Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[C:8]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][C:26]=2[O:35][CH3:36])=[CH:7]1)(=[O:3])[NH2:2].CO.O1CCCC1.O.[OH-].[Li+]>O>[C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[C:8]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]=2[O:35][CH3:36])=[CH:7]1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc(Cc2cn(CCC(N)=O)c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1cn(CCC(N)=O)c2ccc(C(=O)NCC3CCCC3)cc12
Reaction time: 12 h
Yield: 79.2 %

Procedure:
A solution of methyl 4-[1-(2-carbamoylethyl)-5-(N-cyclopentylmethylcarbamoyl)indol-3-ylmethyl]-3-methoxybenzoate (0.13 g) in a combination of methanol (2 ml), tetrahydrofuran (2 ml), and water (1 ml) was treated with lithium hydroxide monohydrate (0.07 g). The mixture was stirred for 12 hours and then concentrated to remove the organic solvents. The resultant aqueous solution was acidified with 10% (v/v) hydrochloric acid. The white precipitate which formed was collected by filtration, washed with water, and dried under vacuum to give the title compound (0.10 g, 79%) as a white powder, mp 129°-131° C.
Reaction SMILES: CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C.[O:20]1[CH2:24][CH2:23][O:22][CH:21]1[CH2:25][NH:26][CH2:27][C:28]1[N:29]=[C:30]2[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][N:31]2[CH:38]=1.[F:39][C:40]1[CH:55]=[C:54]([F:56])[CH:53]=[C:52]([F:57])[C:41]=1[C:42]([C:44]1[CH:45]=[C:46]([C:49](O)=[O:50])[NH:47][CH:48]=1)=[O:43].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>>[C:36]([C:34]1[CH:33]=[CH:32][N:31]2[CH:38]=[C:28]([CH2:27][N:26]([CH2:25][CH:21]3[O:20][CH2:24][CH2:23][O:22]3)[C:49]([C:46]3[NH:47][CH:48]=[C:44]([C:42](=[O:43])[C:41]4[C:40]([F:39])=[CH:55][C:54]([F:56])=[CH:53][C:52]=4[F:57])[CH:45]=3)=[O:50])[N:29]=[C:30]2[CH:35]=1)#[N:37]
Reactant: N#Cc1ccn2cc(CNCC3OCCO3)nc2c1
Reactant: O=C(O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: N#Cc1ccn2cc(CN(CC3OCCO3)C(=O)c3cc(C(=O)c4c(F)cc(F)cc4F)c[nH]3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a DMF 3 mL solution of product obtained in step A (410 mg, 1.58 mmol) were added 4-(2,4,6-trifluoro-benzoyl)-1H-pyrrole-2-carboxylic acid (427 mg, 1.58 mmol), EDC (396 mg, 2.06 mmol), HOBt (316 mg, 2.06 mmol) and triethylamine (0.443 mL, 3.17 mmol). The reaction mixture was stirred overnight at room temperature. The resulting suspension was filtered and diluted with EtOAc, washed with sat. ammonium chloride aq., sat. sodium bicarbonate aq. and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as foam (430 mg). LC/MS: m/z 510(M+H).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[CH2:20]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:20]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:18][CH3:19])=[CH:17][CH:16]=3)=[CH:37][CH:38]=2)[CH2:29][CH2:30]1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC[C@H](C)CCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(O)cc2)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(OC(=O)c3ccc(OCCCCC[C@@H](C)CC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (S)-4-(6-methyloctyloxy)benzoyl chloride obtained was dissolved in 20 ml of toluene and then added dropwise to a solution of 0.26 g of 4-[2-(trans-4-pentylcyclohexyl)ethyl]phenol in 2 ml of pyridine. The reaction mixture was stirred at room temperature overnight, then poured into ice-water and extracted with diethyl ether. The extract was washed four times with 25 ml of 1N hydrochloric acid each time, then washed with 25 ml of 2N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Chromatography of the residual oil on silica gel with toluene gave 0.2 g of (S)-4-(6-methyloctyloxy)benzoic acid 4-[2-(trans-4-pentylcyclohexyl)ethyl]phenyl ester. The product was recrystallized several times from ethanol until the phase transition temperatures were constant. M.p. (C-S) 58°, transition S-S*C 58.5° C., transition S*C -Ch 93° C., cl.p. (CH-I) 140° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[CH3:8]>C(Cl)Cl>[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:14])=[CH:11][CH:10]=1)[CH3:8]
Reactant: C1COCCN1
