Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:24][CH:23]([C:25](O)=[O:26])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:65][C:66]([F:70])([F:69])[CH2:67][NH2:68]>CN(C=O)C>[F:65][C:66]([F:70])([F:69])[CH2:67][NH:68][C:25]([CH:23]1[CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH2:11][C:10]([C:4]4[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=4)([C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:16][CH:17]=2)[CH2:24]1)=[O:26]
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a stirred solution of 1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 12, 0.1 g, 0.203 mmol) in DMF (3 mL) was added DIPEA (0.052 g, 0.406 mmol), HOBt (0.027 g, 0.203 mmol), EDCl.HCl (0.058 g, 0.304 mmol) and 2,2,2-trifluoro-ethylamine hydrochloride (0.027 g, 0.203 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (50 mL), extracted with EtOAc (3×20 mL). Combined organic layer was washed with saturated NaHCO3 (2×50 mL), dried over sodium sulphate and evaporated in vacuo to get 0.170 mg crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 0.8% methanol in DCM to afford pale yellow solid, which was re-purified by DCM in pentane (1:9) to afford pale yellow solid (0.082 g, 71%). 1H-NMR (400 MHz, CDCl3) δ: 3.43-3.48 (m, 1H), 3.62 (d, 1H, J=17.04), 3.93-4.00 (m, 2H), 4.04 (d, 1H, J=17.0), 4.09-4.14 (m, 4H), 5.94 (t, 1H, J=6.06 Hz), 6.43 (d, 2H, J=8.72 Hz), 7.47-7.50 (m, 2H), 7.63 (s, 2H); LC-MS (m/z): [M−H] 571.70.
Reaction SMILES: C([O:3][C:4]([CH2:6][S:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)=[O:5])C.[C:17]([O:21][C:22](=[O:28])[NH:23][CH2:24][CH2:25][NH:26][CH3:27])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:23][CH2:24][CH2:25][N:26]([CH3:27])[C:12]([C:11]1[CH:10]=[CH:9][C:8]([S:7][CH2:6][C:4]([OH:3])=[O:5])=[CH:16][CH:15]=1)=[O:14])=[O:28])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)CSc1ccc(C(=O)O)cc1
Reactant: CNCCNC(=O)OC(C)(C)C
Product: CN(CCNC(=O)OC(C)(C)C)C(=O)c1ccc(SCC(=O)O)cc1

Procedure:
{4-[(2-Tert-butoxycarbonylaminoethyl)methylcarbamoyl]phenylthio}acetic acid was prepared in analogy to the procedure described in example 80 using 4-ethoxycarbonylmethylsulfanylbenzoic acid and commercially available (2-methylamino-ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]1([C:5]2[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH:2]=1.[CH3:20][S:21]([CH2:24][C:25]([NH2:33])([CH3:32])[C:26]1[N:30]=[C:29]([CH3:31])[O:28][N:27]=1)(=[O:23])=[O:22]>>[C:1]1([C:5]2[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([NH:33][C:25]([C:26]3[N:30]=[C:29]([CH3:31])[O:28][N:27]=3)([CH3:32])[CH2:24][S:21]([CH3:20])(=[O:23])=[O:22])=[O:13])=[N:9][CH:10]=2)[CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2=CCC2)cn1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3=CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(cyclobuten-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 127d) and 2-Methanesulfonyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 109d) as starting materials and isolated (25 mg, 14%); MS (ESI, m/z): 475.5 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:27]2[C:32]([F:33])=[CH:31][C:30]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:29][C:28]=2[F:38])=[CH:22][C:23]=1[C:24]([NH2:26])=[O:25]>>[F:38][C:28]1[CH:29]=[C:30]([C:34]([OH:37])([CH3:36])[CH3:35])[CH:31]=[C:32]([F:33])[C:27]=1[C:21]1[S:20][C:19]([NH:18][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][C:9]([NH:11][C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[O:10])[N:7]=2)=[C:23]([C:24]([NH2:26])=[O:25])[CH:22]=1
Reactant: Cn1cc(NC(=O)Cc2cccc(Br)n2)cn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cn1cc(NC(=O)Cc2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-(6-bromopyridin-2-yl)-N-(1-methyl-1-H-pyrazol-4-yl)acetamide (217 mg, 0.74 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (230 mg, 0.74 mmol) as starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.[S:23](N)(N)(=[O:25])=[O:24]>N1C=CC=CC=1>[O:24]=[S:23]1(=[O:25])[N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: NS(N)(=O)=O
Reactant: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Solvent: c1ccncc1
