Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.Br[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 106.9 %

Procedure:
4-(3,4-Dichlorophenoxy)piperidine (10 g) was dissolved in N,N-dimethylformamide (DMF; 50 ml) and triethylamine (14.8 ml) was added. 1,1-Dimethylethyl (3-bromopropyl)-carbamate (10 g) was added and the solution was stirred at room temperature for 24 hrs. The solvent was evaporated and the resulting solid was dissolved in ethyl acetate and water was added, the organic phase was separated, dried with MgSO4 and evaporated to give the subtitle compound as a solid (17.51 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@@H:8]([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].O[N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:24]=[C:15]1[C:16]2[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:19])[N:14]1[O:10][CH2:9][C@@H:8]([NH:7][C:6](=[O:12])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:11]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CON1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
To a mixture of tert-butyl[(1S)-2-hydroxy-1-methylethyl]carbamate 57 (4.03 g, 23.0 mmol), N-hydroxyphthalimide (5.63 g, 34.5 mmol) and triphenylphosphine (9.05 g, 34.5 mmol) in anhydrous THF (172 mL) at 0° C. under nitrogen was added DIAD (6.69 mL, 34.5 mmol) in anhydrous THF (40 mL) over 15 minutes. The mixture was stirred at 0° C. for 30 min and at room temperature for 2.5 h. Solvent was evaporated off and the residue was subjected to chromatography to give a white solid 58 (7.38 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][C@H:6](/[CH:8]=[CH:9]/[C:10]2[N:11](C(C)C)[C:12](=[O:27])[C:13]3[C:18]([C:19]=2C2C=CC(F)=CC=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:5][C:4](=[O:31])[CH2:3]1>C(Cl)Cl>[CH:13]1([CH2:12][N:11]2[C:10](/[CH:9]=[CH:8]/[C@H:6]3[O:5][CH:4]([OH:31])[CH2:3][C@H:2]([OH:1])[CH2:7]3)=[C:19]([CH:2]([CH3:7])[CH3:3])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:27])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)n1c(/C=C/[C@H]2C[C@@H](O)CC(=O)O2)c(-c2ccc(F)cc2)c2ccccc2c1=O
Solvent: ClCCl
Product: CC(C)c1c(/C=C/[C@@H]2C[C@@H](O)CC(O)O2)n(CC2CCCCC2)c(=O)c2ccccc12

Procedure:
(4R,6R)-(E)-4-hydroxy-6-[2-(4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl)ethen-1-yl]-3,4,5,6-tetrahydro-2H-pyran-2-one, m.p.207°-209° C. [α]D =-54° (CH2Cl2 at 29° C.) Found: C,71.0; H,5.47; N,3.37%. Required: C,71.2; H,5.74; N,3.32%. [NMR in CDCl3, 1.16 (1H,m), 1.68 (6H,d,J=8 Hz), 1.88 (1H,m), 2.45 (1H,dd,J=17 Hz and J=8 Hz), 2.58 (1H,d,J=5 Hz), 2.90 (1H,m), 4.22 (1H,m), 4.63 (2H,m), 5.50 (1H,dd,J=16 Hz and J=6 Hz), 6.41 (1H,dd,J=16 Hz), 6.98-7.25 (5H,m), 7.49 (2H,m), 8.42 (1H,m)];
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1Cl>CN1C(=O)CCC1>[Br:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[O:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([NH:8][C@@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]3[OH:1])[S:10][C:11]=2[CH:17]=1
Reactant: Clc1ccncc1Br
Reactant: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Oc3ccncc3Br)cc2s1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To the reaction mixture of 2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (12.5 mg, 0.047 mmol) in 0.4 ml of NMP was added Cesium Carbonate (39 mg, 0.118 mmol) and stirred at RT for 1-3 minutes. To this mixture was added 3-bromo-4-chloropyridine (18.2 mg, 0.094 mmol). The reaction mixture was stirred at 90° C. for 4 hours or until done by LC. The crude reaction mixture was filtered, purified on prep HPLC and lyophilized to (1R,2R)-2-(6-(3-bromopyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol as TFA salt (9.2 mg). ES/MS m/z 420.1/422.0 (MH+).
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]1=2)[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH:20]1[C:29](=[O:30])[C:28]2[NH:27][CH:26]=[N:25][C:24]=2[N:23]=[C:21]1[NH2:22]>CO.O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:18]=[N:17][C:16]3[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]2=3)[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:22]1[C:21]1[NH:20][C:29](=[O:30])[C:28]2[NH:27][CH:26]=[N:25][C:24]=2[N:23]=1
Reactant: O=CC(CO)OC(C=O)n1cnc2c(=O)[nH]cnc21
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Solvent: CO
Solvent: O
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@H](CO)C(O)N(c2nc3nc[nH]c3c(=O)[nH]2)C1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 105.5 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde, (inosinedialdehyde), (1.33 g) was dissolved in a mixture of methanol (300 ml) and water (300 ml). To the solution was added guanine (0.76 g). The mixture was stirred at ambient temperature for three days and filtered. The filtrate was evaporated in vacuo at 35° C. The residue was triturated with acetone to give 9-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-hypoxanthinyl)morpholin-2-yl]hypoxanthine (2.20 g).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:21]=[C:20]2[C:11]([CH2:12][C:13]3([C:19]2=[O:22])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].N#N>C(Cl)Cl.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.O.O1CCOCC1>[O:22]=[C:19]1[C:13]2([CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:12][C:11]2[C:20]1=[CH:21][C:8]([C:29]1[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=1)[C:23]#[N:24])=[CH:9][CH:10]=2
Reactant: O=C1c2cc(Br)ccc2CC12CCOCC2
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCOCC2)C3)c1
Temperature: 100 °C
Yield: 38.9 %

