Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH:30]=[C:31]1[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]=2[CH2:35][O:34][C:33]2[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]1=2>C(#N)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[CH:6]1[CH2:11][CH2:10][N:9]([CH2:28][CH2:29][CH:30]=[C:31]2[C:37]3[CH:38]=[CH:39][CH:40]=[N:41][C:36]=3[CH2:35][O:34][C:33]3[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]2=3)[CH2:8][CH2:7]1
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 25 °C
Reaction time: 312 h

Procedure:
To a solution of the product of step 3 (0.251 g, 0.680 mmol) in acetonitrile (4 mL) was added potassium carbonate (0.310 g, 2.24 mmol) in water (2 mL), followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (170 mg, 448 mmol). The resulting orange solution was stirred at rt 13 days. The mixture was diluted with ethyl acetate and washed with water and brine. The washed extracts were dried over magnesium sulfate, filtered and concentrated. Pure titled compound was afforded by silica gel chromatography of the crude material (methylene chloride-98/2 methylene chloride/methanol gradient); 107 mg, 41%.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]2[N:15]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:41])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]1[CH2:18][C:12]2[C:13](=[N:14][C:9]([S:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:41])=[N:10][CH:11]=2)[N:15]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:16]1=[O:26]
Reactant: O=C1N(c2ccccc2Cl)Cc2cnc(SCc3ccccc3)nc2N1C1CCNCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C1N(c2ccccc2Cl)Cc2cnc(S(=O)Cc3ccccc3)nc2N1C1CCNCC1
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
To a solution of 7-benzylthio-3-(2-chlorophenyl)-1-(piperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (920 mg, 1.62 mmol) in dichloromethane (16 mL) cooled to 0° C. was added 3-chloroperbenzoic acid (403 mg, 1.64 mmol). After an hour at room temperature 5 mL of 10% sodium thiosulphate was added. After 10 minutes, the dichloromethane layer was separated and washed with 10% potassium carbonate and brine, dried over magnesium sulfate, concentrated in vacuo to give 650 mg of 3-(2-chlorophenyl)-7-benzylsulfinyl-1-(piperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white foam.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([OH:13])=O)[CH:3]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:11]([C:4]5[CH:3]=[C:2]([CH3:1])[O:6][C:5]=5[C:7]([F:8])([F:9])[F:10])=[O:13])[CH:47]=[CH:46][CH:45]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Cc1cc(C(=O)O)c(C(F)(F)F)o1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C(F)(F)F)o1
Yield: 65.6 %

Procedure:
In the same manner as in Example 18-4 and using 5-methyl-2-(trifluoromethyl)-3-furoic acid (175 mg, 0.904 mmol), tetrahydrofuran (8 mL), oxalyl chloride (118 μL, 1.36 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (72.0 mg, 66%) was obtained as a white solid.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15](OC)=O.[NH3:22]>>[NH2:22][C:1]1[CH:2]=[CH:15][C:14]2[C:13](=[C:12]([O:11][CH:5]([CH3:3])[CH2:6][CH2:7][CH2:8][O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]([NH2:10])=[O:9])[CH:21]=[CH:20][CH:19]=2)[N:10]=1
Reactant: NC(=O)c1ccccc1O
Reactant: N
Reactant: COC(=O)c1cccc(O)c1
Product: CC(CCCOc1ccccc1C(N)=O)Oc1cccc2ccc(N)nc12

Procedure:
The title compound was prepared according to the procedure described in Example 92 substituting salicylamide for methyl 3-hydroxybenzoate. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.76 (dd, 1H), 7.35–7.58 (m, 6H), 7.10 (d, 1H), 7.01 (m, 1H), 4.87 (m, 1H), 4.18 (m, 2H), 1.84–2.05 (m, 4H), 1.40 (d, 3H); MS (DCI/NH3) m/z 366 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[CH2:28][NH2:29])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>C(Cl)Cl>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:17])([CH3:18])[CH3:16])[CH2:10][C@H:9]1[CH2:28][NH:29][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](CN)N(C(=O)OC(C)(C)C)C2)CC1
Solvent: ClCCl
Product: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](CNC(=O)OCc3ccccc3)N(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57012.8 %

