Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:35][N:36]([C@@H:46]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]1)[C:37]1[N:42]=[CH:41][N:40]=[C:39]2[NH:43][N:44]=[CH:45][C:38]=12.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:48]2[CH2:49][CH2:50][CH2:51][C@@H:46]([N:36]([CH3:35])[C:37]3[N:42]=[CH:41][N:40]=[C:39]4[NH:43][N:44]=[CH:45][C:38]=34)[CH2:47]2)=[O:13])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: CN(c1ncnc2[nH]ncc12)[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(c1ncnc2[nH]ncc12)[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)acetic acid (170 mg, 0.77 mmol) in DMF (5 mL) was added HOBt (156 mg, 1.16 mmol) at 0° C. and the reaction mixture was stirred for 10 min, followed by the addition of EDCI (222 mg, 1.16 mmol), (R)—N-methyl-N-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (180 mg, 0.77 mmol) and DIEA (150 mg, 1.16 mmol). The reaction mixture was allowed to warm to rt and was stirred overnight, diluted with EtOAc (50 mL) and washed with water (3×20 mL). The EtOAc layer was dried over Na2SO4 and evaporated in vacuo to give a residue that purified by column chromatography (silica gel, gradient MeOH in DCM) to afford the titled intermediate (50 mg, 14.8%). 1H NMR (400 MHz, DMSO-d6): δ 13.50 (d, J=10.8 Hz, 1H), 8.22 (s, 1H), 8.17 (m, 1H), 6.77 (s, 1H), 6.70 (s, 1H), 6.62 (s, 1H), 6.32 (m, 1H), 4.40 (d, J=12.4 Hz, 1H), 4.00 (m, 3H), 3.28 (s, 3H), 3.02 (t, J=7.8 Hz, 1H), 2.80 (m, 1H), 2.62 (t, J=7.8 Hz, 1H), 2.00 (m, 2H), 1.82 (m, 2H). LC-MS: m/z [M+1]=434.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C@H:26]([CH2:36][O:37][CH2:38][CH3:39])[CH2:27][O:28][Si](C(C)(C)C)(C)C)[N:12]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:22][CH2:23][CH2:24]2)(=[O:19])=[O:20])[CH:14]=[C:13]([O:25][C@@H:26]([CH2:27][OH:28])[CH2:36][O:37][CH2:38][CH3:39])[N:12]=1
Reactant: CCOC[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC[C@H](CO)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-(ethoxymethyl)ethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide, (product from step v) (0.79 g) in THF (10 mL) was added a 1M solution of tetrabutylammoniumfluoride in THF (2.4 mL) with stirring, at ambient temperature, for 72 h. The reaction mixture was diluted with H2O and extracted with EtOAc (×2). The organic layer was washed with H2O then brine and dried (MgSO4), filtered and evaporated. The resulting oil was purified by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) then titurated with DCM followed by ether/iso-hexane to give the title compound as a white solid. Yield: 0.28 g
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[NH4+:32].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)Cl>ClCCCl>[NH2:32][C:9]1[C:8]2[N:18]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 2-[2-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (3.68 g, 8.60 mmol) in 100 mL of 1,2-dichloroethane was heated to 80° C. and treated with 10 mL of concentrated NH4OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (1.87 g, 9.81 mmol) over a 10 min period. The reaction mixture was then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CH2Cl2. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (3×) and brine. The organic portion was dried over Na2SO4 and concentrated to give 3.68 g of tert-butyl 2-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1OS(C1C=CC(C)=CC=1)(=O)=O)=[O:4].[CH2:21]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22][CH2:23][C:24]#[CH:25]>CCCCCCC.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:25]#[C:24][CH2:23][CH2:22][CH2:21][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:4]
Reactant: C#CCCCc1ccccc1
Reactant: COC(=O)c1sccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: COC(=O)c1sccc1C#CCCCc1ccccc1

Procedure:
This product was prepared from 3-(toluene-4-sulfonyloxy)-thiophene-2-carboxylic acid methyl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 4:6; yield (114 mg, 80%); 1H NMR δ (CDCl3): 7.33 (d, J=4.93 Hz, 1H), 7.16-7.09 (m, 5H), 7.01 (d, J=4.95 Hz, 1H), 3.81 (s, 3H), 2.77 (t, J=7.11 Hz, 2H), 2.42 (t, J=7.16 Hz, 2H), 1.94 (p, J=7.22 Hz, 2H); LCMS m/z: 284.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](O)(=[O:24])=[O:23])=[C:6]1[CH3:26].[Cl:28]CCl.P(Cl)(Cl)(Cl)(Cl)Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([Cl:28])(=[O:24])=[O:23])=[C:6]1[CH3:26]
Reactant: ClCCl
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)O)c2cc(F)ccc21
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Temperature: 25 °C

