Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12]CC1C=CC(OC)=CC=1OC)[C:6]([O:24][CH3:25])=[N:5]2.FC(F)(F)C(O)=O>ClCCl>[NH2:12][C:7]1[C:6]([O:24][CH3:25])=[N:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: COc1ccc(CNc2nc3ccc(Cl)cc3nc2OC)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc2cc(Cl)ccc2nc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
To 6-chloro-2-(2,4-dimethoxybenzylamino)-3-methoxyquinoxaline (4.42 g, 12.3 mmol), 50 ml of 50% trifluoroacetic acid in dichloromethane was added at room temperature. The resulting mixture was stirred at room temperature for 18 hours and concentrated under the reduced pressure to remove the solvent. The residue was neutralized with saturated sodium bicarbonate solution and then NaCl solution was added thereto. The product was extracted with dichloromethane and the organic layer was dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (4:1) mixture and concentration gave 1.52 g of the titled compound (yield, 59%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C@H:10]2[C:14]3([CH2:16][CH2:15]3)[C:13](=O)[NH:12][CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1>[H-].[Al+3].[Li+].[H-].[H-].[H-]>[C:1]1([C@@H:7]([NH:9][C@H:10]2[C:14]3([CH2:16][CH2:15]3)[CH2:13][NH:12][CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](N[C@@H]1CNC(=O)C12CC2)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](N[C@@H]1CNCC12CC2)c1ccccc1

Procedure:
A flask was charged with 200 mg of (S)-7-[(S)-1-phenylethyl]amino-4-oxo-5-azaspiro[2.4]heptane, and the atmosphere in the flask was replaced with nitrogen. Next, 5 ml of tetrahydrofuran was added to dissolve the compound in the flask, 5.0 ml of lithium aluminum hydride (1M solution in tetrahydrofuran) was added dropwise to the resulting solution at 0° C. and then the mixture was heated under reflux for 1 hour. After confirming completion of the reaction, the reaction was terminated by adding saturated ammonium chloride solution and then the insoluble matter was removed by filtration. The resulting filtrate was concentrated under a reduced pressure and distributed between ethyl acetate and saturated brine, and the resulting organic layer was dried over anhydrous sodium sulfate. Thereafter, the insoluble matter was removed by filtration and the resulting filtrate was concentrated under a reduced pressure to obtain 181 mg (96%) of colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=[S:15])[NH:7][C:6]=2[CH:16]=1.[OH-].[K+].S([O-])(O[CH3:23])(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([S:15][CH3:23])=[N:7][C:6]=2[CH:16]=1
Reactant: Fc1ccc2c(c1)NC(=S)c1cscc1N2
Reactant: COS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: CSC1=Nc2cc(F)ccc2Nc2cscc21

Procedure:
In a similar manner 7-fluoro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-thione is reacted with potassium hydroxide and methyl sulfate to give 7-fluoro-10-(Methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[F:32][C:33]([F:46])([F:45])C1C=C(CCC(O)=O)C=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:11]([CH2:10][CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:33]([F:46])([F:45])[F:32])[CH:3]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2cccc(C(F)(F)F)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2[-3-[3-(3-Chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(3-trifluoromethyl-phenyl)-propionic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@:11]1([CH3:24])[C@@H:20]2[C@H:16]([CH2:17][O:18][CH2:19]2)[S:15](=[O:22])(=[O:21])[CH2:14][C:13]([NH2:23])=[N:12]1>C(O)C.[Pd].O1CCCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:11]2([CH3:24])[C@@H:20]3[C@H:16]([CH2:17][O:18][CH2:19]3)[S:15](=[O:21])(=[O:22])[CH2:14][C:13]([NH2:23])=[N:12]2)[CH:4]=1
Reactant: C[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)CS(=O)(=O)[C@H]2COC[C@@H]21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@]1(c2cc(N)ccc2F)N=C(N)CS(=O)(=O)[C@H]2COC[C@@H]21
Yield: 104.8 %

