Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[CH:7][C:8]([NH:12]C(OC(C)(C)C)=O)=[N:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
To a stirred sloution of 4-[7-chloro-2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-quinolinyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (2 g, 4.33 mmol) in CH2Cl2 (30 mL) was added TFA (4 mL) at rt. The reaction mixture was kept at reflux for 4 h, then cooled to rt. After removal of the solvent and excess TFA, the mixture was diluted with CH2Cl2, and treated with NaOH (10%) to pH 12. The mixture was extracted with CH2Cl2, washed with brine, and dried over Na2SO4. Concentration in vacuo afforded the product as a free base (1.13 g, 98%). LC-MS: 262 (M++1). 1H NMR (DMSO-d6): 62.90 (s, 8H), 6.20 (s, 1H), 6.4 (s, 2H) 7.08 (d, 1H), 7.35 (s, 1H), 7.68 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][C:11](=O)[C:10](=[C:14](O)[CH3:15])[C:9](=[O:17])[CH2:8]1.O.[NH2:19][NH2:20]>C(O)C>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][C:11]2[NH:20][N:19]=[C:14]([CH3:15])[C:10]=2[C:9](=[O:17])[CH2:8]1
Reactant: CC(O)=C1C(=O)CC(c2sccc2Cl)CC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=O)CC(c1sccc1Cl)C2
Yield: 60 %

Procedure:
A solution of 5-(3-chlorothiophen-2-yl)-2-(1-hydroxyethylidene)-cyclohexane-1,3-dione (2.2 g) and hydrazine hydrate (0.45 g) in ethanol (60 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(3-chlorothiophen-2-yl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (1.3 g).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29](OC(C)(C)C)=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:44][O:45][C@@H:46]([C@@H:64]1[CH2:68][CH2:67][CH2:66][NH:65]1)[C@@H:47]([CH3:63])[C:48]([NH:50][C@H:51]([C:59]([O:61][CH3:62])=[O:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:49].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29]([N:65]3[CH2:66][CH2:67][CH2:68][C@H:64]3[C@H:46]([O:45][CH3:44])[C@@H:47]([CH3:63])[C:48]([NH:50][C@H:51]([C:59]([O:61][CH3:62])=[O:60])[CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[O:49])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
To a stirring mixture of dimer acid #5 (12.1 g, 23.0 mM) and #67 (11.5 g, 23.0 mM) in 75 mL of dichloromethane under nitrogen, HATU (10.8 g, 27.6 mM) was added followed by Hunig's base (12.1 mL, 69.0 mM). The reaction was allowed to stir at room temperature for 15 hours. Reaction was concentrated to a smaller volume, taken up with ethyl acetate and washed with 1 N HCl two times. The organic layer was then washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Residue was then purified by silica gel chromatography (Gradient: 0% to 70% acetone in heptanes), producing #113 (12.3 g, 62%) as a white solid. LC-MS (Protocol Q): m/z 855.3 [M+H+], 877.2 [M+Na+], retention time=2.32 minutes; HPLC (Protocol R): /z 855.5 [M+H+], retention time=9.596 minutes (purity >97%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13]Br>C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][CH2:12][CH2:13][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: BrCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCOc2ccc(C=O)cc2)cc1
Yield: 76 %

Procedure:
10.0 g of 4-hydroxybenzaldehyde and 8.3 g of 1,3-dibromopropane were reacted for 24 hours in 6.2 g of potassium carbonate solution in 100 ml of DMF under reflux. The reaction mixture was poured into cold distilled water to obtain a precipitate. After filtration and vacuum drying the precipitate, the resultant was recrystallized in ethanol to obtain the white product (XII-1). The product yield was 76%.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[CH:6]=[N:5][C:4]=1[C:17](=[N:19]O)[NH2:18].CO.[OH-].[Na+].[C:25](=S)=[S:26]>>[CH:6]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[C:3]2[C:4](=[C:17]([NH2:18])[NH:19][C:25]([N:2]=2)=[S:26])[N:5]=1
Reactant: S=C=S
Reactant: NC(=NO)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 95 %

