Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([NH:6][C:7]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:8]=1[C:9]([O:11]CC)=O)=[O:5])C.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]2)=[CH:20]1>>[OH:18][C:15]1[CH:14]=[C:8]2[C:7](=[CH:17][CH:16]=1)[NH:6][C:4](=[O:5])[N:36]([CH2:35][CH2:34][N:31]1[CH2:30][CH2:29][CH:28]([C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:19][CH:20]=3)[CH2:33][CH2:32]1)[C:9]2=[O:11]
Reactant: NCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: CCOC(=O)Nc1ccc(O)cc1C(=O)OCC
Product: O=c1[nH]c2ccc(O)cc2c(=O)n1CCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 200 °C
Yield: 70 %

Procedure:
A mixture of 12.5 parts of ethyl 2-(ethoxycarbonylamino)-5-hydroxybenzoate and 12 parts of 4-(1H-indol-3-yl)-1-piperidineethanamine was stirred in an oil bath at about 200° C. and under nitrogen atmosphere. The formed ethanol was distilled off. The whole was cooled and the solid product was crystallized from a mixture of ethanol and acetonitrile. The product was filtered off and dried, yielding 14.5 parts (70%) of 6-hydroxy-3-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione; mp. 258.2° C. (compound 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:6](=[O:19])[C:5]12[C:23](=[O:24])[N:22]([CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[F:33])[C:21](=[O:34])[NH:20]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6](=[O:19])[C:5]12[C:23](=[O:24])[N:22]([CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[F:33])[C:21](=[O:34])[NH:20]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(NC(=O)N(Cc3cc(Cl)ccc3F)C2=O)c2cc(Cl)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1C(=O)C2(NC(=O)N(Cc3cc(Cl)ccc3F)C2=O)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.5 %

Procedure:
An ice-cold solution of tert-butyl [5′-chloro-1-(5-chloro-2-fluorobenzyl)-2,2′,5-trioxospiro[imidazolidine-4,3′-indol]-1′(2′H)-yl]acetate (168.00 mg; 0.33 mmol) in DCM (4.00 ml) was treated with trifluoroacetic acid (1.00 ml). After stirring for 4 hours the reaction the solvents were evaporated. Toluene was added twice and evaporated to give the titla compound as a beige solid in 67.5% yield (96.1% purity by HPLC). MS (ESI+): 452.1; MS (ESI−): 454.4
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[CH:4]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.O>CS(C)=O>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:14][C:13](=[O:15])[CH2:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=3)[CH:4]=2)=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: Fc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Cc1cn(Cc2ccc(F)cc2)c2ccccc12)OCc1ccc(F)cc1

Procedure:
100 ml dimethylsulfoxide (DMSO) are added to a three-necked flask under an N2 atmosphere, 2.1 g sodium hydride (mineral oil suspension) are added with vigorous stirring and treated dropwise with a solution of 5 g (17.8 mmol) indole-3-acetic acid in 50 ml DMSO. 2.58 g (35.6 mMol) 4-fluorobenzyl chloride are added with further stirring. After 12 hours at 25° C. the reaction mixture is added to 300 ml water and extracted with ether. The organic phase is dried and the solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([CH3:25])=[N:22]2)=[CH:17][CH:16]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[CH3:25][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][C:15]([O:14][C@@H:10]3[CH2:11][CH2:12][CH2:13][C@H:9]3[OH:8])=[CH:16][CH:17]=2)[N:22]=1
Reactant: Cc1ccc2ccc(O[C@@H]3CCC[C@H]3O[Si](C)(C)C(C)(C)C)cc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc2ccc(O[C@@H]3CCC[C@H]3O)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.2 %

Procedure:
To a stirred solution of crude trans-7-((2-((tert-butyldimethylsilyl)oxy)cyclopentyl)oxy)-2-methylquinoline (3.0 g, 8.4 mmol) in THF (10 mL) was added 1.0 M TBAF in THF (17 mL, 17 mmol). After stirring at ambient temperature for 1 hour, saturated aqueous NH4Cl was added to the reaction mixture. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (2% MeOH in EtOAc) to give trans-2-((2-methylquinolin-7-yl)oxy)cyclopentanol (0.065 g, 3% for two steps).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][N:19]([C@@H](C3C=CC=CC=3)C)[CH2:18][C@@H:17]2[OH:30])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>>[ClH:1].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]2[OH:30])=[CH:12][CH:11]=1
Reactant: C[C@H](c1ccccc1)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@@H](O)C1
Reactant: [H][H]
Agent: Cl
Product: Oc1ccc([C@H]2CCNC[C@@H]2O)cc1

