Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][C@@H:11]([C:13](=[O:20])[CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH2:27]O.Cl>CO.O>[CH:1]1([C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:20][NH:27][C:15](=[O:16])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](C2CCCCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1C1CCCCC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
Cis-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.644 g, 4.84 mmol) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.194 g, 4.84 mmol) dissolved in water (1.500 mL) was added dropwise and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.297 mL, 4.84 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (21 mL, 126.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase dried over Na2SO4 and evaporated to yield a slightly yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using two injections with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-cyclohexyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (814 mg, 55%) was isolated. 1H NMR (400 MHz, cdcl3) δ 0.83-0.98 (m, 2H), 1.01-1.16 (m, 3H), 1.25-1.40 (m, 1H), 1.50-1.88 (m, 6H), 1.95-2.13 (m, 3H), 2.88-3.07 (m, 2H), 3.70 (s, 3H), 3.79-3.89 (m, 1H), 3.95-4.07 (m, 1H), 5.70 (s, 1H). MS m/z 309 (M+H)+
Reaction SMILES: C([O:5][C:6](=[O:33])[C@H:7]([CH3:32])[NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH2:27][CH2:28][Cl:29])[CH2:24][CH2:25][Cl:26])=[C:19]([CH3:30])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][Cl:29])[C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:33])=[O:5])[CH3:32])=[O:31])=[CH:15][CH:14]=2)=[CH:18][C:19]=1[CH3:30]
Reactant: Cc1cc(Oc2ccc(C(=O)N[C@@H](C)C(=O)OC(C)(C)C)cc2)ccc1N(CCCl)CCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Oc2ccc(C(=O)N[C@@H](C)C(=O)O)cc2)ccc1N(CCCl)CCCl
Reaction time: 1 h

Procedure:
N-(4-{4-[bis-(2-chloroethyl)-amino]-3-methyl-phenoxy}-benzoyl)-L-alanine-tert-butyl ester (400 mg; compound 9) was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (8 ml) was added. The mixture was allowed to stand at ambient temperature for 1 hour, evaporated to dryness and azeotroped twice with ethyl acetate to give the titled compound (compound 10; the drug corresponding with the prodrug of Example 21) as an oil (0.43 g, 52% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27](O)=[O:28])[CH:21]=[CH:20]3)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].C(Cl)(=O)C([Cl:37])=O>>[CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]([Cl:37])=[O:28])[CH:21]=[CH:20]3)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)ccc2c1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Treat a solution of 6-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carboxylic acid (0.11 g, 0.246 mmol) in CH2CL2 (1.0 mL) dropwise with oxalyl chloride (0.13 mL, 1.48 mmol). Stir the solution at RT for 1 h and concentrate to give 6-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carbonyl chloride (“the acid chloride”). Treat a mixture of methylglycine HCl (0.031 g, 0.25 mmol) and Et3N (0.51 mL, 0.37 mmol) in CH2CL2 (3 mL) with a solution of the acid chloride (0.057 g, 0.123 mmol) in CH2CL2 (1 mL). Stir the reaction at RT for 16 h and concentrate. Dissolve the residue in THF (0.5 mL) and MeOH (1.0 mL) and treat with 2N NaOH (0.24 mL, 0.48 mmol). Heat the solution to 50° C. for 16 h, concentrate, dilute with CH2CL2 and water (10 mL each). Acidify the resulting mixture to pH 1 using 5N HCl. Wash the organic layer with brine, dry over Na2SO4, and filter. Concentrate the filtrate and purify by silica gel radial chromatography (10:90 MeOH:CH2CL2) to give the title compound as a white solid (0.021 g, 34%). MS (ES) m/e 504 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]1[C:21](=[O:22])[NH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=2)=[N:18]1.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]1[C:21](=[O:22])[NH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:33]#[C:32][C:31]([CH3:35])([CH3:34])[CH3:30])=[CH:25][CH:24]=2)=[N:18]1
Reactant: C#CC(C)(C)C
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C#Cc1ccc(-c2nn(-c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c(=O)[nH]2)cc1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 48.5 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-68, 0.050 g, 0.094 mmol) in DMSO (3.0 mL), 3,3-dimethylbut-1-yne (0.011 g, 0.142 mmol), TBAF (0.074 g, 0.283 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol) were added and the reaction mass was stirred at 80° C. for 5-6 h. After completion of the reaction, the reaction mass was quenched with water and extracted with DCM and concentrated. The obtained crude product was purified with column chromatography on silica gel column and 2.0% EA:DCM as mobile phase to afford 0.022 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 1.09 (s, 9H), 1.25 (s, 9H), 4.31 (br s, 2H), 7.35-7.51 (m, 4H), 7.80 (d, J=8.3 Hz, 2H), 8.18-8.20 (m, 1H); MS (m/z): 481.14 (M−H)−.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].C(N(CC)CC)C.[OH:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[C:30]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]([F:45])([F:44])[F:43])[NH:31][C:32]3=[O:35])=[CH:27][CH:26]=2)[CH2:20]1.[Cl-].[NH4+]>ClCCl>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][NH:1][C:2]([O:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[C:30]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]([F:43])([F:45])[F:44])[NH:31][C:32]3=[O:35])=[CH:27][CH:26]=2)[CH2:20]1)=[O:3])[CH3:9]
Reactant: O=C1O[C@@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: CCOC(=O)CN=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Ethyl isocyanatoacetate (6.6 μL, 0.059 mmol) and triethylamine (10.3 μL, 0.074 mmol) were added to a solution of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14 (20 mg, 0.050 mmol) in dichloromethane, and the mixture was stirred at room temperature for four hours. Aqueous saturated ammonium chloride was added to the mixture, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (methylene chloride:methanol=50:1) to obtain 24 mg (92%) of ethyl{(R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethoxycarbonylamino}acetate as a colorless oil.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14].C=CCCCC.CCCCC=CCCCC.[C:32](OCCCCCCCCC=C)(=[O:34])[CH3:33]>>[C:32]([O:15][CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:34])[CH3:33]
Reactant: C=CCCCCCCCCOC(C)=O
Reactant: CCCCC=CCCCCCCCCO
Agent: CCCCC=CCCCC
Solvent: C=CCCCC
Product: CCCCCCCCCCCCC=COC(C)=O

