Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:21][C:22](O)=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:26]>>[CH2:25]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:22](=[O:23])[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:26]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reactant: CCNCc1ccccn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([O:17]CC)=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1.5 h

Procedure:
To a solution of 1,3-diethyl 2-{[(tert-butoxy)carbonyl]amino}propanedioate XCVI (2.22 g, 8 mmol) in a mixture of ethanol/water (45 mL/5 mL) was added KOH (0.45 g, 8 mmol) in water (3 mL) dropwise. The reaction mixture was stirred for 1.5 hours. The ethanol was evaporated and the residue was acidified to pH=2 by 2 M HCl and washed by DCM. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to give 2-{[(tert-butoxy)carbonyl]amino}-3-ethoxy-3-oxopropanoic acid XCVII as crystals (1.68 g, 6.8 mmol, 85% yield). 1H NMR (CDCl3) 1.31 (t, J=7 Hz, 3H), 1.41-1.45 (m, 9H), 4.23-4.31 9 m, 2H), 4.76 (d, J=4 Hz, 1H), 7.77 (d, J=4 Hz, 1H), 10.84 (brs, 1H); ESIMS found for C10H17NO6 m/z 248 (M+H).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[CH:15]([NH2:18])([CH3:17])[CH3:16].C(O)(=O)C>CO>[CH:15]([NH:18][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NCc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
Under a nitrogen atmosphere, add sodium cyanoborohydride (5.77 g, 91.6 mmol) to a solution of 4-cyanobenzaldehyde (3 g, 22.9 mmol), iso-propylamine (2.03 g, 34.4 mmol) and acetic acid (1.37 g, 22.9 mmol) in methanol (30 mL) at 0° C. with stirring. Warm the mixture to room temperature and stir overnight. Add water (100 mL), saturated aqueous K2CO3 (50 mL), and extract with DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (300 g) eluting with 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the desired intermediate (1.53 g, 38%). MS (APCI+) m/z: 175 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:18])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].C(OCC)(=O)C>C(Cl)Cl>[NH2:18][C:7]1[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Yield: 54.2 %

Procedure:
To a stirred solution of 5-tert-butyl-2-(4-methoxyphenyl)-2H-pyrazol-3-ylamine (5.3 g, 21.6 mmol) in anhydrous DCM (43.2 mL) was added aluminum trichloride (14.4 g, 108.0 mmol, 5.0 eq) proportion wise, and the reaction was stirred at reflux for 18 h. The cooled reaction was poured into ethyl acetate, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. Crystallization from DCM/ether afforded the title compound (2.71 g, 54%) as a white solid. 1H-NMR (DMSO-d6) δ 9.47 (s, 1H), 7.21 (d, J=9.0 Hz, 2H), 6.75 (d, J=8.7 Hz, 2H), 5.25 (s, 1H), 4.91 (broad s, 2H), 1.13 (s, 9H); MS LC-MS [M+H]+=232, RT=1.13 min; TLC (35% EtOAc/hex), Rf=0.13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Cl.[CH3:13]O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:13])=[O:7]
Reactant: CO
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc(Cl)cc1N
Reaction time: 2.5 h

Procedure:
A solution of 10.0 g (58 mmol) of 4-chloroanthranilic acid in 100 ml of methanol was heated under reflux, while gaseous hydrogen chloride was blown through the heated solution for 2.5 hrs. After the heating was terminated, methanol was distilled off. The residue was shaken with chloroform and aqueous sodium carbonate. The organic phase was taken out and dried over anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure to leave 9.68 g of the desired compound as a residual pale brown crystalline product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[NH2-:9].[Na+]>>[NH2:9][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][N:6]=1
Reactant: CCc1ccncc1
Reactant: [NH2-]
Agent: [Na+]
Product: CCc1ccnc(N)c1