Procedure:
reacting (3R,4R)-4-(4-benzyloxy-phenyl)-1-((R)-1-phenyl-ethyl)-piperidin-3-ol hydrochloride with hydrogen to yield (3R,4R)-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrochloride;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:7]2[OH:19].[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([CH3:30])[CH2:28]Cl)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:7]2[O:19][CH2:28][CH:27]([CH3:30])[CH2:26][N:23]1[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: CC(CCl)CN1CCOCC1
Reactant: O=c1oc2c(Cl)cccc2c(O)c1-c1ccccc1
Product: CC(COc1c(-c2ccccc2)c(=O)oc2c(Cl)cccc12)CN1CCOCC1
Yield: 69 %

Procedure:
Prepared by alkylation of 8-chloro-4-hydroxy-3-phenylcoumarin by 3-morpholino-2-methyl-1-chloropropane, in accordance with the method of Example 8. By recrystallisation from ethanol, a solid melting at 120°-122° C. is obtained. Yield 69%.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([CH3:25])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:24])[CH:11]=[CH:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH3:21])=[C:15]([CH3:22])[C:14]=1[CH3:23])C.C([Al]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[OH-].[Al+3].[OH-].[OH-]>CO.C1(C)C=CC=CC=1>[CH3:21][O:20][C:16]1[CH:17]=[C:18]([CH3:19])[C:13]([CH:12]=[CH:11][C:10]([CH3:24])=[CH:9][CH:8]=[CH:7][C:6]([CH3:25])=[CH:5][CH2:4][OH:3])=[C:14]([CH3:23])[C:15]=1[CH3:22]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C
Agent: CC(C)C[Al]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C=CC(C)=CC=CC(C)=CCO)c(C)c1C

Procedure:
In a 5-liter, round bottom flask provided with a stirrer, low temperature thermometer, an inlet for dry nitrogen, a gas outlet, and a dropping funnel connected to a mineral oil bubbler, were placed 150 g (0.436 moles) of 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester and 800 ml of toluene. The contents were stirred until the solids had dissolved, then by means of a dry ice bath, the internal temperature was lowered to -60° C., at which temperature 780 ml of a 25% solution of diisobutylaluminum (DIBAL) hydride in toluene (1.155 moles) was added dropwise. The initially yellow solution or suspension gradually deepened in color and after all the DIBAL had been added, the reaction mixture consisted of a clear, somewhat viscous deep red orange solution. After stirring for one hour, the cooling bath was lowered and the internal temperature allowed to rise to -40° C., at which temperature, 50 ml of a 50% aqueous methanol solution was added dropwise with intermittent cooling so that when the addition was complete the temperature was approximately 10° C. At this point, 140 ml of a saturated solution of sodium sulfate was added dropwise. Allowing the temperature to gradually rise to 25° C. Toward the end of the addition, aluminum hydroxide began to precipitate with the evolution of heat. After stirring for a few minutes, 800 ml of chloroform was added and the suspension stirred for ten minutes. The precipitate was removed by filtration on a twelve-inch Buchner funnel through a layer of filter aid, then washed four times with 500 ml portions of chloroform. The combined filtrates were washed successively with 600 ml of water, 600 ml of water containing 10 ml of 3N hydrochloric acid, 600 ml of saturated sodium bicarbonate solution, and 600 ml of water, then dried over anhydrous sodium sulfate. Distillation of the solvent in the rotary evaporator left 130-145 g of a crystalline residue. To this was added one liter of hexane and the suspension stirred vigorously until the aggregates had been dispersed; any material adhering to the walls was scraped off. The yellow crystalline precipitate was recovered by filtration, washed twice with sufficient hexane to cover the filter cake, then dried in vacuo first at 12-15 mm (water pump), then at 0.5 mm until the weight was constant. The yield of product was 119-123 g, m.p. 127.5°-129.5° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])=[O:5])#[N:2].C([O-])(=O)C.[Na+].[Cl:20][C:21]([Cl:25])([Cl:24])[C:22]#[N:23]>C(O)C>[NH2:23][C:22]([C:21]([Cl:25])([Cl:24])[Cl:20])=[C:3]([C:1]#[N:2])[C:4]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14])=[O:5]
Reactant: COc1ccncc1NC(=O)CC#N
Reactant: N#CC(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccncc1NC(=O)C(C#N)=C(N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
2-Cyano-N-(4-methoxy-3-pyridyl)acetamide 8 (26.4 g, 138.1 mmol) was slurried in ethanol (300 mL). Sodium acetate (23.56 g, 287.2 mmol) was added followed by trichloroacetonitrile (23.92 g, 16.85 mL, 165.7 mmol). The mixture was stirred at room temperature overnight. The suspension was filtered and the solids washed with ethanol. The solids (46.5 g) were slurried for 90 minutes in 10% aqueous ethanol, filtered and dried to afford 3-amino-4,4,4-trichloro-2-cyano-N-(4-methoxy-3-pyridyl)but-2-enamide (37.2 g, 80%). LC-MS (M+H)+ 336.9; 1H NMR (500 MHz, DMSO-d6) δ 8.44 (d, 1H), 7.43-7.47 (m, 1H), 6.35-6.39 (m, 1H), 4.04 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH:12]([C:14]1[CH:19]=[C:18](I)[CH:17]=[CH:16][C:15]=1[CH3:21])[OH:13].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+].[F-].[K+].O.O.O.[S-2].[Na+].[Na+]>[Cu].O.CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH:12]([C:14]1[CH:19]=[C:18]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:17]=[CH:16][C:15]=1[CH3:21])[OH:13]
Reactant: Cc1ccc(I)cc1C(O)c1c(C)cc(C(=O)O)cc1C
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccnc2)cc1C(O)c1c(C)cc(C(=O)O)cc1C
Reaction time: 30 h