Procedure:
To a solution of (2S,4S)-1-BOC-2-(aminomethyl)-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]pyrrolidine (410 mg, 1 mmol) prepared in Step A in DCM (10 ml) was slowly added dropwise benzyl chloroformate (200 mg, 1.2 mmol) at 0° C., and stirred at rt for 3 h. After the reaction finished, the solvent was concentrated in vacuo, the residue was extracted with water and EtOAc, and the organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=1/1) to give the title compound (310 g, 72%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)[CH:5]=[CH:4][C:3]=1[OH:22].[CH2:23](Br)[CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:23]([O:22][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)=[C:7]([F:8])[C:2]=1[F:1])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCBr
Reactant: CCCCC[C@H]1CC[C@H](COc2ccc(O)c(F)c2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H](COc2ccc(OCCCC)c(F)c2F)CC1

Procedure:
0.1 mol of 2,3-difluoro-4-(trans-4-pentylcyclohexyl)methoxyphenol, 0.11 mol of butyl bromide and 0.11 mol of potassium carbonate are heated for 16 hours at 100° in 100 ml of dimethylformamide (DMF). After cooling, the inorganic salts are filtered off with suction, the filtrate is concentrated, and water is added. 1-butyloxy-2,3-difluoro-4-(trans-4-pentylcyclohexyl)methoxybenzene is obtained by extraction with dichloromethane.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>>[CH3:10][O:11][CH2:12][CH2:13][NH:14][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: COCCN
Product: COCCNc1ccccc1C#N

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and 2-methoxyethylamine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:29])=[CH:22][CH:23]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:32])[F:33])#[N:2]
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(=O)O)cc3)C2=S)cc1C(F)(F)F
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
A mixture of 4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}butanoic acid (42c) (0.049 g, 0.1 mmol), 2,4,6-trichlorobenzoyl chloride (0.244 g, 1 mmol), 4-dimethylaminopyridine (0.122 g, 1 mmol) and methanesulfonamide (0.019 g, 0.2 mmol) in dichloromethane was stirred at room temperature for 20 hours. The mixture was concentrated and chromatographed (dichloromethane:acetone, 80:20) to yield N-(4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}-butanoyl)-methanesulfonamide (42f) [RD157] (0.053 g, 0.094 mmol, 94%), the structure of which is illustrated in Formula 8, as a white powder.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3][C:2]1=[O:1])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of benzyl 3-oxopiperazine-1-carboxylate (4.7 g, 20 mmol) in DMF (75 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (24 mL, 24 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with benzyl bromide (2.9 mL, 24 mmol), and stirred at room temperature overnight. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and ethyl acetate. The organic extracted was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 50-50 mixture of ethyl acetate and hexane. Collection and concentration of appropriate fractions provided the benzylated product.
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.Cl.[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1>>[F:15][C:16]([F:26])([F:27])[O:17][C:18]1[CH:19]=[CH:20][C:21]2[NH:24][C:2]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=4[CH2:4][C:3]=3[C:22]=2[CH:23]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: Cl
Product: O=C(O)c1cccc2c1Cc1c-2[nH]c2ccc(OC(F)(F)F)cc12
Yield: 8.5 %

Procedure:
In a manner similar to Example 17, 1-oxo-indan-4-carboxylic acid (1.00 g, 5.68 mmol) and 4-trifluoromethoxyphenylhydrazine hydrochloride (1.30 g, 5.68 mmol) were converted to the title compound (0.160 g, 8%) as an light tan solid: mp 256-265 (dec)° C.; 1H NMR (DMSO-d6): δ 4.03 (s, 2H), 7.05-7.08 (m, 1H), 7.49 (d, 1H), 7.53 (d, 1H), 7.61 (d, 1H), 7,79-7.83 (m, 2H), 11.92 (s, 1H), 13.08 (s, 1H); MS [EI, m/z]: 333 [M]+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([OH:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:16]>C(=O)(O)[O-].[Na+]>[C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([N:7]2[C:11]([Cl:16])=[CH:10][C:9]([OH:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(O)=NN1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CC(c2ccccc2)=NN1c1ccccc1
Product: Oc1cc(Cl)n(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
A mixture of 2,4-dihydro-2-phenyl-5-hydroxy-3H-pyrazol-3-one (1 g, 5.7 mmol) and POCl3 (1 g, 6.5 mmol) was heated at 100° C. for 4 hours and cooled. The mixture was diluted with ice/water and sodium bicarbonate solution was added (to pH=7). The aqueous layer was extracted with methylene chloride (3×), the organic layer was concentrated in vacuo, and the solid was crystallized from methylene chloride and recrystallized from acetonitrile and methylene chloride. The above solid was purified by column chromatography (silica gel, 6-33% ethyl acetate/hexane) to afford 110 mg of 2,4-dihydro-2-phenyl-5-chloro-3H-pyrazol-3-one (Formula III: R1 =Ph; R2 =Cl; R3 =H) and 56 mg of 1-phenyl-3-hydroxy-5-chloropyrazole as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](CCC(O)=O)=[CH:2]1.C(N1C=CN=C1)([N:17]1C=CN=C1)=O.[O:27]1C[CH2:30][CH2:29][CH2:28]1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:30][CH2:29][C:28]([NH2:17])=[O:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Product: NC(=O)CCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-indolepropionic acid (15 g, 79 mmol), 1,1′-carbonyldimidazole (16.7 g, 100 mmol) in anhydrous tetrahydrofuran (150 ml) was allowed to stir for 1.5 hours at room temperature. Then NH3 was bubbled through the solution for 2.5 hours at room temperature. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate (500 ml). The organic solution was washed with water (3×150 ml ), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. The white solid was collected and dried under vacuum 10.42 g (96%); mp 124-125° C. MS EI m/e 188 (M+)
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:27]([N:26]([CH3:30])[CH3:25])=[O:28])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CN(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)S[C@H]1C[C@@H](COC(=O)N(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 20 h