Procedure:
This amine is prepared by the method of Case and Kasper from 4-ethylpyridine (Aldrich Chemical) and sodium amide (Fisher Scientific Co.) in 55% molar yield, mp 66°-70° (lit.1 70°-1°).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1)[OH:4].C(N(CC)CC)C.[OH2:26].Cl>CS(C)=O>[F:18][C:2]([F:1])([F:17])[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1)([OH:26])[OH:4]
Reactant: O=c1nc(-c2cc(C(O)C(F)(F)F)ccn2)[nH]o1
Reactant: O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=c1nc(-c2cc(C(O)(O)C(F)(F)F)ccn2)[nH]o1
Reaction time: 8 h

Procedure:
To 2 ml of dimethyl sulfoxide were added 0.3 g of 3-[4-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl]-1,2,4-oxadiazol-5-one and 0.48 ml of triethylamine, and 1 ml of a solution of 0.55 g of sulfur-trioxide-pyridine complex in dimethyl sulfoxide was added dropwise. After stirring for 8 hours, 0.17 g of sulfur-trioxide-pyridine complex was added, and the mixture was further stirred for 7 hours. To the reaction solution were added water and 10% HCl, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.18 g of 3-{4-[2,2,2-trifluoro-1,1-dihydroxyethyl]pyridin-2-yl}-1,2,4-oxadiazol-5-one (present compound (58)).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH:7]2[CH2:11][CH2:10][CH:9]=[CH:8]2)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1.[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][O:1][C:2]1[C:6]([CH:7]2[CH2:11][CH2:10][CH:9]=[CH:8]2)=[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:4][N:3]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: Oc1noc(-c2ccccc2)c1C1C=CCC1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C1C=CCC1
Yield: 79.7 %

Procedure:
3-Hydroxy-4-(2-cyclopentenyl)-5-phenylisoxazole (227 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (295 mg, 80%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.[C:23]([Cu])#[N:24].O>CS(C)=O>[C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([C:23]#[N:24])[CH:11]=[CH:10]3)[CH2:18][CH2:17]1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Reactant: N#C[Cu]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C#N)ccc3c2)CC1
Temperature: 125 °C
Reaction time: 15 h

Procedure:
Compound 2-bromo-6-((trans)-4-tert-butylcyclohexyloxy)naphthalene (2.0 g, 5.5 mmol, 1.0 eq.) and CuCN (742 mg, 8.34 mmol, 1.5 eq.) was dissolved in DMSO (5 mL). Then the mixture was stirred at 125° C. for 15 h. Water was added and the mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using PE/EA (10/1) to give product as a slight yellow solid (1.423 g, 82%). EDI-MS (M+1)+: 308.0 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.78-7.73 (m, 2H), 7.54 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 4.33-4.30 (m, 1H), 2.29-2.25 (m, 2H), 1.93-1.90 (m, 2H), 1.48-1.26 (m, 2H), 1.25-1.10 (m, 3H), 0.91 (s, 9H).
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:18][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(C)Oc1ccc(CO)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)Oc1ccc(CCl)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
12 gm (0.058 mol) of methyl 2-(4-hydroxymethyl-phenoxy)-propionate were dissolved in 60 ml of hexamethylphosphoric acid triamide, the solution was cooled to -10° C., and 4.4 ml (0.06 mol) of thionyl chloride were added dropwise thereto. The resulting mixture was stirred for 30 minutes at 0° C. and then for one hour at 10° C., and subsequently poured into water. The aqueous mixture was extracted with ether, and the extract solution was washed with water, sodium bicarbonate solution and again with water, and dried. The ether was subsequently removed in vacuo at room temperature, leaving methyl 2-(4-chloromethyl-phenoxy)-propionate as a residue.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CN([CH2:19][C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)C>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[N:10]1[CH2:15][CH2:14][N:13]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:12][CH2:11]1
Reactant: c1ccc2sc(N3CCNCC3)cc2c1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Product: c1ccc2sc(N3CCN(Cc4c[nH]c5ncccc45)CC3)cc2c1
Yield: 53.6 %

