Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[C:10]([F:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.O>C(O)C>[F:11][C:10]1[C:5]([NH:2][NH2:3])=[N:6][CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncc(C(F)(F)F)cc1F
Reaction time: 2 h

Procedure:
To a solution of hydrazine hydrate (100%) (3.45 ml) in ethanol (150 ml) was added dropwise a solution of 2,3-difluoro-5-(trifluoromethyl)pyridine (4.45 g) in ethanol (50 ml) at room temperature, stirred at the same temperature for 2 hours, and then additionally stirred at 80° C. for 2 hours. Then, the mixture was allowed to cool, water was added thereto, and the organic solvent was evaporated in vacuo. The precipitated solid was collected by filtration, and washed with water to give 3-fluoro-5-(trifluoromethyl)pyridin-2-ylhydrazine as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[O:10][CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]([OH:15])[CH2:13][N:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([O:15][CH:12]1[CH:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:10][C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:14][CH2:13]1)=[O:31]
Reactant: O=C=Nc1ccccc1F
Reactant: OC1CN=C(c2ccccc2)OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C(Nc1ccccc1F)OC1CN=C(c2ccccc2)OC1c1ccccc1
Yield: 28.6 %

Procedure:
Working in a manner similar to that described in Example 16, but starting with an oily suspension (50% by weight; 0.31 g) of sodium hydride, (5RS, 6SR)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.52 g) and 2-fluorophenyl isocyanate (0.9 g), and after recrystallization in diisopropyl ether, (5RS, 6SR)-5-(2-fluorophenylcarbamoyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (0.67 g), m.p. 98° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=3)[C:3]=12.Cl.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(=O)Nc1ccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(N)cc2)c2c(N)ncnc21
Yield: 27.3 %

Procedure:
To a solution of Example 107 (0.080 g, 0.149 mmoles) in ethanol (5 ml), Con.HCl (0.5 ml) was added and refluxed for 2 h. The reaction mixture was basified with sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.020 g, 27% yield). MP: 91-94° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.04(dd, J=8.3,1.5 Hz, 1H), 8.02(s,1H), 7.85(m,1H), 7.67(d, J=8.4 Hz, 1H), 7.53(t, J=7.6 Hz, 2H),7.29(m,3H), 7.06(dt, J=8.7,2.3 Hz, 1H), 6.91(br s,1H), 6.68(d, J=8.4 Hz, 2H), 6.00(q, J=7.0 Hz, 1H), 5.42(s,2H), 1.87(d, J=7.0 Hz, 3H). Mass: 492.83(M+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)=[O:13].CCCCCC>CN(C)C=O>[CH2:1]([NH:8][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCl)Nc1ccc2[nH]ncc2c1
Reactant: NCc1ccccc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(CCNCc1ccccc1)Nc1ccc2[nH]ncc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
N-benzylamine (4.0 ml, 36.5 mmol) was added to a solution of 3-chloro-N-(1H-indazol-5-yl)propanamide (1.70 g, 7.60 mmol) in N,N-dimethylformamide (2 ml), and the resulting mixture was stirred at 80° C. for 1 hour. Then, the reaction solution was cooled to 0° C. and hexane was added thereto to effect suspension. The solid precipitated was collected by filtration and purified by a silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N3-benzyl-N1-(1H-indazol-5-yl)-β-alaninamide (1.00 g, 45%).
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O>[Br:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: CC(C)(Br)C(=O)Br
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(Br)C(=O)NCc1ccccc1
Yield: 91 %

