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:36][CH:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:39][CH2:38]4)[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 1.20 g; 3.52 mmol) and Cs2CO3 (2.26 g; 6.94 mmol) in DMF (20 mL) was added tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate (1.32 g; 4.50 mmol) under nitrogen. The reaction mixture was stirred at 90° C. for 2 hours, cooled to r.t., added to water (200 mL) with vigorous stirring. The resulting solid was collected by vacuum filtration to afford 1.60 g (84%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])[CH2:4]1)[CH3:2].[CH3:29][C@H](OC1N=C2C(N=C(OC)N2CCC2CCCNC2)=C(N)N=1)CCC.IC(C)C>>[CH3:28][C@H:24]([O:23][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[C:19]([O:20][CH3:21])[N:11]2[CH2:10][CH2:9][CH:5]2[CH2:6][CH2:7][CH2:8][N:3]([CH:1]([CH3:29])[CH3:2])[CH2:4]2)=[C:16]([NH2:22])[N:15]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Solvent: CC(C)I
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(C(C)C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and 2-iodopropane.