Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[C:19]([O-:22])(=[O:21])[CH3:20].[K+]>CN(C=O)C>[C:19]([O:22][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:21])[CH3:20]
Reactant: BrCCCCn1c2ccccc2c2ccccc21
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCn1c2ccccc2c2ccccc21
Temperature: 110 °C
Reaction time: 12 h
Yield: 93.5 %

Procedure:
Compound 8 (40.1 g, 0.133 mol) and potassium acetate (19.5 g, 1.99 mol) were mixed in 300 mL of DMF under an argon atmosphere. The reaction mixture was stirred for 12 hours at 110° C. The organic phase was separated and extracted with ethyl acetate. The collected organics were then combined and dried over Na2SO4 and filtered. The solvent was evaporated to give the crude product. The resulting product was purified by silica gel column chromatography (eluent: ethyl acetate:methylene chloride=1:30 v/v) to yield 35 g (93%) of 4-(9H-carbazol-9-yl)butyl acetate (Compound 9).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.Br[C:26]1[C:27]([Cl:46])=[C:28]([NH:34][C@@H:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][C@H:36]2[OH:45])[CH:29]=[C:30]([C:32]#[N:33])[CH:31]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:46][C:27]1[C:26]([NH:1][C:2]2[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:5]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]3[N:3]=2)=[CH:31][C:30]([C:32]#[N:33])=[CH:29][C:28]=1[NH:34][C@@H:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][C@H:36]1[OH:45]
Reactant: COC(=O)N1CC[C@@H](Nc2cc(C#N)cc(Br)c2Cl)[C@H](O)C1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(N)nn2c(C#N)cnc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N[C@@H]3CCN(C(=O)OC)C[C@H]3O)c2Cl)nn2c(C#N)cnc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A oven-dried 10 ml microwave flask was loaded with 2-amino-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (16 mg, 0.049 mmol), (3R,4R)-methyl 4-((3-bromo-2-chloro-5-cyanophenyl)amino)-3-hydroxypiperidine-1-carboxylate (19 mg, 0.049 mmol), Pd(OAc)2 (3 mg, 0.013 mmol), XANTPHOS (8 mg, 0.014 mmol) and Cs2CO3 (50 mg, 0.153 mmol). The flask was evacuated and back-filled with nitrogen 4 times. 1,4-Dioxane (0.5 mL) was added and the flask was again evacuated and back-filled with nitrogen 4 times, then heated with stirring to 70° C. for 2 hours. The reaction is complete by LCMS analysis. The reaction mixture was diluted with EtOAc, washed with water, brine and dried over Na2SO4. The solvent removed to afford (3R,4R)-methyl 4-((2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)amino)-3-hydroxypiperidine-1-carboxylate (30.9 mg). The material was used as is.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[CH2:10]([N+:17](C)(C)C)[C:11]1C=CC=C[CH:12]=1>C(#N)C=C.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][C:10]#[N:17])=[CH:4][CH:3]=1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: Cc1ccc(O)cc1
Agent: [OH-]
Solvent: C=CC#N
Solvent: CO
Product: Cc1ccc(OCCC#N)cc1
Yield: 76 %

Procedure:
A solution of 4-methylphenol, (20.0 g 0.185 moles), in acrylonitrile, (150 ml), was treated with benzyltrimethylammonium hydroxide, 40% in methanol (Triton B), (6 ml) and the reaction refluxed for 10 hours, then cooled, and evaporated in vacuo. The residual oil was partitioned between diethyl ether and water and the organic phase separated and washed with water, dilute sodium hydroxide solution, dilute hydrochloric acid, brine and dried (MgSO4). Evaporation of the solvent in vacuo gave 23.44 g of crude product, which was recrystallized from petroleum ether 60°-80° C./diethyl ether to yield 22.93 g, (76%) of pure product as a white crystalline solid, mp 47°-8° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)=O)[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N>CO.C(Cl)Cl>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:14]([C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:35])[F:34])=[CH:27][CH:26]=4)[CH2:22][N:18]4[CH2:19][CH2:20][CH2:21][C@H:17]43)=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CN1CCCC1c1cccc(OCCCN2CCCCC2)c1)c1ccc(OC(F)(F)F)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)cc1
Yield: 79 %

