Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([F:23])[C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:27][C@@H:28]1[C@@H:33]([OH:34])[CH2:32][CH2:31][O:30][CH2:29]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.C(O)C>[F:23][C:13]1[C:12]([CH3:24])=[C:11]([CH2:10][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:26][CH:25]=2)[CH:20]=[C:15]2[C:14]=1[CH2:21][N:27]([C@@H:28]1[C@@H:33]([OH:34])[CH2:32][CH2:31][O:30][CH2:29]1)[C:16]2=[O:17]
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(F)c1C=O
Reactant: N[C@H]1COCC[C@@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)cc2c(c1F)CN([C@H]1COCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.2 %

Procedure:
A mixture of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-2-formyl-4-methylbenzoate (7.97 g), (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (2.65 g), anhydrous magnesium sulfate (5.23 g) and THF (160 mL) was stirred at room temperature for 5 hr under nitrogen atmosphere. The insoluble substance was removed by filtration, and the filtrate was concentrated. The residue was dissolved in a mixed solvent of methanol (120 mL)-THF (150 mL), sodium triacetoxyborohydride (9.59 g) was added thereto, and the mixture was stirred at room temperature for 15 hr. Sodium triacetoxyborohydride (9.59 g) was again added thereto, and the mixture was stirred for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in DMSO-toluene, and the solution was purified by NH silica gel column chromatography (ethyl acetate/hexane). The obtained crude product was dissolved in THF, the solution was washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was washed with a mixed solvent of diisopropyl ether-ethyl acetate to give a crude product. The crude product (5.28 g) was dissolved in hot ethanol (60 mL), and recrystallized over 4 hr under ice-cooling to give the title compound (4.88 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.CC1(C)[O:13][C@H:12]([CH2:14][O:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:23]=3[N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[N:18](CC3C=CC(OC)=CC=3)[N:17]=2)[CH2:11][O:10]1.C(Cl)[Cl:55]>>[ClH:55].[ClH:55].[C:38]1([C:22]2[C:23]([N:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)=[C:24]3[C:16]([O:15][CH2:14][C@@H:12]([OH:13])[CH2:11][OH:10])=[N:17][NH:18][C:19]3=[N:20][CH:21]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: ClCCl
Reactant: COc1ccc(Cn2nc(OC[C@@H]3COC(C)(C)O3)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: OC[C@H](O)COc1n[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
TFA (1 mL) was added to a solution of (R)-tert-butyl 4-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.14 g, 0.22 mmol) in DCM (1 mL), and the resulting solution was stirred at room temperature for 4 hours. The reaction was then concentrated to dryness and dried under vacuum for 1 hour. TFA (2 mL) was next added, and the mixture was stirred at 100° C. in a sealed tube for 18 hours. The reaction was then concentrated to dryness, and the resulting residue was dissolved in DCM (0.5 mL). HCl in ether (2 mL, 2N) and ether (3 mL) were then added, and the resulting solid was collected by filtration to give (S)-3-(5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)propane-1,2-diol dihydrochloride (0.105, 96%) as a solid. MS APCI (+) m/z 370.2 detected.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[CH2:9]([N:17]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:19]=[C:18]1[CH:26]=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:28]([N:36]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][N:38]=[C:37]1[CH:45]=[O:46])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>CS(O)(=O)=O.O>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([O:1][CH:26]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][CH2:9][N:17]3[C:18]2=[N:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21]3)[CH2:3][CH2:4]1.[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([O:46][CH:45]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][CH2:28][N:36]3[C:37]2=[N:38][CH:39]=[C:40]3[C:41]([F:44])([F:43])[F:42])[CH2:3][CH2:4]1
Reactant: CN1CCC(O)CC1
Reactant: O=Cc1ncc(C(F)(F)F)n1CCc1ccccc1
Reactant: O=Cc1nc(C(F)(F)F)cn1CCc1ccccc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCC(OC2c3ccccc3CCn3c(C(F)(F)F)cnc32)CC1
Product: CN1CCC(OC2c3ccccc3CCn3cc(C(F)(F)F)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-N-methylpiperidine (173 mg, 1.5 mmoles) in methanesulfonic acid (2.5 mL) is added a solution of the mixture of 1-phenethyl-4-trifluoromethyl-imidazole-2-carbaldehyde and 1-phenethyl-5-trifluoromethyl-imidazole-2-carbaldehyde (example 1B). The reaction mixture is stirred overnight at room temperature. Water is added and the mixture is basified to pH 9-10 with 12N NaOH. The aqueous phase is extracted three times with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (99:5:0.1) to (95:5:0.5) to give pure 4-(1-methylpiperidin-4-yloxy)-2-trifluoromethyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (compound 1a) and pure 4-(1-methylpiperidin-4-yloxy)-1-trifluoromethyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (compound 1b).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([CH2:15][C:16]([O:18][CH2:19][CH2:20][OH:21])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[C:22](O)(=O)/C=C/C(O)=O.C(O)C(O)C.[PH2](O)=O.C(OP(OCC)OCC)C.[P]>>[CH2:7]([O:6][P:4]([CH:9]([CH2:15][C:16]([O:18][CH2:19][CH:20]([OH:21])[CH3:22])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)C(CC(=O)OCCO)P(=O)(OCC)OCC
Reactant: O=C(O)/C=C/C(=O)O
Agent: CCOP(OCC)OCC
Agent: O=[PH2]O
Agent: [P]
Solvent: CC(O)CO
Product: CCOC(=O)C(CC(=O)OCC(C)O)P(=O)(OCC)OCC

