Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C.N12CCCN=C1CCCCC2>ClCCl>[CH2:29]([C:16]1[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][N:9]2[CH2:2][CH2:3][CH2:4][S:5]2(=[O:7])=[O:6])[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=1)[CH2:30][CH2:31][CH3:32]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCOCCN1CCCS1(=O)=O
Reaction time: 20 h
Yield: 42.6 %

Procedure:
Under a nitrogen atmosphere, chloropropylsulfonyl chloride (0.05 ml, 0.46 mmol) was added dropwise to a solution of 1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (0.12 g, 0.37 mmol) and triethylamine (0.065 ml, 0.46 mmol) in dichloromethane (5 ml). The reaction was stirred for 20 hours followed by removal of the solvent in vacuo. The resulting off-white solid was dissolved in N,N-dimethylformamide (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.087 ml, 0.58 mmol) was added. The reaction was stirred for 18 hours under an atmosphere of nitrogen and then quenched with water and extracted with dichloromethane (2×). The organic fractions were combined, washed with water followed by brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide an off-white solid. Recrystallization from ethyl acetate yielded 0.068 g of 2-butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine as off-white crystals, m.p. 152-154° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: COc1cc(-c2ccc(F)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (61 mg, 79%), MS (ISP) m/z=311.5 [(M+H)+], mp 220° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methoxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 18) (73.8 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: BrC1C(CC2(O)C3C(=CC=C(C)C=3)N(CCC(C)C)C2=O)=NC=CC=1.[CH3:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:31](=[O:44])[C:30]2=[O:45].[CH3:46][O:47][C:48]1[CH:49]=[CH:50][C:51]([CH3:54])=[N:52][CH:53]=1>>[OH:45][C:30]1([CH2:54][C:51]2[CH:50]=[CH:49][C:48]([O:47][CH3:46])=[CH:53][N:52]=2)[C:29]2[C:33](=[CH:34][CH:35]=[C:27]([CH3:26])[CH:28]=2)[N:32]([CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:31]1=[O:44]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCc1ccccc1
Reactant: COc1ccc(C)nc1
Agent: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Product: COc1ccc(CC2(O)C(=O)N(CCc3ccccc3)c3ccc(C)cc32)nc1

Procedure:
This compound was prepared in an analogous manner to 3-((3-bromopyridin-2-yl)methyl)-3-hydroxy-1-isopentyl-5-methylindolin-2-one using 5-methyl-1-phenethylindoline-2,3-dione and 5-methoxy-2-methylpyridine (purchased from Aldrich). 1H-NMR δ 8.29 (d, 1H), 7.34 (m, 2H), 7.25 (m, 3H), 7.18 (dd, 1H), 7.07 (dd, 1H), 6.90 (d, 1H), 6.80 (s, 1H), 6.71 (d, 1H), 5.3 (bs, OH), 3.98 (dt, 1H), 3.91 (s, 3H), 3.81 (dt, 1H), 3.05 (d, 2H), 2.97 (t, 2H), 2.27 (s, 3H). Calculated mass for C24H24N2O3, 388.18. Observed 389.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[C:16](=[O:31])[N:15]=3)[CH2:10][C:9]2([CH2:37][O:38][CH2:39][O:40]C)[CH2:32]OCOC)=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3([CH2:32][O:40][CH2:39][O:38][CH2:37]3)[CH2:10][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[C:16](=[O:31])[N:15]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COCOCC1(COCOC)CN(c2nc(C)n(Cc3ccc(C(F)(F)F)s3)c(=O)n2)CCC1c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1nc(N2CCC(c3ccc(F)cc3)C3(COCOC3)C2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 75.8 %

