Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1)#[CH:7].[F:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[O:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=1.C(N(CC)CC)C>O>[F:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[O:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26]2[CH:7]=[C:6]([C:8]3[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=3)[O:28][N:27]=2)=[CH:21][CH:20]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2F)nc1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3ccccc3F)nc2)no1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
To a tetrahydrofuran (1 mL) solution of 3-ethynyl-pyridin-2-ylamine (9.0 mg, 0.076 mmol) described in Manufacturing Example 1-2-3 and (6-(2-fluoro-phenoxy)-pyridine-3-yl)-acetohydroximoyl chloride (28 mg) described in Manufacturing Example 74-1-4 was added triethylamine (21 μL, 0.15 mmol), which was stirred for 5 hours at 55° C. The mixture was cooled to room temperature and water was added at that temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound as a crude product. This was then purified by reverse-phase high-performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetic acid). Triethylamine was added to make the solvent basic when concentrating the mobile phase, and the eluate was concentrated under a reduced pressure. The resulting residue was washed with water to obtain the title compound (1.0 mg, 4%).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Cl:22][C:23]1[C:28]2[C:29]([CH:32]([CH3:34])[CH3:33])=[N:30][NH:31][C:27]=2[CH:26]=[CH:25][N:24]=1>C(OCC)(=O)C>[Cl:22][C:23]1[C:28]2[C:29]([CH:32]([CH3:34])[CH3:33])=[N:30][N:31]([CH:6]3[CH2:5][CH2:4][CH2:3][CH2:2][O:1]3)[C:27]=2[CH:26]=[CH:25][N:24]=1
Reactant: C1=COCCC1
Reactant: CC(C)c1n[nH]c2ccnc(Cl)c12
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Product: CC(C)c1nn(C2CCCCO2)c2ccnc(Cl)c12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Dihydropyran (10.0 mL) and (+)-10-camphorsulfonic acid (0.062 g) were sequentially added to compound (4a) (0.55 g), followed by stirring at 80° C. for 30 min. After cooling, the reaction solution was distributed between ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain 4-chloro-3-isopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.727 g, 93%) as a colorless oily substance. Subsequently, tetrakis(triphenylphosphine)palladium(0) (0.149 g) was added to a solution of the colorless oily substance (0.727 g), quinoline-3-boronic acid (0.539 g), and an aqueous sodium carbonate solution (1 M, 13 mL) in ethylene glycol dimethyl ether (26 mL) under a nitrogen atmosphere at 85° C. for 25 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After distillation of the solvent, THF (5.2 mL) and concentrated hydrochloric acid (2.6 mL) were added to the residue, followed by stirring at 60° C. for 1 hr. The pH was adjusted to 7 with an aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (4b) (0.395 g, the third yield: 52%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([NH:30][CH2:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[N:26]=[C:25]([S:37][CH3:38])[N:24]=2)=[O:20])[CH2:8][N:9]([O:12]C2CCCCO2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.O>[CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([NH:30][CH2:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[N:26]=[C:25]([S:37][CH3:38])[N:24]=2)=[O:20])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1nc(NCc2nccs2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc(NCc2nccs2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)n1
Reaction time: 72 h
Yield: 46.9 %

Procedure:
[(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-2-(methylthio)-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.2197 g, 0.387 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). This reaction mixture was left to stir over 3 days. The volatiles were evaporated, and the resulting residue was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-(methylthio)-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide as a beige solid (0.0878 g, 47%). LCMS: (M+H)+=484.2.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[C-:14]#[N:15].[Na+].Cl>C(O)C.O>[C:14]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4])#[N:15]
Reactant: [C-]#N
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
To a solution of 2-bromo-4′-nitroacetophenone (30 g, 0.123 mol) in ethanol (200 mL) at 0° C. was added a solution of NaCN (18 g, 0.368 mol) in H2O (60 mL) dropwise over 1 h. Upon completion of the addition, the mixture was stirred at 0° C. for an additional hour and then diluted with H2O (200 mL). The solution was treated with 1N aq. HCl solution, to a pH of 2, and extracted with CH2Cl2 (2×500 ML). The combined organic layers were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified by flash chromatography on silica gel eluting with 1:1 hexane/EtOAc to obtain 2-cyano-4′nitroacetophenone as an orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[C:15]([C:18]1[O:22][CH:21]=[N:20][C:19]=1[CH3:23])(=[O:17])[CH3:16].C(=O)([O-])O.[Na+]>C(OCC)C>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15]([C:18]1[O:22][CH:21]=[N:20][C:19]=1[CH3:23])([OH:17])[CH3:16]
Reactant: COc1ccccc1Br
Reactant: CC(=O)c1ocnc1C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccccc1C(C)(O)c1ocnc1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-Bromoanisole (4.86g) in anhydrous diethylether (10 ml) was added dropwise to a stirred solution of n-butyllithium (2.5M solution in hexane, 10.4 ml) in diethylether (30 ml) at -70° C. under an atmosphere of dry nitrogen. After 45 minutes, 5-acetyl-4-methyloxazole (2.5g) in diethylether (loml) was added dropwise. After a further 1 hour at -70° C. the reaction mixture was allowed to warm to room temperature and was stirred overnight. Saturated aqueous sodium hydrogen carbonate was added. The organic layer was separated and the aqueous layer was extracted with diethylether. The combined organic layers were further processed to give the title compound as a white solid, m.p. 74-75° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.C([Li])CCC.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:17]3([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[S:8][C:7]=2[CH:11]=1
Reactant: COc1ccc2ccsc2c1
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2cc(C3(O)CCCCC3)sc2c1