Procedure:
A process for preparing 9-tetradecenyl alcohol by reacting 1-hexene or 5-decene with 9-decenyl acetate in accordance with the method of claim 7 to obtain tetradecenyl acetate and then reacting the acetate with water to obtain said alcohol.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:11])[C:4](=[N:8][O:9][CH3:10])[C:5](O)=[O:6].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>ClCCl>[Br:1][CH2:2][C:3](=[O:11])[C:4](=[N:8][O:9][CH3:10])[C:5]([Cl:13])=[O:6]
Reactant: CON=C(C(=O)O)C(=O)CBr
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CON=C(C(=O)Cl)C(=O)CBr

Procedure:
To a solution of 30.20 gm (0.154 moles) of 4-bromo-2-methoxyimino-3-oxo-butyric acid in dichloromethane (230 ml) cooled to −10° C. under an atmosphere of nitrogen was added phosphorous pentachloride (28.10 gm; 0.134 moles) in portions and the solution of 4-bromo-2-methoxyimino-3-oxo butyric acid chloride (IV) in dichloromethane thus obtained is kept cooled to −10° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:16])([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>>[NH2:15][CH2:14][C:11]1([OH:16])[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Agent: B
Solvent: C1CCOC1
Product: NCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 1-benzyl-4-hydroxy-piperidine-4-carbonitrile (5.00 g, 19.78 mmol) and BH3.THF (59.35 mmol, 59.35 mL, 1M in THF) was heated at 80° C. for 1 h. Cooled to 0° C. and quenched with conc. HCl (20 mL), the reaction solution was then stirred at rt in 1 h. The reaction solution was basified with 10N NaOH to pH8, and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (50 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 4-aminomethyl-1-benzyl-piperidin-4-ol. M.S.(M+1):221.31
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8](Cl)=[CH:7][CH:6]=1.C([O-])(=[O:18])C.[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8](=[O:18])[NH:9][N:10]=1
Reactant: CC(=O)[O-]
Reactant: Fc1ccccc1Cc1ccc(Cl)nn1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc(Cc2ccccc2F)n[nH]1
Temperature: 110 °C
Yield: 65.6 %