Product: O=S1(=O)Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 11.0 g (0.0372 mol) of 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzenemethanamine in 200 ml of pyridine was added dropwise within 1.5 hours and at reflux temperature to a solution of 3.4 g (0.0354 mol) of sulphamide in 200 ml of pyridine and the mixture was then refluxed for 6 hours. The mixture was freed from solvent, the residue was purified by column chromatography using ethyl acetate/methanol 9/1 (v/v) as eluant. 5.5 g (43.5% of theory) of a colourless amorphous substance were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[C:4]([CH3:10])[CH:3]=1.[CH:11](=O)[CH2:12][CH3:13]>CCO.C(=O)CC>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([CH3:10])[CH:3]=1)[NH:8][CH:11]=[C:12]2[CH3:13]
Reactant: CCC=O
Reactant: Cc1cc(Br)ccc1NN
Solvent: CCO
Product: Cc1c[nH]c2c(C)cc(Br)cc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
200 mg of 1-(4-bromo-2-methylphenyl)hydrazine was suspended in 10.0 mL EtOH propionaldehyde (678 μL) was added. The reaction became clear after the addition of propionaldehyde. The resulting solution was then stirred at room temperature for 45 minutes. The reaction was concentrated and zinc(II)chloride (1070.0 mg) was added and the mixture was heated at 170° C. for 30 minutes. The melting mixture was then cooled to room temperature, and diluted with 10% HCl solution. The solution was then extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated. The residue was flash chromatographed (0-10% EtOAc/Haptanes gradient) to obtain 317.0 mg of 5-bromo-3,7-dimethyl-1H-indole. LC-MS @ 222.1 (M−1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:10]2[CH:11]=[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:25][CH:26]([F:28])[F:27])=[N:9]2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 90 °C

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amide (200 mg, 0.49 mmol) was dissolved in DMF (5 mL), 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (263 mg, 0.74 mmol) and cesium carbonate (240 mg, 0.74 mmol) were added and the mixture heated at 90° C. for 2 hours. The mixture was allowed to cool to room temperature, diluted with water and extracted with DCM (×3). The combined organic extract was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant yellow oil was purified by flash chromatography on silica eluting with 0-2% MeOH in DCM. The appropriate fractions were collected and evaporated to afford 4-{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidine-1-carboxylic acid tert-butyl ester a yellow oil. The crude product was taken onto the next step without further purification. LCMS (Method 4) [M+Na]+=610.0; RT=4.30 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[S:16][CH2:15][CH2:14][CH2:13][S:12]2)=[CH:9][S:8][C:7]=1[NH2:24])=[O:5])[CH3:2].[C:25]1(=O)[O:30][C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[S:12][CH2:13][CH2:14][CH2:15][S:16]2)=[CH:9][S:8][C:7]=1[N:24]1[C:28](=[O:29])[C:27]2[C:26](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]1=[O:30])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(C2(c3cccc(Cl)c3)SCCCS2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C2(c3cccc(Cl)c3)SCCCS2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-[2-(3-chlorophenyl)-1,3-dithian-2-yl]thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 27 & 28, Part C) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)N.Cl.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.Cl>C(O)(C)C>[CH3:14][N:15]1[CH2:20][CH2:19][C:18]2[NH:2][C:4]3[C:12]([C:17]=2[CH2:16]1)=[C:8]1[CH:9]=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3
Reactant: NNc1ccc2sccc2c1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CC(C)O
Product: CN1CCc2[nH]c3ccc4sccc4c3c2C1

Procedure:
4 g of 5-hydrazinobenzothiophene hydrochloride, suspended in 100 ml of isopropanol, are combined with 2.8 ml of 1-methyl-4-piperidone hydrochloride under N2. The solution is brought to the boil and 10 ml of isopropanol saturated with HCl re added whilst the solution is hot. After boiling the mixture of 1/2 hour, the solvent is distilled off, the residue is treated with ammonia and the precipitate is filtered off and recrystallised from methanol. 9-Methyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole of melting point 189° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@H:29]([NH:30]C(=O)OC(C)(C)C)[CH2:28][C:27]([CH3:39])([CH3:38])[O:26][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:16][C:15]=2[Cl:25])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@H:29]([NH2:30])[CH2:28][C:27]([CH3:39])([CH3:38])[O:26][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:16][C:15]=2[Cl:25])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2nc(-c3ccc(-c4cn[nH]c4)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C[C@@H](N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(-c4cn[nH]c4)cc3Cl)nc2O1

