Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2)([O-:22])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:32]([C:27]2[NH:28][C:29]3[C:25]([CH:26]=2)=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=3)=[O:33])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2cc(CNC(=O)c3cc4cc([N+](=O)[O-])ccc4[nH]3)ccc2Cl)c1
Yield: 36.7 %

Procedure:
N-({4-Chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-5-nitro-1H-indole-2-carboxamide was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 5-nitro-1H-indole-2-carboxylic acid, (0.025 g, 0.13 mmol), HATU (0.05 g, 0.13 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.015 g, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.36 (s, 1H), 9.34 (t, 1H), 8.67 (d, 1H), 8.04 (dd, 1H), 7.76 (t, 1H), 7.60 (d, 1H), 7.55 (d, 1H), 7.43 (dd, 1H), 7.41 (s, 1H), 7.35 (t, 1H), 7.28 (dd, 1H), 7.25 (d, 1H), 4.50 (d, 2H). MS: m/z 481.0 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>C1COCC1>[C:12]([CH:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)#[N:13]
Reactant: BrCCOC1CCCCO1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.6 %

Procedure:
Sodium hydride (57.4 g, 60% dispersion in oil, 1.43 mol) was added to a 3 L, 3-necked flask (fitted with mechanical stirrer, exit needle and condenser) and suspended in THF (900 ml). A solution of 3,4-dichlorophenylacetonitrile (257 g, 1.38 mol) in THF (400 ml) was added to the ice-cooled flask via cannula over a period of 1 hour. The mixture was then stirred at room temperature for 1.5 hours during which time there was vigorous gas evolution. The reaction mixture was then ice-cooled and 2-(2-bromoethyl)oxytetrahydropyran (288.5 g, 1.38 mol) was added via teflon cannula under nitrogen pressure over a period of 30 mins. After 40 hours the reaction mixture was quenched with ammonium chloride (10 ml), concentrated (to remove the THF) and water was added. The mixture was extracted with DCM and the organic extracts dried (Na2SO4), concentrated and distilled under reduced pressure (174° C., 100 mtorr) to give an oil. This residue was purified by flash column chromatography (hexane to 1:1, hexane: DCM) to give 2-(3-cyano-3-[3,4-dichlorophenyl]propyl)oxytetrahydropyran as an oil (210 g, 0.67 mol).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C[Al](C)C.[Cl:14][C:15]1[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH:22]2[CH2:24][CH:23]2[C:25](OCC)=O)[CH:16]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([C@@H:22]2[CH2:24][C@H:23]2[C:25]2[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:9]=2)[CH:16]=1
Reactant: CNc1ccccc1N
Reactant: CCOC(=O)C1CC1c1cc(Cl)nc(C)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N1-methylbenzene-1,2-diamine (5.08 g, 41.5 mmol) in toluene (100 mL) was added a 2M solution of trimethylaluminum (22.85 ml, 45.7 mmol) in toluene dropwise over 2 h with periodic cooling in an ice bath to prevent an exotherm. After addition was complete, the resulting dark brown mixture was warmed to room temperature and stirred for 15 min. The mixture was re-cooled in an ice bath and a solution of 6-3 (5 g, 20.8 mmol) in toluene (20 mL) was added drop-wise over 2 h, after which the reaction was warmed to room temperature. After stirring for 18 h, the reaction was cooled in an ice bath and slowly quenched with water. The mixture was filtered through a pad of celite washing with ethyl acetate. The filtrate was repeatedly washed with saturated copper (II) sulfate solution until a yellow orange organic layer was obtained and no N1-methylbenzene-1,2-diamine was observed by LCMS. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromatography (0-100% EtOAc/hexanes) to afford racemic 6-4. The racemic compound was further purified by preparative chiral SFC on a ChiralCel OJ-H column (3 cm id×25 cm length) eluting with 70% carbon dioxide/30% methanol with 0.1% triethylamine modifier in isocratic mode at 80 mL/min. The first eluting peak was identified as the desired R,R enantiomer (6-4) and was used in subsequent steps. 1H NMR (400 MHz, CDCl3) δ 7.71-7.66 (m, 1H), 7.31-7.23 (m, 3H), 7.19 (s, 1H), 3.83 (s, 3H), 2.86-2.79 (m, 2H), 2.67 (s, 3H), 1.96 (m, 2H); MS: m/z=299.2 (M+H).
Reaction SMILES: [OH-:1].[Na+].[OH:3][CH:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9]#[N:10].OO.Cl>O.C(O)C>[OH:3][CH:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9]([NH2:10])=[O:1]
Reactant: CCCCCC(O)CCCN(C#N)CCCCCCC(=O)O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(N)=O