Procedure:
2-{2-[3-(3-Piperidin-1-yl-Propoxy)-phenyl]-pyrrolidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.35 g (79%) of the desired product as a viscous oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C27H33F3N2O3, 474.2; m/z found, 475.5 [M+H]+. 1H NMR (MeOH-d4): 7.77 (d, J=8.7, 2H), 7.11 (d, J=8.5, 2H), 7.05 (t, J=7.9, 1H), 6.82 (d, J=1.4, 1H), 6.78 (d, J=7.5, 1H), 6.64 (dd, J=2.3, 8.1, 1H), 3.80 (m, 3H), 3.3 (m, 2H), 2.31 (m, 5H), 2.21 (m, 1H), 1.96 (m, 1H), 1.81 (m, 3H), 1.60 (m, 2H), 1.45 (m, 4H), 1.31 (m, 2H).
Reaction SMILES: O=[O+][O-].[CH2:4]([C:7]1([C:23]([O:25][CH3:26])=[O:24])[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1)[CH:5]=C.S(OC)(OC)(=O)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[O:28]=[CH:5][CH2:4][C:7]1([C:23]([O:25][CH3:26])=[O:24])[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH2:9][CH2:8]1
Reactant: COS(=O)(=O)OC
Reactant: C=CCC1(C(=O)OC)CCN(C(=O)OCc2ccccc2)CC1
Agent: O=[O+][O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(CC=O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ozone was passed through a solution of 1-benzyl 4-methyl 4-allylpiperidine-1,4-dicarboxylate (10.0 g, 0.0315 mol) in methylene chloride (200.0 mL) at −78° C. until the color of the solution turned to steel blue. The reaction mixture was flushed with an atmosphere of nitrogen. Then to the solution was added dimethyl sulfate (6.0 mL, 0.063 mol) followed by triethylamine (8.8 mL, 0.063 mol). The mixture was stirred at room temperature for overnight, and then concentrated. The residue was dissolved in ethyl acetate, and the resulting solution was washed with saturated NH4Cl solution, NaHCO3 (7.5%), brine, dried over Na2SO4, filtered and concentrated to give 1-benzyl 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](O)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.Cl.[CH2:37]([N:39]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.CN>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH:39][CH3:37])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(C)COC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.4 %

Procedure:
A mixture of {2-[7-(2-methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (250 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg), 1-hydroxybenzotriazole (100 mg), methylamine hydrochloride (100 mg), triethylamine (120 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (160 mg, 62%) as pale yellow prisms. MS 533 (MH+). mp 107-109° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([C:13]2[NH:18][C:17](=[O:19])[C:16]3=[CH:20][N:21]=[C:22]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:15]3[N:14]=2)[CH:10]([CH3:29])[CH2:9]1)=O)(C)(C)C.[ClH:30]>C(Cl)Cl.C(OCC)C>[ClH:30].[CH3:29][CH:10]1[CH2:9][NH:8][CH2:12][CH:11]1[C:13]1[NH:18][C:17](=[O:19])[C:16]2=[CH:20][N:21]=[C:22]([CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:15]2[N:14]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC1c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC1CNCC1c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of compound 8 (130 mg, 0.32 mmol) in CH2Cl2 (10 mL) was added a saturated solution of HCl in diethylether (20 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to dryness to afford compound 9 (110 mg, 100% yield). LC-MS (free base): m/z 304.37 [M+1]+. 1H NMR (400 MHz, D2O-d2): δ 8.02 (s, 1H), 3.98˜3.95 (dd, J=2.8, 8.8 Hz, 2H), 3.64˜3.60 (m, 3H), 3.56˜3.50 (m, 3H), 3.15˜3.09 (m, 1H), 3.01˜2.96 (m, 1H), 2.72˜2.67 (m, 1H), 1.92˜1.87 (m, 4H), 1.09 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CCOC(C)=O.C([O-])(O)=O.[Na+].O>[CH2:27]([O:26][C:24](=[O:25])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:6][CH:7]=1)[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A biphasic mixture of 2-(4-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in example 1Ga step B, and ethyl chloroformate (0.03 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) is prepared at 0° C. and then allowed to warm to room temperature and stirred for 24 h. The reaction is then diluted with H2O and extracted with EtOAc (2×). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 20-40%) gives 48 mg (55%) of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester as an off-white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][C:35]=1[OH:36])[C:10]([NH:12][NH:13][C:14]([C:16]1[O:17][CH:18]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15])=[O:11])#[N:6].C(N(CC)CC)C.ClCCl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([O:36][C:35]1[CH:34]=[CH:33][C:9]([C:10]([NH:12][NH:13][C:14]([C:16]2[O:17][CH:18]=[C:19]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[O:11])=[CH:8][C:7]=1[C:5]#[N:6])(=[O:3])[CH3:2]
Reactant: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1C#N
Reaction time: 0.5 h