Procedure:
The crude (3aR,8S,8aS)-rel-8-(2-fluoro-5-nitro-phenyl)-8-methyl-4,4-dioxo-3,3a,4,5,8,8a-hexahydro-1H-2-oxa-4λ6-thia-7-aza-azulen-6-ylamine (73 mg, 204 μmol) was hydrogenated under atmospheric pressure at room temperature in ethanol (5 ml) using palladium on carbon (5%; 39 mg, 18.3 μmol) as the catalyst. After 3 hours the catalyst was filtered and the filtrate evaporated at reduced pressure. In order to complete the reaction, the residue was hydrogenated in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml) under the aforementioned conditions during 20 hours. Thereafter, the catalyst was filtered, and the filtrate was evaporated at reduced pressure. The crude (3aR,8S,8aS)-rel-8-(5-amino-2-fluoro-phenyl)-8-methyl-4,4-dioxo-3,3a,4,5,8,8a-hexahydro-1H-2-oxa-4λ6-thia-7-aza-azulen-6-ylamine (70 mg) was obtained as brown semisolid material and was engaged in the next step without purification. MS (ISP): m/z=328.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](C(Cl)C2C=CC=C(CC)C=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.CC[N:38]([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])C.N[C:46]1[CH:53]=[CH:52][C:49]([C:50]#N)=[CH:48][CH:47]=1.C(Cl)Cl>CC#N.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([N:38]([CH2:39][C:41]2[CH:46]=[CH:53][CH:52]=[C:49]([CH2:48][CH3:47])[CH:50]=2)[C:42]2[CH:43]=[CH:13][C:8]([C:7]#[N:5])=[CH:9][CH:44]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1cccc(C(Cl)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1cccc(CN(c2ccc(C#N)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 188.9 %

Procedure:
To a suspension of the chloro intermediate (0.382 mmol) in 3 mL CH3CN at rt, was added DIEA (0.133 mL, 0.764 mmol), 4-aminobenzonitrile (67.7 mg, 0.573 mmol) and 1 mL CH2Cl2. The mixture was stirred at 50° C. for 3 h, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (O to 50% EtOAc/hexanes gradient) to afford 225 mg of Intermediate 175.3 as a colorless oil. LCMS (4 min gradient, 50 to 100% B, A=95% H2O/5% CH3CN/0.1% TFA, B=95% CH3CN/5% H2O/0.1% TFA) RT=5.20 min, 623.13 (M+H)+.
Reaction SMILES: N1([C:7]2[CH2:11][CH2:10][CH2:9][CH:8]=2)CCCCC1.[C:12]1(=O)[CH2:16]CCC1.N1CCCCC1.[S:24]([O-])([O-:27])(=[O:26])=[O:25].[Mg+2]>O.CCCCCC>[C:9]1([CH3:8])[CH:10]=[CH:11][C:7]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:12][CH:16]=1
Reactant: O=C1CCCC1
Reactant: C1=C(N2CCCCC2)CCC1
Reactant: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCNCC1
Solvent: CCCCCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
1-piperidino-1-cyclopentene was-synthesized as follows. In a 1-L 3-necked round-bottom flask equipped with an overhead stirrer, 20.0 g cyclopentanone was added to 120 mL hexane. 18.43 g piperidine was then added to the solution. 38.0 g anhydrous magnesium sulfate was then added to scavenge the water produced in the reaction, and 0.25 g p-toluenesulfonic acid was added as a catalyst. The mixture was then refluxed with overhead stirring over the course of 4 days. The suspension was allowed to cool, and the magnesium salts were removed by filtration. The hexane solution was then rotoevaporated at about 77° C. and 60 torr in order to remove the hexane solvent and unreacted piperidine.
Reaction SMILES: Cl.Br[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[CH3:13][N:14]1[C:18]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2B(O)O)=[CH:17][CH:16]=[N:15]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:13][N:14]1[C:18]([C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=2[C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][NH:7][CH2:8]3)=[CH:17][CH:16]=[N:15]1
Reactant: Brc1cccc2c1CCNC2
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1B(O)O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2c1CCNC2
Temperature: 90 °C