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (78 mg) was dissolved in 1 ml of dry pyridine, and 135 mg of 4-N,N-dimethylaminopyridine and 119 mg of dimethylaminocarbonyl chloride were added successively thereto, followed by stirring at 90° to 100° C. for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed successively with water, dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyloxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](C)=COC)=[C:18]([CH3:27])[CH:17]=2)=[C:12]([CH:28]([CH3:30])[CH3:29])[CH:11]=[N:10]1.BrC1C=CC([O:36]CC2N(C3C(Cl)=CC=CC=3Cl)N=CC=2C(C)C)=CC=1C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[O:36])=[C:18]([CH3:27])[CH:17]=2)=[C:12]([CH:28]([CH3:30])[CH3:29])[CH:11]=[N:10]1
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1Br
Reactant: COC=C(C)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C=O
Yield: 75 %

Procedure:
The title compound (1.51 g, 75%) is prepared essentially according to the preparation of 1-(2,6-Dichloro-phenyl)-4-isopropyl-5-[4-(2-methoxy-1-methyl-vinyl)-3-methyl-phenoxymethyl]-1H-pyrazole using 5-(4-bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-pyrazole. 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 7.73 (s, 1H), 7.68 (d, 1H, J=8.8 Hz), 7.44-7.40 (m, 2H), 7.31 (dd, 1H, J=8.6, 7.3 Hz), 6.71 (dd, 1H, J=8.6, 2.4 Hz), 6.61 (d, 1H, J=2.4 Hz), 4.89 (s, 2H), 3.01 (sept, 1H, J=6.6 Hz), 2.60 (s, 3H), 1.32 (d, 6H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11](C(F)(F)F)[NH:12]2)=[CH:8][CH:7]=1)=[O:4].O.C([O-])([O-])=[O:23].[K+].[K+]>CO>[F:1][C:2]([F:20])([F:19])[C:3]([OH:23])=[O:4].[F:1][C:2]([F:20])([F:19])[C:10]1[C:9]2[C:13](=[CH:14][C:6]([NH2:5])=[CH:7][CH:8]=2)[NH:12][CH:11]=1
Reactant: O=C(Nc1ccc2cc(C(F)(F)F)[nH]c2c1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1ccc2c(C(F)(F)F)c[nH]c2c1
Product: O=C(O)C(F)(F)F
Yield: 212.2 %

Procedure:
2,2,2-trifluoro-N-(2-(trifluoromethyl)-1H-indol-6-yl)acetamide (28 mg, 0.09 mmol) was dissolved in MeOH (0.9 mL) and water (0.4 mL) in the presence of K2CO3 (90 mg, 0.65 mmol) and stirred overnight at room temperature. Purification (10 to 99% ACN in water) by LC-MS provided 3-(trifluoromethyl)-1H-indol-6-amine 2,2,2-trifluoroacetate (30 mg, quantitative yield). LC/MS: m/z 201.1 (M+H)+ at 0.90 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][CH:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:4]=2[S:3]1.[Si:13]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>N1CCCCC1.C1C=CC=CC=1.C(OCC)(=O)C>[Si:13]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:1]/[CH:2]2[N:7]=[CH:6][C:5]3[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:4]=3[S:3]2)[CH:23]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C=O)c1
Reactant: CC1N=Cc2cc(Cl)ccc2S1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(/C=C/C2N=Cc3cc(Cl)ccc3S2)c1
Reaction time: 30 h