Procedure:
To a 10 mL CEM microwave test tube was charged with Cs2CO3 (232 mg, 0.712 mmol), PdCl2(PPh3)2 (20 mg, 0.028 mmol), 6-bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-1(3H)-one (100 mg, 0.356 mmol), 3-cyanophenylboronic acid (78 mg, 0.534 mmol), dioxane (4 mL) and H2O (0.4 mL), the system was swept with N2 and capped, and heated in a CEM microwave reactor at 100° C. for 10 min. The reaction mixture was diluted with DCM, washed with brine, dried over anhydrous Na2SO4, and filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with EA in hexane (0-30%) to give 42 mg of 3-(1-oxo-1,2′,3,3′,5′,6′-hexahydrospiro[indene-2,4′-pyran]-6-yl)benzonitrile. MS ESI+ve m/z 304 (M+H)30.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[H-].[Na+].[CH2:27](Br)[CH2:28][CH3:29].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:27][CH2:28][CH3:29])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CCCBr
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4.94 g (15 mmol) of N-benzyloxycarbonyl-tyrosine-methyl ester is dissolved in 25 ml of anhydrous N,N-dimethylformamide and mixed at 5° C. under argon with 0.61 g (15.5 mmol) of sodium hydride dispersion (60% in mineral oil). The batch is allowed to stir for 10 minutes, then 1.91 g (15.5 mmol) of propyl bromide is added, the reaction temperature is allowed to increase to room temperature and it is stirred for another two hours. For working-up, the batch is taken up in ethyl acetate and shaken out several times against aqueous sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate, filtered and concentrated by evaporation. The residue is chromatographed for purification on silica gel with hexane/diethyl ether/triethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[OH-:11].[Na+]>CN(C)C=O.CCOCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:11][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(COCc2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 93 %

Procedure:
Sordaricin benzyl ester (161.2 mg) was dissolved in 6 mL of N,N-dimethylformamide and p-methoxybenzyl chloride (1 mL) was added followed by excess sodium hydroxide (50 mg of a 60% dispersion in mineral oil). The mixture was stirred overnight. The mixture was diluted with ether and carefully washed with water. The ether layer was dried over anhydrous sodium sulfate and the volatiles removed in vacuo. The residue was purified by silica gel chromatography to give 192.5 mg (93%) of the p-methoxybenzyl ether.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]([NH2:25])[CH3:24])[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]([NH:25][C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[CH3:24])[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Reactant: CC(N)c1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Yield: 0 %

