Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1)=[O:6]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)c2c(OC)cccc2OC)cc1
Yield: 37 %

Procedure:
A mixture of 2 g (10 mmol) of 2,6-dimethoxybenzoyl chloride, 1.65 g (10 mmol) of ethyl 4-aminobenzoate, 1.11 g of triethylamine and 61 mg of 4-dimethylaminopyridine in 10 ml of dichloromethane is refluxed for 20 hours. The mixture is diluted with water and the organic layer separated. The organic layer is washed with water, 1N HCl, 1N Na2CO3, brine and dried (Na2SO4). The solvent is removed to give a solid which is crystallized from ethyl acetate to give 1.22 g of ethyl 4-[(2,6-dimethoxybenzoyl)amino]benzoate as crystals, m.p. 183°-185° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([CH3:16])[C:5]=1[OH:17].Cl[C:19]1[N:24]=[C:23]([Cl:25])[N:22]=[C:21]2[NH:26][N:27]=[CH:28][C:20]=12>>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([CH3:16])[C:5]=1[O:17][C:19]1[N:24]=[C:23]([Cl:25])[N:22]=[C:21]2[NH:26][N:27]=[CH:28][C:20]=12
Reactant: Cc1cc(-c2ccncc2)cc(C)c1O
Reactant: Clc1nc(Cl)c2cn[nH]c2n1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(-c2ccncc2)cc(C)c1Oc1nc(Cl)nc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.2 eq) is added to 2,6-dimethyl-4-(pyridin-4-yl)phenol (prepared according to literature procedures, see Combellas et al., Tetrahedron Letters, 1992, 33, 4923) (1.2 eq) in 1-methyl-2-pyrridone (2 ml/mmol) at 0° C. The reaction mixture is stirred at room temperature for 30 min and a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (1 eq) in 1-methyl-2-pyrridone (1 ml/mmol) is added. The resulting mixture is heated to 100° C. for 16 h, cooled to room temperature, poured into ice water and extracted with CHCl3 (×3). The combined organic layers are washed with water and brine, dried (Na2SO4), concentrated to dryness and purified by silica gel chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.ClS([N:12]=[C:13]=[O:14])(=O)=O>ClCCl>[CH3:1][C:2]12[NH:12][C:13](=[O:14])[CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3]2
Reactant: CC1=CCCCC1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: CC12CCCCC1C(=O)N2
Temperature: -10 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
Following the procedure of Spurr et al, J. Am. Chem. Soc., 1983, 105, 4735, a solution of 1-methyl-1-cyclohexene (1 g, 10.4 mmol) in dichloromethane (30 mL) was cooled to −20° C. and chlorosulfonylisocyanate (1.08 mL, 12.5 mmol) was added drop wise. The reaction was warmed to −10° C. over 3 h, then warmed to room temperature and stirred for 1 h. The reaction mixture was then concentrated, and taken up in ether (15 mL) and dimethylethyleneglycol (5 mL) to homogenize. To the reaction mixture was added 25% Na2SO3 (25 mL), followed by 10% sodium hydroxide solution to keep the pH between 7-8. The reaction was stirred overnight, taken up in ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated to afford racemic (1S,6R)-6-methyl-7-azabicyclo[4.2.0]octan-8-one (0.95 g, 66%). MS: 140.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18](NC(C)C)([CH3:20])[CH3:19].C([Li])CCC.C1(=O)CCC1>>[O:15]=[C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[S:10][C:11]=2[C:17]2([CH2:20][CH2:18][CH2:19]2)[O:16]1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: O=C1CCC1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)Nc1nc2c(s1)C1(CCC1)OC2=O

Procedure:
Methyl 2-(tert-butoxycarbonylamino)thiazole-4-carboxylate (purchased from Combi-Blocks), diisopropylamine, butyllithium, and cyclobutanone (purchased from Aldrich) were processed using the procedure as described for Example 3D to obtain the title compound. MS (ESI+) m/z 297 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1Br.CC([N:15]([CH2:19][C@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C(=O)[O-])(C)C.[NH2:28][CH:29](CC1C=CC=CC=1)[CH2:30][CH2:31][NH:32][C:33](=O)OC(C)(C)C>>[NH2:15][CH2:19][C@H:20]([NH:27][C:8]([C:4]1[S:5][CH:6]=[C:2]([C:31]2[N:32]([CH3:33])[N:28]=[CH:29][CH:30]=2)[CH:3]=1)=[O:10])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)NCCC(N)Cc1ccccc1
Reactant: CC(C)(C)N(C[C@H](N)c1ccccc1)C(=O)[O-]
Reactant: O=C(O)c1cc(Br)c(Br)s1
Product: Cn1nccc1-c1csc(C(=O)N[C@@H](CN)c2ccccc2)c1