Procedure:
10.0 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide oxime hydrochloride was dissolved in 200 ml of an aqueous solution containing 175 ml of methanol, and the resulting solution was adjusted to a pH of 9 with sodium hydroxide. 50 ml of carbon disulfide was added to the solution, and the mixture was allowed to react in an autoclave at a temperature of 120° C for 5 hours under autogenous pressure (about 10 Kg/cm2) followed by working up in the same manner as described in Example 1 to obtain 9.7 g of 2-thioadenosine having a melting point of 198° C (with decomposition) in a 95% yield.
Reaction SMILES: Cl.[C:2]1(/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[C:30]([C:35]([OH:37])=[O:36])[CH:29]=[CH:28]3)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C2CCCCO2)[N:14]=[CH:13]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.[OH-].[Li+]>O>[NH:15]1[C:16]2[C:12](=[CH:11][C:10](/[C:9](/[C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]=[C:30]([C:35]([OH:37])=[O:36])[CH:29]=[CH:28]4)=[C:8](/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)\[CH2:38][CH3:39])=[CH:18][CH:17]=2)[CH:13]=[N:14]1
Reactant: CC/C(=C(/c1ccc2cc(C(=O)O)ccc2c1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC/C(=C(/c1ccc2cc(C(=O)O)ccc2c1)c1ccc2[nH]ncc2c1)c1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Hydrochloric acid (1 mL, 2M in ethyl ether) was added to a solution of (E)-6-(2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)-2-naphthoic acid (190 mg, 0.38 mmol) and EtOH (5 mL). The reaction was heated at 70° C. for 30 min, concentrated, and then redissolved in THF:EtOH (1:1, 5 mL). Lithium hydroxide (90 mg, 3.8 mmol) in H2O was added. The reaction was stirred at room temperature for 2 h, acidified to pH 3 with 1.0 M aqueous HCl soln, and then extracted with EtOAc (×2). The organic layers were combined, washed with water then brine, dried over Na2SO4, and concentrated. The crude material was purified on a reversed phase C-18 column eluted with 70-90% acetonitrile in water in the presence of 0.1% TFA affording the title compound as a beige solid (42 mg, 26%). 1H NMR (DMSO-d6, 300 MHz): δ 13.08 (br, 2H), 8.39 (s, 1H), 8.09 (d, 1H), 7.82-7.65 (m, 4H), 7.53 (d, 1H), 7.44 (s, 1H), 7.21-7.06 (m, 7H), 2.49 (q, 2H), 0.93 (t, 3H); LCMS: 419 (M+H)+.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].C1COCC1.[CH:10]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:49]([NH:51][S:52](=[O:57])(=[O:56])[N:53]([CH3:55])[CH3:54])=[O:50])=[CH:21][C:22]=3[N:23]3[CH2:29][C:28]([C:30]([N:32]4[CH2:39][C:38]56[CH2:40][NH:41][CH2:42][C:34]5([CH2:35][O:36][CH2:37]6)[CH2:33]4)=[O:31])=[CH:27][C:26]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:25]=4[C:24]=23)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C=O>CO>[CH:10]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:49]([NH:51][S:52](=[O:56])(=[O:57])[N:53]([CH3:54])[CH3:55])=[O:50])=[CH:21][C:22]=3[N:23]3[CH2:29][C:28]([C:30]([N:32]4[CH2:39][C:38]56[CH2:40][N:41]([CH3:1])[CH2:42][C:34]5([CH2:35][O:36][CH2:37]6)[CH2:33]4)=[O:31])=[CH:27][C:26]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:25]=4[C:24]=23)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc2c(c1)C=C(C(=O)N1CC34CNCC3(COC4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)N1CC34COCC3(CN(C)C4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
A 1M solution of sodium cyanoborohydride in THF (0.15 mL, 0.15 mmol) was added to a solution of 13-cyclohexyl-N-(dimethylsulfamoyl)-3-methoxy-6-(3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-ylcarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (Example 20) (10 mg, 0.015 mmol) and formaldehyde (37 wt. % in water) (0.01 mL, 0.1 mmol) in MeOH (1 mL) and the mixture was stirred at rt for 16 h. The reaction was filtered and purified by preparative HPLC (H2O-MeOH with 0.1% TFA buffer) to yield product 13-cyclohexyl-N-(dimethylsulfamoyl)-3-methoxy-6-((10-methyl-3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (8.5 mg, 10 μmol, 68% yield) as a bright yellow solid. LCMS: m/e 688 (M+H)+. LCMS retention time: 1.91 min. (Column: SunFire C18 5u 4.6×50 mm. Solvent A=90% Water/10% Acetonitrile/0.1% TFA. Solvent B=10% Water/90% Acetonitrile/0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=4 mL/min.) 1H NMR (400 MHz, MeOD) δ ppm 8.07 (br s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.54 (br d, J=8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.14 (dd, J=8.5, 2.5 Hz, 1H), 7.09 (d, J-2.5 Hz, 1H), 7.06 (s, 1H), 5.23 (br d, J=14.8 Hz, 1H), 4.37-3.06 (in, 10H), 4.25 (br d, J=14.8 Hz, 1H), 3.89 (s, 3H), 2.98 (s, 6H), 2.94-2.76 (m, 4H), 2.15-1.69 (m, 6H), 1.52-1.10 (m, 4H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[CH2:22]([N:29]1[CH2:34][CH:33]=[C:32]([C:35]2[N:40]=[C:39](Cl)[CH:38]=[CH:37][N:36]=2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[CH2:30][CH:31]=[C:32]([C:35]2[N:36]=[C:37]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:38]=[CH:39][N:40]=2)[CH2:33][CH2:34]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Clc1ccnc(C2=CCN(Cc3ccccc3)CC2)n1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C4=CCN(Cc5ccccc5)CC4)n3)cnc2n1

