Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[O:9]=[C:10]1[NH:19][C@H:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:17]2[C:16](=[O:32])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1.CI.O>CN(C)C=O>[CH3:1][N:19]1[C@H:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:17]2[C:16](=[O:32])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:42])[F:40])[CH:34]=2)[C:10]1=[O:9]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)[C@H]1c1ccc(C#N)cc1S(C)(=O)=O
Reaction time: 1 h

Procedure:
Lithium diisopropylamide (1.8 M in tetrahydrofuran, 62 μL, 0.11 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18A, 50 mg, 0.10 mmol) in N,N-dimethylformamide (1 mL). Methyl iodide (8 μL, 0.13 mmol) is added and the mixture is stirred for 1 h. Water is added and the mixture is purified by reversed phase HPLC (Agilent ZORBAX™ SB-C18, gradient of acetonitrile in water, 0.15% formic acid). Yield: 20 mg; ESI mass spectrum [M+H]+=504; Retention time HPLC: 1.04 min (Z017_S04).
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)[C:20]=1[S:21][CH2:22][CH3:23])=[O:15])[CH2:10]2>CO>[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[C:20]=1[S:21][CH2:22][CH3:23])=[O:15])[CH2:10]2
Reactant: CCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 91.8 %

Procedure:
2M aqueous sodium hydroxide (2.446 mL, 4.89 mmol) was added in one portion to methyl 4-[4-(2-adamantylcarbamoyl)-5-ethylsulfanyl-pyrazol-1-yl]benzoate (Intermediate #99) (430 mg, 0.98 mmol) in methanol (20 mL). The resulting mixture was stirred at 20° C. for 18 hours. The reaction mixture was concentrated, diluted with water (50 mL) and adjusted to pH 3 with 2M HCl. The precipitate was collected by filtration, washed with water (20 mL) and dried under vacuum to afford 4-[4-(2-adamantylcarbamoyl)-5-ethylsulfanyl-pyrazol-1-yl]benzoic acid (383 mg, 92%) as a white solid.
Reaction SMILES: C([O:8][C:9](=[O:41])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:40])[C:18]([CH3:39])([CH3:38])[CH:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>CO.[OH-].[Pd+2].[OH-]>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:21]([NH:20][CH:19]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:18]([CH3:39])([CH3:38])[C:17]([N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][C:9]([OH:41])=[O:8])[CH2:16][CH2:15]2)=[O:40])=[O:31])=[CH:27][CH:26]=1)(=[NH:29])[NH2:30]
Reactant: [H][H]
Reactant: CC(C)(C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1)C(NC(=O)c1ccc(C(=N)N)cc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C(=O)N1CCC(CC(=O)O)CC1)C(NC(=O)c1ccc(C(=N)N)cc1)c1ccccc1
Yield: 89.7 %

Procedure:
N-4-Amidinobenzoyl-β-phenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid benzyl ester (63 mg, 0.114 mmol) was dissolved in an 80% aqueous methanol solution (10 ml) containing 2% acetic acid. To the reulting solution was added palladium hydroxide (50 mg) and the mixture was stirred in a hydrogen atmosphere for 15 minutes. The solvents were distilled off and the res idue was dissolved in a 1N aqueous solution of acetic acid. The resulting solution was purified with a high performance liquid chromatography (HPLC) under the same conditions as described in (3) to yield a powder of N-(N-4-amidinobenzoyl-β-phenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid (47.5 mg, 89.9%). The obtained product was identified by NMR, MS and HPLC analyses to be the same compound as prepared by the solid phase method.
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH2:7][CH2:8][CH3:9])[C:4]([OH:6])=[O:5])#[N:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](O)[CH3:23]>>[C:1]([C:3]([CH3:10])([CH2:7][CH2:8][CH3:9])[C:4]([O:6][CH2:22][CH3:23])=[O:5])#[N:2]
Reactant: CCCC(C)(C#N)C(=O)O
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCC(C)(C#N)C(=O)OCC
Yield: 90 %

