Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C@H:3]1[C:9]([OH:11])=O.[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH2:20])=[N:17][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>C(Cl)Cl.CO>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH:20][C:9]([C@@H:3]2[CH2:4][C:5]([CH3:7])([CH3:8])[CH2:6][N:2]2[CH3:1])=[O:11])=[N:17][CH:18]=1
Reactant: CN1CC(C)(C)C[C@H]1C(=O)O
Reactant: NNc1ccc(F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(C)(C)C[C@H]1C(=O)NNc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of Intermediate 87a (1.70 g, 5.00 mmol), (5-fluoro-pyridin-2-yl)-hydrazine (600 mg, 5.00 mmol) and DIPEA (1.29 g, 10.0 mmol) in DCM was added HATU (2.28 g, 6.00 mmol) and the mixture stirred at RT for 1 h. The reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as a yellow oil (950 mg, 71%). 1H NMR (400 MHz, CDCl3): 1.13 (3H, s), 1.15 (3H, s), 1.74 (1H, dd, J 12.5, 6.2), 2.12 (1H, dd, J 11.6, 10.0), 2.29 (1H, d, J 8.9), 2.46 (3H, s), 2.88 (1H, d, J 8.9), 3.15 (1H, dd, J 9.7, 6.5), 6.56-6.65 (2H, m), 7.28 (1H dt, J 8.6, 2.9), 8.03 (1H, d, J 2.5), 9.09 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11](=[O:12])[CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][NH:18]2)[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CC(CC(=O)C1NCCc2ccccc21)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (10 g, Example 1, Step C) in CH2Cl2 (300 mL) at 0° C. was treated sequentially with 1,2,3,4-tetrahydroisoquinoline (6.0 mL), triethylamine (6.7 mL) and N,N-dimethylaminopyridine (472 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 (500 mL) and washed with 1N HCl (1×200 mL) and water (1×200 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (14 g).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)[C:9]#[C:10][CH3:11].[NH2:22][CH2:23][C:24]([N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26]>O1CCCC1>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][N:33]([C:24]([CH2:23][NH:22][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([O:12][CH2:8][C:9]#[C:10][CH3:11])=[CH:14][CH:15]=2)([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH2:34][CH2:35]1)=[O:40])([CH3:44])([CH3:45])[CH3:43]
Reactant: CC#CCOc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C(CN)(C(=O)OC)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(C(=O)NCC(C(=O)OC)(C(=O)OC)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
2 ml (14.2 mmol) of triethylamine then 2.9 g (14.2 mmol) of 4-but-2-ynyloxybenzoyl chloride diluted in 30 ml of tetrahydrofuran are added to a solution of 4 g (11.6 mmol) of dimethyl 2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate (prepared as described in example 1-3) in 40 ml of tetrahydrofuran. The reaction medium is stirred at ambient temperature for 1 h, then hydrolysed and the product is extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. The crude product obtained is purified by chromatography over silica gel eluted with a 5/5 heptane/ethyl acetate mixture. 4.2 g (70%) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzoylamino)methyl]malonate are obtained in the form of a beige solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15](=[O:25])[C:16]1C=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1O.Cl>N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:15](=[O:25])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][C:5]=2[O:4][C:2]1=[O:3]
Reactant: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(O)c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(=O)n(-c3ccc(F)cc3F)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl chloroformate (0.1 mL, 1.2 mmole) was added dropwise to a stirred solution of compound 4a (0.28 g, 1 mmole) in dry pyridine (8 mL) at 0° C. The mixture was refluxed for 2 hr. After 16 hr stirring at room temperature, the pH of the reaction mixture was adjusted to pH=6 from 1 M HCl(aq). The resulting white mixture was cooled to obtain solid compound. The product was filtered off and recrystallized from hot ethanol. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][C@H:3]1[CH:14]=[CH2:15].[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH3:1][C:2]([CH3:16])([C@@H:3]([O:4][CH2:5][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:14]=[CH2:15])[CH2:7][OH:6]
