Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([N:15]1C(=O)C2=CC=CC=C2C1=O)[CH2:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:15][C@@H:10]([CH2:11][CH2:12][CH:13]=[CH2:14])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC[C@@H](COCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: C=CCC[C@H](N)COCc1ccccc1
Yield: 0.1 %

Procedure:
To a stirred solution of 1-benzyloxy-2-(S)-phthalimido-5-hexene (2.95 g, 8.80 mmol) in EtOH (30 ml) was added hydrazine hydrate (80% in water, 460 ml, 11.4 mmol) at rt, and the resulting mixture was heated under reflux for 7.5 h with stirring. The solution was filtered, and the filtrate was concentrated in vacuo. The residue was poured into aq.NaHCO3 and extracted with CHCl3. The organic layer was dried over anhydrous Na2SO4, then concentrated in vacuo to give 2-(S)-amino-1-benzyloxy-5-hexene (1.90 mg, quant.) as a colorless oil. 1H-NMR (CDCl3) δ1.37-1.55 (series of m, 4 H), 2.08-2.19 (m, 2 H), 2.99-3.03 (m, 1 H), 3.25 (dd, J=9.2, 7.6 Hz, 1 H), 3.45 (dd, J=9.2, 4.0 Hz, 1 H), 4.53 (s, 2 H) 4.94-5.06 (series of m, 2 H), 5.76-5.85 (m, 1 H), 7.27-7.37 (m, 5 H); MS (ESI) m/z, 206 (M++H), 247 (M++H+CH3CN).
Reaction SMILES: COC1C=CC(C(O[C:10]2[C:15]([NH:16][C:17](=[O:30])[C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)=[CH:14][C:13]([O:31]C)=[CH:12][C:11]=2[Br:33])=O)=CC=1C(F)(F)F.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:33][C:11]1[C:10]2[O:30][C:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:26]([F:28])([F:29])[F:27])[CH:19]=3)=[N:16][C:15]=2[CH:14]=[C:13]([OH:31])[CH:12]=1
Reactant: COc1cc(Br)c(OC(=O)c2ccc(OC)c(C(F)(F)F)c2)c(NC(=O)c2ccc(OC)c(C(F)(F)F)c2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Oc1cc(Br)c2oc(-c3ccc(O)c(C(F)(F)F)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 20, Step d (Route a), from 2-bromo-4-methoxy-6-{[4-methoxy-3-(trifluoromethyl)benzoyl]amino}phenyl 4-methoxy-3-(trifluoromethyl)benzoate and p-toluenesulfonic acid monohydrate. The product was obtained as an off-white solid, m.p. 183–185° C.; MS m/e 402 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31](C)[C:30]([CH:34]=O)=[C:29](C)[CH:28]=1.OOS([O-])=O.[K+]>CN(C=O)C.O>[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:34]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[CH:31][CH:32]=1
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)cc1
Reaction time: 0.33 h

Procedure:
To a mixture of 3,4-diamino-N-quinolin-2-yl-benzamide (1.0 g, 3.92 mmol) and 3-(4-formyl-3,5-dimethyl-phenyl)-propionic acid methyl ester (1.09 g, 3.92 mmol) in DMF (10 mL) and water (1 mL) was added oxone (1.62 g, 2.63 mmol) and the mixture was stirred atambient temperature for 20 min. The mixture was quenched with water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (1:3) to give 3-{4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl}-propionic acid methyl ester as a pale yellow solid. 1H NMR (Methanol-d4, 400 MHz): δ 8.45 (d, 1H), 8.38 (d, 1H), 8.29 (s, 1H), 8.04 (d, 1H), 7.93 (d, 2H), 7.83 (s, 1H), 7.75 (m, 1H), 7.55 (m, 1H), 7.09 (s, 2H), 3.67 (s, 3H), 2.97 (t, 2H), 2.71 (t, 2H), 2.16 (s, 6H). MS (m/z) 479.2 (M+1); Retention time: 1.48 min (Method 10).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:15][CH2:16][CH2:17][CH3:18])[CH3:14])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37](=[O:40])[N:36]([CH2:41][CH2:42][CH2:43][CH:44]=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37](=[O:40])[N:36]([CH2:41][CH2:42][CH2:43][CH2:44][N:15]([C@@H:13]([CH3:14])[CH2:12][C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:7][CH:8]=2)[CH2:16][CH2:17][CH3:18])[CH2:35][CH2:34]1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: CCCN[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CCCC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCN(CCCCN1CCN(C(=O)OC(C)(C)C)CCC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.8 %