Procedure:
Prepared in 91% yield (10.7 g, 42 mmol) from the reaction of 2-bromo-2-methylpropanoyl bromide (10.6 g, 46 mmol) with benzylamine (5.1 mL, 46 mmol) via general procedure A. Rf=0.84 (3:1, hexanes:EtOAc); mp 73.4-75.5° C.; 1H NMR (400 MHz, CDCl3): δ 7.41-7.23 (m, 1H), 7.03 (br s, 1H), 4.46 (d, J=5.8 Hz, 1H), and 1.99 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 172.0, 137.8, 128.8, 127.6, 127.6, 62.8, 44.4, and 32.6; IR (neat) 3291 (br), 3065, 301, 3008, 2938, 2919, 1642 (s), 1533 cm-1; HRMS (ESI) calculated 256.0332 C11H15BrNO [M+H]+, observed 256.0329.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:25]2=[O:40])[CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC(Cl)C.C(N(CC)CC)C.[C:52]1(=O)[CH2:56][CH2:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:52]1([N:37]2[CH2:38][CH2:39][N:34]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:31]=3[C:32](=[O:33])[N:24]([C@@H:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[C:25]4=[O:40])[CH2:35][CH2:36]2)[CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: COc1ccc([C@@H](CCCNS(=O)(=O)c2cccs2)N2C(=O)c3cccc(N4CCNCC4)c3C2=O)cc1OC
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1ccc([C@@H](CCCNS(=O)(=O)c2cccs2)N2C(=O)c3cccc(N4CCN(C5CCCC5)CC4)c3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
A 50-mL round bottom flask was charged with Compound 167 (10.0 mg, 0.016 mmol) and dichloroethane (2.3 mL). Triethylamine (2.5 μL, 0.018 mmol) was added followed by cyclopentanone (7.1 μL, 0.06 mmol) and sodium triacetoxyborohydride (4.7 mg, 0.022 mmol). The mixture was stirred at room temperature for 3 h. The mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (50 mL). The organic layer was dried using Na2SO4, filtered through Celite®, and concentrated in vacuo. The crude oil was purified on a on a Gilson HPLC with a reversed phase Kromasil column (10u, 100 Å C18, column length 250×50 mm, gradient 75:25-0:100 H2O:MeCN) to give 5.1 mg of Compound 193 as a yellow solid. 1H NMR (300 MHz, CDCl3) 7.53-7.64 (m, 3H), 7.44 (d, J=7.2 Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 6.91-7.06 (m, 3H), 6.79 (d, J=8.0 Hz, 1H), 6.56 (s, 1H), 5.13-5.19 (m, 1H), 4.51-4.64 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.73-3.83 (m, 2H), 3.42-3.64 (m, 2H), 2.78-3.22 (m, 6H), 2.48-2.61 (m, 1H), 1.88-2.31 (m, 4H), 1.47-1.69 (m, 4H), and 1.27-1.33 (m, 4H); MS (ES+) 653 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([CH:15]([CH3:17])[CH3:16])[CH2:3]1.C(Cl)[Cl:19]>CO.Cl.O1CCOCC1>[ClH:19].[ClH:19].[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][C@@H:4]([CH:15]([CH3:17])[CH3:16])[CH2:3]1
Reactant: CC(C)[C@H]1CN(C)CCN1C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)[C@H]1CN(C)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl (2S)-4-methyl-2-(1-methylethyl)-1-piperazinecarboxylate (2.18 g crude, 8.76 assumed mmol) was dissolved in a mixture of MeOH (5 mL), CH2Cl2 (5 mL), and 4 N HCl in dioxane (8 mL). After stirring overnight at room temperature, another 8 mL of 4 N HCl in dioxane and 8 mL of MeOH were added, which dissolved the white precipitate that had formed and pushed the reaction to completion. Evaporation of the solvents in vacuo provided (3S)-1-methyl-3-(1-methylethyl)piperazine, dihydrochloride (1.97 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH3:32])=[O:30])[NH2:25]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:25][C:24]3[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:22]([Cl:21])[CH:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: COC(=O)c1ccc(N)cc1Cl
Product: COC(=O)c1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1Cl