Procedure:
To a solution of sodium hydroxide (0.4 g., excess) in water (50 ml.) and ethanol (50 ml.) is added 7-[N-(4-hydroxynonyl)cyanamido]heptanoic acid (1.5 g., 0.005 mole). The clear solution that is obtained is treated with 30% hydrogen peroxide (1.25 ml., excess). At the end of two hours the reaction mixture is poured into water (150 ml.), acidified with hydrochloric acid (dil.) and extracted with methylene chloride (3 × 75 ml.). The organic layer is washed with brine then dried over sodium sulfate. Evaporation of the solvent affords an oil which becomes solid on standing. The solid is crystallized from butyl chloride to give 7-[1-(4-hydroxynonyl)ureido]heptanoic acid. The yield is 1.4 g. (85%) of natural melting at 75°-76° C.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)C.C(N(CC)CC)C>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([N:12]=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCN(N)CC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)N1CCN(N=Cc2ccc(F)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of 1-acetyl-4-aminopiperazine dihydrochloride (300 mg) in ethanol (10 ml) and triethylamine (0.78 ml) was added p-fluorobenzaldehyde (0.164 ml), and the mixture was heated at 80° C. for 2 hours. After removal of the solvent in vacuo, the residue was triturated with ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was crystallized from diisopropyl ether to give 1-acetyl-4-(4-fluorobenzylidene)aminopiperazine (0.15 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1.[F:15][C:16]([F:26])([F:25])[CH:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)CCl.S(=O)(=O)(O)O.O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([F:15])([F:25])[F:26])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCC(O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Solvent: O
Product: CCCCCCC(OC(=O)c1ccc2cc(O)ccc2c1)C(F)(F)F
Reaction time: 48 h
Yield: 31.9 %

Procedure:
To a solution of 2-hydroxy-6-carboxynaphthalene (2 g) and optically active 1,1,1-trifluoro-2-octyl alcohol (2.2 g) in ethylene chloride (50 ml) was added a few drops of conc. sulfuric acid, and the solution was refluxed under stirring for about two days. The solution obtained was poured in water in order to collect the organic layer. The layer was washed with aqueous sodium hydroxide solution and water, in this order, and dried over anhydrous magnesium sulfate. The solution was distilled to remove the solvent. The residue was purified by silica-gel column chromatography (developer : chloroform) to obtain the titled compound (1.2 g).
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCCCCBr
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (410 mg, 1.62 mmol) and 1-bromoheptadecane (2.07 g, 6.47 mmol), alcohol 44 was obtained as a colorless oil (427 mg, 53% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][C:25](=O)[CH2:24]3)=[CH:19][CH:18]=1)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH3:4].[N:29]1([C:35](=[O:37])[CH3:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[C:35]([N:29]1[CH2:34][CH2:33][N:32]([CH:25]2[CH2:26][CH2:27][N:23]([C:20]3[CH:21]=[CH:22][C:17]([N:11]4[CH2:10][CH2:9][C:8]5[C:13](=[CH:14][CH:15]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=5)[C:12]4=[O:16])=[CH:18][CH:19]=3)[CH2:24]2)[CH2:31][CH2:30]1)(=[O:37])[CH3:36]
Reactant: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CCC(=O)C3)cc1)C2=O
Reactant: CC(=O)N1CCNCC1
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CCC(N4CCN(C(C)=O)CC4)C3)cc1)C2=O