Procedure:
6-(2-Fluorobenzyl)-3-chloropyridazine (2.5 g, 11.2 mmol) [prepared as described above] was dissolved in acetic acid (15 ml). Sodium acetate (3.37 g, 24.8 mmol) was added and the reaction mixture was heated at 110° C. under a nitrogen atmosphere. After 1.5 h the reaction mixture was diluted with water and the product was extracted into ethyl acetate. The organic extracts were washed with water, aqueous NaHCO3 and brine, and dried over MgSO4. The solvent was removed in vacuo and the crude product was chromatographed on a silica gel column (50% ethyl acetate in hexanes) to give 6-(2-fluorobenzyl)-2H-pyridazin-3-one (1.5 g, 55% yield) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.[H-].[Na+].Cl[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]=[C:28]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:27]=1>CN(C)C=O>[C:38]1([C:28]2[N:29]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:31]=[C:26]([N:13]3[C:12]4[CH:11]=[C:10]5[C:2]([CH3:22])([CH3:1])[C:3]6[C:8]([C:9]5=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:7][CH:6]=[CH:5][CH:4]=6)[N:27]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8 g (28.2 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene are dissolved in 225 ml of dimethylformamide under a protective-gas atmosphere, and 1.5 g of NaH, 60% in mineral oil (37.5 mmol), are added. After 1 h at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (8.5 g, 31.75 mmol) in 75 ml of dimethylformamide is added dropwise. The reaction mixture is then stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene. The yield is 12 g (23 mmol, 83%).
Reaction SMILES: [F:1][CH2:2][C@H:3]1[O:7][CH2:6][C@@:5]([NH:15][C:16]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[S:17])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C@@H:4]1[CH2:27]O.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>>[F:1][CH2:2][C@@H:3]1[C@@H:4]2[C@@:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])([N:15]=[C:16]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:17][CH2:27]2)[CH2:6][O:7]1
Reactant: O=C(NC(=S)N[C@@]1(c2ccccc2F)CO[C@H](CF)[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3ccccc3F)CO[C@H](CF)[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 94.2 %

Procedure:
N-(((3S,4R,5S)-5-(fluoromethyl)-3-(2-fluorophenyl)-4-(hydroxymethyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide (78.70 g, 193.63 mmol) was dissolved in pyridine (391 mL, 5190.48 mmol), and the mixture cooled to 0° C. Trifluoromethanesulfonic anhydride (43.98 mL, 261.40 mmol) was added dropwise over 40 min (internal temperature increased from 4° C. to 18° C.). The reaction was stirred in an ice bath for 1 h and 25 mins. It was quenched by the slow addition of ammonium chloride (sat., aq., 260 mL) and then water (390 mL). The aqueous layer was extracted with EtOAc (3×500 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo and purified by silica gel column chromatography (20% to 60% EtOAc/hex) to obtain the title compound (70.86 g, 94%). 1H NMR (400 MHz, CDCl3) δ ppm 2.83 (dd, J=13.64, 3.79 Hz, 1H) 3.30 (dd, J=13.89, 3.54 Hz, 1H) 3.38-3.47 (m, 1H) 4.07 (dd, J=9.22, 2.65 Hz, 1H) 4.51-4.78 (m, 4H) 7.15 (ddd, J=12.44, 8.15, 1.14 Hz, 1H) 7.22 (td, J=7.58, 1.26 Hz, 1H) 7.34-7.41 (m, 1H) 7.41-7.48 (m, 3H) 7.49-7.56 (m, 1H) 8.10-8.18 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:41])[C:6]=1[C:7]1[CH:39]=[CH:38][C:10]([C:11]([NH:13][C@@H:14]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[O:12])=[CH:9][C:8]=1[F:40].NN>CO.C1COCC1>[NH2:16][CH2:15][C@@H:14]([NH:13][C:11](=[O:12])[C:10]1[CH:38]=[CH:39][C:7]([C:6]2[N:5]([CH3:41])[N:4]=[CH:3][C:2]=2[Cl:1])=[C:8]([F:40])[CH:9]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35]
Reactant: Cn1ncc(Cl)c1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1F
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc(Cl)c1-c1ccc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-3-fluorobenzamide (90 mg, 0.15 mmol) in MeOH/THF (2 mL, 1:1) at RT was added hydrazine (0.12 mL, 3.93 mmol). After stirring for 18 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound (14 mg, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:14])=[C:8]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)[CH2:7][CH2:6]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[O:14])=[C:8]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc(C(=O)C2=C(c3cccc(OC)c3)CCc3cc(OC)ccc32)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)c2c(-c3cccc(OC)c3)ccc3cc(OC)ccc23)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of [3,4-dihydro-6-methoxy-2-(3-methoxyphenyl)-1-naphthalenyl](4-methoxyphenyl)methanone (14.0 g, 35.0 mmol) was dissolved in anhydrous dioxane (400 mL) under an atmosphere of nitrogen. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 7.0 g, 31 mmol) was added and the solution was refluxed for 16 hours. The reaction mixture was allowed to cool to ambient temperature and the solid dihydroquinone byproduct (8.8 gm) was removed by filtration and discarded. The filtrate was concentrated to dryness and the residue was purified by silica gel chromatography with chloroform as the isocratic elution solvent. Appropriate fractions gave 13.1 g, (94%) of the desired product as an oil. Although the oil contained some minor impurities, it was used without additional purification. 1H NMR (CDCl3) δ 7.88 (d, J=8.6 Hz, 1H), 7.71-7.54 (m, 4H), 7.21 (d, J=2.6 Hz, 1H), 7.18-7.05 (m, 2H), 6.99-6.89 (m, 2H), 6.78-6.70 (m, 3H), 3.94 (s, 3H), 3.78 (s,3H), 3.69 (s,3H); MS (FD) m/e 398 (M+); Anal. Calcd. for C26H22O4 : C, 78.37; H, 5.57. Found: C, 78.22; H, 5.83.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:14])([F:15])[F:16])[C:3]=1[C:17]([N:43]1[CH2:42][CH2:41][N:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:46])([F:47])[F:32])[CH:35]=2)[CH2:45][CH2:44]1)=[O:19]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 66.8 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (424 mg, 1.84 mmol), a gel-like required compound (593 mg, 1.23 mmol, 67%) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH:10]([OH:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH:10]([OH:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 97.1 %

