Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:20][C:21]1([F:29])[CH2:25][NH:24][C@@H:23]([C:26]([NH2:28])=[O:27])[CH2:22]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([N:24]3[CH2:25][C:21]([F:29])([F:20])[CH2:22][C@H:23]3[C:26]([NH2:28])=[O:27])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@H]1CC(F)(F)CN1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and (R)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 719267-96-6) as starting materials and isolated (33 mg, 44%); MS (ESI, m/z): 394.5 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](N=O)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=[O:25])=CC=1.C(N(CC)CC)C.O>CC(N(C)C)=O>[C:1]([C:5]1[C:6](=[O:17])[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9](=[O:25])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 117.6 %

Procedure:
270 g (1.15 mols) of 2,6-ditert.butyl-4-nitrosophenol are dissolved in 2.5 liters of dimethylacetamide. A solution of 256 g (1.35 mols) of p-toluenesulphonic acid chloride in 1.1 liters of dimethylacetamide is added dropwise at room temperature. 112 g (1.10 mols) of triethylamine are then added rapidly and the mixture is stirred for 2 hours at 80° C. After cooling, it is poured into 15 liters of water and the precipitated product is filtered off. After drying it is recrystallised from hexane. 298 g of 2,6-ditert.butyl-benzoquinone monoxime p-toluenesulphonate of melting point 110° C are thus obtained.
Reaction SMILES: [Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25].[CH2:26]([Mg]Br)[CH:27]([CH3:29])[CH3:28]>C1COCC1.C(Cl)Cl.O>[Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]([OH:25])[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Reactant: CC(C)C[Mg]Br
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(O)c1c(Br)sc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.5 %

Procedure:
To a solution of 6-bromo-1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (400 mg, 0.92 mmol) in THF (5 mL) was added isobutylmagnesium bromide (0.92 mL, 0.92 mmol) dropwise. The reaction was stirred at RT for 5 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 6-bromo-5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (70 mg, 15.4% yield) as a solid. LCMS: MH+ 405 and TR=1.922 min.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][CH2:12][CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[CH2:9][C:8]=2[CH:24]=1.[BrH:27].CC(O)=O>C(OCC)C>[BrH:27].[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[CH:24]=1.[BrH:27]
Reactant: O=C(OCc1ccccc1)N1CCSc2ccc(OC(F)(F)F)cc2C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: FC(F)(F)Oc1ccc2c(c1)CNCCS2

Procedure:
The starting material 30 (200 mg) was treated with 3 mL of HBr/AcOH solution for 1 h. To the reaction mixture was added diethyl ether (20 mL). The white solid was filtered to give the title compound as HBr salt. Yield: 182 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:21][OH:22])=[NH:15])[CH:11]=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#Cc1cc(C(F)(F)F)cc(-c2ccc(Cl)cc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1cc(C(F)(F)F)cc(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
A mixture of 6-(4-chloro-phenyl)-4-trifluoromethyl-pyridine-2-carbonitrile (example B.5) (3.6 g, 13 mmol), hydroxylamin-hydrochloride (3.275 g, 47 mmol) and sodium carbonate (2.7 g, 47 mmol) in EtOH (60 ml) and water (60 ml) was stirred under argon atmosphere at 100° C. for 4 h. The EtOH was evaporated, the mixture was diluted with water and stirred for 1 h at 0° C. The crude product was filtered and dried in HV to give the pure title compound as a light yellow solid (3.54 g, 88%). MS (ISP) 316.1 [(M+H)+] and 318 [(M+2+H)+]; mp 180-186° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH:24]([C:33]([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28].C1CCC([N:56]=C=NC2CCCCC2)CC1>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:33]([NH:24][C@H:25]([C:30]([NH2:56])=[O:32])[CH2:26][CH:27]([CH3:29])[CH3:28])([O:35][CH2:36][CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:34]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Yield: 74.9 %