Procedure:
3.2 g of 6-methoxybenzo[b]thiophene was dissolved in 3 ml of THF and the solution was cooled with ice. 18.6 ml of n-butyllithium (15% hexane solution) was gradually added in a stream of nitrogen and the mixture was stirred. A THF solution of 3.1 ml of cyclohexanone was added and the mixture was stirred at room temperature for 6 hours. 35 ml of saturated aqueous ammonium chloride solution was added to the reaction mixture, the resultant mixture was extracted with ether, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resultant crude product was purified by TLC (developing solvent, chloroform) to obtain 2.8 g of 6-methoxy-2-(1-hydroxycyclohexyl)benzo[b]thiophene.
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[CH:54]([C:57]1[O:58][C:59]([CH3:65])=[C:60]([C:62](O)=[O:63])[N:61]=1)([CH3:56])[CH3:55]>C(Cl)Cl>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:2])=[O:53])=[O:22])[N:24]([C:62]([C:60]5[N:61]=[C:57]([CH:54]([CH3:56])[CH3:55])[O:58][C:59]=5[CH3:65])=[O:63])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:38][CH:39]=1
Reactant: Cc1oc(C(C)C)nc1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)c3nc(C(C)C)oc3C)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (30 mg) was reacted with 2-isopropyl-5-methyl-oxazole-4-carboxylic acid (according to a procedure in Synthesis, Vol. 10, pp. 1569-71 (2005)) in DCM (3.0 mL) according to General Procedure A and directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (8 mg). LCMS (m/z) 892.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]1([C:29]2[CH:33]=[C:32](B(O)O)[O:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:32]4[O:31][N:30]=[C:29]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:33]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1cc(-c2ccccc2)no1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cc(-c5ccccc5)no4)c3)cnc2c1F
Yield: 5 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-phenylisoxazole-5-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(3-phenylisoxazol-5-yl)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (6 mg, 5%): m/z (ES+) 432 [MH+].
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11](=O)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[N:5]1)([CH3:3])[CH3:2].Br.Br.[NH2:23][CH2:24][C:25]([NH2:27])=[NH:26].C[O-].[Na+].O>CO.CCOC(C)=O>[NH2:27][C:25]1[N:26]=[C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:23][CH:24]=1
Reactant: N=C(N)CN
Reactant: CC(C)n1nc(C(=O)C(=O)c2ccccc2)ccc1=O
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)n1nc(-c2nc(N)cnc2-c2ccccc2)ccc1=O
Reaction time: 1.5 h
Yield: 7.6 %

Procedure:
A mixture of 1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-phenyl-1,2-ethanedione (300 mg), aminoacetamidine dihydrobromide (259 mg) and sodium methoxide (238 mg) in MeOH (3 ml) was stirred for 1.5 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain 6-(6-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (25.6 mg) as white powder.
Reaction SMILES: [C:1]1([C:14]([OH:16])=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:17]1([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[CH:21]=[N:20][N:19]=[CH:18]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[N:19]1[N:20]=[CH:21][N:17]([C:22]2[CH:23]=[C:24]([NH:25][C:14]([C:1]3[C:13]4[NH:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:16])[CH:26]=[CH:27][CH:28]=2)[CH:18]=1
Reactant: Nc1cccc(-n2cnnc2)c1
Reactant: O=C(O)c1cccc2c1[nH]c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(-n2cnnc2)c1)c1cccc2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.3 %

Procedure:
To a suspension of 9H-carbazole-1-carboxylic acid (112 mg) and 3-(1,3,4-triazol-1-yl)aniline (147 mg) in dichloromethane (3 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188 mg) and 4-dimethylaminopyridine (43 mg). The mixture was stirred at ambient temperature for 24 hours and diluted with dichloromethane. The solution was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with methanol. The resulting precipitate was collected by filtration and dried to give N-(3-([1,2,4]triazol-4-yl)phenyl)-9H-carbazole-1-carboxamide (38 mg, 15.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1.[CH3:24][C@H:25]1[CH2:30][NH:29][C@H:28]([CH3:31])[CH2:27][NH:26]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:26]2[CH2:27][C@@H:28]([CH3:31])[NH:29][CH2:30][C@@H:25]2[CH3:24])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(Cl)c2ccc(Br)cc2)c1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)CN1
Yield: 62 %