Procedure:
Acetyl chloride (0.080 ml) was added to a mixture of the compound of Example 18 (0.42 g), 4-dimethylaminopyridine (0.013 g), triethylamine (0.17 ml) and dichloromethane (5 ml) at 0° C., and stirred for 0.5 hours at this temperature. The reaction solution was diluted with ethyl acetate, washed with water and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane, thereby giving 0.26 g of the desired compound. Melting point: 131-133° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:7](/[CH:10]=[C:11](/[C:21]2[NH:25][N:24]=[N:23][N:22]=2)\[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:7](/[CH:10]=[C:11](/[C:21]2[NH:25][N:24]=[N:23][N:22]=2)\[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2ccc(OC)cc2)c2nnn[nH]2)n1Cc1ccccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCc1ncc(/C=C(\Cc2ccc(O)cc2)c2nnn[nH]2)n1Cc1ccccc1Cl

Procedure:
The title compound was prepared by reacting (E)-1-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(1H-tetrazol-5-yl)-3-(4-methoxyphenyl)-1-propene with boron tribromide in methylene chloride at room temperature. The product was isolated as the hydrobromide salt; mp 218°-221° C.
Reaction SMILES: [CH3:1]/[C:2](=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[CH2:3][CH2:4][C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1]/[C:2](=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: COC(=O)CC/C(C)=C/c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C(=C\c1ccccc1)CCCO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 102.1 %