Procedure:
To a suspension 19.8 g of α-(2,6-dimethyl-4-carboxyphenyl)-2-methyl-5-iodobenzenemethanol, 5.1 g of imidazole, 13.8 g of potassium carbonate and 120 ml of dimethylformamide are added 0.4 g of potassium fluoride and 0.4 g of copper powder, and the mixture is stirred at 135°-140° C. for 30 hours. After cooling, to the reaction mixture is added 240 ml of water and further 0.45 g of sodium sulfide trihydrate. The whole mixture is stirred for 30 minutes. The precipitated copper sulfide is filtered with sellaite under reduced pressure and the filtrate is adjusted to pH 4 with concentrated hydrochloric acid under heating and stirring. The precipitated crystals are collected by filtration, washed with water and dried. Recrystallization from dimethylformamide gives α-(2,6-dimethyl-4-carboxyphenyl)-2-methyl-5-(1-imidazolyl)benzenemethanol, melting at 309°-311° C. with decomposition in high yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]([O:15]C)=[O:14])=[CH:5]2.[OH-].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]([OH:15])=[O:14])=[CH:5]2
Reactant: COC(=O)c1cc2cc(Br)c(OC)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Product: COc1cc2[nH]c(C(=O)O)cc2cc1Br

Procedure:
Following the general procedure of PREPARATION 63 and making non-critical variations but starting with methyl 5-bromo-6-methoxyindole carboxylate (PREPARATION 81, 3.31 g) and potassium hydroxide (0.98 g), the title compound is obtained, NMR (300 MHz, CD3OD) 7.79, 7.03, 7.01 and 3.89 δ.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1([CH3:22])[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH2:19][CH2:20][NH2:21])[C:13]=2[O:12][CH2:11]1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:20][CH2:19][C:18]2[C:13]3[O:12][CH2:11][C:10]([CH3:22])([CH3:9])[C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH:7]=1
Reactant: CC1(C)COc2c(CCN)cccc21
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC1(C)COc2c(CCNc3cc(Cl)ncn3)cccc21
Temperature: 90 °C

Procedure:
As shown in step 3-vi of Scheme 3, a solution of 4,6-dichloropyrimidine (111.6 mg, 0.726 mmol), 2-(3,3-dimethyl-2H-benzofuran-7-yl)ethanamine (139 mg, 0.726 mmol), Na2CO3 (231.1 mg, 2.180 mmol) in i-PrOH (5.56 mL) was sealed in a microwave-type tube and heated at 90° C. in an oil bath for 18 hours. The reaction mixture was filtered through a pad of diatomaceous earth, the volatiles removed under reduced pressure, and the residue purified by medium pressure chromatography on silica gel (0 to 100% EtOAc in hexanes) to give 6-chloro-N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)pyrimidin-4-amine (Compound 2006) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 6.94 (d, J=7.3 Hz, 1H), 6.88 (d, J=7.4 Hz, 1H), 6.78 (t, J=7.4 Hz, 1H), 6.25 (s, 1H), 4.20 (d, J=5.9 Hz, 2H), 4.05 (d, J=7.1 Hz, H), 3.47 (s, 2H), 2.83 (t, J=6.6 Hz, 2H), 1.50 (s, 2H) and 1.27 (s, 6H) ppm; ESMS (M+H)=304.06.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][CH:26]([F:27])[C:24]1[CH:23]=[C:22]([C:29]2[CH:30]=[N:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.6 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.46 g) in dichloromethane (7 ml) was added TFA (7 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH) yielded the title compound as a white solid (0.16 g, 31%). MS (ISP) 513.2 [(M+H)+]; mp 245.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C@H:16]([CH2:28][NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1.N12CCCN=C1CCCCC2>C(Cl)Cl>[CH3:33][S:30]([N:29]1[CH2:28][C@H:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:4]2[C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=[CH:7][C:6]=3[N:15]=[C:3]2[CH2:2]1)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNS(C)(=O)=O)n1c(CCl)nc2cnc3ccccc3c21
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3cnc4ccccc4c3n21
Yield: 82.2 %