Procedure:
To a 1,4-dioxane solution (600 μL) of 4-{4-(4-fluorophenyl)-3,3-bis[(methoxymethoxy)methyl]piperidin-1-yl}-6-methyl-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (10.0 mg, 16.6 μmol) synthesized in Reference Synthesis Example 362, 12 M hydrochloric acid (200 μL) was added and the resultant mixture was stirred at 60° C. for 2 hours. To saturated sodium carbonate-chloroform solution, the reaction solution was added dropwise and extraction from the resultant mixture with chloroform was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/4→0/1) to obtain the title compound (6.60 mg, yield 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:22]3(O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:22]1([C:11]2[S:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1ccc(-c2cc(C3(O)CCCCC3)sc2-c2ccc(OC)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cc(C3CCCCC3)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of 1-[4,5-bis(4-methoxyphenyl)thien-2-yl]cyclohexanol (5.8 g, 14.7 mmole) in 125 ml of methylene chloride at 0° was treated sequentially with triethylsilane (4.7 ml, 2 equiv.) and trifluoroacetic acid (1.3 ml, 1.14 equiv.). The reaction mixture was stirred for 40 minutes at 0° and for 2 hours at room temperature, and then partitioned between methylene chloride and water. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried and concentrated in vacuo. Recrystallization from ethanol provided the title compound (3.9 g, 70%), m.p. 95°-98°. Proton NMR and infrared (IR) spectra were consistent with the assigned structure. MS: m/z 378 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[C:28]([Cl:29])=[CH:27][C:26]([Cl:30])=[CH:25][N:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+].[CH2:39](O)[CH3:40]>C1COCC1.C(OCC)(=O)C.Cl>[CH2:39]([CH:7]1[CH2:6][CH:5]([C:32]([OH:34])=[O:33])[C:4]2[C:9](=[CH:10][C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([Cl:30])=[CH:25][N:24]=4)=[CH:15][CH:14]=3)=[C:2]([Cl:1])[CH:3]=2)[O:8]1)[CH3:40]
Reactant: CCO
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ncc(Cl)cc4Cl)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC1CC(C(=O)O)c2cc(Cl)c(Oc3ccc(C(=O)NCCc4ncc(Cl)cc4Cl)cc3)cc2O1
Reaction time: 3 h
Yield: 100 %

Procedure:
Ethyl 6-chloro-7-(4-(2-(3,5-dichloropyridin-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (40 mg, 0.073 mmol) was diluted with THF (500 μl) followed by the addition of NaOH (364 μl, 0.36 mmol) and ethanol (300 μl). After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the desired compound (38 mg, 0.073 mmol, 100% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:19](=[O:38])[CH2:18][S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].OO.C(OCC)(=[O:43])C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:12]([C:9]1[CH:8]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:19](=[O:38])[CH2:18][S:17]2=[O:43])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:14])([CH3:15])[CH3:13]
Reactant: CN(CCCN1C(=O)CSC1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(CCCN1C(=O)CS(=O)C1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxy-phenoxy)-ethyl]amino]propyl]-1,3-thiazolidin-4-one (0.30 g) obtained in Example 26-A or 26-B in acetic acid (5 ml) was added 35% aqueous solution of hydrogen peroxide (0.20 g), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was added to a mixture of ethyl acetate and a 5% aqueous solution of sodium carbonate and stirred. The organic layer was separated, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 98:2) to afford 0.12 g (39%) of the title compound as a colorless oil. MS (m/z): 558 (M+) NMR (CDCl3) (200 MHz) δ: 1.41 (18H, s), 1.4-2.0 (2H, m), 2.28 (3H, s), 2.3-2.7 (2H, m), 2.72 (2H, t, J=5.7 Hz), 2.9-3.2 (1H, m), 3.37 and 3.69 (2H, ABq, J=16 Hz), 3.8-4.2 (3H, m), 5.40 (1H, s), 5.61 (1H, s), 5.87 (2H, s), 6.1-6.8 (3H, m), 6.94 (2H, s)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH2:21])[C:18]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:21][C:19]1[C:18]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[O:31])=[CH:17][N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:20]=1
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 285.8 %