Procedure:
The procedure according to Example 1 was repeated using similar apparatus and under essentially similar conditions allowing for the differences in quantities of materials employed. In this example, for the materials of Example 1, 1 mol fumaric acid, 1 mol of propylene glycol, 0.1% of hypophosphorous acid and 1 mol of triethylphosphite were employed. The product of the reaction had analytical values of acid value, hydroxyl, free triethylphosphite and phosphorus content comparable to those reported in Example 1.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:13][NH:14][O:15][CH3:16].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:13][N:14]([O:15][CH3:16])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:1]=[CH:2][NH:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2nc[nH]c2c1
Reaction time: 24 h
Yield: 43.4 %

Procedure:
To a suspension of 5-benzimidazolecarboxylic acid (1.62 g, 10 mmol) in CH2Cl2 (30 mL) was added N,O-dimethylhydroxylamine (1.17 g, 12 mmol), N-methylmorpholine (1.65 mL, 15 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.3 g, 12 mmol), respectively at room temperature. After stirring for 24 h, the reaction mixture was filtered to remove solid and rinsed thoroughly with CH2Cl2. The combined filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using 5% MeOH/CH2Cl2 as an eluent to obtain 890 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.02 (s, 2H); 7.59 (d, J=7.6 Hz, 2H); 3.58 (s, 3H); 3.4 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]([O:15]C)=[O:14])=[O:6])([CH3:3])[CH3:2].[OH-].[K+].Cl>O.C(O)C>[CH:1]([NH:4][C:5]([C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]([OH:15])=[O:14])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1c(C)noc1C(=O)NC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1noc(C(=O)NC(C)C)c1C(=O)O
Yield: 73.8 %

Procedure:
2.6 g of the ester from Example 1 and 0.8 g of potassium hydroxide in 20 ml of water and 20 ml of ethanol are stirred for 16 hours at room temperature. Thereafter, the mixture is diluted with water, acidified with concentrated hydrochloric acid and extracted by shaking with dichloromethane. Evaporating down gives 1.8 g of 5-isopropylaminocarbonyl-3-methylisoxazole-4-carboxylic acid as colorless crystals of melting point 86°-92° C. (compound No. 1004).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH3:23])[CH3:22])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[CH3:22][N:21]([CH2:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)[CH3:23]
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(CN(C)C)c2)ccc1=O
Product: CN(C)Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-dimethylaminomethyl-phenyl)-1H-pyridazin-4-one (A-25) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=390.1 (M+H)+
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:20]=1[NH2:21]>CS(C)=O>[CH2:13]([CH:12]([NH:11][C:6]1[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([NH:21][C:20]2[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:19]=2[CH3:18])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Temperature: 130 °C
Yield: 43.4 %

