Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.C1(OC)C=CC=CC=1.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCCCCCC>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:42][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Solvent: CCCCCCC
Solvent: COc1ccccc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Temperature: 142 °C
Reaction time: 0.03 h

Procedure:
To a 22-L reactor was charged compound 7 (650 g, 1.82 mol), anisole (3.25 L, 5 vol, anhydrous) and benzylamine (600 mL, 0.92 vol, 3 equiv). The batch (approximately 18° C.) was heated to 142±5° C. over 1 hour 44 minutes, with dissolution occurring at 30° C. The batch was maintained at 142±5° C. for 69 hours 30 minutes at which point HPLC analysis indicated that compound 7 was 0.9% by conversion (specification ≦1.7% by conversion). The batch was cooled to 45-50° C. over 5 hours 12 minutes (to aid cooling the nitrogen flow was increased once the batch was approximately 72° C.). At that temperature range, the batch was poorly stirring and on mixing, the batch temperature increased to 52° C. It was >50° C. for ≦15 minutes. The batch was aged for 2 hours 2 minutes once initially <50° C., then n-heptane (9.75 L, 15 vol, 99%) was added to the batch over 1 hour 56 minutes, maintaining the batch temperature at 45-50° C. The heating was then discontinued and the batch cooled to 25° C. over 10 hours 32 minutes and then to approximately 20° C. over 20 minutes. The total time the batch was maintained ≦25° C. was 4 hours 50 minutes (2 hours 47 minutes at approximately 20° C.). The batch was filtered under suction via a 24-inch polypropylene filter funnel (fitted with a PTFE cloth) and the reactor rinsed with anisole/n-heptane (1.3 L, 4:1) and the rinse transferred to the cake. The cake was then washed successively with two portions of n-heptane (1.3 L, 0.65 L). The total filtration time was 39 minutes. The batch (net wet weight 1004 g of KX2•391) was transferred to three glass trays and placed into a vacuum oven set at 50° C. and dried to constant weight over 96 hours 26 minutes.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([C:16]([O:18]CC)=[O:17])[N:13]=[C:12]3[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.O.CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[N:13]=[C:12]3[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)OCCO3)c(-c2ccc(C)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(C(=O)O)cn2-c2ccc3c(c2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.62 g (1.7 mmol) of the compound from Step B in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 0.80 mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow foam. LC/MS 337.3 (M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].Br[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.O>CN(C)C=O>[O:8]=[C:4]1[N:5]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:6][CH2:7][N:3]1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: O=C1NCCN1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2CCN(Cc3ccc(C#N)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To sodium hydride (2.4 g, 60 mmol) in dimethylformamide (50 mL) at 0° C. was added imidazolin-2-one (2.6 g, 30 mmol). After stirring for 20 minutes 4-(bromomethyl)benzonitrile (13 g, 66 mmol) was added and the mixture was warmed to ambient temperature. After stirring for 1 hour the reaction was poured into water and a solid formed. The solid was ritered to give 4,4'-[(2-oxoimidazolin-1,3-diyl)bis(methylene)]-bis(benzonitrile). NMR (CDCl3) 7.65 (d,4), 7.4 (d,4), 4.45 (s,4), 3.2 (s,4) ppm.
Reaction SMILES: C([O:4][C:5]([C:7]1([NH:10][C:11]([C:13]2[N:17]3[C@@:18]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][CH:33]=4)([CH3:30])[C:19](=[O:29])[N:20]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=4)[C:16]3=[N:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1)=[O:6])C=C.N1CCOCC1>C1COCC1.CCOC(C)=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>[Br:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C@@:18]2([CH3:30])[N:17]3[C:13]([C:11]([NH:10][C:7]4([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]4)=[O:12])=[CH:14][N:15]=[C:16]3[N:20]([C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)[C:19]2=[O:29])=[CH:33][CH:34]=1
Reactant: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(Br)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester (200 mg, 0.32 mmol) and morpholine (0.282 mL, 3.24 mmol) in 2 mL of THF was added Pd(Ph3P)4 (19 mg, 0.016 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with 30 mL of EtOAc and washed with 10 mL each of 10% HCl solution, water, and brine, dried over Na2SO4, filtered, and concentrated. The residue was applied to a SiliaBond Carbonate preloaded cartridge (2 g, 0.7 mmol/g, Silicycle). The column was eluted with 30 mL of 10% MeOH in CH2Cl2 followed by 200 mL of 0.1:1:9 TFA/MeOH/CH2Cl2 to furnish 142 mg 76%) of the title compound as a colorless foam, m/z 579.4 [M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:12][C:13]=1Cl.OC(C(O)(C)C)(C)C.[OH:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=[O:32]>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:12][C:13]=1[O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=[O:32]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cccc(O)c1
Agent: CC(C)(O)C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 25 °C