Procedure:
A mixture of [5-fluoro-2-methyl-3-(2-sulfobenzyl)indol-1-yl]acetic acid methyl ester (0.30 g) and dichloromethane (1.5 mL) was treated portion wise with phosphorus pentachloride (0.15 g), followed by N,N-dimethylformamide (0.070 mL), and the resulting mixture was heated at reflux overnight. The mixture was cooled to room temperature, concentrated under reduced pressure and diluted with dichloromethane. The mixture was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane to afford the title compound as a yellow solid (1.3 g).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[OH:11])([CH3:3])[CH3:2].[OH-].[K+].Cl[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:27])=[C:20]([CH:28]([CH3:30])[CH3:29])[CH:19]=1)=[O:17].Cl>CN1CCCC1=O>[OH:27][C:21]1[C:22]([CH:24]([CH3:26])[CH3:25])=[CH:23][C:18]([C:16](=[O:17])[CH2:15][O:11][C@@H:5]2[CH2:6][C@H:7]([CH3:10])[CH2:8][CH2:9][C@H:4]2[CH:1]([CH3:3])[CH3:2])=[CH:19][C:20]=1[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(C(=O)CO[C@@H]2C[C@H](C)CC[C@H]2C(C)C)cc(C(C)C)c1O
Reaction time: 16 h
Yield: 34 %

Procedure:
To a solution of 15.63 g (100 mmol) of (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanol and 16.5 g (250 mmol) of potassium hydroxide in 100 ml of N-methylpyrrolidone a solution of 12.73 g (50 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone in 400 ml of N-methylpyrrolidone is added dropwise at room temperature and under inert atmosphere. After the addition is completed stirring is continued for additional 16 hours. Then the reaction mixture is acidified with 1N HCl and extracted with ethyl acetate. The collected organic phases are washed with water and brine, dried and evaporated. Crystallization of the crude product from hexane gives 6.37 g of compound 110, m.p. 83-84° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[N:15]([C:16](=[O:26])[CH:17]=[C:18]([C:23]([OH:25])=[O:24])[CH:19]=2)[CH:14]=1)=O)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[N:15]([C:16](=[O:26])[CH:17]=[C:18]([C:23]([OH:25])=[O:24])[CH:19]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc2cc(C(=O)O)cc(=O)n2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCOc1ccc2cc(C(=O)O)cc(=O)n2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a mixture of 7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carboxylic acid (18 mg, 0.050 mmol) in anhydrous dichloromethane (1 ml) under nitrogen atmosphere was added trifluoroacetic acid (1 ml). The mixture was stirred for 2 hours at room temperature, concentrated and triturated with ether to give 17.3 mg (92% yield) of desired compound as a yellow solid which was characterized by 1HNMR (300 MHz, CD3OD) δ: 2.22-2.29 (m, 2H), 3.20-3.23 (m, 2H), 4.28-4.31 (m, 2H) 7.09 (d, J=1.5 Hz, 1H), 7.46-7.49 (dd, J=9.5 and 2.5 Hz, 1H) 7.52 (s, 1H), 7.90 (d, J=9.5 Hz, 1H), 8.71 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([O:27][CH2:28][CH3:29])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Yield: 97.6 %

Procedure:
2-Ethoxy-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}acrylic acid ethyl ester (1.47 g; 3.38 mmole) was hydrogenated for 3 hours at atmospheric pressure in ethyl acetate (50 ml) using Pd/C (5%; 0.75 g) as catalyst. The reaction mixture was filtered through celite and dried (magnesium sulfate). The solvent was evaporated in vacuo to give (1.44 g; yield 98%) of 2-ethoxy-3-[4(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic acid ethyl ester.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[S:14][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH2:28])=[CH:21][CH:20]=1.[BH4-].[Na+]>CC(O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][NH:28][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[S:14][C:10]=4[CH:9]=3)[CH2:4][CH2:3]2)=[CH:23][CH:24]=1
Reactant: NCCCc1ccc(F)cc1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)sc3c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4)CC3)cc2s1
Reaction time: 4 h