Procedure:
4-[4-Amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.96 g, Example 10) was dissolved in dichloromethane (25 mL), cooled to 0° C. and treated with trifluoroacetic acid (12.5 mL). After stirring 1 hour at 0° C., the reaction mixture was concentrated in vacuo to give 4.29 g of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone as the trifluoroacetic acid salt. A portion of the crude product was purified on HPLC and then neutralized with sodium carbonate, washed with brine and dried to give [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone free base. HRMS, observed: 328.1771; Calcd for (M+H)+: 328.1768.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:13][CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[OH:16].[BH4-].[Na+]>CO.O.CCOC(C)=O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCC(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CNCC(O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.32 ml of 4-tert-butylbenzaldehyde (1.8 mmol) and 250 mg of [rac]-2-amino-1-(3,4-dichloro -phenyl)-ethanol (1.2 mmol) were dissolved in 10 ml methanol at rt, and after stirring for 5 min at rt, were refluxed for 2 h. After cooling down to rt, 68 mg (1.8 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was then refluxed for 2 h. After cooling down to rt, the residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was stirred with diethylether/heptane, filtered and the solid dried under high vacuo, leading to 147 mg of [rac]-(4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-amine as a light yellow solid (35%). MS (ISP) 352.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]([CH2:36][C:37](O)=[O:38])#[N:35]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:37](=[O:38])[CH2:36][C:34]#[N:35])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: N#CCC(=O)O
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)CC#N)cc2)cc1

Procedure:
The titled compound was prepared following the procedure H using methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate and cyanoacetic acid, as a pale yellow oil (96%). M− (ESI): 507.4; M+ (ESI): 509.4. HPLC, Rt: 5.22 min (Purity: 86.2%).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH:9]=[C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[CH3:21])=[O:12])[C:4]=2[N:3]=1.Cl.[NH:36]1[CH2:39][CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>CCO>[N:36]1([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:32])([F:33])[F:34])=[O:24])[CH:9]=[C:10]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=4[CH3:21])=[O:12])[C:4]=3[N:3]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(Cl)nc12
Reactant: C1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(N3CCC3)nc12
Yield: 32.4 %

Procedure:
A solution of 2-chloro-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (80 mg, Example 135), azetidine hydrochloride (60 mg) and N,N-diisopropylethylamine (208 μL) in EtOH (1.8 mL) was reacted at 120° C. for 20 minutes in a microwave reactor (Biotage, Initiator). The reaction mixture was concentrated under reduced pressure, and the residue was purified on column chromatography to obtain 2-(azetidin-1-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (27 mg). This was dissolved in MeOH (1 mL), 2N hydrogen chloride/MeOH solution (1 Eq) was added, and it was stirred and concentrated. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (21 mg) as white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[CH2:21]([O:20][C:18]([CH:17]1[CH:10]2[CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]2=[O:14])=[O:19])[CH3:22]
Reactant: O=C1C=CCCN1Cc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Mo]
Agent: [C-]#[O+]
Product: CCOC(=O)C1C2CCN(Cc3ccccc3)C(=O)C21

Procedure:
These compounds can be prepared from 1-benzyl-5,6-dihydro-2(1H)-pyridinone by reaction with ethyl diazoacetate with molybdenum hexacarbonyl catalyst to provide 3-benzyl-2-oxo-3-azabicyclo[4.1.0]heptane-7-carboxylic acid ethyl ester, which can be reduced with lithium aluminum hydride to provide 3-benzyl-7-hydroxymethyl-3-azabicyclo[4.1.0]heptane. Utilization of the methods in Section VIII then yields the desired 7-R7 -substituent.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17]>>[CH3:3][CH:2]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Br:10])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CCCC(C)Br
Reactant: Oc1ccccc1Br
Product: CC(C)CCCC(C)Oc1ccccc1Br

Procedure:
2-bromo-6-methyl-heptane was reacted with o-bromo-phenol to obtain o-bromo-phenyl 1,5-dimethyl-hexyl ether (boiling point =190°-193° C/17 mmHg);
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][C:36]([F:48])([F:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])[C:29]([O:31]CC)=[O:30])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][C:36]([F:48])([F:47])[C:37]([F:45])([F:46])[C:38]([F:43])([F:44])[C:39]([F:40])([F:41])[F:42])[C:29]([OH:31])=[O:30])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCCCCCC1c2ccc(O)cc2OCC1(C)c1ccc(O)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Yield: 80.7 %