Procedure:
6-Butoxy-2-[4-(3-oxopyrrolidin-1-yl)phenyl]-3,4-dihydro-2H-isoquinolin-1-one was reacted with 1-piperazin-1-ylethanone by method J. The product with the molecular weight of 490.65 (C29H38N4O3) was obtained in this way; MS (ESI): 491 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:32]1[C:40]2[C:35](=[C:36](B3OC(C)(C)C(C)(C)O3)[C:37]([F:41])=[CH:38][CH:39]=2)[CH:34]=[CH:33]1)(C(C)(C)C)(C)C>>[F:41][C:37]1[C:36]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:35]2[C:40](=[CH:39][CH:38]=1)[NH:32][CH:33]=[CH:34]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2nc(CC3CCOCC3)ccc2n1
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CC3CCOCC3)ccc2n1

Procedure:
4-(2-chloro-6-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (0.05 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 38.8 mg of 154 following reverse phase HPLC purification. MS (Q1) 448.2 (M)+
Reaction SMILES: [BH4-].[Na+].[Br-].[CH2:4]([N+:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CO>[CH2:4]([N:11]1[CH2:16][CH2:15][C:14]([CH3:17])=[C:13]([NH:18][C:19](=[O:20])[O:21][CH3:22])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Nc1c[n+](Cc2ccccc2)ccc1C
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)NC1=C(C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
Sodium borohydride (4.4 g, 116 mmol, 1.20 equiv.) was added in several batches to a solution of 1-benzyl-3-methoxycarbonylamino-4-methyl-pyridinium bromide (35 g, 104 mmol, 1.00 equiv.) in methanol (300 mL). The resulting solution was stirred at ambient temperature for about 16 hours, and then water (200 mL) was added. After concentrating the mixture in vacuo, standard extractive workup with ether (3×200 mL) gave a crude residue that was then purified by silica gel column chromatography (dichloromethane/methanol (20:1)) to afford the title product as a yellow solid (18 g; yield=66%). LC-MS: m/z=261 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O-:13].[Na+]>CN(C)C=O.CO>[CH3:12][O:13][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: C[O-]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(N)c1
Temperature: 80 °C
Yield: 99 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (5.0 g) in dimethylformamide (25 ml) was added 24% sodium methoxide in methanol (11 ml) and the mixture was heated at 80° C. for 4 hours. At the end of this time, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The extract was washed with 20% aqueous sodium chloride solution and insoluble material was filtered off. The filtrate was concentrated in vacuo to give the desired compound (4.8 g, yield 99%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:18][C:19]1([CH3:43])[CH2:28][CH2:27][C:26]2[N:25]=[CH:24][N:23]=[C:22]([N:29]3[CH2:35][C:34]4[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:33]=4[O:32][CH2:31][CH2:30]3)[C:21]=2[CH2:20]1>>[NH2:1][C:2]1[C:7]([S:8]([CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5]([C:37]2[CH:38]=[CH:39][C:33]3[O:32][CH2:31][CH2:30][N:29]([C:22]4[C:21]5[CH2:20][C:19]([CH3:18])([CH3:43])[CH2:28][CH2:27][C:26]=5[N:25]=[CH:24][N:23]=4)[CH2:35][C:34]=3[CH:36]=2)=[CH:4][N:3]=1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CC(C)(O)CCS(=O)(=O)c1cc(Br)cnc1N
Product: CC(C)(O)CCS(=O)(=O)c1cc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)cnc1N

Procedure:
Prepared according to the method of example 5 by using 4-[(2-amino-5-bromopyridin-3-yl)sulfonyl]-2-methylbutan-2-ol (reagent preparation 41) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.52 (s, 1H), 8.35 (s, 1H), 8.14 (s, 1H), 7.50 (s, 1H), 7.43 (d, 1H), 7.06 (d, 1H), 4.70 (s, 2H), 4.30 (m, 2H), 3.95 (m, 2H), 3.35 (m, 2H), 2.79 (t, 2H), 2.48 (s, 2H), 1.82 (m, 2H), 1.68 (t, 2H), 1.15 (s, 6H), 0.90 (s, 6H); MS (EI) for C29H37N5O4S: 552 (MH+).
Reaction SMILES: [N+:1]([C:4]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.O>[CH3:11][C:10]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: Cc1cccc(N)c1[N+](=O)[O-]
Reactant: OCCc1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]
Temperature: 200 °C
Yield: 20.7 %

