Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([N:14]=[CH:15][C:16](=[O:23])[N:17]2[CH2:20][CH:21]=O)=[CH:12][CH:11]=1.[NH2:24][CH2:25][C@@H:26]1[CH2:30][N:29]([C:31]2[CH:32]=[CH:33][C:34]3[O:39][CH2:38][C:37](=[O:40])[NH:36][C:35]=3[CH:41]=2)[C:28](=[O:42])[CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.O.CN(C)C=O>[CH3:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([N:14]=[CH:15][C:16](=[O:23])[N:17]2[CH2:20][CH2:21][NH:24][CH2:25][C@@H:26]2[CH2:30][N:29]([C:31]3[CH:32]=[CH:33][C:34]4[O:39][CH2:38][C:37](=[O:40])[NH:36][C:35]=4[CH:41]=3)[C:28](=[O:42])[CH2:27]2)=[CH:12][CH:11]=1
Reactant: NC[C@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CCNC[C@H]3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2c1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Under a nitrogen gas atmosphere, anhydrous sodium sulfate (1.4 g) was added at room temperature to a solution of (7-methoxy-2-oxoquinoxalin-1(2H)-yl)acetaldehyde (synthesized with reference to WO2009/1126; 167 mg, 0.765 mmol) and 6-[(4R)-4-(aminomethyl)-2-oxopyrrolidin-1-yl]-2H-1,4-benzoxazin-3(4H)-one (200 mg, 0.765 mmol) in dichloromethane (3 ml)/N,N-dimethylformamide (1 ml) and the mixture was stirred at the same temperature for 2 hours. Dichloromethane (3 ml) was added to the reaction solution, sodium triacetoxyborohydride (243 mg, 1.15 mmol) was subsequently added thereto and the mixture was stirred at the same temperature for 15 hours. Water (10 ml) was added to the reaction solution to dissolve the insoluble material and then a mixture of dichloromethane and a saturated sodium hydrogen carbonate aqueous solution was poured thereinto and the resultant was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol) to yield 321 mg (90%) of the title compound in the form of a light yellow amorphous solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:22]
Reactant: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C

Procedure:
A solution of tert.-butyl (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetate (4.13 g., 0.01 mole) and p-toluenesulfonic acid (0.3 g.) in benzene (50 ml.) is refluxed for ten minutes then cooled to 25° C. affording (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 113°-114° C. after recrystallization from acetic acid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:23][CH2:22][CH2:21][N:20]4C(OC(C)(C)C)=O)=[CH:15][CH:14]=3)[NH:9][C:8]=2[CH:7]=[C:6]([Cl:31])[CH:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:6]1[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]2[N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:23][CH2:22][CH2:21][NH:20]4)=[CH:17][CH:18]=3)[NH:9][C:8]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cc(Cl)cc3[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(Cl)cc2[nH]c(-c3ccc(C4CCCN4)cc3)nc12
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 44C (410 mg) in dichloromethane (20 mL) was treated with TFA (4 mL), stirred for 1 hour and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN; 0-100% gradient). 1H NMR (DMSO-d6) δ 2.04-2.20 (m, 3H), 2.41-2.52 (m, 2H), 3.33-3.46 (m, 2H), 4.65-4.71 (m, 1H), 7.72 (d, J=8.29 Hz, 2H), 7.81-7.84 (m, 1H), 7.95 (s, 1H), 8.34 (d, J=8.29 Hz, 2H), 8.94 (s, 1H), 9.14 (s, 1H), 9.73 (s, 1H).
Reaction SMILES: [CH:1]([S:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:27](Br)[C:28]#[CH:29]>O1CCCC1>[CH:1]([S:14][C:15]1[N:19]=[N:18][N:17]([CH2:29][C:28]#[CH:27])[N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCBr
Reactant: c1ccc(C(Sc2nnn[nH]2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCn1nnc(SC(c2ccccc2)c2ccccc2)n1
Reaction time: 2.5 h
Yield: 42.9 %