Procedure:
2,2,2-Trifluoro-1-(2,4-difluorophenyl)ethanone (0.66 g, 3.13 mmol), 1-(3,5-dichlorophenyl)ethanamine (0.59 g, 3.13 mmol) and N,N-diisopropylethylamine (0.81 g, 6.3 mmol) were stirred at 45° C. in dry acetonitrile (25 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (0.11 mg, 9% yield). 1H NMR (400 MHz, CDCl3): δ 9.23 (s, 1H), 7.87 (t, 1H), 7.28 (s, 1H), 7.19 (s, 2H), 6.41 (t, 1H), 6.11 (d, 1H), 4.51 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: [OH:1][C:2]1[C:28]([O:29][CH3:30])=[CH:27][C:5]2[NH:6][C:7](=[O:26])[C:8]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=4)=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[CH3:30][O:29][C:28]1[C:2]([O:1][CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[CH:3][C:4]2[NH:10][C:9]3[CH:11]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=4)[CH:13]=[CH:14][C:8]=3[C:7](=[O:26])[NH:6][C:5]=2[CH:27]=1
Reactant: BrCC1CCCCO1
Reactant: COc1cc2c(cc1O)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCC1CCCCO1)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A mixture of Example 476I (40 mg, 0.098 mmol), 2-bromomethyl-tetrahydro-2H-pyran (0.13 mL, 0.98 mmol), K2CO3 (136 mg, 0.98 mmol) and DMF (2 mL) was heated at 100° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel with 49:1 dichloromethane/methanol to provide 23 mg (47%) of the desired product. MS (ESI) m/e 506 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 9.66 (s, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.35 (dd, J=1.7, 8.5 Hz, 1H), 7.26-7.31 (m, 2H), 6.69 (s, 1H), 6.64 (s, 1H), 4.03 (s, 3H), 3.72-3.94 (m, 3H), 3.67 (s, 3H), 3.60 (m, 1H), 3.39 (m, 1H), 1.82 (m, 1H), 1.64 (m, 1H), 1.41-1.55 (m, 3H), 1.27 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.F[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][N:2]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: CN[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc(S(C)(=O)=O)cc1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (R)—N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (100 mg, 0.287 mmol) and 1-fluoro-4-(methylsulfonyl)benzene (150 mg, 0.861 mmol) and K2CO3 (158 mg, 1.142 mmol) in DMF (2 mL) was stirred at 120° C. overnight and then cooled to ambient temperature, poured into water, and extracted with EtOAc. The EtOAc layer was concentrated, purified by preparative TLC to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[N+:11]([O-])[C:10]([CH3:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-].[Cl:23]C1C=CC(B(O)O)=CC=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O.CCO>[Cl:23][C:4]1[CH:5]=[CH:6][C:1]([C:7]2[CH:8]=[CH:9][C:10]([CH3:14])=[N:11][CH:12]=2)=[CH:2][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1ccc(-c2ccccc2)c[n+]1[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 25 °C

Procedure:
The trifluoromethane sulfonate from Step 1 (500 mg) was dissolved in 10 mL of toluene, 5 mL of EtOH, and 1.6 mL of 2M aqueous Na2CO3. Then 203 mg LiCl, 411 mg of 4-chlorobenzeneboronic acid (Lancaster) and 832 mg of tetrakis (triphenylphosphine) palladium were added successively. The resulting reaction mixture was heated up to 90°-95° C. for 1 hour. The reaction mixture was cooled down to room temperature, EtOAc was added and the organic phase was washed with 1N NaOH, brine, dried over MgSO4, filtered and concentrated. Purification by flash chromatography using hexane:EtOAc 3:2 gave the title compound.
Reaction SMILES: O.Cl.[CH:3]1([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.[OH-].[NH4+]>[Fe].C(O)C>[CH:3]1([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=[N+]([O-])c1ccccc1OC1CCCC1
Agent: [Fe]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1OC1CCCC1
Yield: 63.3 %