Procedure:
A mixture of [(S)-2-(4-methanesulfonylphenyl)-1-methylethyl]-propylamine hydrochloride (2.05 g, 7.03 mmole), triethylamine (0.98 mL, 7 mmole), 5-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (2.0 g, 7.03 mmole), and sodium triacetoxyborohydride (2.23 g, 10.5 mmole) in 1,2-dichloroethane (40 mL) was stirred at room temperature for 15 hours. The mixture was concentrated, and the residue was partitioned between diethyl ether and saturated sodium carbonate. The organic phase was dried (magnesium sulfate) and concentrated to give 4-(4-{[(S)-2-(4-methane-sulfonylphenyl)-1-methylethyl]propyl-amino}butyl)-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.6 g) as a heavy syrup. M+H=524. The hydrochloride salt was recrystallized from acetone/diethyl ether, m.p. 156-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([CH3:18])[C:16](I)=[C:12]3[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][OH:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:16]2[C:15]([CH3:18])=[N:14][N:13]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[CH:9][C:10]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[CH2:24][OH:25])=[N:11][C:12]=23)=[CH:30][CH:29]=1
Reactant: Cc1nn2c(-c3cccc(Cl)c3)cc(N3CCC[C@H]3CO)nc2c1I
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(C)nn3c(-c4cccc(Cl)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
(S)-(1-(7-(3-Chlorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (30 mg), 4-methoxyphenylboronic acid (15 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (10 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred overnight at 90° C. under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (21 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH3:10]
Reactant: Oc1c(Br)cccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: COc1c(Br)cccc1Br
Reaction time: 4 h
Yield: 58.9 %

Procedure:
A mixture of 2,6-dibromophenol (25 g, 0.099 mol), powder potassium carbonate (28 g, 0.2 mol, 2 equiv) and dimethyl sulfate (12.6 g, 0.099 mol) in acetonitrile (400 mL) was kept at reflux with good stirring for 4 hr. After cooling, the solids were removed by filtration and the solvent was removed in a rotary evaporator. The residue was taken in 2:1 heptane/ethyl acetate mixture (800 mL) and washed with water (2×400 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in a rotary evaporator, leaving almost pure 1 (15.5 g, 96%).
Reaction SMILES: [F-].[Cs+].[CH2:3]([C:7]1[N:8]([CH2:41][CH2:42][CH3:43])[C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:40])(=[O:39])[N:26]([CH2:35][CH2:36][O:37][CH3:38])COCC[Si](C)(C)C)=[CH:21][CH:20]=3)[N:13]=2)=[CH:10][N:11]=1)[CH2:4][CH:5]=[CH2:6]>CN(C=O)C.O>[CH2:3]([C:7]1[N:8]([CH2:41][CH2:42][CH3:43])[C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([S:25](=[O:40])(=[O:39])[NH:26][CH2:35][CH2:36][O:37][CH3:38])=[CH:23][CH:24]=3)[N:13]=2)=[CH:10][N:11]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)N(CCOC)COCC[Si](C)(C)C)cc3)n2)n1CCC
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOC)cc3)n2)n1CCC

Procedure:
A mixture of caesium fluoride (180 mg, 1.2 mmole), and 4-(2-(but-3-enyl)-1-propylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine (Method 100; 100 mg, 0.17 mmol), in DMF (3 ml), was heated at 140° C. under nitrogen for 24 hours. The mixture was diluted with water and extracted with EtOAc. The extracts were washed with water and brine, dried, and the solvent evaporated. The residue was purified by chromatography on silica gel eluting with EtOAc to give the title compound. (8 mg, 10%). NMR: 0.7 (t, 3H), 1.52 (q, 2H), 2.80 (t, 2H), 2.85-2.89 (m, 2H), 3.19 (s, 3H), 3.18-3.22 (m, 2H), 3.30 (t, 2H), 4.52 (t, 2H), 4.98 (d, 1H), 5.10 (dd, 1H), 5.95-5.89 (m, 1H), 7.20 (d, 1H), 7.44 (t, 1H), 7.70 (s, 3H), 7.74 (d, 2H), 7.89 (d, 2H), 8.45 (d, 1H), 9.80 (s, 1H); m/z: 471.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@@H:13]([CH3:16])[CH2:14][OH:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.N1C=C[CH:21]=[CH:20][CH:19]=1.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:20]([C:21]1[N:12]([C@@H:13]([CH3:16])[CH2:14][OH:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:19]
Reactant: C[C@@H](CO)Nc1c(N)cnc2ccccc12
Reactant: c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1nc2cnc3ccccc3c2n1[C@@H](C)CO
Temperature: 90 °C
Reaction time: 20 h
Yield: 609.3 %

