Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:4](Cl)Cl)[CH2:2][CH3:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:3]([C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)[CH2:2][CH2:1][PH2:4])=[CH:10][CH:9]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCCP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: PCCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Bis(p-chlorophenyl)propylphosphine was prepared by reacting 0.2 mole of propyldichlorophosphine with 0.4 mole of p-chlorophenylmagnesium bromide. The product was isolated by chloroform extraction and distillation as previously described. The portion boiling between 160° and 165° C. under a pressure of 2 mm. Hg was collected. The analysis corresponded to bis(p-chlorophenyl)propylphosphine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:30]=1[OH:44]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:25])[CH3:26])[CH2:19][CH2:18]2)=[CH:3][C:2]([C:33]2[CH:32]=[CH:31][C:30]([OH:44])=[C:29]([O:28][CH3:27])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(CN(C)C)CC4)c3c2)ccc1O
Yield: 45.3 %

Procedure:
Following general procedure D, (6-bromo-4-{4-[(dimethylamino)methyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (47 mg, 0.113 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (55 mg, 0.220 mmol) to afford the desired product (23.5 mg, 45%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.81 (s, 1H), 8.29 (d, J=1.6 Hz, 1H), 8.10-8.00 (m, 2H), 7.30 (d, J=2.0 Hz, 1H), 7.22 (dd, J=8.2, 2.1 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 3.97 (s, 3H), 3.56 (d, J=12.6 Hz, 2H), 3.27-3.15 (m, 4H), 2.95 (s, 6H), 2.65-2.55 (m, 1H), 2.15-2.25 (m, 1H), 1.95 (d, J=12.6 Hz, 2H), 1.78-1.67 (m, 2H), 1.38-1.28 (m, 2H), 1.28-1.19 (m, 2H); ESI MS m/z 460 [C28H33N3O3+H]+; HPLC 95.9% (AUC), tR=9.74 min.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)=C.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:14][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([CH:1]=[O:16])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)C(=O)N(C)CC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCc2ccc(C=O)cc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
To a solution of 7-ethenyl-2-methyl-3,4-dihydro-1(2H)-isoquinolinone (181 mg, 0.968 mmol) in 1,4-dioxane (I 5 ml) and water (3 ml) at 0° C. was added sodium periodate (476 mg, 2.226 mmol) and osmium tetroxide (1.1 ml of a 4% aqueous solution). The reaction mixture was warmed to room temperature and stirred for 0.5 h before evaporation of the reaction mixture. The residue was dissolved in 1,4-dioxane (20 ml) and evaporated again. The mixture was then dissolved in dichloromethane (100 ml), dried with magnesium sulphate and evaporated. Chromatography on silica, eluting with 0-100% Ethyl Acetate/Hexane, gave the product (136 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12]([N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][CH2:21][O:22][CH3:23])[CH2:15]3)=[N:13][C:4]=2[CH:3]=1.C=O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:28])[C@@H:16]([CH2:20][CH2:21][O:22][CH3:23])[CH2:15]3)=[N:13][C:4]=2[CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sccc32)CCN1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sccc32)CCN1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.4 %

Procedure:
Combine (S)-7-chloro-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (571.5 mg, 1.52 mmol), formaldehyde (135.4 μL, 1.67 mmol, 37% in water), and dichloromethane (20.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (482.0 mg, 2.27 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (90:10) to give 418.3 mg (71%) of the title compound as a brown foam: mass spectrum (ion spray): m/z=391.1 (M+1).
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH:17]1([NH:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrC1CCCCCC1
Reactant: CCCCCCCCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCc1ccc(NC2CCCCCC2)cc1
Reaction time: 7 h
Yield: 53.2 %

Procedure:
A mixture of 10.0 g of 4-octylaniline, 8.6 g of bromocyclo-heptane, 13.5 g of potassium carbonate and 50 ml of hexamethylphosphoramide (HMPA) was stirred at 90° to 100° C. for 7 hours. After cooling, a saturated saline solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=50:1) to give 7.79 g of N-cycloheptyl-N-(4-octylphenyl)amine (yield: 53%, brown oily product, IR (film): 3390, 2925, 2854, 1617, 1518 cm-1).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25](=[O:28])[CH:26]=[CH2:27])[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[BrH:29].C(OC(C)C)(C)C>C(O)(=O)C>[Br:29][CH2:27][CH2:26][C:25]([C:23]1[N:22]=[CH:21][NH:20][CH:24]=1)=[O:28]
Reactant: Br
Reactant: C=CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: O=C(CCBr)c1c[nH]cn1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
1-(1-Trityl-1H-imidazol-4-yl)-2-propen-1-one (29.0 g) was dissolved in acetic acid (130 ml) and the mixture was cooled to 10° C. A 25% solution of hydrogen bromide in acetic acid (100 ml) was added and the mixture was stirred at room temperature for 2 h. Isopropyl ether was added to the reaction mixture and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give the title compound (22.3 g) as a pale yellow powder.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])C=C.O.C(OCC)(=O)C.CN(C)[C:23]1[CH:28]=CC=C[CH:24]=1>>[CH2:28]([C:12]1[C:5]([OH:4])=[C:6]([CH:9]=[CH:10][C:11]=1[OH:13])[CH:7]=[O:8])[CH:23]=[CH2:24]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cc(O)ccc1C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCc1c(O)ccc(C=O)c1O

