Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1ccc(-c2ccccc2)cc1

Procedure:
3.56 g (20 mmol) of sodium p-toluenesulfinate, 3.14 g (20 mmol) of bromobenzene, 0.0225 g (0.1 mmol) of palladium acetate, 0.0478 g (0.12 mmol) of 1,2-bis(diphenylphosphino)-ethane, 60 ml of N-methyl-2-2pyrrolidone and each compound given in Table 3 were placed in a 100 ml round bottom flask and reacted at 150° C. in a nitrogen gas stream for 6 hours. After the completion of the reaction, the amount of 4-methylbiphenyl formed was analyzed by means of high performance liquid chromatography. The results are shown in Table 3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH3:23])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:26])[CH3:25]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH3:23])[C:20]([NH:26][CH2:24][CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Product: CCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 0.92 h

Procedure:
A solution of 325 mg (1.0 mmole) of (3R, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 2) in 10 ml of a 23% by volume methanolic solution of ethylamine was allowed to stand at room temperature for 3 hours and 55 minutes, after which the solvent was removed by distillation under reduced pressure. The residue was then recrystallizated from diisopropyl ether, to afford 321 mg of the title compound as white crystals, melting at 126°-127° C.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22](C(=O)C)[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1
Reactant: CC(=O)N1CCc2nc(N3CCN(Cc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCNC2
Temperature: 65 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
To a solution of 1-(2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethanone (0.367 g, 0.826 mmol) in MeOH (4 mL) was added NaOH, 15% solution (2.201 g, 8.26 mmol) at 23° C. The reaction mixture was stirred at 65° C. for 16 hr, cooled to 23° C., and neutralized with 1N HCl (9.5 mL) to furnish a suspension. The crude mixture was concentrated via rotary evaporation, cooled to 23° C., and stirred overnight. The resulting solid was filtered, rinsed with water, and dried in vacuo to give the title compound (253 mg, 76%) as a yellow foam. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (d, J=6.8 Hz, 6H), 2.42 (br s, 1H), 2.51-2.61 (m, 6H), 2.89-3.00 (m, 6H), 3.58 (s, 2H), 3.63 (s, 2H), 4.00-4.10 (m, 1H), 5.15 (d, J=8.3 Hz, 1H), 7.04-7.11 (m, 1H), 7.21 (td, J=10.0, 2.4 Hz, 1H), 7.44-7.52 (m, 1H); ESI-MS m/z [M+H]+ 403.0.
Reaction SMILES: [CH3:1][C:2]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.CCO.O.Cl>O1CCOCC1>[CH3:1][C:2]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:4][C:5](=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C1(C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
In a 50 mL round-bottom flask was mixed with ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-6a, 1.99 g, 8.72 mmol), EtOH (10 mL), H2O (5 mL), and 4N HCl in 1,4-dioxane (5 mL). The resulting solution was stirred at room temperature for 64 hours. At this time, the solvent was removed in vacuo and the residue was taken up in DCM. The suspension was washed with saturated NaHCO3(aq) and the organic layer was dried over Na2SO4. The resulting product was taken on without further purification. Yield=1.00 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([Cl:14])=[CH:4][C:3]=1[OH:15].CC(C)([O-])C.[K+].NC[C@@H]1C[C@H](O)C1.CS(O[C@H:34]1[CH2:37][C@@H:36]([CH2:38][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH3:40])[CH2:35]1)(=O)=O>CS(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[C:5]([Cl:14])=[CH:4][C:3]=1[O:15][C@H:34]1[CH2:37][C@H:36]([CH2:38][N:39]([CH3:40])[C:41](=[O:42])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[CH2:35]1
Reactant: CN(C[C@H]1C[C@@H](OS(C)(=O)=O)C1)C(=O)OC(C)(C)C
Reactant: Oc1cc(Cl)c(CN2CCCC2)cc1Cl
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: NC[C@H]1C[C@@H](O)C1
Solvent: CS(C)=O
Solvent: CCOCC
Product: CN(C[C@H]1C[C@H](Oc2cc(Cl)c(CN3CCCC3)cc2Cl)C1)C(=O)OC(C)(C)C