Procedure:
(Z)-1-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-ethene (1.92 g, 6.1 mmols), 2.58 g (7.3 mmols) of Fmoc-L-Leu, 1.5 g (7.3 mmols) of DCC and 1.1 g (7.3 mmols) of HOBtH2O were dissolved in 40 ml of N,N-dimethylformamide, and the mixture was reacted at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate, then filtered and concentrated. The product was purified through silica-gel column chromatography (mixture of ethyl acetate and hexane at a ratio by volume of 1:2) to produce 3.05 g of the final product in a yield of 76.9%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:10])[CH2:9][CH2:8][CH2:7]1)=[O:5].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1([NH:10][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N+:11]([O-:13])=[O:12])(=[O:21])=[O:22])[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)C1(N)CCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
methyl-1-aminocyclobutanecarboxylate hydrochloride (300 mg, 1.81 mmol) was dissolved in CH2Cl2 (7 ml), and added with 2-nitrobenzene-1-sulfonyl chloride (441 mg, 1.99 mmol) and triethylamine (1 ml, 7.24 mmol), followed by stirring at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-1-(2-nitrophenylsulfonamido)cyclobutanecarboxylate (512 mg, 1.63 mmol, 90%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=1.[C:21](=[O:23])=[O:22]>O1CCCC1>[Cl:20][C:16]1[N:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=1[C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: Clc1cccc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine 3.76 g in tetrahydrofuran 25 ml is dropped at −78° C. n-butyllithium (23.2 ml). The mixture is stirred at 0° C. for 10 minutes and thereto is added 2,6-dichloropyridine 5.0 g in tetrahydrofuran 25 ml at −78° C. over a period of 20 minutes. The mixture is stirred at −78° C. for 3 hours. The reaction mixture is poured into powdered dry ice and is left at room temperature overnight. After removal of the solvent the residue is dissolved in a mixture of ethyl acetate and a 10% aqueous sodium hydroxide solution, and the water layer is separated and made acid with concentrated hydrochloric acid. The resulting colorless precipitate is filtered and washed with cold water to give 2,6-dichloronicotinic acid 4.50 g. mp 148-150° C., MS(ESI): 190(M−H)−
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[S:19][CH2:20][CH2:21][CH2:22][NH2+:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CCN(CC)CC.[C:39](Cl)(=[O:44])[CH2:40][CH2:41][CH2:42][CH3:43]>ClCCCl>[C:2]([O:6][C:7](=[O:8])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[S:19][CH2:20][CH2:21][CH2:22][N:23]([C:39](=[O:44])[CH2:40][CH2:41][CH2:42][CH3:43])[CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)Cn1c(SCCC[NH2+]CCc2ccccc2)nc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)N(CCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C)CCc1ccccc1
Reaction time: 2 h

Procedure:
[3-(1-tert-Butoxycarbonylmethyl-1H-benzoimidazol-2-ylsulfanyl)-propyl]-phenethyl-ammonium chloride (Precursor U-01b, 11.6 mg, 0.025 mmol) and Et3N (12.2 mg, 17.2 μl, 0.1 mmol) are dissolved in 1,2-dichloroethane (0.2 ml). To this solution is added valerylchloride (9 mg, 8.95 μl, 0.075 mmol) and the stirring is continued for 2 h. Then 1,2-dichloroethane (0.4 ml) and tris-(2-aminoethyl)amine polystyrene (3.4 mmol/g, 22 mg, 0.075 mmol) are added. After 30 min of shaking the resin is filtered off. Then methylisocyanate polystyrene (2.5 mmol/g, 30 mg, 0.075 mmol) is added as well as 1,2-dichloroethane (0.5 ml) and the resulting suspension is stirred for 2 h. It is filtered and the organic filtrate is washed with an aqueous KH2PO4 solution (pH=4) and water. Finally the organic phase is dried over Na2SO4 and evaporated to dryness yielding the title compound: tR=2.62 min (LC-2), ESI-MS (pos.): m/z 510.49 [M+H]+; 1H-NMR (DMSO-d6 at 100° C.): δ (ppm) 0.80 (t, 3H, CH2CH3), 1.19 (m, 2H, CH2CH3), 1.37 (m, 2H, CH2CH2CH3), 1.40 (s, 9H, tBu), 1.91 (m, 2H, CH2CH2N), 2.08 (m, 1H, COCHa), 2.24 (m, 1H, COCHb), 2.71-2.83 (m, 2H, CH2Ph), 3.30 (m, 2H), 3.32-3.43 (m, 4H), 4.98 (m, 2H, CH2CO2), 7.12-7.26 (m, 7 Harm), 7.50 (m, 2Harom).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.Br[CH:22]([CH3:25])[C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][CH:22]([CH3:25])[C:23]#[N:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(Br)C#N
Reactant: Oc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C#N)Oc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
A mixture of the phenol from Step 1 (150 g), (+) 2-bromo-propionitrile and milled potassium carbonate in methylethyl ketone (1 L) was refluxed for 8 hrs. The reaction mixture was cooled and filtered. Recrystallization from ethyl acetate/hexane afforded the title compound m.p. 118°-120°.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]([C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1CO)[CH3:26]>C1COCC1>[CH3:26][O:25][C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1[CH2:1][Br:5]
Reactant: COc1ccc(OC)c(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(CBr)c1
Reaction time: 2 h