Procedure:
tert-Butyl (4S)-4-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-5-[(methylsulfonyl)amino]pentylcarbamate (8.08 g, 16.3 mmol) was dissolved in 200 mL of CH2Cl2 and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.91 mL, 19.5 mmol) After 1 hour, the reaction mixture was washed successively with H2O and brine and the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 3% methanol/CHCl3) gave tert-butyl 3-[(11S)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (6.16 g) as a light yellow foam.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>ClCCl>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:24](=[O:27])[CH:25]=[CH2:26])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CC(=O)Cl
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 101.2 %

Procedure:
To a solution of 390 mg (1.6 mmol) D-Proline benzyl ester hydrochloride and 0.47 ml (3.4 mmol) triethylamine in 20 ml dichloromethane at 0° C. was added dropwise 0.2 ml (2.4 mmol) acryloyl chloride and stirring continued for 24 h at room temperature. The reaction mixture was then washed sequentially with water, 1 M hydrochloric acid and once more with water, and the aqueous phases back-extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo to afford 420 mg (100%) of the title compound (R)-1-acryloyl-pyrrolidine-2-carboxylic acid benzyl ester as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:4]1[N:3]=[C:2]([NH:15][CH2:14][C:13]2[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=2)[C:10]#[N:9])[CH:7]=[N:6][CH:5]=1
Reactant: N#Cc1cccc(CN)c1
Reactant: Clc1cncc(Cl)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1cccc(CNc2cncc(Cl)n2)c1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A mixture of 2,6-dichloropyrazine (75 mg, 0.503 mmol), 3-aminomethyl-benzonitrile (73 mg, 0.553 mmol), sodium t-butoxide (58 mg, 0.604 mmol), BINAP (12.5 mg, 0.020 mmol), and Pd2(dba)3 (9.2 mg, 0.010 mmol) in toluene (2 mL) was heated at reflux under nitrogen for 10 h. The solution was cooled to room temperature and filtered through a celite pad. The celite pad was washed with ethyl acetate several times. The combined filtrate was concentrated in vacuo to give the crude title compound. The product was purified by chromatography (silica, 5% MeOH/dichlormethane) to give 37.6 mg 3-[(6-chloro-pyrazin-2-ylamino)-methyl]-benzonitrile I-4n.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[C:4]([CH2:13][CH3:14])[CH:3]=1.C1C=C([O:21]O)C(C(O)=O)=C(C(O)=O)C=1.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]2[C:6](=[O:12])[O:11][C:7](=[O:21])[NH:8][C:9]=2[CH:10]=1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CCc1cc(Br)cc2c1C(=O)C(=O)N2
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(Br)cc2[nH]c(=O)oc(=O)c12

Procedure:
A stirred solution of 6-bromo-4-ethyl-1H-indole-2,3-dione (2.64 g, 10.4 mM) and the hexahydrate magnesium salt of monoperoxyphthalic acid (80% pure, 3.54 g, 5.73 mM) in glacial acetic acid (30 mL) was stirred at 60° C. for 1 hr during which time a precipitate formed. The cooled reaction mixture was then poured into cold water and the resulting mixture was filtered to separate (2.04 g, 73%) the title compound as a tan solid. Recrystallization of a portion of this material from ethyl acetate/hexane provided an analytical sample of the title compound as off white crystals, mp 208.5°-210.5° C.; MS(CI): 270 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[NH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[NH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Nc3cccc(F)c3)c2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]nc(Nc3cccc(F)c3)c2c1
Temperature: 25 °C

Procedure:
To a solution of (3-Fluoro-phenyl)-(5-nitro-1H-indazol-3-yl)-amine (0.36 g, 1.3 mmol) in methanol (10 ml) was added 10% Pd/C (72 mg). The mixture was allowed to stir at room temperature under H2 atmosphere. After TLC showed the starting material to be consumed, the reaction was passed through a plug of celite. The filtrate was concentrated to give the title compound as an off-white solid. MS (ESI) m/z=243 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][OH:47])[CH:43]=[C:42]([F:48])[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH:43]=[C:42]([F:48])[CH:41]=1)[CH:46]=[O:47])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(F)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(F)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Reaction time: 24 h
Yield: 80.2 %

Procedure:
Manganese dioxide (740 mg) was added to a solution of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-fluoro-5-(hydroxylmethyl)phenyl]-D-glucitol (0.5 g) in chloroform (10 ml), and the mixture was stirred for 24 hours. After filtration through celite, washing with chloroform was carried out, and the filtrate was concentrated. The resulting residue was dried to obtain 3-(-2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-5-fluorobenzaldehyde (0.4 g).