Yield: 45.4 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (340 mg, 1 mmol) and m-chloro-p-methoxycarbonylaniline (200 mg, 1.08 mmol) to give 230 mg of the title compound (45%): mp 167° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.04 (bs, 1H), 10.48 (s, 1H), 7.89 (d, 1H, J=2 Hz), 7.86 (d, 2H, J=8.6 Hz), 7.53 (dd, 1H, J=8.6, 2 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 5.17~5.26 (m, 1H), 3.83 (s, 3H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.84 (dm, 1H, J=17.1 Hz), 2.57~2.69 (m, 2H), 2.12 (dm, 1H, J=13.5 Hz), 1.83~1.97 (m, 1H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH:14]=[CH:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.[N:21]1C(C)=CC=C[C:22]=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CN>C(Cl)Cl>[CH3:22][NH:21][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH:14]=[CH:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1
Reactant: Cc1cccc(C)n1
Reactant: OCCCn1c(C=Cc2ccsc2)cc2ccccc21
Agent: CN
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CNCCCn1c(C=Cc2ccsc2)cc2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A solution of 1-(3-hydroxypropyl)-2-[2-(thiophen-3-yl)vinyl]indole (121 mg) in 3 ml of methylene chloride was treated with 120 μl of 2,6-lutidine and cooled to 0° C. Trifluoromethanesulfonic anhydride (100 μl) was added, and after stirring for 30 minutes 5 ml of 40% aqueous methylamine was introduced, and the reaction mixture stirred at 25° C. for 3 hours. After stirring for a further 12 hours at 0° C., the reaction mixture was partitioned between methylene chloride and water, the organic layer dried, and solvent was removed under reduced pressure. Preparative TLC on silica gel (eluting with 10% methanol/methylene chloride) gave 83 mg of 1-[3-(methylamino)propyl)-2-[2-(thiophen-3-yl)vinyl]indole (67%). This product was dissolved in 3 ml of methylene chloride containing 150 μl of pyridine and trifluoracetic anhydride (40 μl) was added. After 30 minutes, the mixture was partitioned between diethylether and aqueous sodium bicarbonate, the organic layer dried, and solvent was removed under reduced pressure. Preparative TLC on silica gel (eluting with 3:1 hexane/EtOAc) gave 80 mg of 1-[3-(N-methyltrifluoromethylacetamido)propyl)-2-[2-(thiophen-3-yl)vinyl]indole (73%).
Reaction SMILES: [C:1]([CH2:3][CH:4]=[CH:5][C:6]1[C:7]([NH2:22])=[N:8][C:9](=[O:21])[N:10]([CH:20]=1)[C@@H:11]1[O:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]1[OH:13])#[N:2]>[Pd].CO>[C:1]([CH2:3][CH2:4][CH2:5][C:6]1[C:7]([NH2:22])=[N:8][C:9](=[O:21])[N:10]([CH:20]=1)[C@@H:11]1[O:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]1[OH:13])#[N:2]
Reactant: N#CCC=Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)nc1N
Agent: [Pd]
Solvent: CO
Product: N#CCCCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(3-cyanopropen-1-yl)cytidine (0.73 mmol) and 20 ml methanol in a 250 ml hydrogenation flask is added 25 mg of 10% Pd/C. The system is evacuated, repressurized with two atmospheres hydrogen gas and then stirred at room temperature. After about two hours, the system is evacuated and the resulting black suspension removed by filtration. The colorless methanolic filtrate is evaporated to dryness affording a white amorphous solid. Recrystallization of the solid from acetonitrile or water, or column chromatography on molecular exclusion resin (such as Bio-Gel P-2) gives 5-(3-cyanoprop-1-yl)cytidine as a white amorphous solid; decomposes upon heating; UV λmaxH2O 278 nm (ε8400), λminH2O 254 nm (ε4700); 1H NMR (D2O) δ:7.72 (s,1), 5.95 (narrow m,1), 4.3 (m,3), 3.92 (narrow m,2), 2.3 (broad m,4), 1.5 (m,2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[CH:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][NH2:16])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cc1ccccc1C=CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Cc1ccccc1CCN
Yield: 66.9 %