Procedure:
A solution of methyl (4E)-4-methyl-5-phenyl-4-pentenoate (3.5 g, 0.016 mol) in dry THF (100 ml) was treated, at −78° C. under nitrogen, with solid lithium aluminum hydride (1 g, 0.025 mol) in one portion. After 5 minutes, the cooling bath was removed and the reaction allowed reaching room temperature and then cooled to 0° C. and treated successively with water (1 ml), 5% aqueous sodium hydroxide (3 ml) and water (1 ml). The reaction was stirred at room temperature for 30 minutes. Anhydrous solid sodium sulfate was added (3 g) and stirring continued for 5 minutes. The solid was filtered off, rinsed with diethyl ether and the filtrate was evaporated under vacuum. The product was purified by bulb-to-bulb distillation (84° C./0.002 mbar). 2.88 g (yield=100%) of the desired product were obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[F:27][CH:28]([F:32])[C:29](O)=O.[C:33]([O:37][C:38](=[O:69])[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:59](=[O:60])[C:58]4[C:53](=[C:54]([NH2:62])[C:55]([NH2:61])=[CH:56][CH:57]=4)[O:52][C:51]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34]>C(Cl)(Cl)(Cl)Cl.ClCCCl.C1CCCCC1.C(OCC)(=O)C>[C:33]([O:37][C:38](=[O:69])[NH:39][C:40]1([C:44]2[CH:45]=[CH:46][C:47]([C:50]3[C:59](=[O:60])[C:58]4[CH:57]=[CH:56][C:55]5[N:61]=[C:29]([CH:28]([F:32])[F:27])[NH:62][C:54]=5[C:53]=4[O:52][C:51]=3[C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)=[CH:48][CH:49]=2)[CH2:43][CH2:42][CH2:41]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N)c(N)ccc4c3=O)cc2)CCC1
Reactant: O=C(O)C(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nc(C(F)F)[nH]c54)c3=O)cc2)CCC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
To a stirred solution of triphenylphosphine (126 mg, 0.48 mmol) in CCl4 (1 mL) at 0° C. was added triethylamine (67 μL, 0.48 mmol) and difluoroacetic acid (11 μL, 0.18 mmol). After 10 min, {1-[4-(7,8-diamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (80 mg, 0.16 mmol) in 1,2-dichloroethane (1 mL) was added, the temperature raised to 80° C. After 2.5 hours, the reaction mixture was allowed to cool to RT and the solution was directly subjected to flash chromatography (SiO2, 40% ethyl acetate in cyclohexane) to give the title compound as a pale yellow solid (64 mg, 72%). LCMS (Method G): RT=3.93 min, [M+H]+=558.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][C@@H:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:14][C:4]=1[C:5]=23)#[N:2].CCN(CC)CC.[C:29]1([C:35](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:35]([N:8]1[C:9]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[C:4]3[CH2:14][C@H:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:12][C@H:6]([C:5]=23)[CH2:7]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCCN(CCC)[C@H]1Cc2c(C#N)ccc3c2[C@H](CN3)C1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c(C#N)ccc3c2[C@@H](C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
To a sol of (2aR,4R)-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (1 g, 3.5 mmol) and Et3N (354 mg, 3.5 mmol) in 50 mL of methylene chloride was added a sol of triphenylmethyl chloride (trityl chloride) (0.98 g, 3.5 mmol) in 10 mL of methylene chloride dropwise at RT. The reaction mixture was stirred for 16 hr at RT. The reaction mixture was extracted with water and cold 1 N HCl. The organic sol was washed with sat'd NaHCO3 sol and with sat'd brine sol. The organic sol was dried (MgSO4) and conc to dryness in vacuo to give a residue. The residue was slurried with warm hexanes, cooled and filtered to remove insolubles. The filtrate was conc to an oil. The oil was chromatographed (silica gel, 20% EtOAc in hexanes) to provide 1.5 g of (2aR,4R)-1-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27]C(=O)C)[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>>[N:1]1([C:6]2[CH:32]=[CH:31][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27][S:36]([CH:33]5[CH2:35][CH2:34]5)(=[O:38])=[O:37])[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Product: O=S(=O)(Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-n4cccn4)ccc32)c1)C1CC1