Procedure:
The title compound was prepared as a white solid according to the procedure of Example 20, except substituting 4-bromo-2-thiophenecarboxylic acid (83 mg, 0.4 mmol) for 4,5-dibromo-2-thiophenecarboxylic acid and substituting 1,1-dimethylethyl[(2R)-2-amino-2-phenylethyl]carbamate (94 mg, 0.4 mmol) [prepared according to the procedure of Preparation 1] for 1,1-dimethylethyl (3-amino-4-phenylbutyl)carbamate: LC-MS (ES) m/z=327 (M+H)+, 1H NMR (CD3OD, 400 MHz) δ ppm 3.44 (d, J=4.29 Hz, 1H) 3.63 (br. s., 1H) 4.18 (s, 3H) 5.47 (dd, J=10.36, 4.55 Hz, 1H) 6.88 (d, J=2.78 Hz, 1H) 7.38 (d, J=7.07 Hz, 1H) 7.44 (t, J=7.33 Hz, 2H) 7.55 (d, J=7.83 Hz, 2H) 8.08 (d, J=2.53 Hz, 1H) 8.18 (d, J=1.26 Hz, 1H) 8.42 (d, J=1.26 Hz, 1H).
Reaction SMILES: C(P([CH:7]([CH:13]([CH3:15])C)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(CC)=O)C.[H-].[Na+].C([O:25][C:26]1[CH:33]=[CH:32]C(C=O)=[CH:28][CH:27]=1)C1C=CC=CC=1>O1CCCC1.CN(C)C=O.O>[OH:25][C:26]1[CH:27]=[CH:28][C:15]([CH2:13][CH:7]([O:25][CH:26]([CH3:33])[CH3:27])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C(C(C)C)P(=O)(CC)CC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(O)cc1)OC(C)C
Reaction time: 0.33 h
Yield: 151.4 %

Procedure:
5.2 g of Ethyl 2-(diethylphosphoryl)-2-isopropylacetate was dissolved in 40 ml of tetrahydrofuran, and 0.53 g of 60% sodium hydride was added under ice-cooling, and the mixture was stirred for 20 minutes under ice-cooling. The reaction solution was treated with a solution of 3.0 g of 4-benzyloxybenzaldehyde in 15 ml of tetrahydrofuran and 10 ml of N,N-dimethylformamide, and stirred at room temperature for 16 hours. The reaction solution was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography, and the fraction eluting with 5% ethyl acetate-hexane was concentrated. The residue was dissolved in 40 ml of ethanol, and 0.4g of 10% palladium carbon was added, the atmosphere was replaced with hydrogen, and the mixture was stirred at room temperature for 5 hours. Then, the atmosphere was replaced with nitrogen, the catalyst was filtered off, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (20% ethyl acetate-hexane), to give 2.7 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[O-]CC.[Na+].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](OCC)=[O:16]>O1CCCC1>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:16])[CH2:1][C:2](=[O:3])[CH3:4]
Reactant: CCOC(=O)c1ccccn1
Reactant: CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 8.71 g (150 mmol) of dry acetone in 100 ml of absolute tetrahydrofuran is added under argon to a solution of 20.42 g (300 mmol) of sodium ethoxide in 300 ml of absolute tetrahydrofuran. A solution of 22.68 g (150 mmol) of ethyl pyridine-2-carboxylate in 100 ml of absolute tetrahydrofuran is subsequently added dropwise over the course of 20 minutes. The mixture is stirred for 15 hours at room temperature and for 4 hours at the boiling point. The mixture is evaporated on a rotary evaporator, admixed with 150 ml of water and rendered neutral with glacial acetic acid. It is extracted twice with diethyl ether, the organic extracts are combined and dried (sodium sulfate), evaporated on a rotary evaporator, and 1-pyridin-2-ylbutane-1,3-dione is obtained as an orange oil. 1H-NMR (360 MHz, CDCl3) for enol tautomer: 15.8-15.5 (br s, OH); 8.60-8.55 (dm, 1H); 8.20-7.95 (dm, 1H); 7.79-7.71 (tm, 1H); 7.35-7.29 (m, 1H); 6.74 (s, 1H); 2.15 (s, 3H). Keto tautomer: CH2 group at 4.20 ppm (ratio of enol/keto form=87:13).
Reaction SMILES: C1C=CC2N([OH:10])N=NC=2C=1.C(N)C1C=CC=CC=1.[CH2:19]1[CH2:24][CH2:23][CH:22]([N:25]=[C:26]=[N:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:21][CH2:20]1>C(#N)C>[C:26]([NH:25][CH:22]1[CH2:21][CH2:20][CH2:19][CH2:24][CH2:23]1)([NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:10]
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: NCc1ccccc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 16 h