Procedure:
A solution of Intermediate 25, 2,5-Dichloro-4-pyrrolidin-1-ylmethyl-phenol (1.8 g, 7.5 mmol) and potassium tert-butoxide (0.85 g, 7.5 mmol) in DMSO (20 mL) was heated to 100° C. under vigorous stirring in a flow of argon. The mixture was stirred at this temperature for 15 min. A solution of intermediate 6, cis-3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}cyclobutyl methanesulfonate (1.1 g, 3.8 mmol) in DMSO (10 mL) and tetrabutylammonium bromide (0.36 g, 1.14 mmol) were added. The mixture was stirred at 100° C. for 1 h, cooled, and diluted with Et2O (50 mL). The solution was washed with water (50 mL), 1N NaOH (3×25 mL), brine, dried with Na2SO4, and evaporated. The residue was purified by chromatography (silica gel 63-100μ, 20 mL, hexane/CHCl3 (20:80→0:100), then CHCl3/MeOH 100:0→80:20). The product containing fractions were collected and concentrated to give the title compound (0.93 g, 55%) as a yellow oil. 1H NMR-data (DMSO-d6): 7.49 (s, 1H, Ar—H); 6.95 (s, 1H); 4.85-5.00 (m, 1H); 3.60 (br.s, 2H); 3.35 (d, 2H, J=8. Hz); 2.78 (s, 3H, NCH3); 2.52-2.62 (m, 1H); 2.41-2.53 (m, 4H+DMSO); 2.22-2.30 (m, 2H); 2.08-2.20 (m, 2H); 1.65-1.74 (m, 4H); 1.43 (s, 9H, Boc).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[CH3:23])=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[C:19]([O:18][C:16]([NH:15][CH:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:23])[CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1cc2c(cc1C)C(NC(=O)OC(C)(C)C)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc2c(cc1C(=O)O)SCCC2NC(=O)OC(C)(C)C
Yield: 89.8 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 6 using 4-(tert-butoxycarbonylamino)-6-methylthiochromane-7-carboxylic acid methyl ester (2.80 g) and potassium carbonate (3.44 g), the objective 4-(tert-butoxycarbonylamino)-6-methylthiochromane-7-carboxylic acid (2.41 g) was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][N:14]=[C:15]([O:16]CC)[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.ClC1C2C=CN=C(Cl)C=2C2C(=CC=NC=2)N=1.[Cl:35][C:36]1[CH:42]=[C:41]([I:43])[CH:40]=[C:39]([Cl:44])[C:37]=1[NH2:38]>>[Cl:35][C:36]1[CH:42]=[C:41]([I:43])[CH:40]=[C:39]([Cl:44])[C:37]=1[NH:38][C:2]1[C:11]2[CH:12]=[CH:13][NH:14][C:15](=[O:16])[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1
Reactant: CCOc1nccc2c(Cl)nc3ccncc3c12
Reactant: Nc1c(Cl)cc(I)cc1Cl
Agent: Clc1nc2ccncc2c2c(Cl)nccc12
Product: O=c1[nH]ccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccncc3c12

Procedure:
The title compound was synthesized following the procedure in Example 155, Steps 1, 2, and 3 using 6-chloro-10-ethoxypyrido[4,3-c]-1,6-naphthyridine (Example 133, Step 3), 6,10-dichloropyrido[4,3-c]-1,6-naphthyridine (124 mg, 0.495 mmol) (Example 133, Step 3), and 2,6-dichloro-4-iodoaniline as the starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C[O:11][C:12]1[CH:17]=CC=C[C:13]=1C=CC(=O)C>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:13][C:12](=[O:11])[CH3:17]
Reactant: O=Cc1ccccc1Br
Reactant: COc1ccccc1C=CC(C)=O
Product: CC(=O)C=Cc1ccccc1Br

Procedure:
The title compound was prepared from 2-bromo-benzaldehyde (30 g, 162 mmol), following the procedure describing the synthesis of 4-(2-methoxy-phenyl)-but-3-en-2-one (example 1/a stage 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(C(C(F)(F)F)=C)C=C(Cl)C=1.[Br:40]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl.O>[Br:40][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:22]([F:24])([F:23])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[F:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Agent: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Solvent: O
Product: Fc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1CBr
Temperature: 25 °C

Procedure:
In a solution of 1.50 g of 5-(3,5-dichlorophenyl)-3-(3-fluoro-4-methylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole synthesized from 3-fluoro-4-methylphenylaldoxime and 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene similarly to Step 2 of Synthetic Example 3 in 50 ml of 1,2-dichloroethane, 0.68 g of N-bromosuccinic acid imide and a catalytic amount of azobisisobutyronitrile were added, and stirred under nitrogen atmosphere and under reflux with heat for 1 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, poured in 50 ml of water, extracted with chloroform (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain crude aimed product as pale yellow oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:29]#[N:30])[CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.O>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([C:29]#[N:30])[CH2:26][CH2:27][CH2:28]4)=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: CC(N)c1ccc(C2(C#N)CCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C2(C#N)CCC2)cc1