Procedure:
A solution of {2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-vinyl]-phenyl}-acetic Acid tert-butyl ester (1.97 g) and hydrazine hydrate (1.97 mL) in EtOH (75 mL) was heated at reflux for 90 minutes. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and the solution was washed with saturated NaHCO3 followed by brine. The organic solution was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (CHCl3:MeOH 97.5:2.5 to 95:5 to 9:1) provided the title amine (853 mg). MS 236 (M+1).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@:24]12[CH2:33][O:32][C@@H:31]([CH:34]([OH:39])[CH2:35][CH2:36][CH2:37]O)[CH2:30][C@H:29]1[CH2:28][S:27][C:26]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:25]2.CC1C=CC=C(C)N=1>ClCCl>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@:24]12[CH2:33][O:32][C@@H:31]([CH:34]3[CH2:35][CH2:36][CH2:37][O:39]3)[CH2:30][C@H:29]1[CH2:28][S:27][C:26]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:25]2
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C(O)CCCO)C[C@H]2CS1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CCCO3)C[C@H]2CS1)c1ccccc1
Temperature: 0 °C

Procedure:
Trifluoromethanesulfonic anhydride (12.5 μL, 76 μmol) was added drop-wise to a −78° C. solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(1,4-dihydroxybutyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C12) (18 mg, 38 μmol) and 2,6-dimethylpyridine (17.6 μL, 152 μmol) in dichloromethane (0.65 mL), and the reaction mixture was allowed to gradually warm to 0° C. over 30 minutes. The reaction mixture was partitioned between dichloromethane (10 mL) and water (5 mL), and the organic layer was washed with water (2×5 mL) and with saturated aqueous sodium chloride solution (5 mL), then dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane) afforded the product as an off-white foam. Yield: 14.7 mg, 32.1 μmol, 84%. LCMS m/z 459.2 [M+H+]. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 8.23 (br d, J=7.6 Hz, 2H), 7.36-7.55 (m, 4H), 6.84-6.97 (m, 2H), 4.17 (br d, J=12 Hz, 1H), 3.76-3.94 (m, 4H), 3.63-3.70 (m, 1H), 3.11-3.20 (m, 1H), 3.03 (dd, J=12.8, 4.2 Hz, 1H), 2.65 (br d, J=13 Hz, 1H), 1.83-2.06 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[C:17]3[C:12](=[C:13]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Fc1ccc(I)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-fluoro-4-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3) δ 7.66–6.92 (m, 12H), 6.65 (d, 1H, J=3.2 Hz), 3.69 (s, 2H), 3.15–3.02 (m, 2H), 2.58–2.40 (m, 2H), 2.20–2.04 (m, 2H), 1.94–1.76 (m, 4H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 470.6 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C@H:3]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([CH3:26])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:4].[Br:34]Br>O>[F:33][C:2]([F:1])([F:32])[C@H:3]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][C:20]([Br:34])=[C:19]([CH3:26])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH3:4]
Reactant: Cc1ccc2c(C#N)c(-c3ccc(S(=O)(=O)N[C@H](C)C(F)(F)F)cn3)n(C3CCCC3)c2c1
Reactant: BrBr
Solvent: O
Product: Cc1cc2c(cc1Br)c(C#N)c(-c1ccc(S(=O)(=O)N[C@H](C)C(F)(F)F)cn1)n2C1CCCC1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of (R)-6-(3-cyano-1-cyclopentyl-6-methyl-1H-indol-2-yl)-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide (0.48 g, 1.05 mmol) in acidic acid (3 mL) was added bromine (0.35 g, 2.1 mmol) dropwise. The solution was stirred at 90° C. for 30 min, cooled to room temperature and then diluted with water (20 mL). The precipitate was collected and washed thoroughly with water, then dried to give (R)-6-(5-bromo-3-cyano-1-cyclopentyl-6-methyl-1H-indol-2-yl)-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide as a light yellow solid (0.54 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([N+:30]([O-])=O)=[CH:22][CH:21]=1>>[CH3:3][C:2]1([CH3:15])[NH:30][C:23]2[C:24]3[C:29]([C:20]([N:19]=[N:1][C:2]4[C:15]5[C:6](=[CH:7][C:8]6[C:13]([CH:14]=5)=[CH:12][CH:11]=[CH:10][CH:9]=6)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=4)=[CH:21][CH:22]=2)=[CH:28][CH:27]=[CH:26][C:25]=3[NH:1]1
Reactant: Nc1ccc([N+](=O)[O-])c2ccccc12
Reactant: Nc1ccc([N+](=O)[O-])c2cc3ccccc3cc12
Product: CC1(C)Nc2cccc3c(N=Nc4ccc([N+](=O)[O-])c5cc6ccccc6cc45)ccc(c23)N1