Procedure:
A mixture of 2-nitro-3-methylaniline (Newman, M. S.; Kannan R. J. Org. Chem., 1976, 41, 3356., 1.9 g, 12.4 mmol), 4-bromophenylethyl alcohol (2.5 g, 12.4 mmol), K2CO3 (1.7 g, 12.4 mmol) and CuI (230 mg, 1.24 mmol) was placed in a sealed tube and heated at 200° C. for 2 h. After cooling, the mixture was poured into water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous NaOH (100 mL) and brine (100 mL), then dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 700 mg (21%) of the title compound as an orange oil: 1H-NMR (CDCl3) δ 7.77 (1H, br.s), 7.09–7.45 (6H, m), 6.69 (1H, d, J=6.3 Hz), 3.83 (2H, t, J=6.6 Hz), 2.82 (2H, t, J=6.6 Hz), 2.59 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH:11]([CH3:20])[CH:12](OS(C)(=O)=O)[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:21][C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C.CCOC(C)=O>[N:28]([CH:12]1[CH:11]([CH3:20])[N:9]2[C:10]3[C:6]([C:7]([CH2:21][C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23])=[C:8]2[CH2:14][CH2:13]1)=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])=[N+:29]=[N-:30]
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)C(C)C(OS(C)(=O)=O)CC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)Cc1c2n(c3c(F)cccc13)C(C)C(N=[N+]=[N-])CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Propyl {4-fluoro-6-methyl-7-[(methylsulfonyl)oxy]-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl}acetate was dissolved in DMF (1 M) and treated with NaN3 (2.0 eq.), warmed to 80° C. and stirred overnight. The reaction mixture was diluted with EtOAc and extracted with sat'd NH4Cl, water, dried (Na2SO4) and concentrated. Chromatography on SiO2 (0-100% EtOAc/hexanes) gave propyl (7-azido-4-fluoro-6-methyl-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate: 1H NMR (600 MHz, CDCl3) δ 7.30 (d, J=7.9 Hz, 1 H), 6.96-6.99 (m, 1 H), 6.80 (dd, J=12.6, 7.6 Hz, 1 H), 4.87 (dd, J=13.2, 6.5 Hz, 1 H), 4.10 (d, J=7.0 Hz, 1 H), 4.02 (t, J=6.2 Hz, 2 H), 3.61 (m, 2 H), 3.01 (m, 2 H), 2.10-2.20 (m, 2 H), 1.57-1.63 (m, 2 H), 1.43 (d, J=6.8 Hz, 3 H), 0.87 (t, J=7.3 Hz, 3 H); MS (EI) calc'd for C18H22FN4O2 [M+1]+345.2, found 345.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:17]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19].CN1CCOCC1>C(Cl)Cl>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:17]([N:11]2[C:12]3[C:8](=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[C:14]([F:16])[CH:13]=3)[CH:9]=[CH:10]2)([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19])=[CH:29][CH:28]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cc(F)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cc(F)cc21
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.23 g, 2 mmol) was added to a stirred solution of methyl 2-(4-amino-6-fluoro-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (0.6 g, 1.7 mmol) and 4-methylmorpholine (0.25 g, 2.5 mmol) in DCM (8 mL) at 0° C. After 30 min, an additional portion of methanesulfonyl chloride (0.1 g, 1 mmol) was added. After 1 h, the reaction mixture was partitioned between DCM and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE: EA=2:1) to afford the title compound. LC/MS m/z=439.1 [M+H]+.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][N:11]2[C:16](=[O:17])[CH2:15][CH2:14][CH:13]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:27][NH:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([Cl:39])[CH:33]=5)=[O:30])[CH:24]=4)[C:19]3=[O:40])[C:12]2=[O:41])=[O:8])[CH2:3][CH2:2]1.Cl>CCOCC>[ClH:39].[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][N:11]2[C:16](=[O:17])[CH2:15][CH2:14][CH:13]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:27][NH:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([Cl:39])[CH:33]=5)=[O:30])[CH:24]=4)[C:19]3=[O:40])[C:12]2=[O:41])=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)N(COC(=O)C4CCN(C(=O)OC(C)(C)C)CC4)C2=O)C3=O)cc1Cl
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)N(COC(=O)C4CCNCC4)C2=O)C3=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 209.4 %