Procedure:
0.30 g (2.1 mM) of (-)-2-cyano-2-methylpentanoic acid was dissolved in 3 ml of dry ethanol. To the mixture under stirring, 0.49 g (3.2 mM) of phosphorus oxychloride was added dropwise. After the reaction for 3 hours at 80° C., 6 ml of 1N-sodium carbonate aqueous solution was added, followed by extraction with diethyl ether. The resultant ether solution was dried on anhydrous sodium sulfate, followed by distilling-off of the solvent and distillation to obtain 0.32 g (1.9 mM) of (-)-ethyl 2-cyano-2-methylpentanoate. Yield:90%, b.p.:110° C./22 mmHg, [α]D -3.0 degrees, [α]435 -4.5 degrees, (c1, methanol)
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.ClS(O)(=O)=O.O.CCCCCCC>C(Cl)Cl>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)Cl
Solvent: O
Solvent: CCCCCCC
Solvent: ClCCl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.03 h

Procedure:
9α-Hydroxyandrostenedione (5.00 g.) is dissolved in methylene chloride (50 ml.) and cooled to 0°-5°. A solution of chlorosulfonic acid (2.5 ml.) in methylene chloride (10 ml.) is added slowly over a period of 4 minutes. At the end of the addition TLC shows the reaction is completed. Water (60 ml.) is added to the reaction mixture keeping the temperature at 3°-15°. The mixture is stirred for 2 minutes and heptane (135 ml.) is added. The organic phase is separated and washed twice with water (30 ml. each time). The organic phase is concentrated with heat to about 30 ml. with crystals forming as the solution cools. The mixture is cooled to 0°-5°, filtered, washed with a minimum amount of heptane, and dried at 70° to give androsta-4,9(11)-diene-3,17-dione; 4.45 g. (89.0% weight yield, 94.7% chemical yield), m.p. 195.5°-202°; [α]D +220° (chloroform); UV (methanol) λmax = 240 nm (ε = 16,300).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][N:15]=[C:14]3[NH:21][CH:22]=[C:23]([C:28]([O:30]C)=O)[C:24]([O:26][CH3:27])=[O:25])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C1(OC2C=CC=CC=2)C=CC=CC=1>[O:30]=[C:28]1[N:15]2[CH:16]=[N:17][C:18]3[CH:19]=[CH:20][C:11]([NH:10][C:8](=[O:9])[CH2:7][CH2:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:12][C:13]=3[C:14]2=[N:21][CH:22]=[C:23]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C(=CNc1ncnc2ccc(NC(=O)CCC3CCCC3)cc12)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cnc2c3cc(NC(=O)CCC4CCCC4)ccc3ncn2c1=O
Temperature: 255 °C
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
A mixture of dimethyl [[6-(3-cyclopentylpropionamido)-4-quinazolinylamino]methylene]propanedioate (6.9 g) in diphenyl ether (53 ml) was stirred at 255° C. for 15 minutes and cooled to ambient temperature. The resulting solid was collected, washed with hexane and dried. There was obtained methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (4.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH2:10])=[O:4].C(=O)([O-])O.[Na+].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][C:22](Cl)=[O:23].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:22](=[O:23])[CH2:21][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)Cc1cccs1
Yield: 80 %

Procedure:
To a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 10 ml of tetrahydrofuran and 5 ml of 1N-sodium hydrogen carbonate, which is previously stirred under ice-cooling, is added dropwise a solution of 0.32 ml of 2-thienyl acetyl chloride in 10 ml of tetrahydrofuran. To the mixture, after being stirred for 10 minutes, are added 100 ml of ethyl acetate and 20 ml of a saturated aqueous solution of sodium chloride, followed by stirring, and the organic layer is separated. The aqueous layer is subjected to extraction with 30 ml of ethyl acetate, and the extract is combined with the organic layer. The whole organic layer is washed with a saturated aqueous solution of sodium chloride (20 ml×3), dried and concentrated under reduced pressure. To the residue is added 4 ml of a mixed solution (ethyl acetate:hexane=1:2), and the resulting crystals are collected by filtration and dried to afford 430 mg (80%) of cis-3-(2-thienylacetamido)-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 133°-136° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:20][N:19]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:18]2[N:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)=[CH:22][N:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc(-c2cnc(Cl)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Temperature: 25 °C
Yield: 9 %