Reactant: CCc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: CCc1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a cooled solution of 9.6 g (0.11 mole) of morpholine in 25 ml methylene chloride is added 8.4 g (0.05 mole) of 4-ethylbenzoyl chloride dropwise. The reaction is stirred 30 minutes and a white precipitate formed. The mixture is washed three times each with 25 ml of water, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 10.6 g of yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:13]1[CH:14]=[CH:15][CH:16]=[N:17][C:12]=1[N:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[CH:19]2)[CH2:7][CH2:8]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: BrCCCCN1CCN(c2ncccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CCCCn3cnc4ccccc43)CC2)nc1

Procedure:
A mixture of 6 g (20 mmol) of 2-[4-(4-bromobutyl)-1-piperazinyl]-pyrimidine, 2.36 g (20 mmol) of benzimidazole and 4.1 g (30 mmol) of potassium carbonate in 60 ml of dimethylformamide is refluxed for 14 hours. The reaction mixture is evaporated under vacuum, chloroform is added, the mixture is washed with water, dried over sodium sulphate and evaporated under vacuum and 4.8 g of 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}-1H-benzimidazole are obtained, which may be recrystallised from ethyl ether, with a melting point of 85°-88° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[S:14]1[C:23]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:17]=2[NH:16][C:15]1=[O:24]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:21][CH2:22][C:23]4[S:14][C:15](=[O:24])[NH:16][C:17]=4[CH2:18][CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=c1[nH]c2c(s1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2[nH]c(=O)sc2CC1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-Bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 3,4,5,6,7,8-hexahydro-thiazolo[4,5-d]azepin-2-one. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 40 mg (49% of theory). ESI-MS: m/z=394 (M+H)+; Rt(HPLC): 1.11 min. (Method J).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43](O)=[O:44])=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29](OCC)=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:46][C@H:47]1[CH2:52][CH2:51][C@H:50]([OH:53])[CH2:49][CH2:48]1>>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:44])[N:46]([CH:47]3[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]3)[C:29](=[O:30])[N:28]([CH2:34][C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])[C:13]=2[S:14][C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:20][CH:21]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(C2CCC(O)CC2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 52.2 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylic acid (3.19 g, 5 mmol) and trans-4-aminocyclohexanol (1.44 g, 12.5 mmol) gave the title compound (1.80 g, 52%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][N:20]([CH3:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([N:20]([CH3:35])[CH3:19])[CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(N(C)C)c3)n2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.59 min; [M+H]+=436.27.
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]1=[O:9].[I-].[I-].[CH4:12]>C(OCC)C.[Zn]>[C:2]12([C:3](=[O:9])[CH:4]3[CH2:8][CH:7]1[CH2:6][CH2:5]3)[CH2:12][CH2:1]2
Reactant: C
Reactant: C=C1C(=O)C2CCC1C2
Agent: [I-]
Agent: [Zn]
Solvent: CCOCC
Product: O=C1C2CCC(C2)C12CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc powder (15.10 g) was suspended in diethyl ether (70 mL) and to which cuprous chloride (2.29 g) was added at room temperature, followed by 30 minutes' refluxing in nitrogen atmosphere. The suspension was cooled to 0° C. and to which 3-methylenebicyclo[2.2.1]heptan-2-one (7.0 mL) was added at 0° C. Into the reaction mixture, methane diiodide (7.0 mL) was slowly dropped at 0° C. and after the end of the dropping, the reaction mixture was refluxed for 30 hours in nitrogen atmosphere. Cooling the reaction mixture to room temperature, the insoluble matter was filtered off with Celite® and the filterate washed twice with 5% aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by distillation, and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=100/1−7/1) to provide 4.89 g of the title compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:12]1)C(=O)OC(C)(C)C)[CH3:2].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>ClCCl>[CH2:1]([NH:3][CH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:12]1)[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
