Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])C(OCC)=O)C.[OH-].[Na+].C(=O)=O>C(O)C>[CH3:1][O:3][C:4](=[O:17])[CH2:5][CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14]
Reactant: CCOC(=O)C(CC(OC)OC)C(=O)OCC
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)CCC(OC)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 0.5 moles of diethylmalonate in 0.5 liters of dry benzene is added 0.5 moles of sodium hydride cautiously and the mixture stirred until hydrogen evolution ceases. Then 0.5 moles of bromoacetaldehydedimethylacetal [(CH3O)2 --CH--CH2 --Br] in 100 ml. of benzene is added and the mixture stirred overnight followed by refluxing for 2 hours. The reaction mixture is cooled, washed with water and purified by vacuum distillation to give β,β-dimethoxyethylmalonic acid diethyl ester. A mixture of 5 g. of this ester in 100 ml. of ethanol containing 5 g. of sodium hydroxide is heated under reflux until evolution of carbon dioxide ceases. The reaction mixture is then saturated with carbon dioxide and evaporated to dryness under vacuum. The residue is suspended in 50 ml. of dry dimethylformamide to which is added a large excess of methyl iodide. The reaction mixture is stirred at room temperature for about 24 hours and then poured into water. The resulting mixture is extracted with ether and the ether extracts combined, washed with water and evaporated to give 4,4-dimethoxybutyric acid methyl ester which is purified by distillation. A mixture of 4 g. of this methyl ester, 50 ml. of dry tetrahydrofuran and 1.1 equivalents of lithium aluminum hydride is refluxed overnight. The reaction mixture is allowed to cool and then filtered with water. This mixture is extracted with ether and the ether extracts are combined, washed, dried and evaporated to dryness to afford 4,4-dimethoxybutanol [(CH3O)2 --CH--CH2 --CH2 --CH2 --OH].
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=1)(=[O:3])[CH3:2]>CCO.O=[Pt]=O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCOCCC#Cc1cccc([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(=O)OCCCCCCOCCCCc1cccc(N)c1
Yield: 103.7 %

Procedure:
6-{[4-(3-Nitrophenyl)but-3-ynyl]oxy}hexyl acetate (2.973 g) was hydrogenated over PtO2 (300 mg) in EtOH over 1 h. The catalyst was removed by filtration and washed with EtOH. The combined filtrate and washings were concentrated under reduced pressure to give the title compound (2.844 g) LCMS RT=3.30 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([NH:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(NS(C)(=O)=O)CC1
Reaction time: 0.67 h

Procedure:
To a stirred solution of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (Altech, 1.24 g, 5.79 mmol) in methylene chloride (50 mL) at 0° C., triethylamine (202 mg, 6.95 mmol) and methansulfonylchloride (Aldrich, 796 mg, 6.95 mmol) were added successively and the mixture was stirred for 40 minutes. The solvent was removed and the residue was washed with water to give a white solid, which was directly used for the next step.
Reaction SMILES: [F-].[K+].[C:3]([O:7][C:8](=[O:26])[CH2:9][C@H:10]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:11](=[O:14])[CH2:12]Br)([CH3:6])([CH3:5])[CH3:4].[F:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([F:35])=[C:30]([F:36])[C:29]=1[OH:37]>CN(C=O)C>[C:3]([O:7][C:8](=[O:26])[CH2:9][C@H:10]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:11](=[O:14])[CH2:12][O:37][C:29]1[C:30]([F:36])=[C:31]([F:35])[CH:32]=[C:33]([F:34])[C:28]=1[F:27])([CH3:6])([CH3:5])[CH3:4]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)CBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)COc1c(F)c(F)cc(F)c1F
Reaction time: 18 h
Yield: 93.5 %