Procedure:
3-Bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (287 mg, 0.77 mmol) and 2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-4-chloropyrimidine: (266 mg, 0.93 mmol) were reacted together as described in Example 39, Step 1. Purification by column chromatography on silica, using 4-7.5% MeOH/CH2Cl2, gave 3-[2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine: m/z (ES+) 540 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(NC(C)C)(C)C>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]1(/[CH:12]=[CH:11]/[C:2]2[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=Cc1ccccc1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: O=[N+]([O-])c1cccc(/C=C/c2ccccc2)c1

Procedure:
A mixture of 3-bromonitrobenzene (1 g), styrene (1.7 mL), palladium(II) acetate (95 mg), tris(2-methylphenyl)phosphine (0.3 g) and N,N-diisopropylamine (5 mL) was heated for reflux for 24 hours. The reaction mixture was diluted with diethyl ether, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =10/1) to give 3-((E)-2-phenylvinyl)nitrobenzene (0.76 g). To the solution of the obtained 3-((E)-2-phenylvinyl)nitrobenzene (0.26 g) in methanol (10 mL) was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.22 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[N:4][C:5]([CH3:14])=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CN(C)C1C=CC=CC=1.[Br:29][CH2:30][C:31](Br)=[O:32]>ClCCl>[Br:29][CH2:30][C:31]([NH:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[N:4][C:5]([CH3:14])=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13])=[O:32]
Reactant: COCCOc1nc(C)cc(OCC(F)(F)F)c1N
Reactant: O=C(Br)CBr
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: COCCOc1nc(C)cc(OCC(F)(F)F)c1NC(=O)CBr

Procedure:
3-Amino-2-[(2-methoxyethyl)oxy]-6-methyl-4-[(2,2,2-trifluoroethyl)oxy]pyridine (1.39 g, 4.96 mmol) was dissolved in dichloromethane (15 mL). N,N-dimethylaniline (0.76 g, 6.27 mmol) was added to the solution. Under stirring on an ice bath, bromoacetyl bromide (1.16 g, 5.75 mmol) in dichloromethane (5 mL) was added dropwise to the mixture, followed by stirring at the same temperature for 30 minutes. The reacion mixture was directly subjected to silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1→n-hexane/acetone=1/1) for purification, to thereby yield 2-bromo-N-[2-[(2-methoxyethyl)oxy]-6-methyl-4-[(2,2,2-trifluoroethyl)oxy]pyridin-3-yl]acetamide as a colorless solid (1.98 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6](=[S:28])[NH2:8])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: NC(=S)c1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 4-chloro-3,5-bis(trifluoromethyl)benzamide (1.2 g) in toluene (20 mL) was added Lawesson's reagent (3.32 g, 2.0 eq.). The reaction mixture was stirred at 90° C. for 8 h before being cooled to room temperature and filtered. The filtrate was poured into water and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (3×50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford 2 g of crude compound. The crude compound was purified by combi-flash chromatography (eluting with 7% EtOAc:hexane) to afford 1.0 g of desired compound (yield: 79%).
Reaction SMILES: [OH:1][C@@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[C@H:3]([CH3:16])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].CS(O[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)(=O)=O>>[CH:30]1([CH2:29][O:23][C:19]2[CH:18]=[C:17]([C@H:2]([OH:1])[C@H:3]([CH3:16])[CH2:4][N:5]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:15])[CH:22]=[CH:21][CH:20]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CS(=O)(=O)OCC1CCCC1
Reactant: C[C@H](CN1C(=O)c2ccccc2C1=O)[C@@H](O)c1cccc(O)c1
Product: C[C@H](CN1C(=O)c2ccccc2C1=O)[C@@H](O)c1cccc(OCC2CCCC2)c1

Procedure:
2-((2R,3R)-3-Hydroxy-3-(3-hydroxyphenyl)-2-methylpropyl)isoindoline-1,3-dione (82) was reacted with cyclopentylmethyl methanesulfonate following the method described for Example 72 to give 2-((2R,3R)-3-(3-(cyclopentylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)isoindoline-1,3-dione as a colorless oil. Yield (0.295 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.80 (m, 4H), 7.13 (t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.66-6.69 (m, 1H), 5.30 (d, J=4.5 Hz, 1H), 4.38-4.41 (m, 1H), 3.77 (d, J=7.0 Hz, 2H), 3.70 (dd, J=5.5, 13.7 Hz, 1H), 3.40 (dd, J=9.4, 13.7 Hz, 1H), 2.20-2.30 (m, 2H), 1.70-1.78 (m, 2H), 1.46-1.62 (m, 4H), 1.26-1.34 (m, 2H), 0.65 (d, J=6.85 Hz, 3H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([O:25][C:26](Cl)=[O:27])[CH3:24]>>[CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:17][CH2:18][N:19]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH2:20][CH2:21]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cl
Reactant: O=C1c2cc(N3CCNCC3)ccc2CN1C1CCCCC1
Product: CCOC(=O)N1CCN(c2ccc3c(c2)C(=O)N(C2CCCCC2)C3)CC1