Procedure:
In the manner described in Example 8, substituting 12.0 grams of 1-amino-4-nitroanthracene for the 1-amino-4-nitronaphthalene, the desired compound is obtained.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26]C)=[O:24])[C:17]([O:19][CH2:20]C)=[O:18])=[CH:13][C:12]([Br:28])=[C:11]2[C:7]=1[C:8]([Cl:29])=[N:9][NH:10]2)(=O)C.CO.C[O-].[Mg+2].C[O-]>>[Br:28][C:12]1[CH:13]=[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:17]([O:19][CH3:20])=[O:18])[C:6]([CH2:5][OH:4])=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[Cl:29]
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Cl)c2c1COC(C)=O)C(=O)OCC
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: COC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Cl)c2c1CO)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
(S)-Diethyl 2-((4-(acetoxymethyl)-7-bromo-3-chloro-1H-indazol-5-yl)methyl)succinate (550 mg, 1.123 mmol) was dissolved in methanol (15 mL, 370 mmol). 6-10% Magnesium methoxide in methanol (3.4 mL, 2.57 mmol) was added to the mixture. Reaction stirred at room temperature for 18 hours. Reaction was quenched with 6 mL of 1N hydrochloric acid. Mixture stirred at room temperature for 10 minutes. Mixture was concentrated by roto-vap. Residue was suspended in water. Mixture was made basic with aqueous sodium bicarbonate. Material was extracted twice and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 96% yield. MS (M−H)−=419.0.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:19]([O:21][C:22](=[O:30])[CH2:23][NH:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:20].C(OCC)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.Cl>[CH2:19]([O:21][C:22](=[O:30])[CH2:23][N:24]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:20]
Reactant: CCOC(=O)CNC1CCCC1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1CCCC1
Temperature: 25 °C

Procedure:
CBZ-L-Valine (15.1 g, 0.06 mol) was dissolved in CH2Cl2 (250 mL) and the following reagents were added in equal molar amounts in the stated order; 4-Dimethylaminopyridine (DMAP), ethyl-N-(cyclopentyl)glycinate and WSCDI. The reaction mixture was allowed to stir at room temperature over night. Evaporation of the solvent yielded a viscous semisolid which was treated with ethyl acetate and then diluted with HCl (4:1) and separated. The organic extract was washed with 1N HCl followed by 5% aqueous Na2CO3 and saturated aqueous NaCl-solution. After drying over MgSO4, filtration and evaporation under reduced pressure yielded an oil (25.1 g) which was purified over silica gel using CH2Cl2 as eluent. The product was collected (6.6 g) as a semisolid. (Rf=0.3, silica gel, CH2Cl2 :CH3OH; 97:3).
Reaction SMILES: [P:1]([OH:5])([O-:4])([O-:3])=[O:2].[Ca+2:6].[S:7]([O-:11])([O-:10])(=[O:9])=[O:8].[K+:12].[K+]>>[OH:3][P:1]([O-:5])([OH:4])=[O:2].[K+:12].[S:7]([O-:11])([O-:10])(=[O:9])=[O:8].[Ca+2:6]
Reactant: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [K+]
Product: O=P([O-])(O)O

Procedure:
The monocalcium phosphate solid was then reacted with a stoichiometric amount of potassium sulfate in aqueous solution to form KH2PO4 and calcium sulfate. The calcium sulfate precipitate is separated by filtration and recovered. The solution or filtrate from this filtration is subjected to evaporation for the precipitation of potassium dihydrogen phosphate which is then recovered by filtration.
Reaction SMILES: O[C@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[CH2:3][CH2:4][C:5]([O:7]C)=[O:6]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C@H:2]2[O:7][C:5](=[O:6])[CH2:4][CH2:3]2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CC[C@H](O)c1cccc(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc([C@@H]2CCC(=O)O2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
The (S)-methyl 4-hydroxy-4-(3-methoxyphenyl)butanoate (985 mg) is dissolved in CH2Cl2 (10 mL), and the solution is cooled to 0° C. Trifluoroacetic acid (˜4 drops) is added and the mixture is stirred for 8 h at room temperature to complete the lactonization. The reaction is quenched with aqueous sodium bicarbonate, and the organic layer is washed with water, dried (Na2SO4), and concentrated to yield 827 mg (100%) of (S)-dihydro-5-(3-methoxyphenyl)furan-2(3H)-one as a colorless oil.