Procedure:
To a solution of 5-benzhydrylthio-1H-tetrazole (29 g) in tetrahydrofuran (145 ml) were added triethylamine (12.0 g) and 2-propynyl bromide (19.3 g) at room temperature. The resulting mixture was stirred for 2.5 hours at 40° to 45° C. The reaction mixture was filtered and the filtrate was evaporated. The residue was shaken with a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated. The residual oil (27.7 g) was subjected to column chromatography on silica gel, and eluted with a mixture of n-hexane, chloroform and ethyl acetate (5.5:4.5:0.5), to give 5-benzhydrylthio-2-(2-propynyl)-2H-tetrazole (14.2 g), mp 85° to 86° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[N:24]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[N+:25]=[N-:26]
Reactant: CS(=O)(=O)OCCCCCCCCCCCCCCCC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCCCCCCCCCC(=O)O
Temperature: 80 °C
Reaction time: 12 h
Yield: 85.2 %

Procedure:
To the suspension of 16-hydroxyhexadecanoic acid (0.7 g) in dichloromethane (20 ml) was added triethylamine (1.80 ml). Methanesulfonyl chloride (0.8 ml) was added dropwise to the reaction mixture while it was ice-cooled and stirred. Stirring was continued directly at 0° C. for 1 hour. The reaction mixture was extracted with chloroform, and the chloroform layer was washed with 1% aqueous sodium hydrogen carbonate and then with water, dried with anhydrous sodium sulfate and concentrated. The residue was subjected to chromatography on a silica gel column with an eluent system of chloroform-methanol (3:1) to give 16-methanesulfonyloxyhexadecanoic acid (0.74 g). To 16-methanesulfonyloxyhexadecanoic acid (325 mg) dissolved in N,N-dimethylformamide (DMF, 15 ml) was added sodium azide (268 mg), and the mixture was stirred at 80° C. for 12 hours. The reaction mixture, after having been cooled, was then distributed into ethyl acetate and water, and the ethyl acetate layer was dried over anhydrous sodium sulfate to give 16-azidohexadecanoic acid (235 mg). To the solution of 16-azidohexadecanoic acid (226 mg) in DMF were added N-hydroxysuccinimide (90 mg) and N,N'-dicyclohexylcarbodiimide (160 mg), and the mixture was stirred for 48 hours. The reaction mixture was filtered and concentrated to give the active ester of 16-azidohexadecanoic acid. To the active ester dissolved in DMF were further added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (310 mg) and triethylamine (1 ml), and the mixture was stirred for 24 hours. The solvent was removed by distillation, and the residue was subjected to chromatography on a silica gel column with an eluent system of chloroform-methanol (6:1) to give SPK226 in the yield of 92 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH:16]=O)=[CH:4][CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[CH2:16][N:28]2[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]2)=[CH:6][CH:7]=1
Reactant: CC1(C)CCC(C=O)=C(c2ccc(Cl)cc2)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)CCC(CN2CCN(C(=O)OC(C)(C)C)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
To a 2 L three neck RB flask provided with a mechanical stirrer were charged a solution of 4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbaldehyde (50.0 g) in toluene (250 mL), BOC-piperazine (48.2 g) and anhydrous THF (250 mL). The yellow solution was stirred at 20° C. for 5 min. Sodium triacetoxyborohydride (52.7 g) was added in portion (note: the internal temperature rose to ˜29.5° C. in 15 min cooling may be needed). The yellow mixture was stirred at ˜25° C. for NLT 4 hrs. A conversion of starting material to product of 99.5% was observed by HPLC after a 3 hour reaction time.
Reaction SMILES: C([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2C=CC=C[CH:13]=2)[CH:4]1[OH:18])C.C(N([CH2:24][CH3:25])CC)C.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:12]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:3]([C:25]1[CH:24]=[CH:5][CH:4]=[CH:3][CH:11]=1)[C:4]2=[O:18])[CH3:13]
Reactant: CCN(CC)CC
Reactant: CCC1Cc2c(-c3ccccc3)cccc2C1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCc1cccc2c1CC(c1ccccc1)C2=O
Temperature: 0 °C
Yield: 134.6 %