Procedure:
Carbon tetrabromide (0.47 g, 1.25 mmol) and triphenylphosphine (0.47 g, 1.25 mmol) were added to a solution of 2,5-dimethoxylbenzylalcohol (0.2 g, 1.19 mmol) in THF (10 ml) at room temperature. The mixture was stirred for two hours to form a precipitate which the preciptate was filtered off. The filtrate was evaprated and the crude product was chromatographed (ethyl acetate and hexane 7:3). The desired compound was isolated as a white solid (0.25 g, 93%).
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].C(=O)CCC.C=O>>[CH2:6]([C:3]([CH2:8][OH:9])([CH2:4][CH3:5])[CH:1]=[O:2])[OH:7].[CH2:6]([CH:3]([CH2:4][CH3:5])[CH:1]=[O:2])[OH:7]
Reactant: CCC(CO)(CO)CO
Agent: C=O
Solvent: CCCC=O
Product: CCC(C=O)(CO)CO
Product: CCC(C=O)CO

Procedure:
The industrial preparation of trimethylolpropane (TMP) starts out from n-butyraldehyde and formaldehyde that are reacted in a two-stage reaction process. In a first reaction step, 2,2-dimethylolbutanal is formed first in a base-catalyzed aldol condensation via the intermediate 2-methylolbutanal. In a subsequent cross Cannizzaro reaction, trimethylol-propane together with formate salts are formed in the presence of stoichiometric amounts of a base.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)[N:27]=1.N1CCNCC1>>[N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:22])=[O:23])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:6][CH2:5][NH:27][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCCC3)n2)c1
Agent: C1CNCCN1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCNCC3)n2)c1

Procedure:
B11 was prepared following the procedure reported for B1 using A1 and piperazine. MS (ES) C14H19N7O2S requires: 349. found: 350 (M+H)+.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:10][C:11](=[O:25])[NH:12][CH:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:24])[C:20]([NH:22][CH3:23])=[S:21])[CH2:15][CH2:14]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(C#N)(C)=O>[CH2:3]([O:10][C:11](=[O:25])[NH:12][CH:13]1[CH2:14][CH2:15][CH:16]([N:19]([CH3:24])[C:20](=[N:22][CH3:23])[S:21][CH3:1])[CH2:17][CH2:18]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[IH:2]
Reactant: CI
Reactant: CNC(=S)N(C)C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: CC(=O)C#N
Product: CN=C(SC)N(C)C1CCC(NC(=O)OCc2ccccc2)CC1
Product: I

Procedure:
0.18 ml of methyliodide are added to a solution of 0.64 g [4-(1,3-dimethyl-thioureido)-cyclohexyl]carbamic acid benzylester in 30 ml of AcCN. The mixture obtained is refluxed for 2.5 hours and solvent is evaporated. [4-(1,2,3-Trimethyl-isothioureido)-cyclohexyl]-carbamic acid benzylester in the form of a hydroiodide is obtained.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[OH:3].[H-].[Na+].[H][H].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[N:23]1[C:27](S(C)(=O)=O)=[C:26]([C:32]#[N:33])[CH:25]=[N:24]1.N1C=CC=N1>O1CCCC1>[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][C:14]=1[N:23]1[C:27]([O:3][CH:2]([C:1]([O:6][CH3:7])=[O:5])[CH3:4])=[C:26]([C:32]#[N:33])[CH:25]=[N:24]1
Reactant: COC(=O)C(C)O
Reactant: [H][H]
Reactant: CS(=O)(=O)c1c(C#N)cnn1-c1ccc(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Agent: c1cn[nH]c1
Solvent: C1CCOC1
Product: COC(=O)C(C)Oc1c(C#N)cnn1-c1ccc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
1.1 g (0.011 mol) of methyl lactate are added dropwise to a suspension of 0.4 g (0.11 mol) of sodium hydride in 100 ml of anhydrous tetrahydrofuran. When the hydrogen evolution has ceased, a solution of 3.5 g (0.01 mol) of 1-(2-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-methanesulphonyl-pyrazole (Ex. I-4) in tetrahydrofuran is added dropwise. After stirring at room temperature for 1 hour, some starting pyrazole can still be detected by thin-layer chromatography. After addition of a further 0.04 g of sodium hydride and 0.1 g of methyl lactate and stirring f 2 hours, starting pyrazole can no longer be detected by thin-layer chromatography. The reaction batch is concentrated in vacuo, the residue is distributed between water and methylene chloride, and the methylene chloride phase is washed with water, dried over sodium sulphate and concentrated in vacuo. The oily residue crystallizes overnight. After trituration with petroleum ether and filtering off, 2.3 g (62% of theory) of 1-(2-chloro-4-trifluoromethyl-phenyl)-4-cyano-5 -(1-methoxycarbonylethoxy)-pyrazole of melting point 82°-85° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][N:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=3)[CH:17]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(F)(F)F)cn2)cn1
Temperature: 120 °C
Yield: 82.4 %