Procedure:
To a solution of ketone 25 (2.3 g, 9.3 mmol) in 2-propanol (30 mL) was added 4 Å molecular sieves and 3-(4-fluorophenyl)-1-propylamine (1.76 g, 9.3 mmol). The reaction mixture was stirred for 4 hours. Sodium borohydride (0.49 g, 13.03 mmol) was added, and the reaction mixture was stirred overnight, quenched with MeOH, and concentrated under reduced pressure. Purification by flash chromatography (silica, 9.5:5:1 CH2Cl2:MeOH:NH4OH) gave 6-{trans-4-[3-(4-fluorophenyl)propylamino]cyclohexyl}-3H-benzthiazol-2-one (0.24 g, 7%): 1H NMR (500 MHz, DMSO-d6): δ 7.39 (s, 1H), 7.25-7.06 (m, 6H), 3.01 (m, 1H), 2.86 (t, J=8 Hz, 2H), 2.61 (t, J=8 Hz, 2H), 2.37 (m, 1H), 2.01 (m, 2H), 1.92-1.81 (m, 4H), 1.49-1.36 (m, 4H).
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:26](C)[C:27](=O)OC(C)(C)C)[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=[O:3])[NH2:2].[ClH:35]>ClCCl>[ClH:35].[CH3:27][NH:26][CH:23]1[CH2:24][CH2:25][CH:20]([O:19][C:10]2[C:9]3[C:8]4[C@@H:7]([CH2:6][O:5][CH2:4][C:1]([NH2:2])=[O:3])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:21][CH2:22]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCC(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCC(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-[(carbamoylmethoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (115 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (4 mL) cooled down to 0° C. was added hydrochloric acid (12 M, 0.5 mL). The resulting solution was stirred for 1 h at 0° C. and concentrated in vacuo to give 2-[[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide hydrochloride (100 mg, crude) as a light yellow solid. The crude hydrochloride (100 mg) dissolved in methanol (3 mL) was added HCHO (37%, 0.5 mL) and stirred for 1 h at 0° C. Then NaBH3CN (44.35 mg, 0.71 mmol) was added and the resulting solution was stirred for 2 h at room temperature. The reaction mixture was diluted with water, extracted with 3×20 mL of chloroform/i-PrOH. The combined organic layers were concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 53.0% in 13 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide (35 mg) as a white solid. MS (ES): m/z 405 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.44 (1H, s), 5.28-5.21 (1H, m), 3.94-3.88 (3H, m), 3.61-3.56 (2H, m), 3.14-2.97 (2H, m), 2.67-2.54 (2H, m), 2.42-2.31 (10H, m), 2.02 (2H, d), 1.62-1.43 (4H, m).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2].Cl[CH2:19][C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[O:22][N:21]=1>>[CH2:1]([C:3]1[N:4]([CH2:19][C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)[O:22][N:21]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:13])[F:14])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 145B from 2-ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole. MS (ESI): m/z 465 (M+1).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5](=[O:11])[CH2:6][C:7](OC)=[NH:8])[CH3:3].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C(O)C>[ClH:1].[CH2:2]([O:4][C:5](=[O:11])[CH2:6][C:7]([NH:15][CH:12]1[CH2:14][CH2:13]1)=[NH:8])[CH3:3]
Reactant: NC1CC1
Reactant: CCOC(=O)CC(=N)OC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(=N)NC1CC1
Reaction time: 8 h

Procedure:
To 13.3 g of 3-methoxy-3-imino propanoic acid ethyl ester hydrochloride in absolute ethanol was added 4.18 g of cyclopropylamine. The modest exotherm was controlled using a cold water bath and the reaction was stirred overnight. The ethanol was removed with rotary-evaporation to give a viscous oil. This oil was triturated with ethyl ether (1000 ml) to give a colorless solid. Yield=13.44 g.
Reaction SMILES: [NH2:1][C@H:2]([CH3:24])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=2)[CH2:7][CH2:6]1)=[O:4].[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:25](=[O:27])[CH3:26])[CH3:24])[CH2:6][CH2:7]2)=[CH:20][CH:19]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(OCCCN2CCN(C(=O)[C@@H](C)N)CC2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N[C@H](C)C(=O)N1CCN(CCCOc2ccc(C(C)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A 0° C. solution of Example 29 (1 mmol) and TEA (1.1 mmol) in dichloromethane (10 mL) was treated with acetyl chloride (1 mmol). After stirring for four hours at 0° C., the reaction mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified through silica gel chromatography to afford the desired product in 83% yield.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([CH2:30][CH2:31][CH3:32])[CH:5]=1)=[S:3].Cl[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C:35]1=O>CCO>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][C:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C:35]=5[N:1]=4)=[CH:5][C:6]=3[CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Reactant: O=C1CCCCC1Cl
Solvent: CCO
Product: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of ethyl ((1S)-5-{3-[4-aminocarbonothioyl)-2-propylphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (90 mg, 0.2 mmol) (Example 144) and 2-chlorocyclohexanone (239 mg 1.8 mmol) in EtOH (anhydrous, 8 mL) was stirred at 70° C. for 48 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v) 1:2) gave 45 mg (43%) of the title compound as a clear oil. LC-MS: RT=4.69 min; (M+H)+ 534.3.
Reaction SMILES: C([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:5][CH:4]=1)#N.Cl.[C:27](=[O:30])(O)[O-:28].[Na+]>C(O)(=O)C>[C:27]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:5][CH:4]=1)([OH:28])=[O:30]
Reactant: Cc1c(-c2cccnc2)n(Cc2ccc(C#N)cc2)c2ccccc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C(=O)O)cc2)c2ccccc12
Temperature: 0 °C