Procedure:
To a 1-liter four-necked round flask (equipped with a stirrer, a dropping funnel and a thermometer) were fed 29.3 g (123.9 mmol) of 2-ethyl-1-hydroxy-4-phenylindane, 51.6 g (371.4 mmol) of triethylamine, 0.75 g (6.3 mmol) of 4-dimethylaminopyridine and 294 ml of methylene chloride. Then, a solution obtained by dissolving 19.2 ml (247.5 mmol) of methanesulfonyl chloride in 19.5 ml of methylene chloride was dropwise added slowly to the system while cooling with ice in a nitrogen atmosphere. After the addition was completed, the resulting mixture was reacted for another 3.5 hours at the same temperature. The reaction mixture was poured in 500 ml of ice water, then the organic phase was separated, and the aqueous phase was further extracted twice with 150 ml of methylene chloride. The whole organic phase was successively washed with a saturated NaHCO3 solution and a saturated salt solution, and dried with anhydrous Na2SO4. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography (developed with hexane), to obtain 19.7 g of the aimed product (mixture of two kinds of isomers) as a light yellow liquid (yield: 73%)
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]1([NH2:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[C:20]=1[N+:26]([O-:28])=[O:27].[NH4+].[Cl-]>C1COCC1>[Cl:18][C:19]1[C:20]([N+:26]([O-:28])=[O:27])=[C:21]([NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1c(F)cccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(Cl)cccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
LiHMDS (1.0M in THF, 23 mL) was added to a stirred solution of phenylamine (1.12 g, 12.0 mmol) in THF (15 mL) at −78° C. under a nitrogen atmosphere. Stirring was continued for 30 min then 1-chloro-3-fluoro-2-nitrobenzene (1.92 g, 10.9 mmol) in THF (15 mL) was added. The reaction mixture was stirred at −78° C. for 30 min, then slowly warmed to RT and stirred at RT for 2 h. The reaction mixture was poured into a saturated solution of NH4Cl and then extracted with EtOAc (×2). The combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo affording (3-Chloro-2-nitrophenyl)phenylamine as a dark brown oil (2.85 g, quantitative). 1H NMR (CDCl3, 400 MHz): δ 7.41-7.25 (3H, m), 7.23-7.12 (5H, m), 6.96-6.91 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.[Li]CCCC.[I:32]I>C(OCC)C.C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][C:13]=1[I:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)nc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(C(F)(F)F)cc1I
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
A solution of (6-trifluoromethylpyridin-3-yl)carbamic acid tert-butyl ester (0.90 g, 3.43 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.29 mL, 8.55 mmol) in 25 mL of anhydrous diethyl ether was cooled to −78° C. under an argon atmosphere. The resulting mixture was treated dropwise with n-BuLi (2.5 M in hexanes, 3.42 mL, 8.55 mmol) over 5 minutes, and the mixture was allowed to warm to −10° C. After 30 minutes, the mixture was cooled to −78° C. and a solution of I2 (1.14 g, 4.5 mmol) in 5 mL of anhydrous THF was added rapidly. The resulting mixture was warmed to room temperature, stirred for 1 hour, and quenched with 50 mL of water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified on SiO2 (10% ethyl acetate in dichloromethane) to afford the title compound (150 mg, 11.3% yield).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@@H:9]([NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][O:25]3)=[CH:18][CH:17]=1)[CH2:8][CH2:7]2)[CH3:3].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.C(N(C(C)C)C(C)C)C>C(#N)C>[N:1]1([C@@H:2]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][C@@H:9]([NH:14][C:15](=[O:29])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][O:25]4)=[CH:18][CH:17]=2)[CH2:8][CH2:7]3)[CH3:3])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: BrCCCCCCBr
Reactant: C[C@@H](N)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2)N1CCCCCC1
Temperature: 40 °C