Reactant: C=C[C@@H]1OC(c2ccccc2)OCC1(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: C=C[C@H](OCc1ccccc1)C(C)(C)CO
Yield: 87.7 %

Procedure:
Following the general procedure for the reductive ring opening of benzylidene-type acetals of 1,3-diols of Description 9, 9.5 g (43.5 mmol) of (4S)-5,5-dimethyl-2-phenyl-4-vinyl-1,3-dioxane (7c) was reacted with 25.0 mL (19.9 g, 140.0 mmol) of diisobutylaluminum hydride [(iBu)2AlH, DIBAL(H)] in 150 mL of anhydrous dichloromethane (DCM). After acidic aqueous work-up, the crude material was purified by silica gel column using mixtures of methyl tert-butyl ether (MTBE) and hexane (Hxn) as eluent (MTBE/Hxn=1:9→MTBE/Hxn=1:6→MTBE/Hxn=1:3) to provide 8.4 g (88% yield) of the title compound (7) as a colorless liquid. Rf=0.45 (Et2O/Hxn=1:1). 1H NMR (400 MHz, CHCl3): δ=0.91 (s, 3H), 0.92 (s, 3H), 2.82 (t, J=5.9 Hz, 1H), 3.38 (dd, J=10.8, 6.0 Hz, 1H), 3.55 (dd, J=10.8, 6.0 Hz, 1H), 3.64 (d, J=8.0 Hz, 1H), 4.31 (d, J=12.0 Hz, 1H), 4.62 (d, J=11.6 Hz, 1H), 5.22-5.28 (m, 1H), 5.36-5.40 (m, 1H), 5.81 (ddd, J=17.2, 10.4, 8.4 Hz, 1H), 7.27-7.38 (m, 5H) ppm. MS (ESI) m/z: 221.1 (M+H)+, 243.1 (M+Na)+. The analytical data for the compound was consistent with the proposed structure and the data given in the literature (Ito et al., Synthesis 1993, 137-140; and Mandel et al., Org. Lett. 2004, 6(26), 4801-4803).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[H-].[Na+].[CH2:13](I)[CH3:14]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:13][CH3:14])=[C:4]([F:10])[CH:3]=1
Reactant: CCI
Reactant: Oc1c(F)cc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1c(F)cc(Br)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A solution of 4-bromo-2,6-difluorophenol (1.04 g) in dry N,N-dimethylformamide (10 cm3) was added over 5 minutes to a well stirred mixture of sodium hydride (0.24 g of a 50% dispersion in oil) in dry N,N-dimethylformamide (5 cm3). After 30 minutes, ethyl iodide (0.78 g) was added in one portion. After stirring the reaction mixture for 30 minutes, analysis by gas liquid chromatography appeared to show no reaction; further ethyl iodide (5 g) was therefore added, and the reaction mixture was heated at 80° C. for 15 minutes. Later analysis showed similar retention times for both starting material and product, and the reaction may already have been complete prior to the second addition of ethyl iodide. The reaction mixture was washed, poured into water, and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate and evaporated under reduced pressure to give a red oil. The oil was purified by column chromatography on a silica gel support, eluting with an 8:1 parts by volume mixture of n-hexane and ethyl acetate to give 4-bromo-2,6-difluorophenetole as a colourless oil (1.02 g).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:38])=[N:13][C:14]2[CH2:15][CH2:16][N:17]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O.CCOC(C)=O>[CH2:31]([O:30][C:28]([N:17]1[CH2:16][CH2:15][C:14]2[N:13]=[C:12]([CH3:38])[C:11]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[C:19]=2[CH2:18]1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(C(=O)OCc1ccccc1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(-c2c3c(nc(C)c2C(OC(C)(C)C)C(=O)O)CCN(C(=O)OCc2ccccc2)C3)cc1
Yield: 85.4 %

Procedure:
A solution of benzyl 3-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (intermediate 14) (25 mg, 0.048 mmol) in MeOH (1.5 mL) with 1N NaOH (0.48 mL) was stirred at 65° C. for 1 h then at room temperature overnight. The mixture was diluted with water and EtOAc, then neutralized with 1N HCl (0.48 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC (10% MeOH/90% H2O/0.1% CF3CO2H, Phenomenex-LUNA 21.1×100 mm, C18, 5 μm column). The product-containing fractions were combined and MeOH removed and the remaining aqueous solution lyophilized to provide 2-(6-((benzyloxy)carbonyl)-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetic acid (20.6 mg, 81% yield) as a white powder. 1H NMR (400 MHz, CDCl3) δ ppm 7.29-7.59 (m, 8H), 7.05 (br. s., 1H), 5.13 (br. s., 2H), 5.03 (s, 1H), 4.44 (d, J=18.10 Hz, 1H), 4.13 (d, J=18.10 Hz, 1H), 3.22-3.47 (m, 2H), 2.85 (s, 3H), 2.48 (s, 3H), 1.01 (s, 9H). LCMS (M+H) calcd for C30H35N2O5: 503.25. found: 503.1.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC.C([O-])(O)=O.[Na+]>[O:1]=[C:2]1[CH2:3][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:5]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(O)C4)c3)ncnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(=O)C4)c3)ncnc21
