Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]3[C:13]=2[CH2:14][CH2:15][C@H:16]3[O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([O:33]C)=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)=[C:7]([CH3:37])[CH:6]=1)#[N:4]>O1CCCC1.O.CO>[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]3[C:13]=2[CH2:14][CH2:15][C@H:16]3[O:22][C:23]2[CH:36]=[CH:35][C:26]3[C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)=[C:7]([CH3:37])[CH:6]=1)#[N:4]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C#N)cc5C)ccc(F)c43)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C#N)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
LiOH×H2O (38 mg) is added to a solution of methyl 2-((S)-6-((R)-4-(4-cyano-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (85 mg) in tetrahydrofuran (1 mL), water (1 mL) and methanol (1 mL) at room temperature. The mixture is stirred at room temperature for 12 hours. The mixture is concentrated, cooled to 0° C., diluted with water and acidified with 4 M aqueous HCl solution. The resulting mixture is extracted with dichloromethane. The organic phase is dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol/acetic acid 9:0.05:0.05) to give the title compound. Yield: 41 mg; LC (method 20): tR=6.91 min; Mass spectrum (ESI−): m/z=456 [M−H]−.
Reaction SMILES: [CH3:1][S:2]SC.[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.C(OCC)C>C(#N)C>[CH3:1][S:2][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CSSC
Reactant: C=CCCCCCC
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCSC
Yield: 64.8 %

Procedure:
The procedure of Example 1 was repeated using dimethyldisulphide (96 mg; 1.02 mmol) and 1-octene (358 mg; 3.19 mmol) in acetonitrile (15 ml) at +1.20 V until 2 coulomb equivalents of charge had been passed. After the addition of water and extraction with diethyl ether, there was obtained 106 mg of methylthio-octane. Mass Spec. m/e 217 (M+) and 44 (100%). I.R. 3300 and 1650 cm-1.
Reaction SMILES: [C:1](O)(=[O:4])[CH2:2][OH:3].C[Na].[CH2:8]([O:10][CH:11]([O:18][CH2:19][CH3:20])/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH3:9].O>CS(C)=O>[CH2:19]([O:18][CH:11]([O:10][CH2:8][CH3:9])[CH:12]1[CH:13]([C:14]([O:16][CH3:17])=[O:15])[C:2](=[O:3])[CH2:1][O:4]1)[CH3:20]
Reactant: O=C(O)CO
Reactant: CCOC(/C=C/C(=O)OC)OCC
Agent: C[Na]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(OCC)C1OCC(=O)C1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The starting material is prepared as follows: To the suspension of 7.15 g of methyl sodium glycolate in 50 ml of dimethylsulfoxide and 25 ml of diemthylformamide, cooled to 0°, are added at once 9.5 g of methyl 4,4-diethoxy-crotonate and the mixture is stirred at room temperature for 3 hours. It is poured into water, washed with diethyl ether and the aqueous layer is acidified with cold N hydrochloric acid. It is extracted twice with diethyl ether, the extract dried, evaporated and the residue distilled, to yield the methyl 2-diethoxymethyl-4-oxo-tetrahydrofuran-3-carboxylate boiling at 123°-126°/0.5 mm Hg.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=C=O.[CH2:26]([N:28]1[C:40]2[CH:39]=[CH:38][C:37]([NH2:41])=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:27]>>[CH2:26]([N:28]1[C:40]2[CH:39]=[CH:38][C:37]([NH:41][C:10]([C@@H:9]3[CH2:13][C:14](=[CH2:16])[CH2:15][N:8]3[C:6]([NH:17][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:7])=[O:12])=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:27]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C=Nc1ccccc1
Product: C=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)Nc2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, isocyanatobenzene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 66% purity by LC/MS. MS(ESI+): m/z=439.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][N:25]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].O.[OH-].[Li+].C1COCC1>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][N:25]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: COC(=O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)-methyl 6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinate (11.5 g, 24.61 mmol) in MeOH (140 mL, Aldrich) was added lithium hydroxide hydrate (2.065 g, 49.2 mmol, Aldrich). The mixture was stirred at room temperature for 5 min followed by the addition of THF (5 mL, Aldrich) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, cooled to 0° C. and was adjusted to pH=6-7 with concentrated HCl. EtOAc (300 mL) was added to the adjusted pH mixture, and the resulting mixture was stirred at room temperature for 15 min. The organic layer was collected and the aqueous phase was extracted with EtOAc (1×200 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was then dissolved in MeOH (400 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The solid mixture was then purified by silica gel flash column chromatography using ISCO instrument (solid loading, 40% EtOAc/hexane, then 10% MeOH in EtOAc) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.75 (br. s., 1H), 9.85 (d, J=7.4 Hz, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.58 (d, J=4.7 Hz, 1H), 8.48 (dd, J=8.1, 2.1 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.83 (t, J=9.3 Hz, 1H), 7.50-7.61 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 6.58 (d, J=7.2 Hz, 1H). MS (ESI, positive ion) m/z: 454.0 (M+H)
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])(=O)C.CCO.[OH-].[Na+].O>CCOCC>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([CH:11]=1)[CH2:5][OH:4]
Reactant: CC(=O)OCc1cc(Br)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: OCc1cc(Br)ccc1F

Procedure:
A solution of the compound (1b) (3.2 g, 14.5 mmol), EtOH (20 mL) and 1N NaOH (20 mL, 20 mmol) was stirred at reflux under N2 for 1.5 hours. The reaction mixture was cooled and distributed between H2O (150 mL) and Et2O (150 mL). The organic layer was separated and washed with H2O (2×100 mL), dried and the clear faint yellow solution was evaporated. Distillation of the residue provided the compound (1c) as a clear colorless oil; bp 82°-87° C. (0.4 mm); NMR 3.3 (H, br s), 4.6 (2H, s), 6.81 (H3, t, J=9 Hz), 7.15-7.37 (H4, m), 7.44 (H6, dd, J=3 and 6 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:12]([CH:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:29][NH2:30]>CO>[OH:21][CH:18]1[CH2:19][CH2:20][CH:15]([C:12]([CH2:13][CH3:14])=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:30][CH3:29])=[CH:6][CH:7]=2)[CH2:16][CH2:17]1
Reactant: CN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)C1CCC(O)CC1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)C1CCC(O)CC1
Yield: 3 %

Procedure:
Following the same procedure as described in example 11, step D, 4-(1-(4-(2-chloroethoxy)phenyl)-2-(4-hydroxycyclohexyl)but-1-enyl)phenol (0.8 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) at reflux to give 20 mg desired product (3% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 6.71 (d, J=8.4 Hz, 2H), 4.04 (t, J=4.8 Hz, 2H), 2.96 (t, J=4.8 Hz, 2H), 2.50 (s, 3H), 2.36-2.47 (m, 1H), 2.04 (q, J=7.6 Hz, 2H), 1.90-2.01 (m, 2H), 1.40-1.80 (m, 6H), 0.87 (t, J=7.6 Hz, 3H); m/z=396[M+1]+.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:21]=[C:20]2[N:8]([CH2:9][C:10]3[C:11]2=[N:12][C:13]2[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:22])[C:6]=1[CH3:23])[CH2:3][CH3:4].[Cl:24][CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1>O>[Cl:24][CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:1][CH:2]([C:5]2[CH:21]=[C:20]3[N:8]([CH2:9][C:10]4[C:11]3=[N:12][C:13]3[C:18]([CH:19]=4)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:22])[C:6]=2[CH3:23])[CH2:3][CH3:4])=[O:31])=[CH:28][CH:27]=1
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reactant: O=C(O)c1ccc(CCl)cc1
Solvent: O
Product: CCC(OC(=O)c1ccc(CCl)cc1)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
The title compound was prepared according to the procedure in Example 3A except using (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one and 4-(chloromethyl)benzoic acid. 1H NMR (CDCl3) d 8.33 (s, 1H), 8.16 (m, 3H), 7.91 (br d, J=7.3 Hz, 1H), 7.78 (m, 1H), 7.61 (m, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.40 (s, 1H), 6.11 (dd, J=8.1, 6.1 Hz, 1H), 5.26 (s, 2H), 4.63 (s, 2H), 2.45 (s, 3H), 2.21-1.93 (m, 2H), 1.08 (t, J=7.3 Hz, 3H). Anal. Calcd for C27H23ClN2O3.1/2 H2O: C, 69.30; H, 5.17; N, 5.99. Found: C, 69.39; H, 5.16; N, 6.02.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6].C1(N=C=NC2CCCCC2)CCCCC1.[C:26](=S)=[S:27]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][N:6]=[C:26]=[S:27]
Reactant: S=C=S
Reactant: NCc1cc(F)cc(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: Fc1cc(F)cc(CN=C=S)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 3,5-difluorobenzylamine (11.6 g., 0.081 mole) in ether (20 ml.) was added dropwise to a solution of dicyclohexylcarbodiimide (16.7 g., 0.081 mole) and carbon disulfide (32.4 ml., 0.539 mole) in ether (100 ml.) at -5°to -10° C., and the mixture was stirred for 17 hours at 25° C. The mixture was filtered and the solvent was removed under vacuum. The resulting oil was dissolved in hexane-ether (19:1), filtered, and the solvent removed under vacuum. The oil was then dissolved in hexane and purified by flash chromatography (silica) to give 3,5-difluorobenzylisothiocyanate as an oil (5.40 g., 36%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:13](N)([NH2:16])(=[O:15])=[O:14]>O1CCOCC1>[NH2:16][S:13]([N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:15])=[O:14]
Reactant: NS(N)(=O)=O
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCC(c2ccccc2)CC1
Temperature: 100 °C

Procedure:
4-Phenyl-piperidine (10 g, 62 mmol) was dissolved in dioxane (100 mL). Sulfamide (23.8 g, 248 mmol) was then added and the reaction mixture heated to 100° C. for 14 h. The reaction mixture was then cooled to room temperature, quenched by addition of 1N HCl and then concentrated to remove dioxane. The product was extracted with ethyl acetate (100 mL), dried (Na2SO4), filtered and concentrated to yield the title compound as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH3:1][C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)[CH2:26][CH2:27]3)=[CH:16][CH:15]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1
Reactant: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCNCC4)cc3)c2n1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCN(C5CCOCC5)CC4)cc3)c2n1
Reaction time: 0.25 h
Yield: 53.6 %

Procedure:
A solution of Compound 157 (0.250 g, 0.69 mmol) in 1,2-dichloroethane was added with tetrahydro-4-pyranone (0.096 mL, 1.04 mmol) followed by stirring for 15 minutes. The mixture was added with sodium triacetoxyborohydride (0.439 g, 2.07 mmol) followed by stirring at room temperature for 5 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and extracted with dichloromethane three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:2 mol/L ammonia-methanol solution=19:1). The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 158 (0.166 g, 0.37 mmol, 54%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:40]1[S:39][CH:43]=[CH:42][CH:41]=1)(=[O:20])=[O:21])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Reactant: OB(O)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccs3)c2c1
Yield: 36.5 %

Procedure:
2-Methylsulfonyl-N-(3-thiophen-2-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 47 from 1.5 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 339 mg of 2-thiopheneboronic acid, 50 ml of dimethylformamide, 4.8 ml of a saturated aqueous sodium hydrogencarbonate solution and 64 mg of tetrakis(triphenylphosphine)palladium[0]. 350 mg of 2-methylsulfonyl-N-(3-thiophen-2-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of an ochre solid melting at 246° C. (analysis C18H15N3O4S3 % calculated C, 49.87; H, 3.49; N, 9.69; O, 14.76; S, 22.19. % found C, 49.82; H, 3.67; N, 9.08; S, 20.42).
Reaction SMILES: Cl[CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]C)[C:3]([O:5][CH3:6])=[O:4].[CH3:21][O-:22].[Li+].[CH2:24]=O>CN(C=O)C>[CH3:24][CH:7]([C:2]1([O:22][CH2:21]1)[C:3]([O:5][CH3:6])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCC(Cl)C(=O)OC
Reactant: C[O-]
Reactant: C=O
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC(C)C1(C(=O)OC)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl α-chloropalmitate (6.1 g, 0.02 m) was dissolved in 40 ml DMF and treated with lithium methoxide (0.84, 0.022 m) followed by portionwise addition of paraformaldehyde (0.63 g, 0.021 m) over a period of about eight hours. The reaction mixture was stirred at room temperature overnight. The reaction was worked up by neutralization to pH 7 with methanol-HCl, evaporation of the DMF; the residue was dissolved in ether and filtered. Evaporation of the ether led to 99.5 percent recovery of methyl 2-tetradecylglycidate as an oil. Crystallization from methanol (twice) gave material with a melting point of 40°-42°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CCN(C(C)C)C(C)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][N:13]2[C:38]([NH:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:39])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: O=C=Nc1cccnc1
Reactant: Fc1cc(C2NCCc3ccccc32)ccc1C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)c(F)c1

Procedure:
1-(3-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.1500 g, 0.508 mmol, Example 71 Step 3) was dissolved in 3 mL CH2Cl2 and DIEA (0.0884 mL, 0.508 mmol) and 3-pyridyl isocyanate (0.0732 g, 0.610 mmol) were added at RT. The mixture was stirred over night and hydrolyzed with 2 mL water. The reaction was extracted 3 times with EtOAc (3×20 mL), dried over MgSO4 and evaporated. The crude product was purified via glass column chromatography providing 1-(3-fluoro-4-(trifluoromethyl)phenyl)-N-(pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI, positive ion) m/z: 416.0 (M+H). The majority of the material was submitted for chiral purification (SFC):
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-])=O)=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CO.[H][H]>[Pd].O1CCCC1>[NH2:15][C:4]1[C:3]([O:2][CH3:1])=[CH:12][C:11]([O:13][CH3:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(OC)cc(OC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)cc(OC)c1N

Procedure:
A mixture of methyl 3,5-dimethoxy-2-nitrobenzoate (Ger 501,609, April 2, 1927; CA. 24, 47929) (39.0 g; 0.162 mole), 5% Pd on charcoal (2.0 g), methanol (200 ml) and tetrahydrofuran (200 ml) is shaken in an atmosphere of hydrogen at 52 lb pressure for 46 h when theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized from methanol. Yield 28.6 g; mp 93°-5°.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH:11]([CH:16]3[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]3)[C:12]2=[O:15])=[CH:8][CH:7]=1)(=[O:4])=[O:3].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[Cl:39]C(OC(Cl)=O)C>ClCCCl>[ClH:39].[CH3:1][S:2]([NH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH:11]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:12]2=[O:15])=[CH:8][CH:7]=1)(=[O:3])=[O:4]
Reactant: CN1CCC(C2Cc3ccc(NS(C)(=O)=O)cc3C2=O)CC1
Reactant: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C(C1CCNCC1)C2
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 1.35 g (0.00419 mol) of 6-methanesulfonamido-2-(1-methyl-4-piperidyl)indan-1-one in 46 mL of 1,2-dichloroethane was added 1.35 g (0.0063 mol) of 1,8-bis(dimethylamino)naphthalene. The solution was cooled in an ice bath and 1.80 g (0.0126 mol) of 1-chloroethylchloroformate was added dropwise over 5 minutes. The mixture was allowed to warm to room temperature and then was refluxed for 5 hours. The cooled mixture was filtered through a small column of silica gel using methylene chloride to wash the column. The eluate was evaporated in vacuo. The residual 1.35 g of thick oil was dissolved in 10 mL of methanol, and the solution was refluxed for 24 hours. Evaporation of the methanol and crystallization of the residue from methanol afforded 6-methanesulfonamido-2-(4-piperidyl)indan-1-one hydrochloride as a hemi methanol solvate salt: mp 254°-256° (dec.).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14].[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18]>ClCCCl>[C:15]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][C:6](=[O:14])[CH2:7]2)(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 50 °C
Yield: 26.2 %