Procedure:
To a 300 ml, 3-necked flask equipped with a condenser, stirrer, drying tube and thermometer is charged dimethylsulfoxide (100 ml), anhydrous potassium carbonate (30 g. >0.20 mole), 3,4-dichlorobenzotrifluoride (21.5 g., 0.10 mole), pinacol (10 g.) and 3-hydroxybenzoic acid (13.8 g., 0.10 mole). The reaction temperature is then taken slowly to 140°-5° C. while stirring vigorously and maintained as such for 4 days. The reaction mixture is then cooled to room temperature and the inorganic solids removed by filtration prior to pouring the filtrate into water (1200 ml). The aqueous solution is then triturated with CCl4 (2 × 200 ml), decanted and then acidified to pH1 (conc. HCl) to give a tan colored solid, 25,6 g., mp 114°-17° C. This solid is further purified by dissolving in CCl4 (500 ml) and drying with anhydrous MgSO4. The CCl4 solution is reduced in vacuo to give 19.6 g. (62%) of a yellow solid, mp 116°-19° C. Recrystallization of the yellow solid from hexane gives a tan colored solid, 3-(2-chloro-4-trifluoromethylphenoxy)-benzoic acid, mp 122°-3° C.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].Cl.CN.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH:13]2[CH2:22][CH:23]=O>CO>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH:13]2[CH2:22][CH2:23][NH:2][CH3:1]
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)C(CC=O)CC(=O)N2C
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCCC1CC(=O)N(C)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Sodium cyanoborohydride (1.2 g) was added to a solution of 10.0 g of methylamine hydrochloride and 4.6 g of 1,2,3,4-tetrahydro-6-methoxy-1-methyl-2-oxo-4-quinolineacetaldehyde in 142 ml of methanol. The solution was stirred at room temperature for 19 hours, quenched with 10% hydrochloric acid solution and extracted with ethyl acetate. The aqueous layer was basified with potassium hydroxide and the product extracted into ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. Column chromatography on silica gel (elution with triethylamine-methanol-ethyl acetate) afforded 3,4-dihydro-6-methoxy-1-methyl-4-[2-(methylamino)ethyl]-2(1H)-quinolinone as a solid. To a solution of the amine in methanol was added ethereal hydrochloric acid to pH 1. The solvent was removed, and the residue recrystallized from isopropanol-diethyl ether to afford the hydrochloride salt, m.p. 175°-177° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([O:12]C)=[O:11])=[N:6][C:7]=1[O:8]C.Br[C:15]1[CH:16]=[CH:17][C:18]([C:23](=N)OC)=[N:19][C:20]=1OC.[ClH:27]>CO>[ClH:27].[CH3:23][C:18]1[CH:17]=[C:16]([C:2]2[C:7](=[O:8])[NH:6][C:5]([C:10]([OH:12])=[O:11])=[CH:4][CH:3]=2)[CH:15]=[CH:20][N:19]=1
Reactant: COC(=N)c1ccc(Br)c(OC)n1
Reactant: COC(=O)c1ccc(Br)c(OC)n1
Agent: Cl
Solvent: CO
Product: Cc1cc(-c2ccc(C(=O)O)[nH]c2=O)ccn1

Procedure:
Synthesis of methyl 5-bromo-6-methoxypyridine-2-carboxylate (C30). A stirred solution of methyl 5-bromo-6-methoxypyridine-2-carboximidoate (C29) (9.42 g, 38.4 mmol) in methanol (66 mL) and concentrated hydrochloric acid (6.6 mL) was heated under reflux for 18 hours. The reaction was concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (500 mL) and washed with saturated aqueous sodium bicarbonate solution (250 mL). The aqueous phase was extracted with dichloromethane (200 mL), and the combined organics were washed with water (250 mL), with saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound. The reaction was repeated on additional material (1.65 g, 6.73 mmol), worked up in a similar manner, combined with the first reaction, and purified by silica gel chromatography (Eluant: 10% ethyl acetate in heptane) to provide the title compound as a yellow solid. Yield: 4.48 g, 18.2 mmol, 40%. LCMS m/z 246.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 3.97 (s, 3H), 4.11 (s, 3H), 7.59 (d, J=7.8 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[Br:16][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: BrCCCCCCCc1ccccc1
Reaction time: 0.01 h
Yield: 147.6 %

