Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[N+:15]([O-])([O-:17])=[O:16].[K+]>>[F:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16]
Reactant: N#Cc1ccc(F)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
The largest amount of silica gel that still allowed the resulting slurry to be stirred magnetically at 0° C., was added to conc. sulfuric acid (125 ml). To this mixture 4-fluorobenzonitrile (12.5 g, 103 mmol) was added followed by potassium nitrate (10.4 g, 103 mmol). The reaction mixture was stirred at 0° C. for 20 minutes. The sulfuric acid was removed from the product by passing the mixture through a short column of silica gel and the product was washed out with methylene chloride. The solvent was evaporated to leave the product as a crystalline solid. Yield 6.0 g, mp 86°-88° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[CH2:26]([S:27]([NH:30][C:12]1[C:13]2[C:14](=[O:16])[C:15]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH2:1])[C:7](=[O:18])[C:8]=2[CH:9]=[CH:10][CH:11]=1)(=[O:29])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: Nc1cccc2c1C(=O)c1c(Cl)cccc1C2=O
Reactant: CCCCCCCCS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CCCCCCCCS(=O)(=O)Nc1cccc2c1C(=O)c1c(N)cccc1C2=O

Procedure:
1-(n-octylsulfonylamino)-8-aminoanthraquinone was prepared as follows. 1-amino-8-chloroanthraquinone (1.0g), n-octanesulfonamide (1.0g), potassium carbonate (1.0g), cupric acetate monohydrate (0.85g) and chlorobenzene (16.0g) were refluxed for 5.5 hours. The cooled mixture was filtered and aqueous methanol was added to the filtrate. The supernatant liquid was decanted and the remaining oil was dissolved in dichloromethane. On addition of methanol and partial evaporation of the solvent, the product separated as a red solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11](=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N#N.[CH2:23]([Mg]Br)[CH3:24].COC(C)(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH2:23][CH3:24])([OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2=O
Reactant: CC[Mg]Br
Agent: N#N
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCC1(O)CCN(C(=O)OC(C)(C)C)c2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a flame dried 250 mL round bottom flask equipped with a magnetic stir bar and a N2 gas inlet was added IV (2.23 mg, 8.05 mmol) in dry THF (100 mL). The solution was cooled to 0° C. under a blanket of N2 and a 1.0M solution of ethyl magnesium bromide (EtMgBr) in methyl-tert-butyl ether (16.1 mL, 16.1 mmol, 2 equiv) was added via syringe. The solution was stirred at 0° C. for 1 h. The reaction was quenched with NH4Cl (saturated aqueous solution) extracted with EtOAc, dried (MgSO4), and concentrated to give V as a colorless oil (1.11 g, 3.61 mmol, 45%). Spectral data matched that previously disclosed for this compound.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:29])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:30]OCCOC.[N+](=C)=[N-]>C(O)(=O)C.CCOCC>[CH2:1]([NH:11][C:12](=[O:29])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:28])/[CH:23]=[CH:24]\[C:25]([O:27][CH3:30])=[O:26])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(NC(=O)/C=C\C(=O)O)c1
Reactant: COCCOC
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(NC(=O)/C=C\C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 400 mg. of N-decyl-3-(3-[cis-3-carboxypropenamido]phenyl)propenamide and 15 ml. of 1,2-dimethoxyethane is added a solution of 1.5 mmoles of diazomethane in 5 ml. of ether. The reaction mixture is stirred at room temperature for 16 hours, and then the excess diazomethane is decomposed by the addition of a few drops of acetic acid. The total solvents are removed by evaporation in vacuo, and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with 1 N sodium hydroxide, followed by water, followed by saturated sodium chloride solution, and then dried using sodium sulfate. Evaporation of the dried ethyl acetate solution in vacuo affords the title compound.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][CH2:19][O-:20].[Na+]>C(O)C>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:20][CH2:19][CH3:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and sodium ethylate in ethanol there is obtained ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and therefrom with hydrochloric acid in alcohol there is obtained the hydrochloride, m.p. 158° C. (with decomposition);
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Product: COc1ccc(S(=O)(=O)Nc2cc(Br)ccc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-4-bromo-phenyl)-phenyl-methanone and 103 mg of 4-Methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.72 (s, 3H), 6.75 (d, 2H, J=8.8 Hz), 7.19-7.26 (m, 2H), 7.37-7.43 (m, 4H), 7.57 (m, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.96 (s, 1H), 10.09 (s, 1H). MS: m/z 447.9 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[C:13](Cl)=[N:14][CH:15]=1.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]([Br:9])=[CH:15][N:14]=1
Reactant: COC(=O)CO
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 117.8 %