Procedure:
A mixture of 4-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-[1,2,3]triazole (36 mg, 0.15 mmol), 2-chloro-5(trifluoromethyl)pyridine (27 mg, 0.15 mmol) and potassium carbonate (41 mg, 0.3 mmol) in DMF (0.6 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (48 mg, 84%) as a white solid. MS: m/e=389.2 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:5]=[N:6][S:7][C:8]=1[C:9]([NH:11][NH2:12])=[O:10].[C:13](=S)=[S:14]>O.C(O)C>[SH:14][C:13]1[O:10][C:9]([C:8]2[S:7][N:6]=[N:5][C:4]=2[CH3:3])=[N:11][N:12]=1
Reactant: S=C=S
Reactant: Cc1nnsc1C(=O)NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nnsc1-c1nnc(S)o1
Reaction time: 6.5 h
Yield: 59 %

Procedure:
A solution of 0.3 g of potassium hydroxide in 1 ml water and 0.6 ml of carbon disulfide were successively added to a solution of 1.1 g (7.2 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbohydrazide in 15 ml ethanol. The mixture was stirred for 6.5 hours with heating under reflux. After the reaction was completed, the solvent was distilled off under reduced pressure, water was added to the residue, acetic acid was added for the sake of acidification, and the deposited crystalline product was collected by filtration. Thus, 0.82 g of the objective compound was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CN1CCCC1=O.[CH2:27]([O:34][C:35]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][CH2:62]Br)=[CH:56][C:36]=1[C:37]([NH:39][C:40]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43])=[O:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C.O>[CH2:27]([O:34][C:35]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][CH2:62][CH:17]2[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:15][CH2:16]2)=[CH:56][C:36]=1[C:37](=[O:38])[NH:39][C:40]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCBr)ccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
Potassium carbonate (0.12 g) and 1-(tert-butoxycarbonyl)piperidine (0.15 g) were added to a 1-methyl-2-pyrrolidone (2.0 mL) solution of methyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (0.40 g), followed by stirring at 90° C. for 45 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 80-0% hexane/ethyl acetate] to obtain 0.36 g of tert-butyl 4-(2-(4-(benzyloxy)-3-(2-(methoxycarbonyl)-5-phenylphenylcarbamoyl)phenoxy)ethyl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][O:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][O:17][CH2:16][CH2:15][N:14]2[S:27]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)C2COCCN2)no1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)C2COCCN2S(=O)(=O)c2ccc(Cl)cc2)no1

Procedure:
To a solution of morpholine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (55 mg; 0.19 mmol) in anhydrous DMF (1 mL) is added 4-chlorobenzenesulfonyl chloride (40.1 mg; 0.19 mmol) and N,N-diisopropylethylamine (0.089 mL; 0.513 mmol). The reaction mixture is left stirring at room temperature for 18 hours in the presence of catalytic amount of 4-dimethylaminopyridine. After this time, the reaction mixture is diluted with ethyl acetate and washed with eater 3 times, then brine, dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization from hot methanol provides the title compound, m/z 428 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1.[Br:37]N1C(=O)CCC1=O>C1COCC1>[Br:37][C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[C:3]1[CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:8])[S:6][C:2]=1[Cl:1]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (121 mg, 0.22 mmol) [prepared in Example 25] and N-bromosuccinimide (52 mg, 0.290 mmol) in THF (2 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification: LCMS (ES) m/z=622 (M+H)+.