Procedure:
Potassium fluoride (2.8 g) was added portionwise to a stirred solution of (S)-3-benzyloxycarbonylamino-5-bromo-4-oxo-pentanoic acid tert-butyl ester (18.6 g) and 2,3,5,6-tetrafluorophenol (9.3 g) in anhydrous DMF (250 mL) under nitrogen at room temperature. The mixture was then stirred for 18 hours before being quenched with ethyl acetate and water. The organic layer was removed and washed with sodium bicarbonate solution, dried (magnesium sulfate) and concentrated to give the sub-title product as an off-white solid (21.1 g, 96%). 1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 2.76 (1H, dd), 3.06 (1H, dd), 4.67-4.71 (1H, m), 5.12 (1 h, d), 5.22 (1H, d), 5.86 (1H, d), 7.35-7.38 (5H, m) ppm; 19F NMR (376 MHz, CDCl3) (proton decoupled) δ −139.98, −140.00, −140.04, −140.06, −157.05, −157.07, −157.11, −157.13; MS ES (+) 486.23 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:29])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:24](=[CH2:28])[CH2:25][CH2:26][CH3:27])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:39]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:29])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[S:39])[NH:12][CH:11]3[C:24](=[CH2:28])[CH2:25][CH2:26][CH3:27])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(CCC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C=C(CCC)C1NC(=S)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 30, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (1.4 g, 3.1 mmol) prepared in example 89d was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (1.7 g, 4.25 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-butyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one as a off white solid (Yield 1.2 g, 84%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].[Li+].[Br-].[F:23][C:24]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:25]=1[CH2:26][Zn+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N1C=CN(C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C.O.C1COCC1.CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:26][C:25]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:24]=3[F:23])[CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Reactant: Fc1ccc(C[Zn+])c(F)c1
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3F)cc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a nitrogen-degassed mixture of 6-bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (4.90 g, 15.0 mmol), lithium bromide (3.87 g, 45.0 mmol), (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) dichloride (0.2 g, 0.3 mmol), 1-methyl-2-pyrrolidinone (40 mL) and THF (40 mL) was added a solution of 2,4-difluoro-benzylzinc bromide in THF (0.5 M, 60 mL, 30 mmol) and resulting mixture was stirred at 20° C. for 1 h. The mixture was poured into water (200 mL) and 5% aqueous citric acid (50 mL) and the resulting mixture extracted with Et2O (3×100 mL). The organic phase was washed with water (100 mL), brine (3×100 mL), dried (MgSO4) and evaporated in vacuo to give an oil. Chromatography (SiO2, eluted with petrol-EtOAc 0-30%) gave the title compound (5.7 g, 100%) as an oil. MS: [M+H]+=375.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[CH3:17][C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:19]1>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([N:20]1[CH2:21][CH2:22][N:23]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Br:1])[N:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)=[O:15])[C@@H:18]([CH3:17])[CH2:19]1)=[O:31]
Reactant: C[C@H]1CN(C(=O)c2ccccn2)CCN1
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Br)nccc12
Agent: [K+]
Product: C[C@H]1CN(C(=O)c2ccccn2)CCN1C(=O)C(=O)c1c[nH]c2c(Br)nccc12

Procedure:
Precursor 5n, (S)-1-picolinoyl-3-methyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (7-bromo-6-azaindol-3-yl)oxoacetate, Precursor 4g, and (S)-3-methyl-1-picolinoyl-piperazine. 1H NMR (500 MHz, CDCl3) δ8.63-7.36 (m, 7H), 5.02-3.06 (m, 7H), 1.42-1.26 (m, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH3:25])=[O:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:11][C:22](=[O:23])[O:24][CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: NCc1cccc(-c2ccccc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)NCc1cccc(-c2ccccc2)c1
Yield: 58.5 %

Procedure:
11.18 g of 3-phenylbenzylamine in toluene (250 ml) was mixed with 7.24 g of pyridine at room temperature. The resulting solution was stirred under cooling with ice while 9.58 g of methyl chloroformate was added dropwise and then stirred at room temperature for 2 hours. After the reaction, the reaction solution was poured into aqueous citric acid and extracted with ethyl acetate, and the organic layer was washed with aqueous citric acid, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 8.61 g of methyl N-(3-phenylbenzyl)carbamate as pale yellow crystals. m.p. 49-52° C.
Reaction SMILES: [C:1]12([C:8]3=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=[C:7]3[CH2:6][O:5][CH2:4]1)[CH2:3][CH2:2]2.CN(C)C=O.Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([O:13][C:9]2[C:8]3[C:1]4([CH2:4][O:5][CH2:6][C:7]=3[CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]4)=[N:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1cccc2c1C1(CC1)COC2
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc3c2C2(CC2)COC3)nc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 1H-spiro[2-benzopyran-4,1′-cyclopropan]-5-ol (Intermediate 136, 150 mg) in dry N,N-dimethylformamide (4 ml) potassium carbonate (176 mg, 1.277 mmol) and then 2-chloro-5-nitropyridine (148 mg, 0.936 mmol) were added and the reaction mixture was stirred for 1 h at 110° C. After cooling the reaction was quenched with brine (1 ml), diluted with water (5 ml) and extracted with ethyl acetate (3×15 ml). The organic layer was washed with ice cold brine (2×10 ml), dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane/ethyl acetate as eluents from 100:0 to 7:3. This afforded the title compound as a colourless gum (240 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[O:12][CH3:13]>CO.O.[Ni]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][C:5]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(C#N)cc1OC
Agent: [Ni]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CN)cc1OC
Reaction time: 16 h
Yield: 37.4 %