Procedure:
Following a procedure similar to that described in Example 40(c), 0.84 g of ethyl 2-butyl-4-(1-hydroxyethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] was treated with 75% v/v aqueous acetic acid, to give 0.54 g of the title compound as an amorphous solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:33])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH:34]1([CH:40]=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C([BH3-])#N.[Na+].O>C(O)C.C(O)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:33])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([CH2:40][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:13][CH2:12]1
Reactant: O=CC1CCCCC1
Reactant: CCc1ccc(-c2ccc([C@@]3(CC(=O)NOC4CCCCO4)CCNCCS3(=O)=O)s2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1ccc(-c2ccc([C@@]3(CC(=O)NOC4CCCCO4)CCN(CC4CCCCC4)CCS3(=O)=O)s2)cc1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (100 mg) and cyclohexanecarbaldehyde (46 mg) in ethanol were added sodium cyanoborohydride (26 mg) and acetic acid (1 drop) in an ice-water bath. After 1 hour stirring, to the reaction mixture was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water twice and brine, dried over magnesium sulfate and evaporated. The residue was purified by flash silica gel chromatography eluting with hexane-ethyl acetate=5-1, 2-1, 1-2 to give N-(2-tetrahydropyranyloxy)-2-[(S)-4-(cyclohexylmethyl)-7-(5-(4-ethylphenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (91 mg) as colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:29]3[CH:30]=[CH:31][C:32]4[C:36]([CH:37]=3)=[N:35][N:34]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:33]=4)[CH:9]=[C:10]([C:11]3[N:12]=[C:13]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[S:14][CH:15]=3)[N:6]2[N:5]=[CH:4][N:3]=1.Cl>CO.O1CCOCC1>[CH2:38]([N:34]1[CH:33]=[C:32]2[C:36]([CH:37]=[C:29]([C:8]3[CH:9]=[C:10]([C:11]4[N:12]=[C:13]([CH:16]5[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[S:14][CH:15]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:30]=[CH:31]2)=[N:35]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cs2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncnn2c(-c3csc(C4CCNCC4)n3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.6 %

Procedure:
To a solution of tert-butyl 4-{4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (81 mg, 0.13 mmol) in MeOH (600 μL) was added 4M HCl in dioxane (300 μL). The mixture was stirred at rt for 16 h. The mixture was concentrated and the residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 5 mg (7%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.64 (s, 1 H), 8.59 (s, 1 H), 8.07 (d, 1 H), 7.98 (s, 1 H), 7.46-7.61 (m, 6H), 7.40 (dd, 1 H), 5.86 (s, 2 H), 3.51-3.69 (m, 3 H), 3.25 (t, 2 H), 2.39-2.50 (m, 2 H), 2.12 (q, 2 H); LC-MS [M+H]+=507.30, RT=2.69 min.