Procedure:
In the same manner as in Example 28, the title compound was prepared from the compound obtained in step (e) of Example 1 and ethoxycarbonyl chloride.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:9]([N:13]=[N:14][C:15]1([N:21]=[C:22]=[S:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])([CH3:11])[CH3:10]>CO>[C:9]([N:13]=[N:14][C:15]1([NH:21][C:22]([NH:2][NH:3][C:4]([NH2:6])=[O:5])=[S:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)N=NC1(NC(=S)NNC(N)=O)CCCCC1
Reaction time: 0.25 h

Procedure:
To a solution of 2.49 grams (0.0223 moles) of semicarbazide hydrochloride in 25 ml of methanol in a 50 ml erlenmeyer flask was added 1.75 grams (0.0223 moles) of 50% NaOH and the reaction stirred 15 minutes. To this solution was added 5.15 grams (0.0223 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane and the reaction mixture stirred for 6 days at room temperature. The methanol was evaporated under reduced pressure, the residue slurried in water and filtered. The filter cake weighed 5.0 grams (73% crude yield) after drying and was a pale yellow solid. The product did not melt but decomposed around 180° C. The infrared spectrum of the product contained amide carbonyls at 1620 and 1675 cm-1, a strong band at 1540 cm-1 [-N(H)CS], a strong NH band at 3200 cm-1 and weaker NH bands around 3400 cm-1. The isothiocyanate band at 2040 cm-1 was absent.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Reactant: Fc1ccc(NCc2ncc[nH]2)cc1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(F)cc2)[C@@H]1O
Yield: 68.8 %

Procedure:
The title compound (650 mg, 48%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (800 mg, 2.84 mmol) and 4-fluorophenyl-1H-imidazol-2-ylmethylamine (380 mg, 2.0 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH2:23]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[C:19]2[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=2[N:12]=[CH:11]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Reaction time: 1 h

Procedure:
To a solution of 10 g of adenosine in 400 ml of dimethyl formamide was added 2.25 g of 60% sodium hydride (oil). After one hour, 8.5 ml of 1-bromononane was added. The reaction was stirred for 16 hours. Ice was added and the solution evaporated in vacuo. Water and ethyl acetate were added. The organic phase was separated, dried, and evaporated in vacuo to give a white solid, which was recrystallized from ethanol to yield 4.8 g of the title compound, m.p. 143–144° C. analysis for: C19H31N5O4. Calculated: C, 57.99; H, 7.94; N, 1779. Found: C, 58.13; H, 7.93; N, 17.83.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[C:27]2[C:22](=[N:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[NH:21][CH:20]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:24]3[N:23]=[C:22]4[NH:21][CH:20]=[N:19][C:27]4=[CH:26][CH:25]=3)=[O:29])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1ccc2nc[nH]c2n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccc2nc[nH]c2n1
Yield: 83.4 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.063 g, 0.384 mmol), 3H-imidazo[4,5-b]pyridine-5-carboxylic acid (0.100 g, 0.384 mmol), DIPEA (0.200 ml, 1.151 mmol), HOBt hydrate (0.088 g, 0.575 mmol) and EDCI (0.110 g, 0.575 mmol) using the method of Example 274 affording 0.130 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 4.45 (m, 3H), 6.93 (d, 1H), 7.99 (m, 6H), 8.64 (s, 1H), 8.99 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[NH:4][N:3]=1.Cl.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][C:22]([CH2:24][CH2:25][NH2:26])=[CH:21][CH:20]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][C:22]([CH2:24][CH2:25][NH:26][C:7]([C:5]3[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=3)=[O:9])=[CH:21][CH:20]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Cc1cc(C(=O)O)[nH]n1
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: Cl
Product: Cc1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Yield: 28 %

Procedure:
The title compound was prepared using the method of Example 20 starting from 3-methyl-1H-pyrazole-5-carboxylic acid and 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine hydrochloride. Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% EtOAc/heptane) to obtain 301 mg (28%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.25 (s, 3H), 2.92 (t, 2H), 3.53 (q, 2H), 6.32 (d, 1H), 6.34 (s, 1H), 7.01 (d, 1H), 7.63 (m, 2H), 7.85 (s, 1H), 8.16 (t, 1H), 13.86 (s, 1H).