Procedure:
A mixture of (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine (250 mg, 0.97 mmol) and 2,4,6-trimethylaniline (262 mg, 1.94 mmol) in 4 ml of dry DMSO was heated at 130° C. overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow oil. The oil was purified through silica gel column chromatography to give 150 mg (43%) of the title compound as yellow solid, mp 104-107° C. 1H NMR (CDCl3) δ10.36 (s, 1H), 9.24 (d, 1H), 6.93 (s, 2H), 5.86 (s, 1H), 3.45 (m, 1H), 2.32 (s, 3H), 2.18 (s, 6H), 2.13 (s, 3H), 1.55-1.80 (m, 4H), 0.99 (t, 6H) ppm.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C:25]2([CH2:29][CH2:28][CH2:27][O:26]2)[CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH2:22][C:25]4([CH2:29][CH2:28][CH2:27][O:26]4)[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1COC2(C1)CNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC2(CCCO2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 5-oxa-2-azaspiro[3.4]octane hydrochloride (1359656-11-3) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=380.5 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH:49]([CH:51]=[O:52])[NH2:50]>CN(C=O)C>[CH:51]([NH:49][NH:50][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16])=[O:52]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NNC=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)NNC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-2-methylpropanoic acid (Example 8 a, 1.9 g, 8 mmol), HATU (CAN 148893-10-1, 3.97 g, 10 mmol) and N-methylmorpholine (CAN 109-02-4, 2.43 g, 24 mmol) in DMF (20 mL) was stirred at room temperature for 15 min. Then hydrazinecarboxaldehyde (CAN 624-84-0, 0.53 g, 9 mmol) was added and the reaction mixture was stirred at room temperature overnight. After evaporation of solvents, the residue was diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (30 mL), hydrochloric acid (30 mL, 1 M), brine (30 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left the title compounds as yellow oil (2.1 g, 94%); MS: m/e 280.1 [M+H]+.
Reaction SMILES: [C:1](=[O:11])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:2].O.[C:13]([OH:17])(=[O:16])[CH:14]=[O:15].[C:18]1([CH3:28])[CH:23]=[CH:22]C(S(O)(=O)=O)=CC=1>CCCCCC>[CH2:4]([O:16][C:13](=[O:17])[CH:14]([O:15][CH2:28][CH2:18][CH2:23][CH3:22])[NH:2][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:11])[CH2:5][CH2:6][CH3:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=CC(=O)O
Reactant: NC(=O)OCc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: CCCCOC(=O)C(NC(=O)OCc1ccccc1)OCCCC

Procedure:
A solution of 3.0 g. (0.02 mol.) of benzyl carbamate, 1.8 g. (0.02 mol.) of glyoxylic acid hydrate and 0.1 g. of p-toluenesulfonic acid in 50 ml. of n-butanol was slowly distilled over a 1 hour period. The last of the solvent was removed in vacuo to give a residue which was dissolved in hexane and filtered to remove the p-toluene-sulfonic acid. The filtrate was chromatographed on alumina (Woelm, activity II) and eluted with hexane. Concentration of the eluate in vacuo and molecular distillation of the residue at 130°/0.1 mm. gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2OCC[O:9]2)[CH:5]=[CH:4][C:3]=1[O:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1.[CH:22](OC)(OC)OC>>[NH:20]1[C:17]2[CH:18]=[CH:19][C:14]([O:13][C:3]3[CH:4]=[CH:5][C:6]([CH:8]=[O:9])=[CH:7][C:2]=3[Cl:1])=[CH:15][C:16]=2[N:21]=[CH:22]1
Reactant: Nc1ccc(Oc2ccc(C3OCCO3)cc2Cl)cc1N
Reactant: COC(OC)OC
Product: O=Cc1ccc(Oc2ccc3[nH]cnc3c2)c(Cl)c1

Procedure:
Crude 4-{[2-chloro-4-(1,3-dioxolan-2-yl)phenyl]oxy}-1,2-benzenediamine was heated to reflux in 5 mL of trimethyl orthoformate for 2 hours. The reaction mixture was then concentrated and purified by preparative HPLC, with conconiment loss of the dioxolane protecting group. The HPLC fractions were combined and diluted with 1N NaOH, extracted with ethyl acetate, dried over MgSO4 and concentrated to give 4-(1H-benzimidazol-5-yloxy)-3-chlorobenzaldehyde. (M+1) 272.9, 1.65 min (LC/MS method B)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5]([N:7]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][CH3:15])[CH:9]=1)=[O:6].[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5]([N:7]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][CH3:15])[CH:9]=1)=[O:6])(=[O:38])[CH3:37]
Reactant: CSc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2cccc(N)c2)c1
Reactant: CC(=O)OC(C)=O
Product: CSc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2cccc(NC(C)=O)c2)c1
Yield: 80.7 %

Procedure:
Using 3-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methylthiophenyl)benzamide (196.7 mg, 0.40 mmol) and acetic anhydride (0.046 ml, 0.48 mmol), the procedure of Inventive Example 94 was repeated to obtain 172.2 mg (80.7%) of the title compound in a light brown amorphous form.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:18]1([Mg]Cl)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(Br)cc1
Reactant: Cl[Mg]C1CCCCC1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(C2CCCCC2)cc1

Procedure:
The title product was prepared from the product of Example 27 as described in Example 15, Condition 2, with the exception that cyclohexylmagnesium chloride was used instead of cyclopentylmagnesium bromide.
Reaction SMILES: [OH-:1].[K+].[C:3]([C:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:6][CH2:7][N:8]([CH3:18])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:4]>O.C(O)C>[C:19]1([C:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH2:6][CH2:7][N:8]([CH3:18])[CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]([NH2:4])=[O:1])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(CCCc1ccccc1)CCC(C#N)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(CCCc1ccccc1)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Temperature: 150 °C