Reaction time: 2 h

Procedure:
To a solution of {3-hydroxy-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile (1.62 g, 3.82 mmol) in DCM (50 mL) at 0° C. was added Dess-Martin periodinane (2.1 g, 5.0 mmol). After stirring for 2 hours, the reaction solution was diluted with ether and saturated NaHCO3 solution. The aqueous layer was extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over sodium sulfate, decanted and evaporated. The crude was used in the next step without purification. LCMS (M+H)+: 423.2.
Reaction SMILES: [CH:1]1C=CC=CC=1.[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9].[CH3:13][C@H:14]([NH2:23])[C@H:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C=O>O>[CH3:12][O:11][C:7](=[O:10])[CH2:8][CH2:9][N:23]1[CH:14]([CH3:13])[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:22][CH2:1]1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: C=CC(=O)OC
Reactant: c1ccccc1
Agent: C=O
Solvent: O
Product: COC(=O)CCN1COC(c2ccccc2)C1C

Procedure:
200 ml. of benzene, 43 g. (0.5 moles) of methyl acrylate and 76 g. of l-norephedrine are added to a 500 ml. three neck flask and refluxed overnight. To the solution is slowly added 15 g. (0.5 moles) of paraformaldehyde and the water removed using a dean-stark head. Concentrate the solution in vacuo on a steam bath and distill. The product boils at 137°-139° C./0.5 mm. The yield is 62 g.; n24 d=1.5155.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:39][S:40]([NH:43][C:44]1[CH:45]=[CH:46][C:47]2[O:52][CH2:51][CH:50]([CH2:53][NH2:54])[O:49][C:48]=2[CH:55]=1)(=[O:42])=[O:41]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][NH:54][CH2:53][CH:50]1[CH2:51][O:52][C:47]2[CH:46]=[CH:45][C:44]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:55][C:48]=2[O:49]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CN)CO2
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2[nH]cc(CCCCNCC3COc4ccc(NS(C)(=O)=O)cc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
5-Methoxyindole-3-butyric acid (0.75 g, 3.2 mmole), 1-hydroxybenzotriazole hydrate (0.52 g, 3.8 mmole) and 1,3-diisopropylcarbodiimide (1.2 ml, 7.6 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methylsulfonylamino-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (0.9 g, 3.2 mmole) in 50 ml of DMF and the mixture was further stirred for 48 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using first ethyl acetate and then 2.5% methanol in ethyl acetate as eluants. Fractions were concentrated and washed with a minimum amount of THF to remove a byproduct and to give 1.2 g (79%) of the desired product, (7-methylsulfonyl amino-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-methoxy-1H-indol-3-yl)-butanamide, as a oily white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:14]4[CH2:15][NH:16][CH2:17][CH2:18][C:13]=4[NH:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:19](O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:14]4[CH2:15][NH:16][CH2:17][CH:18]([CH3:19])[C:13]=4[NH:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1[nH]c3c(c12)CNCC3
Reactant: O=CO
Product: CC1CNCc2c1[nH]c1cnc3cc(Cl)ccc3c21
Temperature: 90 °C

Procedure:
A mixture prepared from 3.7 g of 3-chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline, 0.45 g of paraformaladehyde and 100 ml of formic acid was heated at 90° C. for one hour. The reaction was quenched with water and the solution was made alkaline (pH9) with a sodium hydroxide solution. The crystalline product was filtered, washed with water and purified by HPLC using dichloromethane/methanol=8:2 as an eluent. Clean fractions were combined and concentrated, and the crystalline residue was stirred in isopropanol and filtered. The yield was 2.1 g, mp=286°-287° C.