Procedure:
Fmoc-arginine(PMC)—OH AA3 (3.83 g, 5.0 mmol) and HOBT (0.76 g, 5.0 mmol) were combined in acetonitrile (100 mL) and benzylamine (0.54 g, 5.0 mmol) was added dropwise at about rt, followed by DCC (2.06 g, 10.0 mmol) and stirred for about 16 h. A solid was filtered and the filtrate was evaporated in vacuo to an oil, which was then dissolved in ethyl acetate (100 mL) and washed with saturated NaHCO3 (2×), brine (2×), then dried (Na2SO4) and evaporated in vacuo to a solid, which was triturated with hexane (2×) to give a solid (impure with dicyclohexylurea). A portion of this solid (1.17 g, 1.25 mmol) was dissolved in acetonitrile (30 mL), diethyl amine (1.5 mL) was added and the reaction was stirred at about rt for about 1 h. The solution was then evaporated in vacuo to a solid, which was triturated with hexane (2×). The solution was then evaporated in vacuo to a solid, which was then combined in ACN (25 mL) with Fmoc-3,4difluorophenylalanine (0.53 g, 1.25 mmol) and HOBT (0.19 g, 1.25 mmol). DIC (0.32 g, 2.5 mmol) was added and the reaction was stirred at about rt for about 16 h. Fmoc-protected dipeptide was filtered (0.77 g) and stirred in ACN (30 mL) with diethyl amine (1.5 mL) for about 2.5 h. The reaction was evaporated in vacuo to an oil, which was triturated with hexane (3×) to the white solid AA4.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[OH:11])[CH:5]=[CH:4][CH:3]=1.Br[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1.C(N(CC)CC)C.O>CN(C)C(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]([CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:16][CH2:17]2)[OH:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Br
Reactant: Cc1cccc(C#CC(O)C2CCNCC2)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C#CC(O)C2CCN(c3ncccc3[N+](=O)[O-])CC2)n1
Yield: 74.2 %

Procedure:
A well homogenised mixture of Compound 237a (200 mg, 0.86 mmol), 2-bromo-3-nitropyridine (194 mg, 0.95 mmol) and triethylamine (249 μL, 1.74 mmol) in N,N-dimethylacetamide (15 mL) was stirred at r.t. for 4 h. Afterwards, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography eluting with Petroleum Ether-EtOAc 7:3, affording the title product (225 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)=[O:29])=[CH:26][N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([NH:30][C:28]([C:27]2[C:26]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])=[N:25][CH:24]=[N:23][CH:22]=2)=[O:29])[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: COc1cccc(NC(=O)c2cncnc2Cl)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cccc(NC(=O)c2cncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 120 °C
Yield: 24.2 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (15 mg, 0.06 mmol), 4-chloro-N-(3-methoxyphenyl)pyrimidine-5-carboxamide (14 mg, 0.05 mmol, prepared according to R. Tadiparthi et al PCT Int. Appl. 2007031829, 22 Mar. 2007), DIEA (50 μl, 0.29 mmol) and cesium fluoride (17 mg, 0.11 mmol) were suspended in tert-butanol (2 ml) and the mixture was heated at 120° C. in a sealed tube for 18 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (0% to 10%, dichloromethane-methanol) to obtain 6 mg (5% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.ClC(Cl)C.[CH3:36][N:37]([CH3:48])[C:38](=[O:47])[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([NH2:46])[CH:41]=1>>[CH3:36][N:37]([CH3:48])[C:38]([O:39][C:40]1[CH:41]=[C:42]([NH:46][C:14]([C:11]2([CH3:17])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH:43]=[CH:44][CH:45]=1)=[O:47]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: CN(C)C(=O)Oc1cccc(N)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(C)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
1-(tert-Butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (67 mg, 0.28 mmol), EDC (64 mg, 0.33 mmol), HOBT (45 mg, 0.33 mmol) and dichloroethane (2.0 mL) were combined in a pressure rated sealed tube and stirred for 45 min. 3-Aminophenyl dimethylcarbamate (50 mg, 0.28 mmol) was added, and the mixture was heated at 85° C. for 18 hours. The mixture was concentrated and chromatographed (SiO2, 0-2% MeOH:CH2Cl2) to give the title compound in 50% yield. MS (ES+) [M+H]+=406.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:35]=[CH:34][C:22]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])=[CH:21][C:20]=1[Cl:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(C)CC(O)C>[Cl:36][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][C:19]=1[NH:18][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])[C:23]([NH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:24]
Reactant: Nc1ccc(C(=O)NCCN2CCOCC2)cc1Cl
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Solvent: CO
Product: CC(C)N1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NCCN4CCOCC4)cc3Cl)nc21
Yield: 15.5 %