tert-Butyl ethyl(3-(5-(thiophene-2-carboximidamido)-1H-indol-3-yl)cyclopentyl)carbamate (1.25 g, 2.76 mmol) was treated with 20% TFA solution (31 mL) in dichloromethane at 0° C. and the mixture left to stir for 2 hours at 0° C. The reaction then was neutralized with 10% NH4OH solution, the organic layer separated and evaporated. The crude was purified by column chromatography (20% 2N NH3 in MeOH: 80% CH2Cl2) to give the product as a yellow solid (0.87 g, 89%). 1H-NMR (DMSO-d6) δ 1.07 (t, 3H, J=7.2 Hz), 1.45-1.71 (m, 2H), 1.77-2.16 (m, 3H), 2.23-2.40 (m, 1H), 2.64-2.73 (m, 2H), 3.24-3.49 (m, 2H), 6.22 (brs, 2H, NH), 6.63 (d, 1H, J=8.1 Hz), 7.03-7.11 (m, 3H), 7.26 (d, 1H, J=8.4 Hz), 7.58 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.6 Hz), 10.57 (s, 1H, NH); EI-MS (m/z, %) 352 (M+, 50), 243 (80), 158 (100), EI-HRMS (M+) calc. for C20H24N4S, calculated: 352.1722. found: 352.1725.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]5[CH2:36][CH2:35]5)=[O:32])=[C:26]([F:37])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pt]=O>[CH:34]1([NH:33][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]3[C:17]4[CH:16]=[C:15]([C:12]5[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=5)[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:44])[CH3:46])[C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:25][C:26]=2[F:37])=[O:32])[CH2:36][CH2:35]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ncnc21
Agent: O=[Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2ccc(O)cc2)cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
After dissolving 263 mg of 1-(4-(6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenyl)-3-cyclopropylurea in 7 ml of ethanol and 3 ml of tetrahydrofuran, 30 mg of platinum oxide was added and the mixture was stirred overnight at room temperature and ordinary pressure under a hydrogen atmosphere, after which it was filtered with celite and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 160 mg of the title compound.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:19][C:20]([CH3:27])([CH3:26])[CH2:21][C:22]([NH:24][NH2:25])=[O:23]>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:25]/[NH:24][C:22](=[O:23])[CH2:21][C:20]([CH3:27])([CH3:26])[CH3:19])/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: CC(C)(C)CC(=O)NN
Product: CCCCCN1C(=O)/C(=N\NC(=O)CC(C)(C)C)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 3,3-dimethylbutanohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.10 and 1.12 (s for isomers, 9H), 1.36 to 1.39 (m, 4H), 1.55 (s, 2H), 1.67-1.70 (m, 2H), 2.29 (s, 111), 2.75 (s, 1H), 3.70 (t, 2H), 3.86 and 3.87 (s for isomers, 3H), 6.42 (s, 1H), 6.60 (d, 1H), 7.51 and 7.72 (d and br s for isomers, 1H), 12.39 and 12.98 (s and br s for isomers, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[C:13](=[O:22])[C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)=[CH:4][CH:3]=1.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31]Cl>>[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[C:13](=[O:22])[C:14]2[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C)cc(C(=O)c2c(-c3ccc(O)cc3)oc3ccccc23)c1
Reactant: CN(C)CCCCl
Product: Cc1cc(C)cc(C(=O)c2c(-c3ccc(OCCCN(C)C)cc3)oc3ccccc23)c1

Procedure:
Reaction of 2-p-hydroxyphenyl-3-(3',5'-dimethylbenzoyl)benzofuran with 3-dimethylaminopropyl chloride according to the procedure described in Example 7 gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][N:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[C:27]([CH3:33])=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:30]([C:28]2[C:27]([CH3:33])=[N:26][N:25]([CH3:24])[CH:29]=2)=[O:31])=[O:8])[N:6]=1
Reactant: Cc1nn(C)cc1C(=O)O
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1nn(C)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 1,3-Dimethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.69 min; [M+H]+=455.2.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([Si](C)(C)C)([F:19])[F:18]>CN(C)C=O>[CH2:1]([N:3]1[C:7]([CH:8]([OH:9])[C:17]([F:19])([F:18])[F:16])=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCn1cncc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cncc1C(O)C(F)(F)F
Yield: 47.1 %

Procedure:
According to Reference Example 8-2, by use of 1-ethyl-1H-imidazole-5-carbaldehyde (115 mg, 0.926 mmol) dissolved in N,N-dimethylformamide (2.3 mL), potassium carbonate (26 mg, 0.19 mmol) and (trifluoromethyl)trimethylsilane (0.300 mL, 2.04 mmol), the mixture was stirred and reacted at a temperature of room temperature to 50° C. for 6.8 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=10/1) was performed to give 1-(1-ethyl-1H-imidazol-5-yl)-2,2,2-trifluoroethanol (Compound DU) (84.7 mg, yield: 47%).
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O>[Br:1][C:2]1[C:9]([O:10][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(Br)c1O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOc1c(OC)ccc(C=O)c1Br
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
2-Bromo-3-hydroxy-4-methoxybenzaldehyde (225.2 g, 975 mmol) and DMF (660 ml) were mixed, and potassium carbonate (148.2 g, 1.07 mol) and bromopentane (133 ml, 1.07 mol) were successively added to this solution. The mixture was stirred at 90° C. for 1.5 hours and cooled to room temperature. Water (800 ml) was added to stop the reaction. The aqueous layer was extracted successively with diethyl ether (1000 ml, 500 ml) and ethyl acetate (500 ml). The organic layers were combined, washed successively with water (200 ml) and saturated brine (200 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 2-bromo4-methoxy-3-pentyloxybenzaldehyde.
Reaction SMILES: [C:1]([C:3]1([N:21]2[CH2:24][C:23]([F:26])([F:25])[CH2:22]2)[CH2:20][CH2:19][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4]1)#N.[C:27]1([Mg]Br)[CH:32]=[CH:31]C=[CH:29][CH:28]=1>C1COCC1>[F:25][C:23]1([F:26])[CH2:24][N:21]([C:3]2([C:1]3[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=3)[CH2:4][CH2:5][C:6]3([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7]3)[CH2:19][CH2:20]2)[CH2:22]1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(C#N)(N1CC(F)(F)C1)CC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(c1ccccc1)(N1CC(F)(F)C1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
The crude tert-butyl 9-cyano-9-(3,3-difluoroazetidin-1-yl)-3-azaspiro[5.5]-undecane-3-carboxylate was taken up in THF (20 ml) and PhMgBr (12 ml) was added at 0° C. The reaction mixture was stirred at room temperature overnight. The mixture was quenched with NH4Cl solution at 0° C. and was then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (silica gel (100-200)) to obtain the desired compound. Yield: 31%
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)OC)cc3)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)O)cc3)cc21

Procedure:
The mixture of 2.45 g of benzyl 4-(4-methoxycarbonylphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate, 16 ml of tetrahydrofuran and 16 ml of 2N NaOH is stirred at reflux over 18 hours. The reaction mixture is cooled, admixed with 20 ml of 2N HCl and extracted with tert-butyl methyl ether (3×50 ml). The organic phases are washed successively with water (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation to obtain the crude title compound as a white foam. Rt=4.45.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([OH:13])([C:9]([F:12])([F:11])[F:10])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[C:16]1([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:35]12([CH2:45][C:46](Cl)=[O:47])[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([CH2:38]3)[CH2:36]1)[CH2:42]2.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:35]12([CH2:45][C:46]([O:13][C:3]([C:2]([F:1])([F:14])[F:15])([C:9]([F:12])([F:10])[F:11])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6])=[O:47])[CH2:42][CH:41]3[CH2:40][CH:39]([CH2:38][CH:37]([CH2:43]3)[CH2:36]1)[CH2:44]2.[C:29]1([S+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=S(=O)([O-])CC(O)(C(F)(F)F)C(F)(F)F
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CC12CC3CC(CC(C3)C1)C2)OC(CS(=O)(=O)[O-])(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 48.5 %

Procedure:
Into a mixture solution of 2.6 g (5 mmoles) of triphenylsulfonium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate prepared in Synthesis Example 1-9, 1.3 g (6 mmoles) of 1-adamantaneacetyl chloride, and 15 g of methylene chloride was added a mixture solution of 0.63 g (6 mmoles) of triethylamine, 0.12 g (1 mmole) of 4-dimethylaminopyridine, and 5 g of methylene chloride, and they were stirred at room temperature for 5 days. Thereafter, the reaction was terminated by adding 7 g of 5% hydrochloric acid, and then the organic layer was separated, washed by water, and concentrated under reduced pressure. Into the concentrated solution was added methyl isobutyl ketone, and the resulted mixture was concentrated again under reduced pressure to distil the remaining water out. The obtained residue was recrystallized by adding diisopropyl ether, and then the crystals were recovered and dried to obtain the intended triphenylsulfonium 2-(2-adamantane-1-yl-acetoxy)-3,3,3-trifluoro-2-trifluoromethylpropane-1-sulfonate (1.7 g of white crystals (yield 48%)). The structure of the intended product is shown below.