Procedure:
A mixture of N-[(S)-6-((R)-1-aminoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (50 mg), 1,6-dibromohexane (31 mg), ethyldiisopropylamine (0.10 ml) and acetonitrile (1 ml) was heated to 40° C. for 8 hours. The cooled reaction mixture was concentrated and the residue was purified by preparative HPLC. The product was thus obtained with the molecular weight of 476.66 (C30H40N2O3); MS (ESI): 477 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[CH3:20].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>>[CH3:28][O:27][C:25](=[O:26])[CH2:24][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[C:11]([CH3:20])[N:10]2[CH2:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)CBr
Reactant: Cc1cc2c(O)cccc2n1Cc1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1c(Cl)cccc1Cl
Yield: 38.8 %

Procedure:
Using the procedure described in Example 1, Part E, 1-[(2,6-dichlorophenyl)methyl]-4-hydroxy-2-methyl-1H-indole (862 mg, 2.8 mmol) was treated with 112 mg (2.8 mmol) of 60% NaH/mineral oil and then 0.27 mL (2.8 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 411 mg (39% yield) of [[1-[(2,6-dichlorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, mp, 168-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC1CCC(=O)N1)Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CCC(CCC(O)Cc2cccc(Cl)c2)N1
Yield: 79.9 %

Procedure:
Analogous to the procedure described for Compound 1A, Step B, 5-[4-(3-chloro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (1.9 g, 7.15 mmol) was reduced with NaBH4 (135 mg, 3.57 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2 to 8% MeOH in CH2Cl2) provided 5-[4-(3-chloro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (1.53 g). 1H NMR (CDCl3) δ 7.22 (m, 3H), 7.07 (m, 1H), 6.51 (d, 1H), 3.82 (m, 1H), 3.66 (m, 1H), 2.77 (m, 1H), 2.66 (m, 1H), 2.33-2.19 (m, 3H), 2.04 (d, 1H), 1.74-1.45 (m, 5H); MS 268.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([I:11])=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH3:18]>CN(C=O)C.O.C(#N)C.O>[F:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:15][CH2:16][O:17][CH3:18])[N:10]=[C:4]2[C:3]=1[I:11]
Reactant: COCCBr
Reactant: Fc1cnc2cn[nH]c2c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: COCCn1cc2ncc(F)c(I)c2n1
Reaction time: 1.5 h
Yield: 28.4 %

Procedure:
6-Fluoro-7-iodo-1H-pyrazolo[4,3-b]pyridine (150 mg, 0.570 mmol) was dissolved in DMF (5 mL) and sodium hydride (34.2 mg, 0.855 mmol) was added slowly, followed by 1-bromo-2-methoxyethane (0.080 ml, 0.855 mmol). After 90 minutes, the reaction was quenched with crushed ice and the reaction mixture was purified by preparative HPLC eluting with 20/80 (v/v) water/acetonitrile in 10 mmol NH4HCO3 in water on a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column) to give 6-fluoro-7-iodo-2-(2-methoxyethyl)-2H-pyrazolo[4,3-b]pyridine (52 mg, 28.4% yield) as white solid. MS [M+H] found 322.1
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=O.[CH3:23][NH:24][CH3:25].C([BH3-])#N.[Na+]>CO.O.[Cl-].[Zn+2].[Cl-]>[CH3:23][N:24]([CH2:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:25]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)CC1CCN(c2ccc(NC(=O)OC(C)(C)C)cc2)CC1
Reaction time: 0.33 h
Yield: 149.9 %