Procedure:
A solution of 1-(4-cyanobenzyl)-3-methyl-2-(3-pyridyl)indole 5.8 g) in 100 ml of a 1:1 mixture of 20% aqueous hydrochloric acid and glacial acetic acid is heated at reflux for 20 hours. After cooling, the solution is poured into ice water (100 ml) and the pH is adjusted to 4.5-5 with saturated sodium bicarbonate solution. The resulting precipitate is extracted with ethyl acetate, the ethyl acetate extract is washed with water and evaporated to dryness to give 1-(4-carboxybenzyl)-3-methyl-2-(3-pyridyl)indole, m.p. 273°-275°.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](Br)[CH:16]=[CH2:17].[I-].[K+].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:15]([N:14]([CH2:5][CH:4]=[CH2:3])[C:11]1[CH:12]=[CH:13][C:8]([N:7]([CH2:6][CH:1]=[CH2:2])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)[CH:16]=[CH2:17]
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Product: C=CCN(CC=C)c1ccc(N(CC=C)c2ccccc2)cc1
Temperature: 80 °C

Procedure:
A well-stirred intimate mixture of N-phenyl-p-phenylenediamine (10 g, 0.054 mol), allyl bromide (16 ml, 0.18 mol), potassium iodide (1 g, 0.006 mol) and tetrabutylammonium bromide (1 g, 0.003 mol) is treated with an aqueous solution of sodium hydroxide (7.2 g, 0.18 mol). The mixture is heated to 80° C. for five hours. The mixture is then cooled and extracted with diethyl ether. The organic layer is dried over anhydrous magnesium sulfate and concentrated to an oil. The oil is chromatographed (silica gel; hexane:ethyl acetate) to give the title compound in a yield of 13.1 g (80%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:9]1[C:18]2[C:13](=[C:14]([CH3:24])[C:15]([CH2:20][C:21](=[O:23])N)=[C:16]([CH3:19])[CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+].[CH2:27]([OH:30])[CH2:28]C>O>[CH2:1]([N:9]1[C:18]2[C:13](=[C:14]([CH3:24])[C:15]([CH2:20][C:21]([O:30][CH2:27][CH3:28])=[O:23])=[C:16]([CH3:19])[CH:17]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCO
Reactant: CCCCCCCCN1CCCc2c1cc(C)c(CC(N)=O)c2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCN1CCCc2c1cc(C)c(CC(=O)OCC)c2C
Temperature: 130 °C
Reaction time: 20 h

Procedure:
1-Octyl-6-carbamoylmethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline (2.5 g) was dissolved in n-propanol (50 ml) and a solution of NaOH (3.0 g) in water (30 ml) was added, which was followed by stirring at 130° C. for 20 hr under nitrogen. The organic layer of the reaction mixture was separated and the solvent was evaporated under reduced pressure. The residue was dissolved in water (300 ml) and washed with ethyl acetate (100 ml). The aqueous layer was adjusted to pH 1-2 with 6N hydrochloric acid and extracted with chloroform (200 ml). The chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained 1-octyl-6-carboxymethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline was dissolved in ethanol (50 ml), and conc. hydrochloric acid (4 ml) was added, which was followed by stirring at 70° C. for 1 hr. The solvent was evaporated under reduced pressure. The residue was neutralized with saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene) to give 1.0 g of oily 1-octyl-6-ethoxycarbonylmethyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline.