Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([Br:17])P(OC)(OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=1>C1COCC1>[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[C:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:18])[Br:17])=[CH:34][CH:33]=1
Reactant: COP(=O)(OC)C(Br)C(=O)OCc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=C(Br)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a cooled (−78° C.) solution of bromo-(dimethoxy-phosphoryl)-acetic acid benzyl ester (500 mg, 1.5 mmol) in THF (10 mL) was added LHMDS (1.2 mL of a 1M solution in THF, 1.2 mmol). The reaction was warmed to 0° C. and stirred for 30 minutes, then recooled to −78° C. 4-Formyl-benzoic acid methyl ester (163 mg, 1.0 mmol) in THF (2 mL) was added dropwise, and the reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was evaporated to dryness by rotary evaporator and purified by column chromatography on silica gel eluting with 50% ethyl acetate in hexanes to yield 4-(2-Benzyloxycarbonyl-2-bromo-vinyl)-benzoic acid methyl ester (358 mg, 64%) as a mixture of E and Z isomers. 1H NMR (300 MHz, CDCl3): δ 8.33 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.88 (m, 2H), 7.4-7.2 (m, 7H), 5.33 (s, 1H), 5.16 (s, 2H), 3.93-3.91 (s, 3H). LC-MS m/z=376 [C18H15BrO4+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[C:5]([Cl:10])=[CH:4][N:3]=1.[Br:11]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:11][CH2:8][C:6]1[C:5]([Cl:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: OCc1cc(Cl)ncc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(CBr)c(Cl)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
To a suspension of 2,5-dichloro-4-pyridinemethanol (CAN 866039-42-1, 1.10 g, 6.18 mmol) in DCM (25 mL) was added at 0° C. with stirring tetrabromomethane (2.05 g, 6.18 mmol) and a solution of triphenylphosphine (1.62 g, 6.18 mmol) in DCM (5 mL). The resulting mixture was stirred at 0° C. for 1 h and concentrated. The residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient) to give the title compound (619 mg, 42%) as yellow oil. LC-MS (UV peak area, m/z) 98%, 241.0 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([N:4]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[CH2:10]2)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CCCN(CCC)C1CCc2c(cccc2NC(C)=O)C1
Product: CCCN(CCC)C1CCc2c(cccc2N(Cc2ccccc2)C(C)=O)C1

Procedure:
Starting from 2.55 g (0.010 mol) of 5-acetylamino-2-di-n-propylamino-tetraline (Example 4.3.4) and 1.50 g (0.012 mol) of benzyl chloride the title compound is obtained analogously to Example 4.7.1 in the form of a gum in a yield of 3.0 g (79.0% of theory).
Reaction SMILES: [CH:1]([C:4]([CH3:18])([N:7]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17])[C:5]#[N:6])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:20]>>[CH:1]([C:4]([CH3:18])([N:7]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17])[C:5]([NH2:6])=[O:20])([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C#N)N1C(=O)c2cccnc2C1=O
Reactant: O=S(=O)(O)O
Product: CC(C)C(C)(C(N)=O)N1C(=O)c2cccnc2C1=O
Temperature: 0 °C

Procedure:
To 330 mL concentrated sulfuric acid is added portion wise with thorough stirring 298 g of finely divided 5,7-dihydro-alpha-isopropyl-alpha-methyl-5,7-dioxo-6H-pyrrolo[3,4-b]pyridine-6-acetonitrile so that the temperature did not go about 72° C. After the addition the temperature is adjusted to 60°-65° C. and maintained there for 11/2 hours. The mixture is cooled, quenched with ice and finally diluted to approximately 4 liters. After adding 454 g sodium acetate and cooling at 0° C. for 2 hours the mixture is filtered, the solids collected and washed twice with 500 mL water containing sodium acetate followed by water to remove all the sulfuric acid. The solid is dried to give 289 g of product, mp 176°-178° C. Material made in a similar way and analytically pure had mp 188°-190° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:34](O)(=[O:37])[CH:35]=[CH2:36]>C(Cl)Cl.CCOC(C)=O>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:34](=[O:37])[CH:35]=[CH2:36])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: C=CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 4.5 h

Procedure:
4-Nitroaniline (0.4 g, 2.9 mmol) was dissolved in CH2Cl2 (15 ml). To this solution was added EDC (1.67 g, 8.7 mmol), HOBT (1.17 g, 8.7 mmol), DIEA (2.5 ml, 14.5 mmol) and acrylic acid (0.79 ml, 11.6 mmol). The reaction mixture was kept at RT for 4.5 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO41 filtered, and evaporated in vacuo. The residue was purified by column chromatography using 2:1 EtOAc/hexanes as the solvent to give N-(4-nitrophenyl)-acrylamide.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N+:10]([C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)([O-:12])=[O:11].[H-].[Na+]>CN(C)C=O>[N+:10]([C:13]1[N:14]=[CH:15][N:16]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:17]=1)([O-:12])=[O:11]
Reactant: O=Cc1ccc(F)cc1
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2cnc([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Yield: 55.3 %

Procedure:
A suspension of 18.6 g of 4-fluorobenzaldehyde and 18.6 g of 4-nitroimidazole in 70 ml of dimethylformamide was dropwise added to a suspension of 6.6 g of sodium hydride (60% suspension in mineral oil) in 150 ml of dimethylformamide at a room temperature under stirring. The obtained mixture was stirred at 90° C. for about 5 hours, cooled and poured into ice-water to precipitate a solid. This solid was recovered by filtration, washed with water and heated together with ethanol. The mixture was cooled and filtered. The obtained solid was washed with ethanol to obtain 18 g of the title compound as a white powder (yield: 55%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[C:33]([Cl:40])[N:32]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[CH:34]=[C:33]([Cl:40])[N:32]=[C:31]([Cl:30])[CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1cc(Cl)nc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)nc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A microwave tube was charged with Pd(PPh3)4 (4 mg), (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (25 mg), the 2,6-dichloropyridin-4-ylboronic acid (10 mg), dioxane (250 μL) and 2M aq K2CO3 (100 μL). The vessel was sealed and heated to 100° C. overnight. At 16 h, the reaction had only reached ˜60% conversion. The reaction was cooled to 23° C., diluted with absolute EtOH (1.5 mL) and H2O (500 μL), and was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C27H25Cl3N2O3S: 563.1, 565.1, 567.1 (M+H+); Found: 563.1, 565.0, 567.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[S:10][CH:11]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN(C)P(=O)(N(C)C)N(C)C>O>[CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([O:31][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[S:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2)n1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)OCc2ccccc2)C1=O)c1csc(NC(=O)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising 1 g of 5-{1-ethoxycarbonyl-1-[2-(3-phenylureido)thiazol-4-yl]methylene}rhodanine-3-acetic acid, 0.25 g of triethylamine, 0.7 g of benzyl bromide and 10 ml of hexamethylphosphoric triamide was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure. The residue was purified by silica gel column chromatography, using as eluent a 2:1 by volume mixture of hexane and ethyl acetate. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[NH3:14].[OH-].[NH4+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[NH:14][CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Product: O=C1NCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
Methyl 4-bromo-2-(bromomethyl)benzoate (0.157 g, 0.510 mmol) was suspended in ammonia (2M solution in MeOH, 0.255 mL, 1.784 mmol). Ammonium hydroxide (0.517 mL, 7.65 mmol) was added and the mixture was stirred at RT overnight. A resulting white solid was collected by vacuum filtration, washed with water, and dried under high vacuum overnight to give the title compound as a white solid (0.066 g, 61%). 1H NMR (500 MHz, CDCl3) δ ppm 4.45 (s, 2 H), 6.35 (br s, 1 H), 7.60-7.68 (m, 2 H), 7.74 (d, J=8.30 Hz, 1 H); ESI-MS m/z [M+H]+ 212.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>O1CCOCC1.CO>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(-c3cccc(O)c3)cc2)S1
Solvent: CO
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(-c3cccc(O)c3)cc2)S1

Procedure:
In a manner similar to that of Example 1(g), starting with 3 g (10.1 mmol) of 5-(3′-hydroxybiphenyl-4-ylmethylene)thiazolidine-2,4-dione in a dioxane/methanol mixture (50/50), and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (7/3), 800 mg (27%) of the expected product are obtained.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(OCCc2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(OCCc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.30 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 2 mL of methanol and 2 mL of tetrahydrofuran containing 0.19 g of methyl 2-(benzamido)-4-(phenethyloxy)benzoate while ice-cooled, and stirred at room temperature for 14 hours and 30 minutes. The solvent was evaporated under reduced pressure and ethyl acetate and 1.0 mol/L hydrochloric acid were added. The organic layer was separated, the solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to obtain 85 mg of 2-(benzamido)-4-(phenethyloxy)benzoic acid as white solid.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH2:5].[CH3:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]=[C:17]=[S:18]>>[CH3:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]=[C:17]1[NH:5][CH2:4][CH2:3][S:18]1
Reactant: NCCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NCCS1

Procedure:
2-Chloroethylamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1 a to give 2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13](=[O:22])[CH:12]=[CH:11]2)[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[C:13](=[O:22])[CH:12]=[CH:11]4)[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: COc1ccc2c(=O)ccn(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(=O)ccn(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-methoxyquinolin-4(1H)-one (Intermediate 8, 60 mg, 0.20 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol) in dry chloroform/methanol (5 mL, 1:1) was heated over 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixture was cooled to 0° C., and sodium triacetoxyborohydride (127 mg, 0.6 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was then filtered through a 0.45 μm membrane, acidified with conc. HCl to pH 1 and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (50 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to pH10 with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (2×20 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (4:1), containing 0.125% ammonium hydroxide, gave the free base of the title compound as a colorless oil. The free base was taken up in dichloromethane (2 mL), ethanol (7 mL) was added, followed by addition of 1M HCl in ether (0.45 mL). The colorless precipitate was collected by filtration and gave 84 mg (81% yield) of the bis-hydrochloride salt of the product, mp 260° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][C:5]1=[O:27].[Sn](Cl)Cl.Cl>O1CCOCC1>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:12][CH2:11][CH:10]([N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][F:1])[C:5](=[O:27])[CH2:6]3)[CH2:15][CH2:14]2)=[CH:17][C:18]=1[O:25][CH3:26]
Reactant: COc1cc(N2CCC(N3CCN(CCF)C(=O)C3)CC2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1COCCO1
Product: COc1cc(N2CCC(N3CCN(CCF)C(=O)C3)CC2)ccc1N
Temperature: 0 °C
Yield: 90.6 %

Procedure:
1-(2-Fluoroethyl)-4-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-2-piperazinone (0.832 g, 2.19 mmol) was dissolved in 50 mL of dioxane with stirring and cooled to 0° C. Tin(II) chloride (1.66 g, 8.76 mmol) in concentrated HCl (37%, 15.0 mL, 167 mmol) was added dropwise via pipet. The reaction was warmed to rt and stirred overnight. The reaction was quenched by the slow addition of 6N NaOH solution until the pH was greater than 10. The mixture was extracted with EtOAc, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.695 g (91%) of the title compound of step C. 1H NMR (400 MHz, DMSO-d6) δ 6.50-6.40 (m, 2H), 6.25 (dd, J=8.4, 2.0 Hz, 1H), 4.56 (t, J=4.9 Hz, 1H), 4.44 (t, J=4.9 Hz, 1H), 4.15 (br. s., 2H), 3.69 (s, 3H), 3.58 (t, J=4.9 Hz, 1H), 3.52 (t, J=4.9 Hz, 1H), 3.44-3.33 (m, 2H), 3.32-3.23 (m, 2H), 3.10 (s, 2H), 2.69 (t, J=5.4 Hz, 2H), 2.52-2.39 (m, 2H), 2.32-2.20 (m, 1H), 1.74-1.86 (m, 2H), 1.39-1.55 (m, 2H).
Reaction SMILES: O[Li].O.[F:4][C:5]1[CH:10]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:26][C:27]([O:29]C)=O)[C:15]([C:31]([F:34])([F:33])[F:32])=[CH:14][N:13]=2)[CH:8]=[CH:7][C:6]=1[CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1.C1C=CC2N(O)N=[N:54]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.O.CO.CN(C=O)C>[NH2:54][C:27](=[O:29])[CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][C:16]1[C:15]([C:31]([F:34])([F:32])[F:33])=[CH:14][N:13]=[C:12]([NH:11][C:9]2[CH:8]=[CH:7][C:6]([CH:35]3[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:42])[CH2:39][CH2:40]3)=[C:5]([F:4])[CH:10]=2)[N:17]=1
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)ncc1C(F)(F)F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
LiOH.H2O (0.063 g, 1.5 mmol) was added to a solution of tert-butyl 4-(2-fluoro-4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A31) (0.30 g, 0.49 mmol) in THF (10 mL), water (2 mL) and MeOH (1.5 mL) and the resulting mixture was stirred at room temperature for 18 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4) and the volatiles removed in vacuo to give a white solid. The solid was dissolved in dry THF (12 mL) and dry DMF (2 mL) under an atmosphere of nitrogen and HOBt (0.086 g, 0.64 mmol), EDCl.HCl (0.12 g, 0.64 mmol) and DIPEA (0.43 mL, 2.4 mmol) were added. After 10 minutes ammonium carbonate (0.24 g, 2.4 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 18 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (65 mL) and saturated aqueous NaHCO3 (65 mL). The aqueous layer was extracted with EtOAc (2×50 mL) then the combined organic layers were washed with brine (50 mL) and dried over MgSO4. The volatiles were removed in vacuo to afford a pale yellow oil which was purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-80% EtOAc in petroleum benzine 40-60° C.) to give the title compound A32 as a white solid (0.209 g, 69%); 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.44 (s, 1H), 7.61 (dd, J=12.8, 2.2 Hz, 1H), 7.30-7.18 (m, 5H), 7.09 (t, J=8.4 Hz, 1H), 6.31 (s, 1H), 5.69 (s, 1H), 4.39-4.16 (m, 2H), 3.72 (s, 2H), 3.14-3.00 (m, 4H), 2.94 (tt, J=12.1, 3.3 Hz, 1H), 2.81 (t, J=11.4 Hz, 2H), 1.78 (d, J=12.2 Hz, 2H), 1.69-1.53 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 6.710 min; m/z 602.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[N:15][CH:16]=[C:17]([C:20]([NH2:22])=O)[C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[N:15][CH:16]=[C:17]([C:20]#[N:22])[C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)-c1ncc(C(N)=O)c(=O)n1CC2
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)-c1ncc(C#N)c(=O)n1CC2
Yield: 93 %

Procedure:
In a manner similar to that described in Example 23B, 6,7-dihydro-9,10-dimethoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxamide was dehydrated to the nitrile in 93% yield, m.p. 261°-262° from acetic acid.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:27]3[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:34]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[O:44])=[CH:38][CH:37]=1>C1COCC1>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:2]2[CH:3]=[CH:4][C:5]3[C:9]([C:10]([C:12]4[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)=[CH:16][CH:17]=4)=[O:11])=[C:8]([C:27]4[CH:28]=[CH:29][C:30]([C:43](=[O:44])[NH:42][C:39]5[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=5)=[CH:31][CH:32]=4)[S:7][C:6]=3[CH:34]=2)=[O:44])=[CH:38][CH:37]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(-c2sc3cc(C(=O)Nc4ccc(Cl)cc4)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
5.56 g (10.7 mmol) of [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone was dissolved in 200 mL of dry THF and 5.45 g (35.2 mmol) of 4-chlorophenyl isocynate was added. The reaction mixture was stirred at room temperature under an atmosphere of nitrogen. After 18 hours, the solvent was removed by evaporation in vacuo, and redissolved in CHCl3. The CHCl3 solution was cooled to -20° C. for 24 hours and the precipitate formed was filtered off. The remaining solution was chromatographed (Waters Prep 500, HPLC) on a silica gel column, eluted with a linear gradient of CHC13 ending with CHC13 -MeOH (19:1)(v/v). The desired fractions were determined by TLC, combined and evaporated to dryness to afford 4.01 g of the title compound as a tan amorphous powder.