Procedure:
A solution of the product of Step A (364 mg, 0.64 mmol) in 10 mL of 20% TFA in CH2Cl2 was stirred at rt for 2 h. The reaction mixture was concentrated to give the product, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH3:10][NH:11][CH3:12]>>[CH3:10][N:11]([CH3:12])[C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: CNC
Reactant: O=[N+]([O-])c1cc[nH]c1Cl
Product: CN(C)c1[nH]ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
This compound was prepared in a manner analogous to that set forth in Step C of Example 2, using 0.65 gram (0.0045 mole) of 2-chloro-3-nitropyrrole (prepared in Steps D-F of Example 1) and 5.0 mL (excess) of dimethylamine. The microwave chemical reactor was maintained at 100° C. during a 45-minute period, after which time the reaction was considered to be complete. The crude product was purified with column chromatography on silica gel. Elution was accomplished using 25% hexane in diethyl ether, then 100% diethyl ether as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.2 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25](OCC)=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][C:25]3[O:8][N:7]=[C:4]4[CH2:3][CH2:2][O:1][CH2:6][C:5]=34)[CH2:20][CH2:21]2)=[CH:14][CH:15]=1
Reactant: ON=C1CCOCC1
Reactant: CCOC(=O)CCCN1CCN(c2ccc(F)cc2)CC1
Product: Fc1ccc(N2CCN(CCCc3onc4c3COCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using tetrahydro-4H-pyran-4-one oxime and ethyl 4-(4-(4-fluorophenyl)piperazin-1-yl)-n-butyrate, 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-6,7-dihydro-4H-pyrano[4,3-c]isoxazole is obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[CH:17][O:18][CH:19]=1)C1C=CC=CC=1>ClCCl.[Pd]>[O:18]1[CH:19]=[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[N:16]=[CH:17]1
Reactant: c1ccc(COc2ccccc2-c2cocn2)cc1
Agent: [Pd]
Solvent: ClCCl
Product: Oc1ccccc1-c1cocn1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of the oxazole from above (1.99 g, 7.92 mmol) in dichloromethane (20 ml) is added 10% palladium on carbon (1.99 g). The mixture is put under an atmosphere of hydrogen, stirred at room temperature over night, then filtered through Celite. The solvent is removed under reduced pressure to leave 2-(oxazol-4-yl)phenol (1.15 g, 90%), which is used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:31])([F:33])[F:32])[CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)c(C(F)(F)F)c2)CC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of N-tert-butyloxycarbonyl-4-piperidinol (1.0 g, 5.0 mmol) in THF (20 mL) at 0° C. was added potassium tert-butoxide (5.0 mL of a 1.0 M solution in THF, 5.0 mmol). The mixture was stirred for 10 min and 4-fluoro-2-trifluoromethyl-benzonitrile (1.04 g, 5.5 mmol) was added. The mixture was stirred at 0° C. for 1 h and then at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:2 EtOAc:hexanes as eluant to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-trifluoromethylbenzonitrile as a colorless gum.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][OH:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>C1COCC1>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][OH:40])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
Methyl 4-({2-[1-benzhydryl-5-chloro-2-(hydroxymethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 eq) was dissolved in THF (0.07M). Then MeOH (2.5× the volume of THF) was added, followed by a 1N NaOH solution (2 eq). The reaction was stirred overnight and the solvent was then removed. The resulting residue was dissolved in water and 1N HCl was added until solution was acidic. The resulting white precipitate was collected by filtration and it was the title compound in 76% yield. m/z (M−1) 557.6