Procedure:
To a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 20.0 mmol, 1.3 equiv; commercially available) in dry DMF (100 mL) under Ar was added sodium hydride (1.01 g, 23.1 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h 2-chloro-5-(4-methoxy-phenyl)-pyrimidine (3.39 g, 15.4 mmol, 1.0 equiv; commercially available from Peakdale Molecular, UK) was added and the mixture stirred at rt for 48 h. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to provide 0.55 g (9%) of the title compound. MS (ISP): 385.4 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH:19]4[CH:17]([CH:18]4[NH2:21])[CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(CC)CC)C.O>ClCCl>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:16][CH:17]4[CH:19]([CH:18]4[NH:21][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[C:23]([F:22])([F:33])[F:34])[CH2:20]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: NC1C2CN(c3ccc(C(=O)NCCC4CC4)nn3)CC12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NCCC1CC1)c1ccc(N2CC3C(C2)C3NC(=O)c2ccccc2C(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a stirred solution of 6-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.258 g, 0.90 mmol) in dichloromethane (10 mL) was added 2-trifluoromethylbenzoyl chloride (0.2 mL, 1.00 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes, followed by the addition of triethylamine (0.1 mL, 1.000 mmol). The reaction mixture was stirred at ambient temperature for another 10 minutes. Water (5.0 mL) was added to the mixture and the organic phase was separated, washed with brine, dried over MgSO4 and then concentrated in vacuo. The obtained crude product was purified by column chromatography to yield the title compound as a white powder in 15% yield (0.055 g). 1H NMR (300 MHz, CDCl3) δ 7.97 (t, J=5.5 Hz, 1H), 7.92 (d, J=9.5 Hz, 1H), 7.63-7.42 (m, 4H), 6.67 (d, J=9.4 Hz, 1H), 6.51 (s, 1H), 4.00-3.97 (m, 2H), 3.66 (d, J=10.7 Hz, 2H), 3.51-3.44 (m, 2H), 2.63 (m, 1H), 2.03 (s, 2H), 1.49-1.42 (m, 2H), 0.72-0.66 (m, 1H), 0.45-0.39 (m, 2H), 0.07-0.02 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 170.4, 168.9, 163.4, 158.1, 144.4, 135.4, 135.3, 132.0, 129.9, 128.5, 126.7, 112.5, 127.3, 48.9, 39.6, 34.5, 33.8, 24.5, 8.6, 4.2. MS (ES+) m/z 460 (M+1).
Reaction SMILES: B.[NH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=O)[C:10]([F:19])([F:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:4]1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[F:18][C:10]([F:19])([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH2:9][NH:8][C@H:5]1[CH2:6][CH2:7][C@H:3]([NH2:2])[CH2:4]1
Reactant: Cc1ccc(C(F)(F)C(=O)N[C@H]2CC[C@H](N)C2)cc1
Agent: B
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)CN[C@H]2CC[C@H](N)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
1M borane in THF (20 mL, 20 mmol) was added slowly to a stirred solution of N-[(1S,3S)-3-aminocyclopentyl]-2,2-difluoro-2-(4-methylphenyl)acetamide (1.006 g, 3.749 mmol) in dry THF (20 mL) at 0° C. The reaction mixture was warmed to rt. and then was heated to 70° C. for 1 h. The reaction mixture was cooled, quenched with 6N HCl (2.5 mL, 15 mmol) and stirred at rt for 16 h. Aqueous sodium carbonate was added to pH=11, and the mixture was extracted with EtOAc, dried (MgSO4), filtered and concentrated. The resulting oil was purified by silica gel chromatography (eluting with 1.2% NH4OH/10.8% MeOH/CHCl3) to give the title compound as a pale yellow oil (627 mg): MS=255.4 (M+1).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]1.[Cl-].Cl[C:21]1[CH:26]=[CH:25][NH+:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(O)CCC.C(OCC)(=O)C>[N:24]1[CH:25]=[CH:26][C:21]([N:9]2[CH2:10][CH2:11][C:6]3([CH2:1][CH2:2][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][CH2:5]3)[CH2:7][CH2:8]2)=[CH:22][CH:23]=1
Reactant: Clc1cc[nH+]cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccncc1)CC2