Procedure:
Iron 60 mesh (51.9 g, 0.93 mole), water (220 cc), ethanol (244 cc) and concentrated hydrochloric acid (14.2 cc) were heated to reflux under a nitrogen blanket. Then 2-cyclopentoxynitrobenzene (55.2 g, 0.27 mole) was added at reflux over a period of 2 hours. The reaction was maintained at reflux for an additional 3 hours. The pH was adjusted to 7-8 by the addition of concentrated ammonium hydroxide. The reaction mixture then was filtered at 30° C., and the filtrate was washed with 200 cc of ether. The filtrate was extracted with 4×50 cc of ether and the combined ether extracts were subjected to rotary evaporation. The crude product was fractionally distilled at 126°-130° C. at 2.0-2.5 mm. Hg to yield 30.3 g (64.3%) of product.
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[CH:10]([CH2:20][Cl:21])[CH2:9]1)=[O:7])(C)(C)C.Cl.CN(C)CCCN=C=NCC.C([C:37]1[NH:38][C:39]2[C:44]([CH:45]=1)=[CH:43][CH:42]=[C:41]([C:46]([NH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1)=[O:47])[CH:40]=2)(O)=O>Cl.CN(C=O)C>[Cl:21][CH2:20][CH:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[N:8]([C:6]([C:37]2[NH:38][C:39]3[C:44]([CH:45]=2)=[CH:43][CH:42]=[C:41]([C:46]([NH:48][CH2:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[O:47])[CH:40]=3)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2ccc([N+](=O)[O-])cc21
Reactant: O=C(NCCc1ccccn1)c1ccc2cc(C(=O)O)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccn1)c1ccc2cc(C(=O)N3CC(CCl)c4ccc([N+](=O)[O-])cc43)[nH]c2c1
Temperature: 20 °C
Yield: 67.1 %

Procedure:
1-(t-Butoxycarbonyl)-3-(chloromethyl)-6-nitroindoline (248 mg, 0.79 mmol) was stirred in HCl-saturated dioxane (8 mL) at 20° C. for 40 min (until tlc indicated complete reaction) and the mixture evaporated. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.30 g, 1.58 mmol) and 2-carboxy-N-[2-(2-pyridinyl)ethyl]indole-6-carboxamide (245 mg, 0.79 mmol) in DMF (20 mL) were added and the orange solution stirred at 20° C. After 24 h the DMF was evaporated, and the residue triturated with EtOAc and aqueous NaHCO3. The solid was filtered off and recrystallised from MeOH to give 2-[[3-(chloromethyl)-6-nitroindolin-1-yl]carbonyl]-N-[2-(2-pyridinyl)ethyl]indole-6-carboxamide as a yellow solid (267 mg, 67%), mp 204-207° C. 1H NMR [(CD3)2SO] δ12.15 (s, 1H, indole NH), 8.99 (d, J=2.1 Hz, 1H, H-7), 8.61 (t, J=5.5 Hz, 1H, amide NH), 8.55-8.52 (m, 1H, H-6"), 8.04 (dd, J=8.3, 2.3 Hz, 1H, H-5), 8.02 (s, 1H, H-3' or H-7'), 7.75 (d, J=8.6 Hz, 1H, H-4 or H-4'), 7.74 (d, J=8.3 Hz, 1H, H-4 or H-4'), 7.71 (dd, J=7.6, 1.9 Hz, 1H, H-4"), 7.56 (dd, J=8.5, 1.3 Hz, 1H, H-5'), 7.31 (d, J=7.7 Hz, 1H, H-3"), 7.28 (d, J=1.4 Hz, 1H, H-3' or H-7'), 7.23 (ddd, J=7.2, 4.9, 0.8 Hz, 1H, H-5"), 4.86 (t, J=10.1 Hz, 1H, H-2), 4.51 (dd, J=10.7, 5.1 Hz, 1H, H-2), 4.19-4.06 (m, 3H, H-3 and CH2Cl), 3.66 (q, J=6.7 Hz, 2H, NHCH2CH2 py), 3.04 (t, J=7.4 Hz, 2H, NHCH2CH2 py); 13C NMR δ166.7 (CONH), 160.4 (CON), 159.2 (C-2"), 147.6, 144.6, 139.9, 135.7, 131.8, 130.8, 128.9 (C-6,8,9,2',6',8',9'), 149.0, 136.4, 123.1, 121.4 (C-3",4",5",6"), 125.5, 121.6, 119.4, 118.8, 112.0, 111.2, 106.1 (C-4,5,7,3',4',5',7'), 54.0 (C-2), 47.0 (CH2Cl), 42.0 (C-3), 39.3, 37.3 (NHCH2CH2 py). A sample was converted to the hydrochloride salt and triturated with hot EtOH to give 2-[[3-(chloromethyl)-6-nitroindolin-1-yl) carbonyl]-N-[2-(2-pyridinyl)ethyl]indole-6-carboxamide hydrochloride as a pale yellow powder, mp 250-255° C. (dec.). Anal. (C26H22ClN5O4.0.25HCl) C,H,N.
Reaction SMILES: FC1C=CC(S(N)(=O)=O)=CC=1[N+]([O-])=O.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20].F[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][C:24]=1[S:33]([C:36]([F:39])([F:38])[F:37])(=[O:35])=[O:34]>>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH:20][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][C:24]=1[S:33]([C:36]([F:37])([F:39])[F:38])(=[O:35])=[O:34]
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CN(C)CCCN
Agent: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Product: CN(C)CCCNc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F