Procedure:
A suspension of (2S)-2-[(3-aminoquinolin-4-yl)amino]propan-1-ol (0.98 g, 4.49 mmol) in 50 mL of toluene was treated with triethyl orthopropioate (1.1 mL, 5.39 mmol) and pyridine HCl (52 mg, 0.45 mmol), and heated to 90° C. under an atmosphere of N2. After ˜20 hours, the reaction was allowed to cool back to ambient temperature and the solvent was removed under reduced pressure to give an orange solid. Chromatography (AFC, SiO2, 20-40% CMA/CHCl3) gave (2S)-2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)propan-1-ol (0.70 g) as a white solid.
Reaction SMILES: [CH2:1]([S:3]([C:5]1[O:6][C:7]2[C:12]([C:13](=[O:23])[C:14]=1[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=O)[CH3:2].[C:24]([C:28]1[CH:35]=[CH:34]C(CS)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C(#N)C>[C:24]([C:28]1[CH:35]=[CH:34][C:2]([CH2:1][S:3][C:5]2[O:6][C:7]3[C:12]([C:13](=[O:23])[C:14]=2[CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CCS(=O)c1oc2ccccc2c(=O)c1COC1CCCCO1
Reactant: CC(C)(C)c1ccc(CS)cc1
Solvent: CC#N
Product: CC(C)(C)c1ccc(CSc2oc3ccccc3c(=O)c2COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Into a 25 mL round bottom flask is introduced 2-ethylsulfinyl-3-((2-tetrahydropyranyloxy)methyl) chromen-4-one (5 g, 14.87 mmol). Acetonitrile is then added to it followed by 4-tertbutylbenzyl mercaptan (74.3 mmol). The reaction mixture is stirred for 10 hours at room temperature after which the solvent is removed in vacuo. The crude residue obtained is purified by silica gel chromatography (ethyl acetate:hexanes) to obtain the product.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Br:17])=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Br:17])=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: CC=CCC1Cc2ccc(Br)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=CCC1Cc2ccc(Br)cc2C1=O
Reaction time: 1 h
Yield: 80 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 60 minutes while stirring through a solution, cooled to -70°, of 9.86 g of (RS)-2-(2-buten-1-yl)-6-bromo-1-indanone in 150 ml of anhydrous dichloro-methane and 30 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4.09 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 1 50 ml of dichoromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. The crude product obtained was recrystallized from ethyl acetate/hexane. 7.5 g (80%) of (RS)-2-(2-oxoethyl)-6-bromo-1-indanone were obtained as a light yellow solid with m.p. 84°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)=[N:6]1)[CH3:4].[C:22]([C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:22]([C:25]1[CH:29]=[C:28]([C:30]([NH:1][CH2:2][C@@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23]
Reactant: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)n2)[nH]n1
Yield: 77.4 %

Procedure:
The title compound was synthesized from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile (429 mg, 1.45 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (225 mg, 1.45 mmol), HOBt (236 mg, 1.75 mmol), DIPEA (0.305 mL, 1.75 mmol) and EDCI (335 mg, 1.75 mmol) using DCM as solvent using the method of Example 34(d) affording 483 mg of the title compound. 1H NMR (400 MHz; d6-DMSO): δ 1.50 (d, 3H), 2.47 (s, 3H), 3.63 (m, 2H), 4.69 (m, 1H), 7.03 (d, 1H), 7.25 (bs, 1H), 7.90 (d, 1H), 8.18 (m, 2H), 8.27 (m, 1H), 14.15 (bs, 1H).
Reaction SMILES: [C:1]([S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=O)=O>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH:8]([S:5]([C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:7])=[O:6])[C:9]#[N:10])=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)OCCc1ccc(Cl)cc1
Reactant: CC(C)(C)S(=O)(=O)CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)(=O)C(C#N)CCc1ccc(Cl)cc1
Yield: 80 %

Procedure:
Into a 3-neck, 200 milliliter (mL) round bottom flask was charged 2.4 grams (g), 0.06 mole, of 60% sodium hydride (NaH), which had been previously washed two times with successive 30 mL portions of hexane, in 30 mL of dimethylformamide (DMF). While stirring under nitrogen, 7.6 g (0.05 mole) of t-butylsulfonylacetonitrile in 25 mL of DMF was added. The mixture was stirred for 0.5 hour (hr) and 12.8 g (0.055 mole) of 2-(4-chlorophenyl)ethyl methanesulfonate in 25 mL of DMF was added dropwise. The mixture was stirred at room temperature for 3 hrs. and then an additional 96 hrs by which time the mixture had changed to an orange slurry. The mixture was stirred yet an additional 96 hrs at room temperature after which analysis by gas liquid phase chromatography (GLC) indicated the absence of starting material. The reaction was quenched by the addition of 100 mL of diethyl ether and 50 mL of water. The ether was washed with water and the combined aqueous phases were extracted with 50 mL of ethyl acetate. The organic phases were combined, dried with sodium sulfate, filtered and concentrated to give 12.0 g of an orange oil (80.3% yield) which was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]#[CH:9])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25]O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][O:1][C:2]1[C:6]([CH2:7][C:8]#[CH:9])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: C#CCc1c(O)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Product: C#CCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 83.8 %