Procedure:
tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1 g, 3.931 mmol), 4-chloropyridinium chloride (1.765 g, 11.794 mmol) and triethylamine (2.2 ml, 15.725 mmol) were refluxed in 1-butanol (50 ml) for 15 h. Saturated sodium bicarbonate solution (30 ml) and ethyl acetate (80 ml) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2×80 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/hexane/methanol/ammonia (25% aq) 400/40/40/1. Yield: 0.52 g (39%)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:5][C:4]=2[N:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:8]1[CH2:7][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[C:9]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccn1)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(n1)CC(c1ccccn1)CC2=NNC(=N)N
Yield: 91.5 %

Procedure:
A mixture of 2,4-dimethyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.08 g), aminoguanidine hydrochloride (0.037 g), concentrated hydrochloric acid (0.079 ml), water (0.079 ml) and ethanol (10 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from water-ethanol to give 5-guanidinoimino-2,4-dimethyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 87) (0.1 g) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:6][C:7]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:14]([N:16]3[CH2:19][CH:18]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[CH2:17]3)=[O:15])=[C:8]([CH3:10])[N:9]=2)[CH2:2]1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40].O>CN(C)C=O.CC#N>[C:39]([N:1]1[CH2:4][CH:3]([C:5]2[NH:6][C:7]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:14]([N:16]3[CH2:17][CH:18]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[CH2:19]3)=[O:15])=[C:8]([CH3:10])[N:9]=2)[CH2:2]1)(=[O:41])[CH3:40]
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CNC2)nc1C
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(c2nc(C)c(-c3cc(C(=O)N4CC(c5ccc(C#N)cc5)C4)ccc3C)[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 4-(1-(3-(2-(azetidin-3-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)azetidin-3-yl)benzonitrile (compound 189.2, 80 mg, 0.19 mmol) in N,N-dimethylformamide (1 mL). Triethylamine (27 μL, 0.20 mmol) and acetic anhydride (19 μL, 0.20 mmol) were added to the reaction. The reaction mixture was stirred for 2 h at room temperature, then quenched with 10 mL of water. The aqueous phase was extracted with 3×3 mL of ethyl acetate and the combined organic extracts were concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water with 50 mmol NH4HCO3 and MeCN (28% MeCN up to 40% in 7 min, up to 100% in 2 min, down to 28% in 1 min); Detector, Waters 2489 255 and 220 nm. This resulted in 32.8 mg (37%) of the title compound a white solid. m/z (ES+) 454 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@@H:10]([CH3:15])[C:9]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(#N)C.C(Cl)(Cl)(Cl)Cl.O.I([O-])(=O)(=O)=[O:27].[Na+].ClCCl>[Cl-].[Na+].O.[Ru](Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:27])=[O:14])[CH2:11][C@@H:10]([CH3:15])[C:9]1=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of (3R,5S)-1-t-butoxycarbonyl-5-hydroxymethyl-3-methylpyrrolidine-2-one in a solvent mixture of acetonitrile:carbon tetrachloride:water (2:2:3, 266 mL) was added sodium periodate (3 eq, 24.0 g) and ruthenium trichloride (2.2 mol %, 0.174 g). The solution was stirred 2 hr at room temperature and then diluted by the addition of dichloromethane (500 mL) and brine (200 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (3 x 200 mL). The combined organic phases were dried over Na2SO4 then celite added. The solution was filtered under suction through a bed of celite and the filtrate was evaporated to give an oily residue which was crystallized in ethyl acetate and hexane to give 5.03 g product (54%). The mother liquor was purified by flash column chromatography on silica gel, eluting with 70% ethyl acetate in hexane (with 1% of formic acid) to give an additional 1.21 g (13%) of the acid (total 67% yield in two steps). 1H NMR (200 MHz, CDCl3): δ 6.65 (br s, 1H), 4.60 (d, J=8.6, 0.9 Hz, 1H), 2.70 (m, 1H), 2.40 (dd, J=12.5, 8.8 Hz, 1H), 2.0 (m, 1H), 1.55 (s, 9H), 1.25 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:13]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][P:27]([OH:29])[OH:28])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:13]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][P:27]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:28])[OH:29])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CCCCCCCCCCC
Reactant: O=C(NCCCP(O)O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCP(=O)(O)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.30 g of dodecene in 6 ml of dry toluene is heated to 80° under an atmosphere of argon. To this solution a suspension of 2.0 g of 3-benzyloxycarbonylaminopropylphosphonous acid in 30 ml of dry toluene containing 0.6 g of t-butylcyclohexylperdicarbonate is added within 15 minutes. The reaction mixture is then stirred at 80° for 2 hours. An additional amount of 0.6 g of the radical initiator is added and stirring at 80° is continued for 2 hours. Then, the reaction mixture is cooled to room temperature and the solvent is removed by means of a rotary evaporator. The residue is triturated with petroleum ether (60°-80°), filtered and dried to give 3-benzyloxycarbonylaminopropyl(dodecyl)phosphinic acid as a white solid, m.p. 115°-116°; 31P-NMR: δ=±58.7 ppm (CDCl3).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH3:21][S:22]([O:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(C(C#N)=NO)c1
Solvent: CCN(CC)CC
Product: COc1cccc(C(C#N)=NOS(C)(=O)=O)c1
Yield: 47.8 %