Procedure:
A vial was charged with 5-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (ASW Medchem, Brunswick, N.J., 400.42 mg, 1.367 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (Intermediate B, 443 mg, 1.640 mmol), potassium phosphate (1160 mg, 5.47 mmol), and Pd(AmPhos)2Cl2 (Sigma-Aldrich, St. Louis, Mo., 48.4 mg, 0.068 mmol). The vial was flushed with Ar (g), then dioxane (2928 μl) and water (976 μl) were added in sequence. The mixture was heated in a microwave reactor for 30 min at 90° C. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water (and a small amount of brine to break up emulsions, 2×), washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was taken up in MeOH, then loaded onto a 10 g SCX-2 ion exchange column. The column was eluted with MeOH, then with 2M ammonia in MeOH. The basic filtrate was concentrated, and the residue was chromatographed on a 40 g silica gel column with 0 to 10% MeOH/DCM to provide 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as a pale yellow solid. [M+H]+=358.1. 1H NMR (400 MHz, DMSO-d6) δ ppm=7.91-7.80 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.09-6.95 (m, 2H), 6.84 (dd, J=1.3, 7.4 Hz, 1H), 5.96 (d, J=1.9 Hz, 1H), 3.85 (s, 2H), 3.52 (br. s., 3H), 2.93-2.84 (m, 1H), 2.79-2.67 (m, 1H), 2.48-2.39 (m, 1H), 2.09 (td, J=5.3, 16.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=C)=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.I([O-])(=O)(=O)=[O:36].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:36])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2
Reactant: C=Cc1nc([C@H](C)Nc2ncnc3c2ncn3Cc2ccc(OC)cc2)cc2cccc(Cl)c12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C=O)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of (S)—N-(1-(8-chloro-1-vinylisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 2 (3.6 g, 7.6 mmol, 1 eq) in a mixture of 1,4-dioxane (40 mL) and H2O (40 mL) at RT, osmium tetraoxide (5 mg) was added and the resulting mixture was stirred at RT for 30 min. To this mixture, sodium periodate (3.3 g, 15.2 mmol, 2 eq) was added and the resulting mixture was stirred at RT overnight. The reaction mixture was filtered through silica gel (10 g). The filtrate was extracted with DCM (3×60 mL), washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product, (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbaldehyde 5.
Reaction SMILES: [C:1]([NH:9][C:10]([N:12]1[C:16]2([C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=3[F:37])[CH2:17][N:18]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:19][CH:15]2[CH2:14][O:13]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[C:1]([NH:9][C:10]([NH:12][C:16]1([C:30]2[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=2[F:37])[CH:15]([CH2:14][OH:13])[CH2:19][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:17]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)N1OCC2CN(C(=O)OCc3ccccc3)CC21c1cc(Br)ccc1F)c1ccccc1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(NC(=S)NC1(c2cc(Br)ccc2F)CN(C(=O)OCc2ccccc2)CC1CO)c1ccccc1
Yield: 85.6 %

Procedure:
A mixture of benzyl 1-(benzoylcarbamothioyl)-6a-(5-bromo-2-fluoro-phenyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (6.05 g 10.4 mmol) and zinc (dust, <10 micron) (6.77 g, 103.5 mmol) is stirred in acetic acid (52 mL) at room temperature overnight under nitrogen. The reaction is diluted with ethyl acetate and filtered through diatomaceous earth. The solvent is removed in vacuo and the residue is diluted with ethyl acetate, water and saturated aqueous sodium bicarbonate. The mixture is extracted with ethyl acetate (3×), the combined organic layers are combined and dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product is purified over silica gel with a 30 minute 5% to 100% EtOAc in hexanes gradient to give the title compound (5.222 g, 86%). ES/MS (m/e): (79Br/81Br) 586/588 (M+H).
Reaction SMILES: ClC1C([N+]([O-])=O)=CC([N+]([O-])=O)=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:17]NCCN1CC[O:24][CH2:23][CH2:22]1.CC[O:29][CH2:30][CH3:31]>O>[CH3:22][CH2:23][O:24][C:7]([CH3:6])=[O:8].[O:29]([CH:6]([CH3:7])[CH3:10])[CH:30]([CH3:31])[CH3:17]
Reactant: O=C(Cl)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOCC
Reactant: CNCCN1CCOCC1
Solvent: O
Product: CC(C)OC(C)C
Product: CCOC(C)=O