Procedure:
The crude benzhydryl chloride (approx. 135 mmol) was combined with 46.3 g (405 mmol) of trans-2,5-dimethylpiperazine (purified by recrystallization from toluene to mp=115°-119° C.) and 30 mL of toluene and heated at reflux overnight under nitrogen. The toluene was removed under vacuum, and the residue was redissolved in 2000 mL of diethyl ether and washed with 500 mL of 1.0M sodium hydroxide and 1000 mL of water. The ether solution was dried over sodium sulfate and the solvent removed to give a dark oil. The product was purified by chromatography on silica gel with 1-10% ethanol in dichloromethane to give 41.0 g (62%) of (±)-trans-1-(4-bromo-α-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)-2,5-dimethylpiperazine as a 1:1 mixture of diastereomers. NMR (300 MHz, CDCl3); δ 0.15 (s, 6H); 0.9 (m,12H); 1.2 (d,J=6 Hz,3H); 1.4-1.6 (m,2H); 2.2-3.0 (m,5H); 5.2 and 5.3 (s,1H); 6.6-7.5 (m,8H).
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCO[C:42]2[CH:50]=[C:49]3[C:45]([C:46](C4C=CC=CC=4)=C(Br)C3=O)=[CH:44][CH:43]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:42]2[CH:50]=[CH:49][C:45]([CH3:46])=[CH:44][CH:43]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1
Yield: 52 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 of Example 96 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, p-tolylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1>C(O)(=O)C.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[C:7]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[OH:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1ccc(C(O)(c2ccccc2)C(O)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 99.3 %

Procedure:
0.04 g of acetic acid was added to 35.98 g of isopropyl alcohol, and 4.02 g of 4-methoxybenzophenone was dissolved therein. To this solution, ultraviolet rays were irradiated by a high pressure mercury lamp (UVL-100HA, manufactured by Riko Kagaku Sangyo K.K.) to carry out the reaction for 4 hours. After the reaction, the solvent was distilled off to obtain 4.01 g of 1,2-bis(p-methoxyphenyl)-1,2-diphenyl-1,2-ethanediol (compound (C2)).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@H]2CN2CCOCC2)=CC=1)(O)C.FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2CN2CCOCC2)=CC=1)(O)C.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:34][C:2]([F:1])([F:33])[C@@:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:20])[CH2:14][C@H:13]2[CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:10][CH:11]=1)([OH:5])[CH3:4]
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCOCC2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCOCC2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CN2CCOCC2)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CN2CCOCC2)cc1)C(F)(F)F

Procedure:
(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(4-morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(4-morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(4-morpholinylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.89-7.86 (m, 1H), 7.65-7.63 (m, 1H), 7.46-7.41 (m, 2H), 7.27-7.24 (m, 1H), 6.93-6.89 (m, 2H), 4.09-4.03 (m, 1H), 3.99-3.94 (m, 1H), 3.79-3.72 (m, 1H), 3.60-3.55 (m, 4H), 3.50-3.41 (m, 1H), 3.25-3.12 (m, 1H), 2.78-2.71 (m, 1H), 2.68-2.46 (m, 4H), 2.37-2.30 (m, 2H), 2.28-2.21 (m, 1H), 1.67 (s, 3H). m/z (ESI, +ve ion) 519.8 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.230 μM; GK-GKRP EC50 (LC MS/MS)=0.355 μM.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3F)CC2)c(C)c1
Yield: 27.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (780 mg) described in Preparation Example 65 and oxazolidin-2-one (209 mg), the title compound (219 mg) was obtained.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:14][CH2:13][CH:12]2[CH2:11][N:10]([CH3:15])[CH2:9]3)=[CH:4][CH:3]=1.C([O-])(=O)/C=C/[C:19]([O-])=[O:20]>>[CH3:19][O:20][C:3]1[CH:4]=[C:5]([C:8]23[CH2:14][CH2:13][CH:12]2[CH2:11][N:10]([CH3:15])[CH2:9]3)[CH:6]=[CH:7][CH:2]=1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: Cc1ccc(C23CCC2CN(C)C3)cc1
Product: COc1cccc(C23CCC2CN(C)C3)c1

Procedure:
1(p-methylphenyl)-3-methyl-3-azabicyclo[3.2.0]heptane, fumarate
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:5]([N:14]=1)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2.[F:15][C:16]([F:30])([F:29])[C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>CC(C)CCO.[Cu]I>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:9]=[C:4]2[N:3]=[C:2]([N:26]3[CH2:27][CH2:28][N:23]([C:18]4[C:17]([C:16]([F:30])([F:15])[F:29])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:24][CH2:25]3)[NH:14][C:5]2=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cnc2nc(Cl)[nH]c2c1
Agent: [Cu]I
Solvent: CC(C)CCO
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cnc2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-6-trifluoromethyl-1H-imidazo[4,5-b]pyridine from step (d) above (45 mg, 0.203 mmol), 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (47 mg, 0.203 mmol, Fluorochem), triethylamine (59 μL, 0.406 mmol, Aldrich) and copper(I) iodide (1 mg, 0.005 mmol, Aldrich) in 3-methyl-butan-1-ol (0.5 mL, Aldrich) was subjected to microwave irradiation at 220° C. for 0.5 h. The reaction mixture was cooled to room temperature and was filtered. The filtrate was purified by preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title compound as a colorless solid. MS (ESI, positive ion) m/z: 417 (M+1).