Procedure:
To a suspension of tert-butyl [4-(4-formyl-piperidin-1-yl)-phenyl]carbamate (0.20 g, 0.66 mmol) in methanol (5 mL) is added dimethylamine (2.0 M solution in tetrahydrofuran, 0.66 mL, 1.3 mmol). The reaction mixture is stirred for 20 minutes and then a mixture of zinc chloride (53 mg) and sodium cyanoborohydride (50 mg) in methanol (2 mL) is added in a dropwise fashion. After stirring overnight at room temperature, the reaction mixture is diluted with water and extracted 3× with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give tert-butyl [4-(4-dimethylaminomethyl-piperidin-1-yl)-phenyl]-carbamate as a white foam (0.33 g, >100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=CC=CC=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.OC1CCN(C(OC(C)(C)C)=O)C1>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][CH:3]3[CH2:4][CH2:9][NH:1][CH2:2]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: CC(C)(C)OC(=O)N1CCC(O)C1
Product: Clc1ccc2[nH]c3c(OC4CCNC4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is tert-butyl 3-hydroxypyrrolidine-1-carboxylate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.26 (br s, 2 H), 8.35 (s, 1 H), 8.06 (d, J=1.2 Hz, 2 H), 7.39-7.29 (m, 4 H), 5.11 (t, J=3.8 Hz, 1 H), 3.60-3.50 (m, 1 H), 3.34 (d, J=11.6 Hz, 1 H), 3.20 (td, J=10.2, 4.0 Hz, 1 H), 2.88 (dd, J=12.2, 3.2 Hz, 1 H), 2.40-2.30 (m, 1 H), 2.22-2.10 (m, 1 H); MS (ESI) m/z 408.1 (M−H)−; MS (ESI) m/z 410.0 (M+H)+
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:35]=[C:36]([CH:64]=[CH:65][CH:66]=1)[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([C@@H:56]([CH:61]([CH3:63])[CH3:62])[C:57]([O:59]C)=[O:58])[C:52]3=[O:55])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)=[O:38]>>[F:33][C:34]1[CH:35]=[C:36]([CH:64]=[CH:65][CH:66]=1)[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([C@@H:56]([CH:61]([CH3:63])[CH3:62])[C:57]([OH:59])=[O:58])[C:52]3=[O:55])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)=[O:38]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(F)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(F)c4)cc3)cc2C1=O
Yield: 84 %

Procedure:
The compound of example 106 was prepared analogous to compound of example 98 by hydrolysis of compound of example 105.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=3)[C:10]([CH3:20])=[N:9]2)=[CH:5][CH:4]=1.CCOC(C)=O>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[C:10]([CH3:20])=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2nc(C)c3cc([N+](=O)[O-])ccc32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Cn2nc(C)c3cc(N)ccc32)cc1
Reaction time: 0.5 h

Procedure:
1-(4-methoxybenzyl)-3-methyl-5-nitro-1H-indazole (275 mg, 0.93 mmol) from Step 1 of this example was dissolved in MeOH (4.6 ml) and EtOAc (10 ml) to give a clear yellow solution. Pd/C (10%, 98 mg) was added, the vessel evacuated and backfilled with hydrogen (3×) and slurry stirred under a hydrogen atmosphere for 30 minutes. The mixture was filtered through CELITE, the filter cake washed with EtOAc (2×40 ml), the filtrates combined and the volatiles removed in vacuum to give the titled compound.
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30]>O1CCCC1>[CH2:2]([C:3](=[CH:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[C:22]([N+:29]([O-:31])=[O:30])[CH:23]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:1]
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccc(OC)c([N+](=O)[O-])c1)CC
Yield: 93.3 %

Procedure:
Under an argon atmosphere, stirring and cooling with ice, a solution of triethyl 2-phosphonobutyrate (5.00 g, 19.8 mmol) in anhydrous tetrahydrofuran (30 mL) was added dropwise slowly to a solution of sodium hydride (60% oil dispersion, 795 mg, 19.9 mmol) in anhydrous tetrahydrofuran (120 mL). After stirring for 1 hour at 0° C., a solution of 4-methoxy-3-nitrobenzaldehyde (3.26 g, 18.0 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise, and the mixture was stirred for 1 hour at 0° C. and for 3 hours at room temperature. The reaction mixture was concentrated and ice water was added to the residue, which was extracted with ethyl acetate. The extracte was washed with water, brine and dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane:ethyl acetate=8:1→2:1 v/v) to obtain 4.69 g (93%) of ethyl 2-ethyl-3-(4-methoxy-3-nitrophenyl)acrylate as colorless crystals.