Procedure:
Similar reaction of crude 5-chloro-2,4-dinitrobenzoyl chloride in Et2O with 4-[2-(methylamino)ethyl]morpholine (2 equiv) in water, followed by chromatography of the product on alumina-90, eluting with EtOAc, gave 5-chloro-N-methyl-N-[2-(4-morpholino)ethyl]-2,4-dinitrobenzamide (48%), mp (EtOAc/iPr2O) 123-123.5° C. 1H NMR [(CD3)2SO] [rotamer mixture] δ8.94 & 8.94 (2xs, 1H, H-3), 8.13 & 8.09 (2xs, 1H, H-6), [3.63-3.54 (m), 3.51, t (J=4.6 Hz) & 3.28-3.18(m), 6H, O(CH2)CH2, N(CH3)CH2], 3.05 & 2.89 (2xs, 3H, CH3), [2.57 (t, J=6.6 Hz), 2.50-2.38 (m) & 2.25 (t, J=4 3 Hz), 6H, CH2N(CH2)CH2]. Anal. Calcd. for C14H17ClN4O6: C, 45.11,H, 4.60; N, 15.03. Found: C, 45.01;H, 4,43, N, 15.02%.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH3:13][O-:14].[Na+]>CO>[OH:14][CH2:13][C:8]([CH3:10])([CH3:9])[C:7](=[O:11])[C:2]([CH3:1])([CH3:12])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C[O-]
Reactant: COC(=O)C(C)(C)C(=O)C(C)C
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)C(=O)C(C)(C)CO

Procedure:
A mixture of 172 g. (1.0 mole) methyl 2,2,4-trimethyl-3-ketovalerate, 5.4 g. (0.10 mole) sodium methoxide and 33 g. (0.36 mole) paraformalde in 250 ml. methanol is heated at reflux for eight hours. The mixture is quenched by addition of water, neutralized with hydrochloric acid, extracted with ethyl ether, washed with water, brine and solvent evaporated. The residue is purified by vacuum distillation or chromatography on silica gel to provide the purified product.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1CCOCC1.[H-].[Na+].[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])C>O1CCCC1>[CH2:24]([O:23][C:20](=[O:22])[NH:4][C:3]1[N:12]=[C:13]2[CH:14]=[C:15]([Cl:19])[N:16]=[CH:17][N:18]2[CH:2]=1)[CH3:25]
Reactant: OCCN1CCOCC1
Reactant: Nc1cc(Cl)ncn1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cn2cnc(Cl)cc2n1