Procedure:
The title compound was prepared by following the procedure described in Example 10C, replacing Example 10B and 4-fluoro-3-nitrobenzenesulfonamide with N′,N′-dimethylpropane-1,3-diamine and 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide, respectively.
Reaction SMILES: C(O)(=O)C.[CH3:5][C@H:6]1[CH2:11][NH:10][C@H:9]([CH3:12])[CH2:8][N:7]1[C@@H:13]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:5][C@H:6]1[CH2:11][N:10]([CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([F:34])[CH:36]=2)[C@H:9]([CH3:12])[CH2:8][N:7]1[C@@H:13]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)[C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: O=Cc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3cccc(F)c3)C[C@@H]2C)cc1
Yield: 70.7 %

Procedure:
Glacial acetic acid (0.635 mL, 11.1 mmol) was added to a solution of 4-[(R)-((2S,5R)-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (1.98 g, 5 mmol) and 3-fluorobenzaldehyde (1.24 g, 10 mmol) in anhydrous tetrahydrofuran (35 mL). While stirring briskly, sodium triacetoxyborohydride (2.12 g, 10 mmol) was added in 50-100 mg portions, allowing effervescence to subside after each addition. The reaction was monitored for absence of starting material by HPLC. After stirring at room temperature for 16 hours, additional 3-fluorobenzaldehyde (0.62 g, 5 mmol), acetic acid (0.318 mL, 5 mmol), and sodium triacetoxyborohydride (1.06 g, 5 mmol) were added. After stirring an additional 4 hours, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (50 mL) and 3 M hydrochloric acid (25 mL). The layers were separated and the organic layer was extracted again with 3 M hydrochloric acid (25 mL). The aqueous solution was adjusted to pH 9-10 with 5 M sodium hydroxide solution, resulting in the formation of chunky white precipitate. Brief sonication followed by continuous stirring for 60 hours allowed hydrolysis of any residual ethyl acetate, as well as complete precipitation of product. The white solid was filtered, washed with cold water, and further dried under reduced pressure to yield 4-[(R)-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)(3-hydroxyphenyl)-methyl]-N,N-diethylbenzamide (1.78 g, 82.3% yield from 4-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenl)-methyl]-N,N-diethyl-benzamide). The product showed a single peak on HPLC (Zorbax C-8, isocratic 40% 0.01 M NH4OAc in MeOH, 3 min; linear gradient to 100% MeOH, 45 min; isocratic MeOH, 25 min; 1.0 mL/min; δobs=210 nm, Rt=43.51 min). Calc. for C31H38FN3O2.0.5H2O: % C, 72.63; H, 7.67; N, 8.20; F, 3.71. Found: % C, 72.77; H, 7.52; N, 8.18; F, 3.61.