Procedure:
To a solution of 7-phenyl-1-heptanol (29.1 g, 151.3 mmol) in 800 mL CH2Cl2 at room temperature was added CBr4 (60.2 g, 181.6 mmol) then triphenylphosphine (47.6 g, 181.6 mmol). After 30 s, the reaction had turned a light green color. TLC indicated that the reaction was complete at this point. The solvent was removed in vacuo to give a greenish-white semisolid. To this material was added 10% EtOAc:90% Hexanes and the resulting suspension was filtered through a pad of silica gel washing well with the same solvent system. There yielded 57 g of a colorless oil as the desired bromide and triphenylphosphine oxide. This oil was then flash chromatographed (Hexanes) to yield 38.6 g, 100% of the bromide as a colorless oil. 1H NMR (CDCl3) δ 1.30-1.49 (m, 6H); 1.60 (quintet, J=8.18 Hz, 2H); 2.60 (t, J=8.18 Hz, 2H); 3.39 (t, J=8.18 Hz, 2H); 7.13-7.20 (m, 3H); 7.21-7.31 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)C>[C:27]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Solvent: CCO
Product: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
A solution of 6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carbonitrile (Preparation 3) (17 g, 40.1 mmol) in ethanol (850 ml), was treated with 2 M aqueous hydrochloric acid (50 ml) and the mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethanol and the solvent was again removed under reduced pressure. The residue was triturated with diethyl ether, filtered, washed with diethyl ether and pentane and dried to afford the title compound as a solid (13.6 g).
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])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:39])[CH2:37][CH3:38].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:39][CH2:36][CH2:37][CH3:38])=[O:34])=[CH:18][C:17]=1[CH3:23]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: CCCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methyl-aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (48 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, propylamine (20 μl) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 30 mg (yield 47%) of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([Cl:3])=[O:14])=[N:10][CH:11]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(Cl)cn1
Temperature: 25 °C

Procedure:
N,N-Dimethylformamide (one drop) and thionyl chloride (1 mL) were added to a suspension of 5-chloropyridinecarboxylic acid (55.2 mg) in toluene (5 mL). The mixture was heated under reflux for one hour. The reaction solution was cooled to room temperature and then the solvent was evaporated under reduced pressure to obtain 5-chloropyridinecarboxylic acid chloride. A solution of 5-chloropyridinecarboxylic acid chloride in THF (5 mL) and pyridine (115 μL) were sequentially added to a solution of the compound of Preparation Example 2-(2) (111 mg) in THF (10 mL) under ice-cooling. The mixture was warmed to room temperature and stirred for 30 minutes. After confirming completion of the reaction, a saturated sodium bicarbonate solution was added to the mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain an amide compound of a synthetic intermediate. The resulting amide was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added and the mixture was stirred at room temperature for three hours. The reaction solution was diluted with diethyl ether. Then, the reaction mixture was neutralized with a sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by NH-silica gel column chromatography to obtain the title compound (115 mg; >99% ee).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4]C)C.Cl[C:9]([O:11][CH2:12][Cl:13])=[O:10].Cl.[C:15]1(C)[CH:20]=CC=[CH:17][CH:16]=1>>[CH:6]1([N:3]([CH3:4])[C:9](=[O:10])[O:11][CH2:12][Cl:13])[CH2:7][CH2:17][CH2:16][CH2:15][CH2:20]1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)OCCl
Reactant: Cc1ccccc1
Agent: Cl
Product: CN(C(=O)OCCl)C1CCCCC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution (44 ml) of 4.39 ml of N-methylcyclo-N-hexylamine and 5.44 ml of triethylamine in toluene was added dropwise to 27 ml of a solution of 2.67 ml of chloromethyl chloroformate in toluene over a period of 5 min while cooling in an ice bath, and the mixture was stirred at room temperature for 17 hr. 1 N hydrochloric acid (60 ml) was added thereto, followed by separation. The organic layer was then washed with 60 ml of a 5% aqueous sodium hydrogencarbonate solution and 60 ml of 20% brine, was dried over anhydrous magnesium sulfate, and was filtered, and the solvent was removed by distillation under the reduced pressure to give 5.76 g of chloromethyl N-cyclohexyl-N-methylcarbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:30](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH:24]4[CH2:29][CH2:28][CH2:27][O:26][CH2:25]4)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.C(O)(C(F)(F)F)=O.[NH4+].[OH-].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:30][C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH:24]4[CH2:29][CH2:28][CH2:27][O:26][CH2:25]4)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(C5CCCOC5)n43)n1COCC[Si](C)(C)C)cn2C
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(C5CCCOC5)n43)[nH]1)cn2C
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.9 %