Procedure:
2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyanocyclobutyl)phenyl]ethyl}acetamide is synthesized according to example 5 by mixing (7-cyano-1H-benzimidazol-1-yl)acetic acid (95.0 mg, 0.475 mmol) prepared according to scheme 3, 1-[4-(1-aminoethyl)phenyl]cyclobutanecarbonitrile (95 mg, 0.475 mmol) prepared according to scheme 9, Et3N (144 mg, 1.43 mmol, 0.199 mL) and HATU (181 mg, 0.475 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5μ) 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (34.0 mg, 0.0888 mmol, 19%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.40 (d, J=7.03 Hz, 3H) 1.89-2.05 (m, 1 H) 2.15-2.34 (m, 1H) 2.52-2.66 (m, 2H) 2.66-2.80 (m, 2H) 4.88-5.01 (m, 1H) 5.25 (dd, J=22.66, 17.58 Hz, 2H) 7.31-7.46 (m, 5H) 7.71 (dd, J=7.62, 0.78 Hz, 1H) 8.01 (dd, J=8.01, 0.78 Hz, 1H) 8.36 (s, 1H) 8.87 (d, J=7.62 Hz, 1H); MS [M+H], calcd: 384.0. found: 384.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH3:13])[C:9]=1[C:10]([O-:12])=O)=[O:4].[Li+].Cl.Cl.[CH3:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=[C:19]1[CH2:29][CH2:30][NH2:31]>>[CH3:13][N:8]1[C:9]([C:10](=[O:12])[NH:31][CH2:30][CH2:29][C:19]2[N:18]([CH3:17])[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]=2)=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]=[N:7]1
Reactant: Cn1cc(-c2ccccc2)nc1CCN
Reactant: COC(=O)c1nnn(C)c1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1nnn(C)c1C(=O)NCCc1nc(-c2ccccc2)cn1C

Procedure:
The product was obtained starting from lithium 4-(methoxycarbonyl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (150 mg, 785 μmol) and 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethanamine dihydrochloride (226 mg, 824 μmol, example 7, step 4) according to the method described in example 7, step 5 after aqueous work-up and purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light yellow solid (79 mg, 214 μmol, 27.3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].ClC1C=C(C(OO)=[O:21])C=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[N+:4]([O-:21])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)cnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1cc(F)c[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of methyl 5-fluoro-2-methylnicotinate (step 2, 936 mg, 5.53 mmol) in dichloromethane (100 ml) was added 3-chlorobenzenecarboperoxoic acid (2.38 g, 13.8 mmol) and the reaction suspension was stirred overnight at room temperature. The reaction was quenched by the addition of sat. sodium thiosulfate solution and sat. sodium bicarbonate solution was added. The whole mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated to afford 1.12 g (quant.) of title compound:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH2:21][CH2:20][CH2:19][C:18]=1[CH2:22]O.CS([Cl:28])(=O)=O.O>ClCCl>[Cl:28][CH2:22][C:18]1[CH2:19][CH2:20][CH2:21][C:17]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[F:10]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1=C(c2ccccc2F)CCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccccc1C1=C(CCl)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (17.2 mL) was added to a solution of [2-(2-fluorophenyl)cyclopent-1-enyl]methanol obtained in Preparation Example 3-(3) (6.50 g) in dichloromethane (300 mL) in an ice bath. Methanesulfonyl chloride (2.88 mL) was added to the reaction solution at the same temperature. Then, the reaction solution was warmed to room temperature and stirred overnight. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (7.23 g).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N:6]1([S:12]([C:15]2[CH:16]=[C:17]([CH2:21]O)[CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:3][CH2:21][C:17]1[CH:16]=[C:15]([S:12]([N:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(c1cccc(CO)c1)N1CCCCC1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc(CCl)c1)N1CCCCC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Phosphorus oxychloride (1.00 mL) was added to DMF (5.0 mL), and stirred at 80° C. for 30 minutes. A solution prepared by dissolving [3-(piperidin-1-ylsulfonyl)phenyl]methanol (2.00 g) obtained in Reference Example 21 in DMF (5.0 mL) was added to it, and stirred at 80° C. for 30 minutes. At 0° C., aqueous saturated sodium carbonate solution was added thereto, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 50%, gradient) to give the entitled compound (1.26 g, 59%) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH3:20][N:21]([CH3:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[CH3:31][N:21]([CH3:20])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)=[CH:26][CH:25]=1
Reactant: CN(C)CCc1ccc(O)cc1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Product: CN(C)CCc1ccc(OCc2ccc(OC(=O)N(C)c3ccccc3)cc2)cc1
Yield: 52 %