Procedure:
The title compound was prepared in an analogous manner to Example 6, Step 3 using 1-(benzothiophen-2-yl)piperazine (180 mg, 0.83 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (145 mg, 0.83 mmol). Recrystallisation from ethyl acetatehexane afforded the title compound (155 mg, 54%), m.p. 269° C. (dec.); (Found: C, 69.10; H, 5.85; N, 16.08. C20H20N4S requires C, 68.94; H, 5.79; N, 16.08%); δH (DMSO-d6) 2.55 (4H, t, J 5 Hz, 2×piperazinyl CH2), 3.18 (4H, t, J 5 Hz, 2×piperazinyl CH2), 3.70 (2H, s, indole-CH2N), 6.26 (1H, s, 3-H-benzothiophene), 7.04 (2H, m, 2×ArH), 7.19 (1H, m, ArH), 7.05 (2H, m, 2×ArH), 7.63 (1H, d, 8 Hz, ArH), 8.06 (1H, d, 8 Hz, ArH), 8.20 (1H, d, 3 Hz, ArH), and 11.46 (1H, br s, NH); m/z (CI+, NH3) 349 (M+1)+.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=[O:13])[CH2:6][CH2:7][Cl:8]>O>[Cl:2][CH2:3][CH2:4][N:5]([C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13])[CH2:6][CH2:7][Cl:8]
Reactant: COC(=O)c1cccc(N(CCCl)CCCl)c1
Agent: Cl
Solvent: O
Product: O=C(O)c1cccc(N(CCCl)CCCl)c1
Yield: 100 %

Procedure:
Concentrated hydrochloric acid (40 ml) was added to 2.0 g (7.44 mmol) of methyl 3-[N,N-bis(2-chloroethyl)amino]benzoate, followed by stirring under heating for 3 hours over an oil bath which was controlled at 90° C. The reaction mixture was diluted with water. The resulting crystals were collected by filtration and then washed with 50% ethanol, whereby 1.95 g (7.44 mmol) of the title compound were obtained as white crystals (yield: quantitative).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[C:5]([N+:21]([O-:23])=[O:22])[CH:4]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[Cl:20][C:18]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:4][C:5]=2[N+:21]([O-:23])=[O:22])[CH:19]=1
Reactant: COC(=O)c1ccc(Cl)cc1Nc1ccc(CBr)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1Nc1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A mixture of Example 570A (80 mg, 0.2 mmol) and morpholine (35 mg, 0.4 mmol) in 4 mL of toluene was heated under reflux for two hours. After the reaction mixture was cooled to room temperature, it was loaded onto silica gel for purification that yielded 76 mg of the desired product (94%). MS (DCI) m/e 406 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 10.61 (s, 1H), 8.04 (d, J=1.87 Hz, 1H), 7.95 (d, J=8.73 Hz, 1H,) 7.65-7.66 (m, 1H), 7.61 (dd, J=8.73, 1.87 Hz, 1H), 7.46 (d, J=1.87 Hz, 1H), 7.10 (dd, J=8.58, 2.03 Hz, 1H), 3.88 (s, 3H), 3.57-3.59 (m, 4H), 3.39 (s, 2H), 2.28-2.90 (m, 4H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH:27][C:28]2[N:33]=[C:32]([C:34]3[N:38]4[CH:39]=[CH:40][CH:41]=[C:42]([CH:43]([F:45])[F:44])[C:37]4=[N:36][CH:35]=3)[C:31]([C:46]#[N:47])=[CH:30][N:29]=2)[CH3:26])=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[F:45][CH:43]([F:44])[C:42]1[C:37]2[N:38]([C:34]([C:32]3[C:31]([C:46]#[N:47])=[CH:30][N:29]=[C:28]([NH:27][CH:25]([C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:24][CH:23]=4)[CH3:26])[N:33]=3)=[CH:35][N:36]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
208 mg of the 2-{[1-(4-{[t-butyl(diphenyl)silyl]oxy}phenyl)ethyl]amino}-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine-5-carbonitrile [111-1] was dissolved in 5 mL of tetrahydrofuran, then 320 μL of tetrabutylammonium fluoride (1.0M tetrahydrofuran solution) was added under an ice-cold condition, and stirred at room temperature for 1 hour. The reaction solution was diluted in 200 mL of ethyl acetate, and washed with phosphate buffer pH6.8 and saturated brine in the subsequent order. The obtained organic layer was dried over anhydrous magnesium sulfate, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in a small amount of mixture solvent of chloroform and methanol (chloroform:methanol=9:1) and solidified by hexane, to obtain 107 mg of 4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-{[1-(4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carbonitrile [111-2] as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[C:10]([CH3:26])([N:11]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:19]([O:18][C:16]([N:11]1[CH2:12][CH2:13][CH:14]2[CH2:15][NH:8][CH2:9][C:10]12[CH3:26])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCN(C(=O)OCc3ccccc3)C2(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC12CNCC1CCN2C(=O)OCc1ccccc1
Yield: 55.4 %