Procedure:
A solution of 4-(2-hydroxyethyl)morpholine (2.77 g, 21.1 mmol) in dry tetrahydrofuran (5 mL) was added to a refluxing suspension of sodium hydride (557 mg, 23.2 mmol) in tetrahydrofuran (50 mL). This mixture was heated at reflux temperature for 3 h., then 2,5-dibromopyridine (1; 5.00 g, 21.1 mmol) added as a solid (portion wise). The resulting mixture was then heated at reflux for 15 h. After allowing the reaction mixture to cool, it was diluted with ethyl acetate (200 mL), then washed with water (200 mL). The water fraction was back-extracted with ethyl acetate (100 mL). The combined ethyl acetate fractions were washed with water (2×200 mL), then brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the resultant liquor was concentrated under reduced pressure. The resulting yellow oil was purified by chromatography on silica gel (100% dichloromethane gradient to 10% methanol/dichloromethane). Compound 2 was isolated as a yellow oil (yield: 5.06 g, 84%);
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([Cl:19])=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20](Cl)(=[O:24])[C:21](Cl)=[O:22].C[CH2:27][O:28]CC>>[Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[C:20](=[O:24])[C:21]([O:28][CH3:27])=[O:22])=[CH:16][C:15]([Cl:19])=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOCC
Reactant: CC(C)(C)[Si](C)(C)OCc1cc2cc(Cl)ccc2[nH]1
Product: COC(=O)C(=O)c1c(CO[Si](C)(C)C(C)(C)C)[nH]c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indole (1 eq) was dissolved in ether (0.38M) and the solution was cooled to 0° C. Oxalyl chloride (2M in CH2Cl2) (1.2 eq) was added to the above cold solution with vigorous stirring. Precipitation occurred. The suspension was kept stirred at 0° C. for 30 minutes. Then MeOH (3/5 volume of oxalyl chloride solution) was added to the reaction mixture, followed by NEt3 (6/5 volume of oxalyl chloride solution). The resulting mixture was then diluted with MeOH (6/5 volume of oxalyl chloride solution) before it was poured into water (4× volume of oxalyl chloride solution). Extract with EtOAc. Organic phase washed with brine, dried over Na2SO4, and concentrated to give methyl [2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1H-indol-3-yl](oxo)acetate (brown solid) in 65% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl[C:13]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:14].Cl>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:14])=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: COC(=O)CCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)CCCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Chlorobenzene (8.13 ml, 79.9 mmol) was dissolved in 100 ml of 1,2-dichloroethane, and 21.3 g (160 mmol) of aluminum trichloride and 12.15 ml (87.9 mmol) of methyl 4-(chloroformyl)butyrate were added thereto, followed by stirring the mixture at room temperature overnight. The reaction solution was poured into hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica-gel column chromatography (eluent: a mixture of 4% ethyl acetate and hexane) to obtain 15.8 g of the above-mentioned compound (yield 82%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][NH:7][C:6]1=[O:11].CCN(C(C)C)C(C)C.[O:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O.CN(C=O)C>C(Cl)Cl>[C:25]([O:24][C:22](=[O:21])[NH:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][NH:7][C:6]1=[O:11])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCN1C(=O)CNC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN1C(=O)CNC1=O
Reaction time: 0.25 h

Procedure:
3-(2-Aminoethyl)-imidazolidine-2,4-dione hydrochloride (14.7 g., 82 mmol) was suspended in DCM (300 mL) and DIPEA (28 mL, 160 mmol) was added. The mixture was stirred for 15 min, and then BOC2O (19.7 g, 90 mmol) was added. The suspension was stirred for 1 h, and then DMF (45 mL) was added. The stirred suspension gradually became a clear solution over the next several h. Stirring was continued for a further 16 h, after which time a thick precipitate had formed. The mixture was concentrated to dryness in vacuo, ensuring the last traces of DMF were removed, and then dissolved in boiling EtOAc (200 mL). Hexane (800 mL) was added, the mixture cooled and allowed to stand for 1 h. The resulting product was collected by filtration. Yield=14.6 g, 73%.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([NH2:14])=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].Br[C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[CH:22][CH:21]=[C:20]([C:31]([O-:33])=[O:32])[CH:19]=2.N1C2C(=CC=C(C(OC)=O)C=2)C=[CH:35]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([NH:4][C:5]1[C:6]([NH2:14])=[C:7]([C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=[C:20]([C:31]([O:33][CH3:35])=[O:32])[CH:19]=3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=C([O-])c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: CC(=O)Nc1cccc(B(O)O)c1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc(NC(C)=O)c3N)[nH]c2c1
Temperature: 105 °C
Yield: 59 %

Procedure:
[3-(acetylamino)-2-aminophenyl]boronic acid (prepared as described in Example 5, Step 1 above) (1.1 eq) was added to a solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared from commercially available methyl indole-6-carboxylate as described in WO 2004/087714) in dioxane (0.06 M). 2M aqueous Na2CO3 (4 eq) was introduced and the mixture degassed by sonication under a N2 atmosphere prior to introducing bis(triphenylphosphine)palladium(II) dichloride (0.2 eq) and heating at 105° C. for 2 h. The reaction was allowed to cool to RT before partitioning between EtOAc and water. The aqueous phase was extracted a second time with EtOAc and the combined organics washed with water, brine before being dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography (5% MeOH/CH2Cl2) afforded the title compound as a glass (59%). MS (ES+) m/z 406 (M+H)+.