Reaction SMILES: [Li+].C[CH:3]([N-:5][CH:6](C)C)C.CNC.C[O:13][C:14]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=1)=O>>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][N:19]=1)[C:14]([N:5]([CH3:6])[CH3:3])=[O:13]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)c1ccnc(N)c1
Agent: CNC
Agent: [Li+]
Product: CN(C)C(=O)c1ccnc(N)c1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To LDA (7.3 mL, 13 mmol, 1.8M in ether/heptane) at 0° C., add dropwise dimethylamine (13 mL, 26 mmol, 2M in THF) under nitrogen. Stir for 30 minutes and add 2-amino-4-pyridine carboxylic acid methyl ester (2 g, 13 mmol, in 3 mL of anhydrous THF and 2 mL of anhydrous ether). Seal and heat at 85° C. overnight. Cool the mixture to room temperature and quench with water. Dilute with EtOAc and isolate the top organic layer. Extract the aqueous layer further with saturated sodium bicarbonate and ether, then DCM. Pool all the organic layers, dry (MgSO4) and concentrate. Purify by strong cation exchange (SCX) column to obtain the crude product and use in the next step without further purification. LCMS (ES), m/z 166 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15]1[C:27]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][C:16]=1[CH:28]=O.[BH4-].[Na+].O>C(O)C>[CH:15]1[C:27]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][C:16]=1[CH2:28][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:28][C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:26][C:27]=3[CH:15]=2)[CH2:10][CH2:9]1
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: NCCCN1CCN(CCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc2c(c1)Cc1cc(CNCCCN3CCN(CCCNCc4ccc5c(c4)Cc4ccccc4-5)CC3)ccc1-2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 2-fluorenecarboxaldehyde (1.018 g, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2 25×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=4[O:29][CH3:30])=[N:11][C:10]=3[C:9]([CH3:31])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pt]=O.O1CCCC1>[CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=4[O:29][CH3:30])=[N:11][C:10]=3[C:9]([CH3:31])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1ccc(-c2nc3c(C)nn(C4CCCCC4)c3c(=O)[nH]2)c(OC)c1
Agent: O=[Pt]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(-c2nc3c(C)nn(C4CCCCC4)c3c(=O)[nH]2)c(OC)c1
Yield: 81.7 %

Procedure:
To a 2 ml tetrahydrofuran solution of 63 mg (0.15 mmol) of the compound obtained in Example 226, 6 mg of platinum oxide was added, and the mixture was stirred for 3.5 hours in an atmosphere of hydrogen at room temperature and atmospheric pressure. Then, the catalyst was removed by filtration, and the filtrate was distilled under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 52 mg (82%) of the captioned compound.
Reaction SMILES: [OH:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:30][S:31]([O:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1CCCC(O)Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1CCCC(Cc1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a solution of 30d (2.27 g, 7.62 mmol) and Et3N (2.12 mL, 15.2 mmol), MsCl (1.2 mL, 15.2 mmol) was added dropwise at 0° C. After addition was complete, the reaction was stirred at rt until LC-MS analysis indicated the total consumption of the SM. The solvent was removed and the residue was purified by CC using PE:EA=5:1 as mobile phase to afford the desired product (2.9 g, quant.)
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19]C(=O)OC(C)(C)C)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1)[CH3:2].[ClH:27]>O1CCOCC1>[ClH:27].[CH2:1]([C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH2:19])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-{[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (366 mg, 0.98 mmol) in 1,4-dioxane (3 ml) was added HCl in 1,4-dioxane (4M, 3 ml, 12.0 mmol). The reaction was stirred at room temperature for 18 hours and was then concentrated in vacuo and azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:14][CH:11]1[CH2:13][CH2:12]1)=[O:6]
Reactant: NC1CC1
Reactant: O=C(Cl)c1cccc(Br)c1
Product: O=C(NC1CC1)c1cccc(Br)c1
Yield: 86.4 %

Procedure:
By the reaction in the same manner as in Example 45-(i) using 3-bromobenzoyl chloride (5.50 g) and cyclopropylamine (4.30 g), the title compound (5.20 g) was obtained as colorless needle crystals.