Procedure:
A mixture of 4-cyano-2-methoxy-benzoic acid methyl ester (1.01 g, 5.28 mmol) in methanol (50 mL) was added to Raney-nickel 2800 slurry in water (a few grams washed with methanol to remove the water, Aldrich) and it was put under a 50 psi hydrogen atmosphere for 16 hrs. The mixture was filtered through Celite under an argon atmosphere and concentrated and then purified by flash chromatography to give 4-aminomethyl-2-methoxy-benzoic acid methyl ester (385.7 mg, 34.7%).
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][C:11]1[CH:10]=[CH:9][C:8]2[N:14]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[S:1](=[O:3])(=[O:2])[O:6][C:7]=2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C)cc2O)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2c3ccc(C)cc3OS2(=O)=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., a solution of sulfuryl chloride (450 μl, 5.41 mmol) in CH2Cl2 (10 ml) is slowly added dropwise to a solution of N-(2-hydroxy-4-methylphenyl)-4-methylbenzenesulfonamide (1.5 g, 5.41 mmol) and triethylamine (1.5 ml), and the mixture is stirred at −78° C. for one hour. After thawing to RT, the solvent is distilled off under reduced pressure and the residue is purified by RP chromatography.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]2[CH2:21][CH2:22][CH2:23][C:15]=12.CCN(C(C)C)C(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:20][C:19]2[N:14]=[C:15]3[CH2:23][CH2:22][CH2:21][C:16]3=[CH:17][CH:18]=2)[CH:7]=1
Reactant: Nc1ccc2c(n1)CCC2
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc2c(n1)CCC2
Temperature: 80 °C
Yield: 25.6 %

Procedure:
A heavy walled resealable tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (1.5 g, 6.79 mmol), 6,7-dihydro-5H-cyclopenta[b]pyridin-2-amine (1.09 g, 8.14 mmol), acetonitrile (10 mL) and Hunig's base (877 mg, 1.19 mL, 6.79 mmol). The mixture was heated at 80° C. with stirring for 3d, after cooling to room temperature, the solvents were distilled off and the crude residue obtained was purified by chromatography (80 g column, 50 μM from Thomson, 0 to 10% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazine-3-carboxylate (554 mg, 26%) as a light brown solid. 1H NMR (CHLOROFORM-d) δ: 10.51 (s, 1H), 8.94 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 4.46 (q, J=7.2 Hz, 2H), 2.92 (t, J=7.7 Hz, 2H), 2.83 (t, J=7.4 Hz, 2H), 1.87-2.24 (m, 2H), 1.42 (t, J=7.2 Hz, 3H); LC-MS 319.0 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:30]=[CH:29][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH:20]4[CH:25]([C:26]([NH2:28])=[O:27])[NH:24][CH2:23][CH2:22][S:21]4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:8][CH:7]=2)=[CH:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:52]CC1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:30]=[CH:29][C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH:20]4[CH:25]([C:26]([NH:28][OH:52])=[O:27])[NH:24][CH2:23][CH2:22][S:21]4)(=[O:19])=[O:18])=[CH:15][CH:16]=3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: C1CCOC1
Reactant: NC(=O)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(NO)C1NCCSC1S(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a 25° C. solution of 3(S)-N-(tert-butyldiphenylsilyl)oxy-4-(4-(4-(furan-3-yl)phenoxy)benzenesulfonyl-tetrahydro-2H-1,4-thiazine-3-carboxamide (35 mg) in 2 mL of THF was added 0.060 mL of 2M tetrabutylammonium fluoride in THF. After 30 minutes, the solution was partitioned between 1 M pH 7 phosphate buffer and ethyl acetate. The aqueous layer was extracted once with ethyl aceate, and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was triturated with hexane and the resulting solid was collected by filtration to yield 3(S)-4-(4-(4-(furan-3-yl)phenoxy)benzenesulfonyl-N-hydroxy-tetrahydro-2H-1,4-thiazine-3-carboxamide (22 mg). 1H NMR (CDCl3): δ9.69 (bs, 1H), 7.24 (d, 2H, J=8.82 Hz), 7.51 (d, 2H, J=8.46 Hz), 7.05 (t, 4H, J=9.37 Hz), 6.69 (s, 1H), 4.57 (s, 1H), 4.02 (d, 1H, J=12.5 Hz), 3.28-3.12 (m, 2H), 2.50 (d, 1H, J=12.87 Hz), 1.61 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([CH2:4][N:5]([C:7](=[NH:9])[NH2:8])[CH3:6])[OH:3].[OH-].[Na+:11]>O>[CH3:6][N:5]([CH2:4][C:2]([O-:3])=[O:1])[C:7]([NH2:9])=[NH:8].[Na+:11]
Reactant: CN(CC(=O)O)C(=N)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(CC(=O)[O-])C(=N)N