Procedure:
The compound was prepared from the compound of Example 28 using the procedures of Example 29 and cyclopropane sulfonyl chloride. 1H NMR (300 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.0 (s, 1H), 8.64 (d, 1H), 8.27 (d, 1H), 7.99 (dd, 1H), 7.85-7.76 (m, 3H), 7.65-7.62 (m, 2H), 7.54-7.45 (m, 2H), 7.33-7.27 (m, 1H), 6.59-6.57 (m, 1H), 2.95-2.93 (m, 1H), 1.04-1.02 (m, 4H); LC-MS (ESI): Calculated mass: 491.51; Observed mass: 492.1 [M+H]+ (rt: 1.659 min).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:21]2[CH:22]=[C:23]([O:26][C@@H:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C@@H:30]([NH2:37])[CH2:29][CH2:28]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.CCN(C(C)C)C(C)C.[C:47]([C:51]1[CH:55]=[C:54]([NH:56][C:57](=O)[O:58]CC(Cl)(Cl)Cl)[N:53]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:52]=1)([CH3:50])([CH3:49])[CH3:48]>O1CCOCC1>[C:47]([C:51]1[CH:55]=[C:54]([NH:56][C:57]([NH:37][C@@H:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@@H:27]([O:26][C:23]3[CH:24]=[CH:25][C:20]4[N:21]([C:17]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[S:10][CH2:9][CH2:8][O:7][CH:2]5[CH2:3][CH2:4][CH2:5][CH2:6][O:1]5)=[N:18][N:19]=4)[CH:22]=3)[CH2:28][CH2:29]2)=[O:58])[N:53]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:52]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: N[C@H]1CC[C@H](Oc2ccc3nnc(-c4ccccc4SCCOC4CCCCO4)n3c2)c2ccccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@H](Oc3ccc4nnc(-c5ccccc5SCCOC5CCCCO5)n4c3)c3ccccc32)cc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A solution of Example 20 step b (60 mg, 0.11 mmol), DIPEA (26 μL, 0.15 mmol) and 2,2,2-trichloroethyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (56 mg, 0.138 mmol) in dioxane (5 mL) was heated at 80° C. for 20 h. The reaction was allowed to cool to RT, partitioned between H2O-DCM, the organic phase dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC using MeOH in DCM (0 to 5%) to give the title compound as a yellow foam (38 mg, 45%). LCMS (Method 3): Rt 4.09 min, m/z 772 [MH+].
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([C@@H:13]1[O:17][C:16](=[O:18])[C@H:15]([CH3:19])[O:14]1)([CH3:12])([CH3:11])[CH3:10].[F:20][C:21]([F:25])([F:24])[CH2:22]I.[NH4+].[Cl-]>>[C:9]([C@@H:13]1[O:17][C:16](=[O:18])[C@@:15]([CH3:19])([CH2:22][C:21]([F:25])([F:24])[F:20])[O:14]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: C[C@@H]1O[C@H](C(C)(C)C)OC1=O
Reactant: FC(F)(F)CI
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Product: CC(C)(C)[C@@H]1OC(=O)[C@@](C)(CC(F)(F)F)O1
Temperature: -45 °C
Reaction time: 0.75 h
Yield: 38.2 %

Procedure:
To a solution of lithium diisopropylamide (prepared from 13 ml of diisopropylamine and 54 ml of 1.6 M n-BuLi in hexanes in 200 ml of anhydrous THF at 0° C.) at -72° C. was added slowly 2-(s)-t-butyl-5-(s)-methyl-1,3-dioxolan-4-one (12.95 g, 81.9 mmol, Tetrahedron, 1984, 40, 1313) at such a rate as to maintain the internal temperature below -60° C. and the mixture was aged at -72° C. for an hour. 1,1,1-Trifluoro-2-iodoethane (25 g, 119 mmol) was added quickly, the reaction temperature increased to -45° C. and the mixture was aged at -72° C. for 45 min. and then allowed to warm up to -20° C. over 20 min. Saturated aq. NH4Cl was then added and the product was extracted in i-PrOAc, dried over Na2SO4, concentrated and distilled under reduced pressure to afford 7.51 g of a brown oil BP 90° C. /20 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[SH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of 4-chloro-3-nitrobenzoic acid methyl ester (4.00 g, 18 mmol) and 4-mercaptophenol (2.37 g, 18 mmol) in acetone (60 mL) was added Cs2CO3 (5.93 g, 18 mmol) at room temperature, and then the mixture was refluxed for 30 minutes. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated. The residue was diluted with AcOEt (30 mL), washed with H2O (3 times) and brine, dried over MgSO4, and evaporated to give brown oil. The oily residue was separated by silica gel column chromatography (n-hexane/AcOEt=4/3) to give the title compound as yellow amorphous (5.60 g).