Procedure:
3.10 g of 2-allyloxy-4-hydroxybenzaldehyde was dissolved in 6 ml of N,N-dimethylaniline, and the reaction solution was heated to reflux under nitrogen atmosphere. Approximately 2.5 hours later, the reaction solution was stood to cool. Thereafter, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with 5 N hydrochloric acid, water, and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 0.88 g of the subject compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH:19](=O)[CH2:20][CH3:21].O>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:13]([CH2:19][CH2:20][CH3:21])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCCCC1
Reactant: CCC=O
Solvent: O
Solvent: ClCCCl
Product: CCCN1CCCCC(C(=O)OC)=Cc2cc(Br)ccc21
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of methyl 9-bromo-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.0 g) in 1,2-dichloroethane (20 ml) were added propion aldehyde (1.87 g) and triacetoxy sodium borohydride (4.11 g) and the mixture was stirred overnight. Water was added and the mixture was extracted with ethyl acetate, after which it was washed with aqueous saturated sodium bicarbonate solution and saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give methyl 9-bromo-1-propyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.15 g) as a yellow oily material.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C@@H:37]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:38]Br)=[CH:33][C:32]=1[NH:48][CH:49]=[O:50])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O.O>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:38][C@@H:37]([C:34]4[CH:35]=[CH:36][C:31]([O:30][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[C:32]([NH:48][CH:49]=[O:50])[CH:33]=4)[O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])=[CH:16][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCCc1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 130 °C

Procedure:
To a solution of Intermediate 22 (0.4 g, 1.34 mmol) and (R)—N-(2-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)phenyl)formamide (0.62 g, 0.82 mmol) in dimethyl sulfoxide (3 mL) was added sodium iodide (0.59 g, 3.99 mmol) and sodium hydrogen carbonate (0.67 g, 8.03 mmol). The reaction mixture was heated under argon at 130° C. for 1 hour. The mixture was poured into water and extracted with ether. The organic layer was washed with water and brine and the solvent was removed under reduced pressure. The title compound was obtained as yellow foam (0.84 g, 73%) and used in the next step without further purification. MS (M+): 684.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4](Br)[C:3]1=[O:9].O.O.O.C([O-])(=O)C.[Na+].[CH2:18]([SH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CO>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([S:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:3]1=[O:9]
Reactant: CCCCCCS
Reactant: CN1C(=O)C=C(Br)C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCSC1=CC(=O)N(C)C1=O
Yield: 83 %

Procedure:
To N-methyl bromomaleimide (100 mg, 0.53 mmol) and sodium acetate trihydrate (70 mg, 0.53 mmol) in methanol (15 mL) was added hexanethiol (74 μL, 0.58 mmol) in methanol (100 mL) dropwise over 1 hour with vigorous stirring. After 5 minutes solvent was removed in vacuo. Purification by column chromatography (gradient elution in 10% ethyl acetate in petroleum ether to 30% ethyl acetate in petroleum ether) afforded the desired compound as a bright yellow solid (99 mg, 0.44 mmol) in 83% yield. δH (600 MHz, CDCl3) 6.03 (s, 1H, H-2), 3.01 (s, 3H, H3-5), 2.89 (t, 2H, J=7.6, 2H, H2-11), 1.76-1.71 (m, 2H, H2-10), 1.46-1.41 (m, 2H, H2-9), 1.33-1.27 (m, 4H, H2-7 and CH2-8), 0.89 (t, 3H, J=6.5, H3-6); δC (125 MHz, CDCl3) 171.47 (C═O), 169.94 (C═O), 151.84 (C3), 117.27 (C2), 31.92 (C11), 31.31 (CH2), 28.64 (CH2), 27.75 (CH2), 24.10 (C5), 24.10 (C7), 14.09 (C6); IR (oil, cm−1) 2727 (w), 1708 (s); MS (FAB+) m/z (relative intensity): 250 ([M+Na], 40), 228 (35), 199 (30), 176 (100); Exact Mass Calcd for [C11H17NO2S]+Na requires m/z 250.0878 Found 250.0880 (FAB+).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29]>O1CCOCC1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([N:28]([CH3:29])[CH3:27])[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc2c(c(N(C)C)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 80 °C
Yield: 90.8 %