Procedure:
To 1-tert-butyl 4-(3-(5-((3-(3-chloro-4-methylphenyl)ureido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl piperidine-1,4-dicarboxylate (300 mg, 0.44 mmol, obtained as described in previous example) was added 2 N HCl in Et2O (15 mL). The slurry was vigorously stirred for 2 h at rt. The solid was filtered, washed with copious Et2O, and dried in a vacuum oven overnight to give (3-(5-((3-(3-chloro-4-methylphenyl)ureido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl piperidine-4-carboxylate Hydrochloride as a white solid (285 mg, 105% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 3.26 min (98.2%); mp: 234-236 0C; 1H NMR (DMSO-d6) δ 1.62-1.81 (m, 2H, CHH, CHH), 1.87-2.01 (m, 2H, CHH, CHH), 2.02-2.16 (m, 1H, CHH), 2.16-2.29 (m, 3H, CH3), 2.32-2.47 (m, 1H, CHH), 2.59-2.76 (m, 1H, CHH), 2.77-2.99 (m, 3H, CHH, CHH, CHH), 3.00-3.28 (m, 3H, CHH, CHH, CHH), 4.15-4.66 (m, 4H, CH2, CH2), 5.26 (dd, J=4.9, 13.2 Hz, 1H, CH), 5.55-5.80 (m, 2H, CH2O), 7.02 (t, J=5.9 Hz, 1H, NH), 7.09-7.29 (m, 2H, Ar), 7.45 (d, J=7.9 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 7.62-7.82 (m, 2H, Ar), 8.41-8.96 (m, 2H, NH, NH), 9.09 (s, 1H. NH); 13C NMR (DMSO-d6) δ 18.73, 21.46, 24.31, 31.24, 37.30, 42.00, 42.73, 47.20, 52.09, 63.40, 116.31, 117.50, 121.91, 122.99, 126.97, 127.27, 130.09, 130.99, 132.96, 139.69, 142.38, 144.94, 155.21, 167.96, 170.19, 171.29, 172.20; LCMS: MH=582, 584: Anal Calcd for C29H33Cl2N5O6+1.6H2O+0.6 HCl+0.2Et2O+0.4t BuCl: C, 53.35; H, 6.05; N, 9.91; Cl, 13.04. Found: C, 53.13; H, 6.06; N, 9.70; Cl, 13.25.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[CH:6][N:7]=1.C(Cl)Cl.[H][H]>CO.[Pd]>[NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3=CCOCC3)cnc2N)cc1F
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 29.8 %

Procedure:
To a suspension of tert-butyl 4-(3-amino-6-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate (15 g, 40.4 mmol) in MeOH (800 mL) was added DCM (100 mL) until the suspension turned to a homogeneous solution. After degassed by N2 stream for 15 min, Pd/C (10 g, 9.40 mmol) was added to the reaction mixture. To this mixture, hydrogen balloon was equipped after flushed with hydrogen gas three times. The reaction mixture was stirred for 6 h. After the reaction mixture was filtered through Celite® pad, the volatile materials were removed in vacuo. The residue was dissolved in MeOH (200 mL) by heating and cooling down to room temperature and standing overnight. The brown precipitate was filtered off, which afforded 4.5 g of tert-butyl 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate. The filtrate was concentrated and dissolved in EtOH (200 mL) by heating. The second brown precipitate was filtered off to afford 3.9 g of tert-butyl 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate (55.7% combined yield). LCMS (m/z): 374.7 (MH+), 0.90 min.