Procedure:
Hydroxy-acetic acid methyl ester (46 mg, 0.50 mmol) was dissolved in 2 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and sodium hydride (40 mg, 1.0 mmol) was added thereto at room temperature. After stirring for 30 minutes, 5-bromo-2-chloro-3-nitro-pyridine (100 mg, 0.42 mmol) dissolved in 1 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction by adding water, the mixture was extracted with dichloromethane, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain (5-bromo-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester as yellow solid (144 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]([C:9]#[N:10])=[C:6]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[N:7]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1nc(N)nc(-c2cccnc2)c1C#N
Yield: 18.9 %

Procedure:
To a stirred suspension of 2,45 g (10.0 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 65 ml dioxane at room temperature were added 2.18 g (20.0 mmol) 3-pyridineboronic acid, 1.15 g (1.00 mmol) tetrakis(triphenylphosphine)palladium(O) and 20 ml (40.0 mmol) 2M aqueous sodium carbonate. The reaction mixture was heated at reflux for 48 h, then concentrated in vacuo. Chromatography (1/4 ethyl acetate/hexane) afforded 460 mg (20%) 2-amino-4-methylsulfanyl-6-pyridin-3-yl-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 243 (M+, 100), 242 ([M—H]+, 70).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH3:24][NH2:25]>CO>[CH3:24][NH:25][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: CN
Solvent: CO
Product: CNc1cc(C(F)(F)F)cc2nc(NC(=O)c3cccnc3)nn12

Procedure:
The title compound was prepared following procedure and work up described for example 85 but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and methylamine (1.46 mL of a 2M solution in MeOH; 0.73 mmol; 5.0 eq.) as a white solid (15 mg, 30%). HPLC, Rt: 2.47 min. (purity 96.6%). LC/MS, M+(ESI): 337.0, M−(ESI): 335.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:16])[CH3:15])[CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CC[C@H](C(=O)C)[C@@H](C2C=CC(Cl)=CC=2)C1)C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]([OH:16])[CH3:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: CC(=O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Product: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of (RS)-1-[(3SR,4SR)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol (example 5 (d)) the title compounds were synthesized from 1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanone through reduction with LiAlH4. (R)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol was obtained as light yellow viscous oil. MS (m/e): 330.1 [(M+H)+] and (S)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol was obtained as colorless foam. MS (m/e): 330.1 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH2:14][CH2:15][CH3:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:21])[CH:29]=[CH:28][CH:27]=1)(=[O:31])(=[O:32])[NH2:33]
Reactant: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(N)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-propyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.27) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 470.5 [(M+H)+]; mp 252-254° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]3[C:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[CH:22]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)O1.Cl[C:25]1[CH:26]=[C:27]([CH2:31][N:32]2[CH:36]=[CH:35][N:34]=[C:33]2[CH3:37])[N:28]=[N:29][CH:30]=1>>[CH3:37][C:33]1[N:32]([CH2:31][C:27]2[N:28]=[N:29][CH:30]=[C:25]([C:9]3[C:10]4[C:15]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[CH:22]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:26]=2)[CH:36]=[CH:35][N:34]=1
Reactant: CC1(C)OB(c2cc3ccccc3c3ccccc23)OC1(C)C
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2cc3ccccc3c3ccccc23)cnn1

Procedure:
The title compound, MS: m/e=351.4 (M+H+), was prepared from 4,4,5,5-tetramethyl-2-phenanthren-9-yl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].Cl[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[C:15]([CH3:23])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[C:15]([CH3:23])[CH:14]=1
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc2c(c1)CCCC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
4.4 g (29.6 mmol) of 5,6,7,8-tetrahydro-2-naphthol, 5.0 g (26.9 mmol) of 4-chloro-2,5-dimethylnitrobenzene and 5.2 g (37.7 mmol) of potassium carbonate are refluxed in 50 ml of N,N-dimethylformamide for 12 h, poured onto ice, stirred at 0° C. for 15 min, and then filtered. The solid is washed with water and hexane and dried under reduced pressure (6.0 g, 98.0% purity, 70.0% yield, log P (pH 2.3)=5.86).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[CH2:4][C:5]([OH:7])=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:32](O)[CH:33]=[CH2:34]>CC#N.CCOC(C)=O>[CH3:2][N:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[CH2:4][C:5]([O:7][CH2:34][CH:33]=[CH2:32])=[O:6]
Reactant: C=CCO
Reactant: CN(CC(=O)O)Cc1ccc(NS(C)(=O)=O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC(=O)CN(C)Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 75 °C
Yield: 88 %