Procedure:
In general analogy to the process described under 1.2, 27.7 g (0.157 mol) of α-hydroxyimino-3-methoxybenzylcyanide are reacted in the presence of 23.9 g (0.236 mol) of triethylamine with 19.8 g (0.173 mol) of methanesulfonyl chloride. Recrystallisation from toluene gives 19.1 g (48%) of α-(methylsulfonyloxyimino)-3-methoxybenzylcyanide in the form of white crystals having an m.p. of 105-107° C.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9](N)[CH:10]=[CH:11][C:12]=1[S:13][CH3:14].[O:16]1CCCC1.N([O-])=O.[Na+]>O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[Cu-]=O>[F:6][C:7]1[CH:8]=[C:9]([OH:16])[CH:10]=[CH:11][C:12]=1[S:13][CH3:14]
Reactant: CSc1ccc(N)cc1F
Reactant: C1CCOC1
Agent: O=[Cu-]
Agent: [Cu+2]
Agent: O=N[O-]
Solvent: O
Product: CSc1ccc(O)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
Concentrated sulfuric acid (40 mL) was added to a rapidly stirred mixture of 3-fluoro-4-methylsulfanyl-phenylamine (15.5 g, 99 mmol), water (750 mL) and tetrahydrofuran (23 mL). The mixture was cooled to 0° C. and a solution of sodium nitrite (7.5 g, 163 mmol) in water (15 mL) was added. The resulting mixture was stirred for 2 h at 0° C. and it was then added dropwise over 10 min to a stirring solution of copper(II) nitrate (230 g, 1.2 mol) and copper(I) oxide (12.8 g, 89 mmol) in water (1 L). The reaction mixture was stirred for 15 min and then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 20% ethyl acetate/hexanes to give 3-fluoro-4-methylsulfanyl-phenol (3.73 g, 24%) as a brown oil.