Procedure:
10-chloro-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 76; 150 mg, 0.59 mmol), 4-amino-3-chloro-N-(2-morpholin-4-ylethyl)benzamide (Intermediate 52; 168 mg, 0.59 mmol), and p-toluenesulphonic acid monohydrate (281 mg, 1.47 mmol) were heated in 4-methyl-2-pentanol (4 mL) at 140° C. for 2 hours. The reaction mixture was cooled and loaded onto an SCX-3 column pre-wet with Methanol. The column was washed with methanol to remove p-toluenesulphonic acid monohydrate and then washed with 2% 7N ammonia/methanol to elute the crude product. Product containing fractions were evaporated and the resultant material purified by reverse phase HPLC to yield the title compound as an orange gum (46 mg, 15.6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][O:20][C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:26]([O:29][CH2:30][C:31](Cl)=[O:32])(=[O:28])[CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][O:20][C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:31](=[O:32])[CH2:30][O:29][C:26](=[O:28])[CH3:27])[CH2:10][CH2:9]1
Reactant: Fc1cc(C2=NOC(COc3ccon3)C2)ccc1N1CCNCC1
Reactant: CC(=O)OCC(=O)Cl
Product: CC(=O)OCC(=O)N1CCN(c2ccc(C3=NOC(COc4ccon4)C3)cc2F)CC1

Procedure:
(5RS)-3-(3-Fluoro-4-piperazin-1-ylphenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (175 mg, 0.51 mM) was treated with acetoxyacetyl chloride using essentially the conditions of Example 16, to give the desired product after chromatography and precipitation (163 mg).
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:4]1)=O.[C-:15]#[N:16].[Na+].[NH4+:18].[OH-].[NH4+].[Cl-]>CCO.O>[NH2:18][CH:1]([C:15]#[N:16])[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C[C@H]1CC[C@H](C=O)CC1
Reactant: [NH4+]
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C[C@H]1CC[C@H](C(N)C#N)CC1
Temperature: 70 °C

Procedure:
A mixture of ethyl 2-(trans-4-formylcyclohexyl)acetate (0.75 g, 3.78 mmol), NaCN (0.21 g, 4.28 mmol), saturated aqueous NH4OH solution (0.53 mL) and NH4Cl (0.24 g) in EtOH (22 mL) and water (11 mL) was heated at 70° C. overnight. After removal of organic solvent, the residue was extracted with EtOAc, washed with saturated NaHCO3 solution and brine, dried over Na2SO4. Filtration and evaporation to dryness gave the crude product. LC/MC: 225.1 (MH)+.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[CH:27]C(C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[CH3:29][C:30](C)([O-])C.[K+].[CH2:35]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH2:44][CH2:45][C@H:46]2[CH2:51][CH2:50][C@H:49]([C:52]3[CH:59]=[CH:58][CH:57]=[CH:56][C:53]=3[CH:54]=O)[CH2:48][CH2:47]2)[CH2:40][CH2:39]1)[CH2:36][CH3:37].O>C1COCC1>[CH2:35]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH2:44][CH2:45][C@H:46]2[CH2:47][CH2:48][C@H:49]([C:52]3[CH:30]=[CH:29][C:57]([CH:56]=[CH:53][C:54]4[CH:27]=[CH:28][C:3]([Cl:2])=[CH:4][CH:5]=4)=[CH:58][CH:59]=3)[CH2:50][CH2:51]2)[CH2:40][CH2:39]1)[CH2:36][CH3:37]
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccccc3C=O)CC2)CC1
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(C=Cc4ccc(Cl)cc4)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Suspension of 10.7 g of 4-chlorobenzyltriphenyl phosphonium bromide in 100 ml of THF was stirred under nitrogen gas stream and 2.5 g of potassium-t-butoxide was added thereto at room temperature. After stirred at room temperature for 1 hour, a solution prepared by dissolving 6 g of the (trans-4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexyl)benzaldehyde mentioned above in 50 ml of THF was added dropwise. After stirred at room temperature for 2 hours, 300 ml of water was added and extracted with 300 ml of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under a reduced pressure, and then 250 ml of heptane was added thereto. Precipitate thus separated was filtered off and purified by a column chromatography over silica gel by using ethyl acetate/heptane (1/5) as an eluent. Solvent was distilled off under a reduced pressure to obtain 5.4 g of 4-(2-(4-(trans-4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexyl)phenyl)ethenyl)chlorobenzene.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][O:5][N:4]=1.Cl.[NH2:9][CH2:10][CH2:11][SH:12].[BrH:13]>>[BrH:13].[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[CH:7]=[CH:6][O:5][N:4]=1
Reactant: ClCc1ccon1
Reactant: NCCS
Agent: Br
Agent: Cl
Product: NCCSCc1ccon1