Procedure:
A mixture of 2-(methyl(4-(methylsulfonamido)benzyl)amino)acetic acid hydrochloride (1.054 g, 3.41 mmol), CDI (1.107 g, 6.83 mmol), and TEA (0.952 ml, 6.83 mmol) in CH3CN (80 ml) was heated at 75° C. for 3 hours. The solvent was evaporated; the residue was dissolved in prop-2-en-1-ol (30 ml, 439 mmol) and heated at 75° C. for 1 hour. The mixture was diluted with EtOAc and washed several times with NH4Cl sat. sol. The organic phase was dried over Na2SO4, the solvent was removed, and the residue was filtered on SCX cartridge (DCM/MeOH 1/1; conc.aq.NH4OH/MeOH 1/9). The basic fraction was evaporated to dryness to give allyl 2-(methyl(4-(methylsulfonamido)benzyl)-amino)acetate as a brown oil (0.942 g, 3.02 mmol, 88% yield, MS/ESI+ 313.2 [MH]+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][NH2:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2ccccc2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methylquinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH:13]([C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)=O.[BH4-].[Na+].O>CO>[N:18]1[CH:19]=[C:15]([CH2:13][NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[NH:16][CH:17]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: FC(F)(F)Oc1ccc(NCc2cnc[nH]2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 4-trifluoromethoxyaniline (0.89 g, 5 mmol) in methanol (5 ml) was added 4-formylimidazole (0.48 g, 5 mmol). After stirring the mixture overnight at 60° C. the solution was cooled and sodium borohydride (0.28 g, 7.5 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by column filtration (heptane/ethyl acetate=1:1) to yield a light yellow liquid (1.0 g, 78%); MS (ISP): 258.1 ((M+H)+.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH2:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)=[C:16]=[O:17]>C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:16]([NH:15][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]3)=[O:17])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CCC2N
Reactant: O=C=Nc1cccc2cnccc12
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)CCC2NC(=O)Nc1cccc2cnccc12
Reaction time: 2 h

Procedure:
5-tert-Butyl-2,3-dihydro-1H-inden-1-ylamine (150 mg, 1.13 mmol) in diethyl ether (10 mL) was treated with 5-isocyanatoisoquinoline in diethyl ether. The mixture was stirred for 2 hours, filtered, and the filter cake was washed with diethyl ether to provide the title compound. NMR (DMSO-d6) 1.29 (s, 9H), 1.78-1.90 (m, 1H), 2.43-2.54 (m, 1H, buried under DMSO), 2.76-3.05 (m, 2H), 5.19 (m, 1H), 7.27 (m, 2H), 7.31 (m, 1H), 7.43 (d, 1H), 7.89 (t, 1H), 8.05 (d, 1H), 8.63 (d, 1H), 8.69 (d, 1H), 9.33 (s, 1H), 9.73 (s, 1H); MS (ESI+) 360 (M+H)+; Elemental: Calculated for C23H25N3O.HCl.0.5H2O: C68.22, H6.72, N10.38; Found: C68.31, H6.81, N10.16.
Reaction SMILES: [NH:1]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:31])[C@H:16]([C:20]([N:22]1[CH2:30][CH2:29][CH2:28][C@H:23]1[C:24]([O:26]C)=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[Li+].[OH-].O>CO>[NH:1]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:31])[C@H:16]([C:20]([N:22]1[CH2:30][CH2:29][CH2:28][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
31.96 g (57 mmol) Z-Val-Val-MeVal-Pro-OMe (SEQ ID NO: 2) were dissolved in 250 ml methanol. 102.6 ml of a 1 N LiOH solution was added and the mixture stirred overnight at room temperature. After addition of 500 ml water, the aqueous phase was washed three times with ethyl acetate, adjusted to pH 2 at 0° C. and extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness yielding 30.62 g of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[Cl:26].[Cl:27]N1C(=O)CCC1=O.CCOCC.O>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[C:24]([Cl:27])[O:23][C:22]=1[Cl:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cc(Cl)oc1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 5-amino-4-(2-chlorofuran-3-yl)-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.15 g) in tetrahydrofuran (7 ml) was added N-chlorosuccinimide (0.048 g). The mixture was left at room temperature for 24 hours and then heated at 50° C. for 3 hours and then left at room temperature for 96 hours. The reaction mixture was poured into ether (25 ml) and water (25 ml). The organic layer was washed with water (25 ml), then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with hexane:dichloromethane (50:50). Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 193-194° C.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[OH-].[Na+].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>O>[C:12]([O:16][C:17]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1
Yield: 40 %

Procedure:
Water (250 ml) was added to 4-piperidone monohydrate hydrochloride salt (75 g) for dissolution, and 1 N aqueous solution of sodium hydroxide (1000 ml) was added thereto. To the solution, ditertiarybutylcarbonate (120 g) was added dropwise with stirring under cooling on ice, and the mixture was vigorously stirred for 6 hours at room temperature. The reaction mixture was subjected to extraction with ethyl acetate, and the extract was evaporated to dryness under reduced pressure to thereby yield a pale yellow solid. By recrystallization of the solid from hexane, N-t-butyloxycarbonyl-4-piperidone (3) (38.9 g) was obtained in the form of white needle-shaped crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[N:5]=[N:4]1)[CH3:2].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[N:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)nn1

Procedure:
A solution of tert-butyl 4-{1-[(1-ethyl-1H-1,2,3-triazol-4-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (1.27 g; compound B23) in DCM (20 ml) is reacted with trifluoroacetic acid (5 ml) according to the procedure described in example B43 to afford the title compound as a solid.