Procedure:
To 15 g aluminum chloride suspended in 30 mL 1,2-dichloroethane in an ice bath was added 7.5 g of 2-oxindole and then 12 g of butanoyl chloride. The resulting suspension was heated to 50° C. overnight. The mixture was poured into ice water and extracted 3 times with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, and concentrated to dryness to give a brown solid. The solid was chromatographed on silica gel (50% ethyl acetate in hexane) to give 3 g (25%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][C:11]1[C:12]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[N:13][C:14]([Cl:19])=[N:15][C:16]=1[CH2:17][CH3:18].[CH3:30]N(C)C=O>>[ClH:19].[CH3:10][C:11]1[C:12]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])=[N:13][C:14]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[CH3:9])=[N:15][C:16]=1[CH2:17][CH3:18]
Reactant: CCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Reactant: CN(C)C=O
Reactant: Cc1cc(F)ccc1N
Product: CCc1nc(Nc2ccc(F)cc2C)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 22.1 %

Procedure:
After 4-fluoro-2-methylaniline(0.55 ml, 4.95 mmol) was added to a mixture solution of 5-methyl-6-ethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(0.80 g, 2.65 mmol) and dimethylformamide (5 ml), 0.25 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [NH2:1][C:2]1[NH:17][C:5]2=[CH:6][C:7]3[C:8]([CH3:16])([CH3:15])[C:9](=[O:14])[N:10]([CH3:13])[C:11]=3[CH:12]=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>O1CCOCC1>[CH3:13][N:10]1[C:11]2[CH:12]=[C:4]3[N:3]=[C:2]([NH:1][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:17][C:5]3=[CH:6][C:7]=2[C:8]([CH3:15])([CH3:16])[C:9]1=[O:14]
Reactant: CN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of D1 (210 mg) and DIPEA (4 ml; 23 mmol) in 1,4-dioxane (5.5 ml) is added benzoyl chloride (158 μl) at RT. The mixture is stirred for 20 h at RT and 2 h at 80° C. After completion of the reaction water is added and the aqueous layer is extracted with EtOAc. The combined organic layer is washed with saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with CH2Cl2/MeOH (98:2) afforded the desired compound (135 mg).
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:9]([F:19])[CH:8]=1)=[O:5])[CH3:2].Br[CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[NH3:6].[CH2:29]([N:26]([CH2:27][CH3:28])[C:24]([CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:20][CH3:21])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)=[O:25])[CH3:30]
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCNCC2)c(F)c1
Reactant: CCN(CC)C(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Product: N
Yield: 88.8 %

Procedure:
A solution of 2-ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide (0.030 g, 0.084 mmol), 2-bromo-N,N-diethyl-2-phenyl-acetamide (0.025 g, 0.094 mmol), and Na2CO3 (0.013 g, 0.12 mmol) in DMF (2 mL) was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc (25 mL) and washed with H2O (3×15 mL). The organic layer was dried (Na2SO4) and concentrated. Chromatography of the resulting residue (SiO2; 2 M NH3 in MeOH/DCM) gave the title compound (0.018 g, 38%). MS (ESI): mass calcd. for C28H39FN4O2, 482.31. m/z found, 483.5 [M+H]+. 1H NMR (CDCl3): 7.53-7.45 (m, 3H), 7.38-7.31 (m, 3H), 7.10-7.07 (m, 1H), 6.89-6.84 (m, 1H), 3.50-3.37 (m, 2H), 3.30-3.15 (m, 2H), 3.08 (s, 4H), 2.70 (br s, 4H), 2.05-2.01 (m, 1H), 1.75-1.68 (m, 2H), 1.60-1.52 (m, 2H), 1.09-1.02 (m, 6H), 0.97-0.91 (m, 6H).