Procedure:
The product of Example 20F (0.8 g, 2.22 mmol) was treated with TFA (5 mL) in CH2Cl2 (10 mL) at ambient temperature for 1 h. The mixture was then concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 90:9:1 CH2Cl2:MeOH:NH4OH) to give the title compound (0.32 g, 1.23 mmol, 55% yield). 1H NMR (MeOH-d4, 300 MHz) δ 1.42, 1.47 (s, 3H, rotamers), 1.63-1.75 (m, 1H), 1.98-2.13 (m, 1H), 2.37-2.52 (m, 1H), 2.62-2.76 (m, 2H), 3.00-3.12 (m, 1H), 3.26, 3.47 (d, J=12.6 Hz, 1H, rotamers), 3.53-3.62 (m, 2H), 5.08, 5.13 (s, 2H, rotamers), 7.25-7.42 (m, 5H); MS (DCl/NH3) m/z 261 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][O:12][C:5]=2[CH:4]=1)=C.I([O-])(=O)(=O)=[O:14].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][O:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:14])[N:8]=1
Reactant: C=Cc1cc2c(nn1)OCCO2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cc2c(nn1)OCCO2
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro[1,4]dioxino[2,3-c]pyridazine (11.58 g) in 1,4-dioxane/water (600 ml/180 ml), cooled in ice, was treated with an aqueous solution of osmium tetroxide (4% w/v, 25 ml) and sodium periodate (43 g). This mixture was allowed to warm to room temperature and after 7 hours under stirring the mixture was evaporated to dryness and azeotroped with 1,4-dioxane. Silica gel, 1,4-dioxane and chloroform were added and the mixture was evaporated to dryness overnight, then added to a silica column (400 g) and chromatographed, eluting with chloroform then 0-100% ethyl acetate in hexane, to afford a white solid (7.55 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and benzoic acid as starting materials, MS (LC/MS): 407.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[F:32][C:33]([F:62])([F:61])[C:34]1[C:38](B(O)O)=[CH:37][N:36]([C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:35]=1>>[F:30][C:28]([F:29])([F:31])[S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:38]5[C:34]([C:33]([F:61])([F:62])[F:32])=[N:35][N:36]([C:42]([C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=6)([C:55]6[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=6)[C:43]6[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=6)[CH:37]=5)[CH:3]=4)[N:8]=[CH:7][CH:6]=3)[CH2:13][CH2:14]2)=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: O=S(=O)(c1ccc(OC2CCN(c3ccnc4ccc(Br)cc34)CC2)cc1)C(F)(F)F
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Product: O=S(=O)(c1ccc(OC2CCN(c3ccnc4ccc(-c5cn(C(c6ccccc6)(c6ccccc6)c6ccccc6)nc5C(F)(F)F)cc34)CC2)cc1)C(F)(F)F
Yield: 93.4 %