Procedure:
The title compound was prepared in 52% yield as colorless crystals using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 4-(2-dimethylaminoethyl)-phenol. 1H NMR (400 MHz; CDCl3): δ 2.85 (s, 6H), 2.98–3.02 (m, 2H), 3.17–3.21 (m, 2H), 3.42 (br s, 3H), 5.02 (s, 2H), 6.90 (d, 2H), 7.12 (d, 2H), 7.25–7.43 (m, 7H); HPLC-MS: m/z=405.2 (M+1); Rt=2.91 min.
Reaction SMILES: [OH-].[Na+].C([S:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][C:28]([Cl:34])=[CH:29][CH:30]=4)[N:25]=3)=[CH:21][C:8]1=2)(=O)C.O.Cl>C(O)C>[Cl:34][C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[CH:33][C:24]([CH2:23][O:22][C:20]3[CH:19]=[CH:18][C:9]4[O:10][CH2:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[CH:7]([SH:6])[C:8]=4[CH:21]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: CC(=O)SC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: SC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
19 ml of a 1N-sodium hydroxide aqueous solution was added to 3.49 g of 11-acetylthio-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 71 dissolved in 66 ml of ethanol and the mixture was stirred at room temperature for 1 hour. 250 ml of water was added to the reaction mixture and the mixture was adjusted to about pH 4 with 1N-hydrochloric acid. Crystals precipitated were dissolved in 300 ml of methylene chloride and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed to obtain 3.03 g of the title compound as a crude product.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.CCOC(C)=O>[CH2:1]([N:3]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:21](=[O:22])[CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1)[CH3:2]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCNCCc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CCc1ccccn1)C(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
N-Ethyl-N-(2-pyridin-2-ylethyl)amine (0.5 g, 3.32 mmol) and 3-(4-hydroxyphenyl)-propanoic acid (0.50 g, 3.00 mmol) was dissolved in dimethylformamide (5 ml) and cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (1.18 g, 3.66 mmol) and diisopropylethylamine (0.90 g, 7.0 mmol) were added and the solution was warmed to room temperature and stirred overnight. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). The organic phase was dried MgSO4) and EtOAc was removed by evaporation to give 0.913 gram of N-ethyl-3-(4 hydroxyphenyl)-N-(2-pyridin-2-ylethyl)propanamide (yield 91.9%).
Reaction SMILES: [CH2:1]([CH:5]([C:14]#[N:15])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[CH2:22]=[O:23]>[OH-].C([NH+](CC)CC)C.C1C=CC=CC=1>[C:14]([C:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:22][OH:23])#[N:15]
Reactant: CCCCC(C#N)c1ccc(Cl)cc1Cl
Reactant: C=O
Agent: CC[NH+](CC)CC
Agent: [OH-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice cold stirred solution of a-n-butyl-2,4-dichlorobenzyl cyanide (5g., 0.02 mole) in 20 ml. of pyridine containing a suspension of paraformaldehyde (2.4g., 0.08 mole) is added 1 ml. of benzene triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 16 hours. The reaction mixture is poured into 300 ml. of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 5.6g. of a thick oil, which is identified by nmr.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.N[C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1N.IC1C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: Ic1ccccc1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3ccccc3)c3cc(Cl)ccc23)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.252 g, 0.759 mmol), (±)-trans-1,2-diaminocyclohexane (18 μL, 0.15 mmol), iodobenzene (103 μL, 0.911 mmol), K3PO4 (0.402 g, 1.89 mmol) and copper(I) iodide (0.0072 g, 0.04 mmol) were dissolved in toluene (0.750 mL) and the reaction vessel was purged with N2 (g) for 1 minute. The reaction was heated to 120° C. and stirred overnight. Standard workup procedure followed by silica gel chromatography (0-20% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9](C(OC(C)(C)C)=O)[N:8]=[C:7]2[I:20].FC(F)(F)C(O)=O>ClCCl>[F:21][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[I:20]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(OC(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)Oc1ccc2[nH]nc(I)c2c1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a stirred solution of tert-butyl 5-(difluoromethoxy)-3-iodo-1H-indazole-1-carboxylate (410 mg, 1 mmol) in dichloromethane (10 mL) was added drop-wise trifluoroacetic acid (5 mL) at room temperature and the reaction mixture was stirred for 1 hour. The mixture was washed with NaHCO3 aqueous, and then organic was dried over Na2SO4. After filtration and concentration, 5-(difluoromethoxy)-3-iodo-1H-indazole (300 mg, 97%) was obtained as a white solid, used in the next step without further purification. MS: (M+H)+=311.