Procedure:
A mixture of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) and dimethylamine (3M in THF, 0.73 mL, 2.20 mmol) in dioxane (3 mL) was heated to 80° C. for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 2-anilino-5-(dimethylamino)-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (74 mg, 91%): LCMS RT: 1.86 min, MH+: 371.3
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[O:18]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[C:2]([O:24][CH2:23][CH:20]3[CH2:21][CH2:22][O:18][CH2:19]3)=[N:7][CH:6]=[C:5]([CH:4]=2)[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1
Reactant: OCC1CCOC1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Product: O=C(O)c1cnc(OCC2CCOC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example CI using 6-chloro-5-(4-chlorophenyl)-3-pyridine carboxylic acid (CAN 1012792-56-1) and tetrahydro-3-furanmethanol (CAN 15833-61-1) as starting materials; LC-MS (UV peak area/ESI) 91.6%, 334.0833 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:30])[C:17]3[C:12](=[C:13]([F:19])[CH:14]=[CH:15][C:16]=3[F:18])[C:11](=[O:20])[N:10]2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[CH:28])[C:22]=2[F:29])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:31][O:32][C:33]([NH:35][C:36](=NC(OC)=O)SC)=[O:34].[OH-].[Na+]>C(O)(=O)C>[CH3:31][O:32][C:33](=[O:34])[NH:35][C:36]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3([OH:30])[C:17]4[C:12](=[C:13]([F:19])[CH:14]=[CH:15][C:16]=4[F:18])[C:11](=[O:20])[N:10]3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[CH:28])[C:22]=3[F:29])=[CH:3][C:2]=2[N:1]=1
Reactant: C#Cc1cccc(N2C(=O)c3c(F)ccc(F)c3C2(O)c2ccc(N)c(N)c2)c1F
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C#Cc1cccc(N2C(=O)c3c(F)ccc(F)c3C2(O)c2ccc3[nH]c(NC(=O)OC)nc3c2)c1F
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3-(3,4-diaminophenyl)-2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (1.15 g, 2.80 mmol) and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.58 g, 2.80 mmol) was heated to 80° C. for 30 minutes in glacial acetic acid (15.0 mL). The reaction mixture was cooled to room temperature and it was pored into ice water. The pH was adjusted to 8 by the addition of 2M aqueous sodium hydroxide. The precipitated product was extracted with ethyl acetate (350 mL) and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Filtration and evaporation resulted in a crude product. It was purified by reverse phase preparative HPLC (CH3CN/25 mM aqueous ammonium acetate). The fractions were collected, and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an amorphous residue, which was freeze-dried from a mixture of acetonitrile-water (35.0 mL) to give methyl{5-[2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate (1.15 g, 83% yield). 1H NMR (400 MHz, CD3OD): 7.79 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.43-7.36 (m, 4H), 7.31 (t, J=7.2 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 3.92 (s, 3H), 3.78 (s, 1H); MS (EI) for C25H15F3N4O4: 493 (MH+).
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]2[CH2:9][N:10]([C@H:12]3[CH2:17][S:16][CH:15]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[F:25])[C@@H:14]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:13]3)[CH2:11][C:5]=12)(=O)[NH2:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:4]1[NH:8][N:7]=[C:6]2[CH2:9][N:10]([C@H:12]3[CH2:17][S:16][CH:15]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[F:25])[C@@H:14]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:13]3)[CH2:11][C:5]=12)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3n[nH]c(C(N)=O)c3C2)CSC1c1cc(F)ccc1F
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3n[nH]c(C#N)c3C2)CSC1c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
To a stirred solution of tert-butyl N-[(3S,5R)-5-(3-carbamoyl-4,6-dihydro-2H-pyrrolo[3,4-c]pyrazol-5-yl)-2-(2,5-difluorophenyl)tetrahydrothiopyran-3-yl]carbamate (35 mg, 0.073 mmol) in pyridine (4 mL) was added phosphorous oxychloride (0.020 mL, 0.219 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 5.5 h, quenched with water (0.2 mL) and the solvents were removed under vacuum. The residue was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium hydrogen carbonate (1×150 mL), brine, dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by prep-TLC, eluting with 8% MeOH (1N NH3 in MeOH) in CH2Cl2, to give the title compound. MS: 462.1