Procedure:
150 mg 6-bromo-4-[4-(4-trifluoromethylsulfonylphenoxy)piperidin-1-yl] quinoline (compound in Production Example 456) and 160 mg 3-trifluoromethyl-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 31) were reacted in the same manner as in Example 9, to give 221 mg 4-[4-(4-trifluoromethylsulfonylphenoxy)piperidin-1-yl]-6-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl) quinoline. This product was reacted in the same manner as in Example 67, to give 106 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][OH:8].C(O[CH:17](OCC)[CH2:18][Cl:19])C.Cl>O>[Cl:19][CH2:18][CH:17]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[CH2:6][CH2:7][O:8]1
Reactant: COc1ccc(CCO)cc1OC
Reactant: CCOC(CCl)OCC
Agent: Cl
Solvent: O
Product: COc1cc2c(cc1OC)C(CCl)OCC2
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 10 g. of 3,4-dimethoxyphenethylalcohol and 10 g. of chloroacetaldehyde diethyl acetal was added 14 ml of 10% hydrochloric acid. The mixture was stirred at 90° C for 10 minutes. After cooling, 100 ml of water was added to the reaction mixture, followed by extraction with benzene. The extract was rinsed with water, dried and concentrated under reduced pressure. By the above procedure was obtained 12 g of 1-chloromethyl-6,7-dimethoxyisochroman as an oil colored light-tan.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.Cl[C:10]([C:12]1[CH:13]=[C:14]([CH:18]([CH3:21])[C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[S:1]1[C:5]([C:10]([C:12]2[CH:13]=[C:14]([CH:18]([CH3:21])[C:19]#[N:20])[CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2
Reactant: CC(C#N)c1cccc(C(=O)Cl)c1
Reactant: c1cc2sccc2s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C#N)c1cccc(C(=O)c2cc3sccc3s2)c1
Temperature: 20 °C
Reaction time: 17 h
Yield: 61.6 %

Procedure:
A solution of thieno[3,2-b]thiophene (28 g) and 2-(3-chloroformyl-phenyl)propionitrile (56.5 g) in methylene chloride (500 cc) is added dropwise, over a period of 1 hour, to a suspension of anhydrous aluminium chloride (83.5 g) in methylene chloride (500 cc). The mixture is stirred for 17 hours at a temperature of about 20° C. and then poured onto crushed ice (1 kg). The methylene chloride solution is decanted off, washed twice with distilled water (total 600 cc), twice with a 10% (w/v) aqueous sodium carbonate solution (total 600 cc), twice with distilled water (total 600 cc), dried over anhydrous sodium sulphate and evaporated. The residue is taken up in diethyl ether (600 cc), stirred with decolourizing charcoal (5 g) and filtered. The filtrate is evaporated and the residue (60 g), dissolved in methylene chloride (200 cc), is stirred for 2 hours with an N aqueous sodium hydroxide solution. The methylene chloride phase is decanted off, washed three times with distilled water (total 300 cc), dried over anhydrous sodium sulphate and evaporated. The residue (49 g) is dissolved in a boiling mixture of ethyl acetate (40 cc) and ethanol (160 cc). After cooling for 3 hours at 4° C., the resulting crystals are filtered off, washed twice with a mixture (total 40 cc) of ethyl acetate and ethanol (20:80) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. 2-{3-(Thieno[3,2-b]thien-2-yl)carbonyl-phenyl}propionitrile (36.6 g), melting at 75° C., is thus obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([CH:15]=O)=[CH:12][CH:11]=1.[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:15][C:13]3[O:14][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[O:3][C:2]([F:1])([F:17])[F:18])=[CH:11][CH:12]=3)[CH2:32][CH2:31]2)[CH:25]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-c2ccccc2OC(F)(F)F)o1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4ccccc4OC(F)(F)F)o3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-[2-(trifluoromethoxy)phenyl]-2-furaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 487.1 (M+H)+.