Procedure:
A solution of 3-chloromethylisoxazole (5.8 g.) and cysteamine hydrochloride (6.25 g.) in aqueous hydrobromic acid (48%, 100 ml.) was heated under reflux for 6 hours. Concentration in the presence of water and subsequently n-propanol, followed by recrystallisation of the residue from isopropyl alcohol-ethanol afforded 3-[(2-aminoethyl)thiomethyl]isoxazole hydrobromide, m.p. 131°-133°. (Found: Br, 33.6; S, 13.7. C6H10N2OS.HBr requires: Br, 33.4; S, 13.4).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.C(#N)C.C(N(CC)CC)C.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>C1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:27](=[O:28])[CH2:26][O:25][CH3:24])=[C:7]([CH3:12])[CH:6]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: c1ccccc1
Product: CNC(=O)Oc1ccc(NC(=O)COC)c(C)c1

Procedure:
3-methyl-4-aminophenyl N-methylcarbamate (3.6g. 0.02 mole) was dissolved in 35 ml. of benzene and 25 ml. of acetonitrile along with triethylamine (2.23g., 0.022 mole). To this stirred solution was added dropwise a solution of methoxyacetyl chloride in benzene. An exotherm to 45° C. was noted as solids began to form. Further heating at reflux for one hour yielded 2.4g. of Et3N.HCl upon filtration. Solvent removal from the filtrate under reduced pressure gave a product which was recrystallized from ethanol-water. The tan solid (2.4g.) melted at 129.5°-132° C. and the infrared spectrum (KBr) displayed the characteristic double carbonyl (5.7 μ and 5.95 μ).
Reaction SMILES: [C:1]12([N:11]([CH3:13])[CH3:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[S:14]([O:19]C)([O:17][CH3:18])(=[O:16])=[O:15]>O>[S:14]([O-:19])([O-:17])(=[O:16])=[O:15].[C:1]12([N+:11]([CH3:18])([CH3:13])[CH3:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2.[C:1]12([N+:11]([CH3:18])([CH3:13])[CH3:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COS(=O)(=O)OC
Reactant: CN(C)C12CC3CC(CC(C3)C1)C2
Solvent: O
Product: C[N+](C)(C)C12CC3CC(CC(C3)C1)C2
Product: O=S(=O)([O-])[O-]
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A 2.5 m3 stirred vessel is charged with 2.5 t of water and 533 kg of 1-adamantyldimethylamine. Subsequently, 191 kg of dimethyl sulfate are metered in and the resulting reaction mixture is reacted at 30 to 50° C. for 2 hours. Subsequently the tank is heated to 140° C., an internal pressure of 4 bar being attained, and reaction continues at this temperature for 16 hours. The quaternization product is subjected to distillative removal of water, giving a 30% to 33% strength by weight solution of 1-adamantyltrimethylammonium sulfate. Conversion: 99%
Reaction SMILES: [N:1]#[N:2].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])(=[O:15])=[O:14].S(Cl)([Cl:30])=O.[CH3:32]O>>[N:1]#[N:2].[ClH:30].[CH3:32][O:26][C:25](=[O:27])[C@H:17]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])[NH:16][S:13]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1)(=[O:14])=[O:15]
Reactant: CO
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)O
Reactant: O=S(Cl)Cl
Agent: N#N
Product: COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2ccccc2c1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To an ice-cooled suspension of 1.0 gram of N2 -(2-naphthalenesulfonyl)-L-arginine in 15 ml of methanol was added dropwise 0.5 ml of thionyl chloride with vigorous stirring. After being allowed to stand for 2 hours at room temperature, the reaction mixture was refluxed for 2 hours, and was evaporated to dryness (syrup). Treatment of the residual syrup with cold ethyl ether gave crude crystals. After recrystallization from methanol-ethyl ether, colorless N2 -(2-naphthalenesulfonyl)-L-arginine methyl ester hydrochloride was obtained in 90% yield; mp. 183° - 186° C.