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.[CH2:22]([O:26][C:27]([CH2:29][NH:30][C:31]([C:33]1[CH:41]=[C:40]2[C:36]([CH:37]=[C:38](C(O)=O)[NH:39]2)=[CH:35][CH:34]=1)=[O:32])=[O:28])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([O:26][C:27]([CH2:29][NH:30][C:31]([C:33]1[CH:41]=[C:40]2[C:36]([CH:37]=[C:38]([C:6]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=4)[CH:10]([CH2:20][Cl:21])[CH2:9]3)=[O:7])[NH:39]2)=[CH:35][CH:34]=1)=[O:32])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOC(=O)CNC(=O)c1ccc2cc(C(=O)O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2ccc([N+](=O)[O-])cc21
Product: CCCCOC(=O)CNC(=O)c1ccc2cc(C(=O)N3CC(CCl)c4ccc([N+](=O)[O-])cc43)[nH]c2c1
Yield: 69 %

Procedure:
1-(t-Butoxycarbonyl)-3-(chloromethyl)-6-nitroindoline was coupled with N-[(butoxycarbonyl)methyl]-2-carboxyindole-6-carboxamide by the method described above and the product recrystallised from EtOAc to give with N-[(butoxycarbonyl)methyl]-2-[[3-(chloromethyl)-6-nitroindolin-1-yl)carbonyl]indole-6-carboxamide as a yellow solid (69%), mp 286° C. (dec.). 1H NMR [(CD3)2SO] δ12.20 (d, J=1.5 Hz, 1H, indole NH), 8.99 (d, J=2.2 Hz, 1H, H-7), 8.50 (t, J=6.0 Hz, 1H, amide NH), 8.06 (s, 1H, H-3' or H-7'), 8.05 (dd, J=8.2, 2.2 Hz, 1H, H-5), 7.78 (d, J=8.5 Hz, 1H, H-4'), 7.75 (d, J=8.2 Hz, 1H, H-4), 7.60 (dd, J=8.5, 1.4 Hz, 1H, H-5'), 7.30 (d, J=1.6 Hz, 1H, H-3' or H-7'), 4.87 (t, J=10.1 Hz, 1H, H-2), 4.51 (dd, J=10.7, 5.2 Hz, 1H, H-2), 4.19-4.08 (m, 3H, H-3 and CH2Cl), 3.92 (d, J=5.9 Hz, 2H, CONHCH2), 1.44 (s, 9H, t-Bu); 13C NMR δ169.1 (CO2 tBu), 167.1 (CONH), 160.4 (CON), 147.6, 144.6, 140.0, 135.7, 132.0, 130.0, 129.2 (C-6,8,9,2',6',8',9'), 125.5, 121.7, 119.4, 118.9, 112.2, 111.2, 106.1 (C-4,5,7,3',4',5',7'), 80.5 (OCMe3), 54.0 (C-2), 47.0 (CH2Cl), 42.0 (C-3), 41.9 (CH2CO2 tBu), 27.7 (t-Bu). Anal. (C25H25ClN4O6) C, H, N.