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)=[O:4].[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(#N)C>[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)=[O:4])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)Cc1ccc(C(=O)CCl)cc1
Solvent: CC#N
Product: COC(=O)Cc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of methyl 4-chloroacetylphenylacetate (260 mg) in acetonitrile (4 ml) was added dropwise over 15 minutes to a stirred solution of 1-(4-pyridyl)piperazine (375 mg) in acetonitrile (10 ml) and the mixture stirred overnight. The supernatent was decanted from the solid formed, concentrated in vacuo and purified by flash chromatography on neutral alumina, eluting with dichloromethane then 0.25% v/v methanol/dichloromethane and finally 0.5% v/v methanol dichloromethane. Concentration of the fractions in vacuo gave the title compound, 96 mg, as a white crystalline solid: m.p. 127°-129° C.; NMR (d6 DMSO) δ 8.15(2H,d), 7.98(2H,d), 7.41(2H,d), 6.81(2H,d), 3.91(2H,s), 3.78(2H,s), 3.53(3H,s), 3.33(4H,t), 2.64(4H,t); m/e 354(M+H)+ ; calculated for C20H23N3O3 : C, 68.0; H, 6.6; N, 11.9. found: C, 68.2; H, 6.6; N, 11.9%.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:8]2[C@@H:12]([OH:13])[CH2:11][CH2:10][N:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([CH3:44])[CH:43]=1)[CH2:39]Br>COCCOC>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:8]2[C@@H:12]([O:13][CH2:35][C:36]3[CH:37]=[C:38]([CH3:39])[CH:41]=[C:42]([CH3:44])[CH:43]=3)[CH2:11][CH2:10][N:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: CCOC(=O)N1CC[C@H](O)[C@@H]1C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)N1CC[C@H](OCc2cc(C)cc(C)c2)[C@@H]1C(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
To a solution of cis-2-(diphenylmethyl)-3-hydroxy-1-ethoxycarbonylpyrrolidine (Example 1d, 1.00 g, 3.1 mmol) in ethylene glycol dimethyl ether (10.0 ml) was added 0.5M potassium bis(trimethylsilyl)amide (9.00 ml, 4.5 mmol) and stirred at room temperature for 1/2h before addition of 3,5dimethylbenzyl bromide (0.92 g, 4.5 mmol) in ethylene glycol dimethyl ether (2 ml). After stirring for 18 h the solvent was removed in vacuo and the residue partitioned between water/dichloromethane. The organic phase was washed with saturated brine and dried (MgSO4). The residue, after removal of solvent in vacuo, was chromatographed on silica gel using ethyl acetate/hexane (2:3) as eluant to give cis-2-(diphenylmethyl)-3-(3,5-dimethylbenzyloxy)-1-ethoxycarbonylpyrrolidine. 1H NMR (360 MHz, DMSO-d6) δ7.05-7.46 (10H, m), 6.81 (1H, s), 6.58 (2H, s), 4.86 (1H, t, J=7.0 Hz), 4.42 (1H, d, 7.5 Hz), 4.18 (1H, d, J=12.0 Hz), 4.11 (1H, m), 3.97 (1H, d, J=12.0 Hz), 3.83 (1H, m), 3.68 (1H, m), 3.31 (1H, m), 2.98 (1H, m), 2.19 (6H, s), 2.15 (1H, m), 1.95 (1H, m), 1.03 (3H, t, J=7.0 Hz). m/z (CI+) 444 (MH).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][CH:17]([F:29])[CH2:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=1[CH3:28]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:27]([CH2:26][C:23]3[CH:24]=[N:25][C:20]([O:19][CH2:18][CH:17]([F:29])[F:16])=[C:21]([CH3:28])[CH:22]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)cnc1OCC(F)F
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)F
Yield: 44 %

Procedure:
The title compound is prepared in 44% yield (154 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (279 mg, 1.0 mmol, Step-1 of Intermediate-1) and (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride (239 mg, 1.0 mmol, Amine-4) in a similar manner to Step-2 of Intermediate-1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:27])([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(N(CC)CC)C>[CH3:28][S:29]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:27])([CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=1)(=[O:31])=[O:30]
Reactant: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCOS(C)(=O)=O)cc1

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 3-[4-(2-hydroxyethoxy)phenyl]-2-methyl-2-(3-phenylpropyl)propionate (0.95 g), which is the product of Reference example 7(f), triethylamine (1.07 ml) and methanesulfonyl chloride (0.40 ml) and the reaction mixture was treated to afford the desired compound (1.16 g) as a syrup.