Procedure:
3-Hydroxy-5-phenyl-4-propargylisoxazole (1.00 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.96 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (1.44 g, 84%) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NC1CC1
Product: O=[N+]([O-])c1ccc(NC2CC2)cc1
Temperature: 0 °C

Procedure:
1-Fluoro-4-nitrobenzene (3.5 g, 24.8 mmoles) is refluxed for 5 hours with 8.1 g (0.14 moles) of cyclopropylamine. After that, the reaction product is poured onto 250 g of ice/water and the precipitate is filtered off. After recrystallization from ethanol, a yellow solid with a melting point of 126°-128° C. is obtained.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.II.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19]Cl)(=[O:18])=[O:17])=[CH:14][CH:15]=1>O1CCOCC1>[C:10]1([CH3:9])[CH:11]=[CH:12][C:13]([S:16]([N:19]2[CH:6]3[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Reactant: C1=CCCCC1
Agent: II
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2C3CCCCC32)cc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
To a solution of 200 g cyclohexene and 30.7 g iodine in 800 ml of anhydrous dioxane was added 611.7 g of chloramine T. The mixture was stirred at 80° C. for 10 h. After cooling to room temperature the mixture was poured into ice water and extracted with ethyl acetate twice. The combined organic phases were dried over sodium sulphate and concentrated and the residue was purified by chromatography (Silica, hexane/Ethyl acetate) to afford 180 g (29%) of) 7-(Toluene-4-sulfonyl)-7-aza-bicyclo[4.1.0]heptane as a white solid.
Reaction SMILES: Cl.[CH2:2]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH3:13])[CH2:9][CH2:8]1)[CH2:3][C:4]#[CH:5].Br[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([C:5]#[C:4][CH2:3][CH2:2][NH:6][C@H:7]2[CH2:8][CH2:9][C@H:10]([CH3:13])[CH2:11][CH2:12]2)=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: C#CCCN[C@H]1CC[C@H](C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCNC1
Product: CS(=O)(=O)c1ccc(C#CCCN[C@H]2CC[C@H](C)CC2)cc1
Temperature: 50 °C

Procedure:
To a portion of the above but-3-ynyl-(trans-4-methyl-cyclohexyl)-amine hydrochloride (500 mg, 2.48 mmol) dissolved in pyrrolidine (2.5 mL) was added 1-bromo-4-methanesulfonyl-benzene (583 mg, 2.48 mmol) and the solution was degassed by bubbling nitrogen through for 10 min. Tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.025 mmol) was added and the mixture was heated at 50° C. for 16 h before the volatiles were removed by evaporation and the residue purified by HPLC to yield the intermediate [4-(4-methanesulfonyl-phenyl)-but-3-ynyl]-(trans-4-methyl-cyclohexyl)-amine.
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:13][NH:14][C:15]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])=[N:16][N:17]=1>O.C(O)(=O)C>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[N:16][C:15]([C:18]2[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=2[F:24])=[N:14][N:13]=1
Reactant: Fc1cccc(F)c1C1=NN=C(c2ccccc2Br)NN1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Fc1cccc(F)c1-c1nnc(-c2ccccc2Br)nn1
Yield: 95.7 %

Procedure:
A solution of 0.26 g of sodium nitrite in 1 ml of water is dropped to a solution containing 0.62 g of 3-(2-bromophenyl)-6-(2,6-difluorophenyl)-1,2-dihydro-1,2,4,5-tetrazine [prepared in the preceeding step c.)] in 2 ml of glacial acetic acid at room temperature under stirring. The progress of the reaction is followed by thin layer chromatography (TLC). The reddish-violet crystals are filtered, washed with water until neutral and dried to give 0.59 g of crystalline desired product, i.e. the title compound of Example 1. This crude product is recrystallized from a mixture of gasoline and acetone, m.p.: 168° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].Cl.[CH3:11]O>>[NH2:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:11])=[O:4]
Reactant: CO
Reactant: CC(C)CC(N)C(=O)O
Agent: Cl
Product: COC(=O)C(N)CC(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
2-Amino-4-methylpentanoic acid (5.0 g 38.2 mmol) was slowly added to sat. HCl/MeOH (50 mL). The mixture was stirred (RT, 5 h) then heated to reflux (16 h). After the reaction, the solvent was removed under reduced pressure. The residue was diluted with water (50 mL), then NaHCO3 was added to adjust pH=7. The mixture was then extracted with DCM (3×50 mL), the combined organic layers were dried over MgSO4, concentrated under reduced pressure to afford methyl 2-amino-4-methylpentanoate as a colorless liquid (5.3 g, 96%). Mass calculated for C7H15NO2=145.20. found: [M+H]+=145.9. The product was used in next step without further purification.