Procedure:
A solution of potassium hydroxide (0.2 g) in water (10 ml) was added to a solution of 1-cyano-1,1-diphenyl-3-[N-methyl-N-(3-phenylprop-I-yl)amino]propane (0.22 g--see Preparation 23) in ethanol (10 ml) and the mixture was heated at 150° C. for 20 hours in a stainless steel pressure vessel then concentrated in vacuo. Water (30 ml) was added to the residue and the mixture was extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a viscous gum, yield, 0.11 g.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)#[N:4].Cl.[CH3:21][N:22]([CH3:27])[CH:23](C)[CH2:24]Cl.[CH3:28]N(C=O)C>>[C:3]([C:5]1([CH2:28][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)#[N:4]
Reactant: CC(CCl)N(C)C
Reactant: N#CC1c2ccccc2COc2ccccc21
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCC1(C#N)c2ccccc2COc2ccccc21
Temperature: 0 °C
Reaction time: 20 h
Yield: 32 %

Procedure:
Sodium hydride (4.28 g; 0.18 mole) is added portionwise with cooling (5°-10° C.) under nitrogen to a solution of 11-cyano-6,11-dihydrodibenz[b,e]oxepin (16.0 g; 0.72 mole), of Example 1A, in dry DMF (320 ml) and stirred at ambient temperature for 11/2 hours. At this time, 2-dimethylaminopropyl chloride hydrochloride (15.92 g; 0.10 mole) is added portionwise while maintaining the temperature below 10° C. Upon completion of the addition, stirring is continued at 80° C. for 20 hours. The reaction mixture is cooled, poured into 2 liters of ice water and extracted with ether. The ether is back extracted with 2 N HCl and the acidic washes combined and made basic with potassium carbonate. After extraction with ether and drying (K2CO3) the ether is removed in vacuo to give a solid. Trituration with hexane and drying provides 7.0 g (32%) of a solid (m.p. 112°-114° C.) of 11-cyano-11-[3-(dimethylamino)propyl]-6,11-dihydrodibenz[b,e]oxepin.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.COCCOC.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH:27]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:26][C:25]([C:43]([C:49]([F:52])([F:51])[F:50])([C:45]([F:48])([F:47])[F:46])[OH:44])=[N:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH:27]([C:28]2[CH:33]=[CH:32][C:31]([C:2]3[CH:7]=[N:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=3)=[CH:30][CH:29]=2)[CH2:26][C:25]([C:43]([C:49]([F:52])([F:50])[F:51])([C:45]([F:46])([F:47])[F:48])[OH:44])=[N:24]1
Reactant: CC1(C)OB(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)OC1(C)C
Reactant: CSc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CSc1ccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)cn1
Temperature: 88 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
To 5-bromo-2-(methylthio)pyridine (14.0 mg, 0.07 mmol), were added 1,2-dimethoxyethane (1.5 mL) and Pd(PPh3)4 (8.4 mg, cat.). To the reaction mixture, were added 1-(2-chloro-phenyl)-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (25.0 mg, 0.05 mmol) prepared in Step 1, ethanol 183.0 uL, and a 2N sodium carbonate solution (183.0 uL). The reaction mixture was stirred at 88° C. for 2 hours and then distilled water was added thereto. The reaction mixture was extracted with diethyl ether two times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 8.0 mg of the titled compound as a white liquid.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].I(Cl)(=O)=O.[I:10](Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.C1(C)C=CC=CC=1.[CH3:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[C:35]([CH2:41][C:42]([CH3:44])=[CH2:43])[C:34]=1[OH:45]>CO>[I:10][CH2:43][C:42]1([CH3:44])[CH2:41][C:35]2[C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]([CH3:32])[C:34]=2[O:45]1
Reactant: C=C(C)Cc1c(C)cc(C)c(C)c1O
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1C)OC(C)(CI)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 183.4 %

Procedure:
Calcium carbonate (1.37 g, 13.7 mmol) and benzyltrimethylammonium dichloroiodate (4.04 g, 11.6 mmol) were sequentially added to a solution of toluene (20 mL)/methanol (10 mL) containing 2,3,5-trimethyl-6-(2-methylprop-2-en-1-yl)phenol (1.00 g, 5.26 mmol) synthesized in Reference Example 2 under ice-cooling condition, and the mixture was stirred at 0° C. for 30 minutes. After that, the reaction solution was concentrated under reduced pressure, and water and ethyl acetate were added to the residue to separate an organic layer. The organic layer was washed with 10% sodium sulfite aqueous solution and saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 100:0-95:5) to give 3.05 g of the title compound (yield: 92%).