Reaction SMILES: CO.II.OC1C=CC=CC=1CC1(NCC2C=CC=CC=2)CCCCC1.[C:27]([C:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=1[NH:41]CC1C=CC=CC=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[Pd].C(Cl)Cl>[OH:34][CH:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[NH2:41]
Reactant: O=C(C1=C(NCc2ccccc2)CCCC1)c1ccccc1
Agent: [Pd]
Agent: II
Agent: Oc1ccccc1CC1(NCc2ccccc2)CCCCC1
Solvent: CO
Solvent: ClCCl
Product: NC1CCCCC1C(O)c1ccccc1

Procedure:
A 17.9 kg lot of N-[2-(benzoyl)-cyclohexen-1-yl]benzylamine in ethanol solution from Step B above, was hydrogenated at 100 psig over 10% palladium on carbon (1800 g) in a 20 or 30 gallon autoclave. The reduction required 18 days for completion. The hydrogenation reaction was monitored periodically by thin layer chromatography (tlc) analyses using alumina GF plates (Analtech) and 5% methanol in methylene chloride. The plates were visualized with iodine. The reduction proceeds through the intermediate N-[[2(hydroxy)phenylmethyl]cyclohexyl]benzylamine which was evident by the tlc methods.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>C(Cl)Cl>[O:23]([C:21]([O:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: OCCSc1cccc2nccn12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCSc1cccc2nccn12)Oc1ccccc1
Yield: 91.3 %

Procedure:
To a solution of 5-[2-(hydroxy)ethylthio]imidazo[1,2-a]pyridine (5.83 g, 30 mmoles) and pyridine (4.36 ml, 60 mmoles) in methylene chloride (120 ml) was added phenyl chloroformate (7.53 ml, 60 mmoles) with stirring under ice-cooling and the mixture was stirred under ice-cooling for 30 minutes. The reaction solution was washed in turn with an aqueous 5% sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 8.61 g of the desired product (91.3%, oily product).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH2:15])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].[CH3:23][O:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1)=[O:26].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.O>[F:2][C:3]1[CH:4]=[C:5]([C@H:14]([NH:15][C:33]([C:30]2[CH:29]=[CH:28][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:32][N:31]=2)=[O:34])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (17.0 g, 49.9 mmol, Intermediate 6) in DMF (166 mL, Aldrich) was added 5-(methoxycarbonyl)pyridine-2-carboxylic acid (9.94 g, 54.9 mmol, Oakwood Products, Inc.), HATU (20.87 g, 54.9 mmol, Accela ChemBio, Inc.), and DIPEA (18.23 mL, 105 mmol, EMD Biosciences, Inc.). The resulting mixture was then stirred at room temperature for 18 h. Water (400 mL) was then added and the mixture was extracted with EtOAc (2×200 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was then dissolved in MeOH (500 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The solid mixture was purified by silica gel flash column chromatography using ISCO instrument (solid loading, 0-100% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 468 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=1[N:33]=[C:34]=[S:35]>CN(C=O)C>[CH3:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[C:27]=1[NH:33][C:34]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1)=[S:35]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(NC(=S)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
A solution of 4-amino-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (150 mg) in DMF (4.5 ml) was added to sodium hydride (60% dispersion in mineral oil, 0.03 g) and the reaction mixture was stirred at ambient temperature for 20 minutes. 2,6-Dimethylphenyl isothiocyanate (0.162 g) was added and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was evaporated and the residual solid-was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 2M solution of ammonia in methanol as eluent. There was thus obtained the title compound (0.112 g); NM Spectrum: (CDCl3) 1.44-1.61 (m, 2H), 1.87-2.08 (m, 5H), 2.32 (s, 3H), 2.36 (s, 6H), 2.94 (d, 2H), 4.04 (m, 5H), 7.1 (s, 1H), 7.19 (m, 3H), 7.29 (s, 1H), 8.69 (s, 1H), 8.9 (s, 1H), 13.37 (s, 1H); Mass Spectrum: M+H+ 466.