Procedure:
A mixture of 1.08 g of 2-methyl-6-chloro-1,3-benzthiazine 1.51 g of 3-formylbenzyl alcohol t-butyldimethylsilyl ether and 5 drops of piperidine in 60 ml of benzene was heated to reflux in a Dean-Stark trap for 1 hour. An additional 5 drops of piperidine were added and the refluxing continued from 30 hours. The mixture was diluted with 400 ml of ethyl acetate and washed with water (1×40 ml) and brine (1×40 ml). The organic layer was dried over magnesium sulfate and concentrated to 2 g of crude product which was chromatographed on silica gel using 5% ethyl acetate in hexane (v:v), 188 mg, m.p. 58°-60° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC([O:5][CH:6]([CH3:8])C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:35]1[CH:40]2[CH2:41][CH2:42][N:37]([CH2:38][CH2:39]2)[CH2:36]1.[S:43]1C=CC=C1CC(O)=O>O1CCCC1.C(OCC)C.[OH-].[Na+]>[C:6]([S:43][CH:35]1[CH:40]2[CH2:41][CH2:42][N:37]([CH2:38][CH2:39]2)[CH2:36]1)(=[O:5])[CH3:8]
Reactant: O=C(O)Cc1cccs1
Reactant: OC1CN2CCC1CC2
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)SC1CN2CCC1CC2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl azodicarboxylate (31.6 cc) is added dropwise in the course of 30 minutes to a solution, maintained at 5° C. under an atmosphere of nitrogen, of triphenylphosphine (42 g) in tetrahydrofuran (300 cc). The suspension obtained in then stirred for 30 minutes at 5° C. A solution of 3-hydroxyquinuclidine (10.2 g) and thiolacetic acid (11.4 cc) in tetrahydrofuran (600 cc) is then added to this suspension, maintained at 5° C., in the course of 30 minutes. The reaction mixture is then stirred for 20 hours at a temperature in the region of 20° C. It is then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The oil obtained is dissolved in ethyl ether (400 cc), and then washed with hydrochloric acid (3×160 cc). The combined aqueous phases are washed with ethyl ether (100 cc) and then neutralized to a pH in the region of 7 by adding sodium bicarbonate. The pH of the solution obtained is then adjusted to about 9 by adding a few drops of 10N aqueous sodium hydroxide solution. The mixture is extracted with methylene chloride (3×200 cc). The combined organic phases are dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30° C. 3-(Acetylthio)quinuclidine (14.7 g) is thereby obtained in the form of a brown oil [Rf=0.33; eluant: methylene chloride/methanol (90:10 by volume)].
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C@@H:5]1[CH2:10][C@@H:9]([NH:11][S:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:14])=[O:13])[C@H:8]([OH:23])[CH2:7][CH2:6]1)=[O:4].[CH3:25][S:26](Cl)(=[O:28])=[O:27].CN1CCOCC1.Cl>C(#N)C.O>[CH3:25][S:26]([O:23][C@@H:8]1[CH2:7][CH2:6][C@H:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:24])[CH2:10][C@H:9]1[NH:11][S:12](=[O:13])(=[O:14])[NH:15][C:16]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:22])(=[O:28])=[O:27]
Reactant: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](NS(=O)(=O)NC(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CN(C)C(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NS(=O)(=O)NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
Acetonitrile (30 ml) was added to a solution of tert-butyl {[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]sulfamoyl}carbamate (12.1 g) in acetonitrile (30 ml), and the obtained solution was then cooled to approximately 0° C. Thereafter, methanesulfonyl chloride (3.77 ml) was added to the reaction solution. N-methylmorpholine (6.81 ml) was added dropwise to the reaction mixture, and the obtained mixture was then stirred for approximately 3 hours. Thereafter, water (61 ml) was added to the reaction mixture, and a 6 mol/l hydrochloric acid solution was then added thereto to adjust the pH of the mixture to pH 3. Water (93 ml) was further added to the mixture, and the thus obtained mixture was then stirred for approximately 15 hours. Thereafter, the precipitated solid was collected by filtration and was then washed with a 27.5% acetonitrile aqueous solution (30 ml). The obtained solid was dried under reduced pressure to obtain the title compound (13.0 g, yield: 89%). The spectra of the resulting product, which were obtained using various devices, were matched with those obtained in Example 5.