Procedure:
To a mixture of 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-(tetrahydro-2H-pyran-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.245 g, 0.461 mmol; prepared using J.1 from Preparation #I.1 with tetrahydro-2H-pyran-2-carboxylic acid [Acella], and L.1 with mercury(II) trifluoroacetate) in DCM (5 mL) was added TFA (0.887 mL, 11.5 mmol). After stirring at rt for about 15 h, the mixture was concentrated in vacuo. The material was dissolved in MeOH (5 mL) and then treated with a 30% aqueous NH4OH solution (1.79 mL, 13.8 mmol). The mixture was heated to about 60° C. for about 1 h then cooled to rt. Water was added (10 mL) and the solids were collected by filtration then washed with water (10 mL). The material was dried in a vacuum oven at about 60° C. for about 16 h to provide 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-(tetrahydro-2H-pyran-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.072 g, 39%): LC/MS (Table 2, Method a) Rt=2.16 min; MS m/z 402 (M+H)+. Syk IC50=A.
Reaction SMILES: [CH2:1]([N:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])(=[O:6])=[O:5])[CH3:2].ClCCl.C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[S:37][C:38]2[CH2:66][CH2:65][CH2:64][CH2:63][C:39]=2[C:40]=1[C:41]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][CH2:52][C:53]2[CH:62]=[CH:61][C:56]([C:57]([O:59][CH3:60])=[O:58])=[CH:55][CH:54]=2)=[CH:46][CH:45]=1)=[O:42]>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([N:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH:35][C:36]1[S:37][C:38]2[CH2:66][CH2:65][CH2:64][CH2:63][C:39]=2[C:40]=1[C:41]([NH:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:50][CH2:51][CH2:52][C:53]2[CH:54]=[CH:55][C:56]([C:57]([O:59][CH3:60])=[O:58])=[CH:61][CH:62]=2)=[CH:48][CH:49]=1)=[O:42])=[O:11])(=[O:6])=[O:5])[CH3:2]
Reactant: CCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)O)c1
Reactant: COC(=O)c1ccc(CCCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 332 mg of 3-{ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoic acid, one drop of DMF, and 3 mL of dichloromethane was added 0.11 mL of oxalyl chloride under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and then to a mixture of the obtained crude product and 3 mL of dichloromethane were added 0.11 mL of pyridine and 300 mg of methyl 4-[3-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)propyl]benzoate, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate and hexane-chloroform) to obtain 241 mg of methyl 4-(3-{4-[({2-[(3-{ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}propyl)benzoate as a yellow amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2].[H][H].C(OCC)(=[O:35])C>[Pd]>[CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9][C:8](=[O:35])[N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: C=Cc1ccc(Oc2ccc(N3CCCC3(C(=O)OCC)C(=O)OCC)cn2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(CC)cc2)nc1

Procedure:
A mixture of 1-[6-(4-vinyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g), 50 mg of 10% palladium on charcoal and 20 mL of ethyl acetate was shaken under 50 psi of hydrogen gas for 2 hours. The mixture was filtered and concentrated in vacuo, affording 0.20 g of 1-[6-(4-ethyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup. 1H NMR (CDCl3, 500 MHz): 8.08 (d, 1H, J=2.5 Hz), 7.73 (dd, 1H, J=2.5, 8.5 Hz), 7.24 (d, 2H, J=7.5 Hz), 7.05 (d, 2H, J=8.0 Hz), 6.89 (d, 1H, J=9.0 Hz), 4.21 (q, 4H, J=7.0 Hz), 2.74 (m, 2H), 2.65 (m, 4H), 1.27 (t, 3H, J=8.0 Hz), 1.20 (t, 6H, J=7.5 Hz) ppm.