Procedure:
Ethyl 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoate (1.10 g, 1.570 mmol) and potassium hydroxide (880 mg, 15.70 mmol) were added to a methanol/water mixture (2:1, 15 ml), followed by heating under reflux for 4 hours. After the reaction mixture was neutralized with 1N hydrochloric acid, the solvent was distilled off under reduced pressure. The residue was diluted with water, adjusted to pH 2-3 with 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid (852 mg, Yield 81%) as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Br:15][C:16]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[Br:15][C:16]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc(Br)cc1Br
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Br)cc1Br

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2,4-dibromoaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:13]=[CH:12][C:10](N)=[C:9]([F:14])[CH:8]=1.N([O-])=O.[Na+].NS(O)(=O)=O.[C:24]([OH:28])(=[O:27])[CH:25]=[CH2:26]>O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[Br:6][C:7]1[CH:13]=[CH:12][C:10]([CH:26]=[CH:25][C:24]([OH:28])=[O:27])=[C:9]([F:14])[CH:8]=1
Reactant: C=CC(=O)O
Reactant: Nc1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: NS(=O)(=O)O
Solvent: O
Product: O=C(O)C=Cc1ccc(Br)cc1F
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
62 ml of sulfuric acid were added to 236 ml of water and the mixture was cooled to 5° C. 57.0 g of 4-bromo-2-fluoroaniline were added at this temperature and a solution of 24.2 g of sodium nitrite in 45 ml of water was added dropwise at 0 to 2° C. in the course of 30 minutes and the mixture was stirred for 20 minutes. 2.8 g of amidosulfonic acid were then added. 5 ml of the diazonium salt solution were added dropwise at 40° C. to 27.5 g of acrylic acid, 0.23 g of palladium(II) acetylacetonate was added and the residual diazonium salt solution was added dropwise in the course of 20 minutes. The mixture was stirred at 40° C. for 4 hours. It was allowed to cool to room temperature and the product was isolated by filtration. After drying, 54.4 g of 4-bromo-2-fluorocinnamic acid were present (74% of theory; melting point: 218° C.).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[O:10][C:9]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].BrC(C)C.O>CS(C)=O>[CH3:13][C:11]1[O:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([O:7][CH:2]([CH3:3])[CH3:1])[CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1oc(C)cc1O
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)Br
Solvent: O
Product: CCOC(=O)c1oc(C)cc1OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of 1.6 g (14.3 mmol, 1.2 equiv) of potassium tert-butoxide in 11 mL of dimethyl sulfoxide is added to a solution of 2.0 g (11.8 mmol) of ethyl 3-hydroxy-5-methyl-2-furancarboxylate (Takei, H. and Mukaiyama, T., Bull. Soc. Chem. Jpn., 43, 3607 (1970)) in 40 mL of dimethyl sulfoxide under a nitrogen atmosphere. The resulting solution is stirred at room temperature for 1 hour and treated with 5.9 g (47.9 mmol, 4.1 equiv) of 2-bromopropane. The reaction is stirred at room temperature for 7.5 hours under nitrogen and poured onto 100 mL of water. The aqueous solution is extracted with ethyl acetate (4x). The combined extracts are washed with water (2x) and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo to give 1.7 g (2.5 g theo., 68%) of ethyl 5-methyl-3-isopropoxy-2-furancarboxylate as a pale, yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][NH:2][S:33]([CH3:32])(=[O:35])=[O:34])[CH:5]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride ((for a preparation see Intermediate 4) 51 mg, 0.10 mmol) in dry DCM (3 mL) was added methanesulfonyl chloride (8 μL, 0.1 mmol), followed by pyridine (1 mL). The resultant pale yellow solution was stirred at room temperature overnight. LCMS showed only 19% of required product. Triethylamine (14 μL, 0.10 mmol), followed by more methanesulfonyl chloride (8 μL, 0.1 mmol) were added and stirring was continued for a further 30 min. The reaction mixture was then concentrated in vacuo and the residue dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was evaporated in vacuo to give the title product (10.7 mg, 19%) as a white solid. LCMS (System A) RT=1.13 min, ES+ve m/z 541/543 (M+H)+.