Procedure:
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 6.56 g (50 mmol) of creatine is dissolved in 500 ml of water. To this is added 55 ml of 1M sodium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, sodium 2-(1-methylguanidino)acetate, shown below.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1cccc(Nc2ccc(C(C)=O)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with 4′-aminoacetophenone according to general procedure A provided methyl ester of 6 as a white solid (84% yield). 1H NMR (CDCl3, 500 MHz): δ=7.89 (d, J=8.7 Hz, 2H), 7.85 (s, 1H), 7.73 (m, 1H), 7.36-7.42 (m, 2H), 7.03 (d, J=8.5 Hz, 2H), 6.31 (s, 1H), 3.92 (s, 3H), 2.55 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=196.7, 167.0, 147.9, 141.3, 131.8, 130.9, 129.9, 129.8, 124.6, 124.2, 121.2, 115.1, 52.5, 26.4.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:9]([O:11][C:12]([C:14]1[C:18]([N:19]=O)=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:15]=1)=[O:13])[CH3:10].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C.O>[CH2:9]([O:11][C:12]([C:14]1[C:18]([NH2:19])=[C:17]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[N:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:15]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N

Procedure:
1-(2-Chlorophenyl)-5-(4-chlorophenyl)4-nitroso-1H-pyrazole-3-carboxylic acid ethyl ester obtained from the last step was dissolved in ethyl acetate (200 ml) and water (200 ml). Sodium dithionite was added until the disappearance of 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-nitroso-1H-pyrazole-3-carboxylic acid ethyl ester was confirmed by TLC (ethyl acetate/hexane, 50/50). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and the solvent was removed, in vacuo. The red solid obtained was further purified by plug filtration (silica, ethyl acetate/hexane, 50/50) to give 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-2A-1a (21.86 g, 76%). MS: 376.1 (M+1)+.
Reaction SMILES: NC(=O)C([C:5]1[C:9]2[C:10]([O:14][CH2:15]C(O)=O)=[N:11][CH:12]=[CH:13][C:8]=2[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:6]=1[CH3:26])=O.C(OC(=O)[C@H](CC(OCC1C=CC=CC=1)=O)N)C1C=CC=CC=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1.ClCCl>[CH2:19]([N:7]1[C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[C:9]=2[CH:5]=[C:6]1[CH3:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nccc2n1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1nccc2c1cc(C)n2Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-(3-(2-amino-2-oxoacetyl)-1-benzyl-2-methyl-1H-pyrrolo[3,2-c]pyridin-4-yloxy)acetic acid ILY-II-1 (1.5 mmol) in dichloromethane/dimethylformamide (5:1) is added aspartic acid dibenzyl ester (313 mg 1.5 mmol), 4-dimethylaminopyridine (18 mg 0.15 mmol), 1-hydroxybenzotriazole (202 mg, 1.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (286 mg, 1.5 mmol), respectively and reaction mixture allows to stir at room temperature. After 6 hrs the reaction is diluted with dichloromethane and washed twice with 1N HCl and brine. The organic layer is dried with Na2SO4 and evaporated in vacuum. The residue is chromatographed on silica gel to give the titled compound 2.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12](O)[CH3:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.P(Br)(Br)[Br:17]>CCOCC.N1C=CC=CC=1.CCCCCC>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([Br:17])[CH3:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC(O)c1ccc2c(c1)C(C)(C)CCO2
Reactant: BrP(Br)Br
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(Br)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
6.2 g of 4,4-dimethyl-6-(1-hydroxyethyl)chromane were dissolved in 3 ml of absolute ether and 20 ml of hexane and the solution was treated with 3 drops of pyridine. At a temperature of 0°-5° C. there was slowly added dropwise thereto a solution of 5.4 g of phosphorus tribromide in 20 ml of hexane. The mixture was stirred at 0° C. for a further 3 hours, poured onto ice and extracted with ether. The organic phase was washed with dilute sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. There were obtained 4.5 g of 4,4-dimethyl-6-(1-bromoethyl)chromane in the form of a reddish oil which was converted into the phosphonium bromide without further purification.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][C:25](=[O:29])[CH2:26][CH2:27]Br)[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:32]NC.O.C(OCC)(=O)C>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:32][CH2:27][CH2:26][C:25]5=[O:29])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(CCBr)NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1

Procedure:
A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-bromopropionylamino)methylindole (150 mg) obtained in Example 377, a 2 M solution (5.0 ml) of dimethylamine in tetrahydrofuran and toluene (5 ml) was heated at 80 to 90° C. for 1.5 days. Then water and ethyl acetate were added to the reaction mixtures. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by Chromatorex NH-silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (140 mg) as an oil. This oil was crystallized from ethyl acetate by using oxalic acid (28 mg) to give the oxalate (110 mg) of the title compound as a white powder (yield: 66%).