Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:5](=[O:18])[CH:4]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=1)[CH3:2].[CH3:26][N:27]1CCN(C)C1=O>>[CH2:1]([CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:5](=[O:18])[CH:4]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:26]#[N:27])[CH:20]=1)[CH3:2]
Reactant: CN1CCN(C)C1=O
Reactant: CCC1CN(c2cccc(C(F)(F)F)c2)C(=O)C1c1cccc(Br)c1
Product: CCC1CN(c2cccc(C(F)(F)F)c2)C(=O)C1c1cccc(C#N)c1

Procedure:
To 10 ml of 1,3-dimethyl-2-imidazolidinone, 0.7 g of 4-ethyl-3-(3-bromophenyl)-1-(3-trifluoromethylphenyl)-2-pyrrolidinone (Compound No. 25) and 1.2 g of cuprous cyanide were added. After the resultant mixture was stirred at 160° C. for 4 hours, the insoluble matter was filtered off from the reaction mixture and the filtrate was poured into water, followed by extraction with toluene. The extract was dried over anhydrous sodium sulfate, concentrated in an evaporator, and then purified by chromatography on a silica gel column, whereby 0.35 g of the title compound was obtained.
Reaction SMILES: [CH:1]([N:5]1[C:34]([CH2:35][CH3:36])=[C:8]2[N:9]=[C:10]([C:14]3[C:15]([O:31][CH2:32][CH3:33])=[N:16][CH:17]=[C:18]([S:20]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]4)(=[O:22])=[O:21])[CH:19]=3)[NH:11][C:12](=[O:13])[C:7]2=[N:6]1)([CH2:3][CH3:4])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:47][O:48]CCO>>[CH:1]([N:5]1[C:34]([CH2:35][CH3:36])=[C:8]2[N:9]=[C:10]([C:14]3[C:15]([O:31][CH2:32][CH2:33][O:48][CH3:47])=[N:16][CH:17]=[C:18]([S:20]([N:23]4[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH2:28]4)(=[O:21])=[O:22])[CH:19]=3)[NH:11][C:12](=[O:13])[C:7]2=[N:6]1)([CH2:3][CH3:4])[CH3:2]
Reactant: COCCO
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(C(C)CC)nc2c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCOC)[nH]c(=O)c2nn1C(C)CC
Temperature: 130 °C
Reaction time: 22 h

Procedure:
A solution of the title compound from example 4 (129 mg, 0.25 mmol) in 2-methoxyethanol (10 ml) was heated at 110° C. for 15 minutes, then cooled. Potassium bis(trimethylsilyl)amide (249 mg, 1.50 mmol) was added and the reaction stirred at 130° C. for 22 hours. The cooled mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution, and the layers separated. The organic phase was dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (98:2) as eluant to afford the title compound as a yellow foam, 59 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:18]([N:25]=[C:26]=[S:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([NH:25][C:26]([NH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:26](=[S:27])[NH:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1)=[S:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(NC(=O)c2ccc(N)cc2)cc1
Reactant: S=C=NCc1ccccc1
Solvent: CC(C)=O
Product: O=C(Nc1ccc(NC(=S)NCc2ccccc2)cc1)c1ccc(NC(=S)NCc2ccccc2)cc1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
4,4'-Diaminobenzanilide (0.568 g, 2.5 mM) was dissolved in 20 ml of acetone, and 2 equivalents of benzylisothiocyanate (0.746 g, 5 mM) was added. The mixture was stirred at 55° C. for 10 minutes. After cooling, the reaction mixture was filtered, and washed with acetone/n-hexane to obtain 0.57 g (43.4% yield) of a colorless crystal of compound A-16.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH:45]=[O:46])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]#[N:29])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C[OH:50]>ClCCl.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:45][OH:46])=[C:19]([N:23]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:50])[C:25]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[O:38])=[CH:33][CH:32]=4)=[N:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3C=O)ncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carbonitrile (52 mg, 0.0839 mmol) was dissolved in 6 mL of dichloromethane and 2 mL of methanol. Sodium borohydride solution (9.52 mg, 0.252 mmol) in water (0.5 mL) and methanol (1.0 mL) was added in drops. The mixture was stirred at room temperature for 1 hr. LC/MS showed a clean desired product. The mixture was evaporated to dryness and extracted with dichloromethane and water. The organic layer was dried over sodium sulfate and evaporated to give a pure desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carbonitrile (51 mg, 98% yield). LC/MS clacd for C34H32FN7O4 (m/e) 621.25, obsd 622.1 (M+H, ES+); 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (s, 9H), 3.59-3.77 (m, 8H), 4.37 (br. s., 2H), 6.59 (br. s., 1H), 7.43 (d, J=8.6 Hz, 2H), 7.48 (dd, J=7.8, 1.3 Hz, 1H), 7.54-7.61 (m, 4H), 7.66 (t, J=8.1 Hz, 1H), 7.81 (dd, J=8.1, 1.3 Hz, 1H), 8.32 (d, J=2.5 Hz, 1H), 8.74 (s, 1H).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1>C(O)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.[Ru](I)I.[Ru](I)I>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C/C(=C\[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: I[Ru]I
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CCO
Product: C[C@@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of (E)-(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid [2(ii-a)] (20 g, 52 mmol) in degassed ethanol (100 ml) is added a solution of diiodo(p-cymene)ruthenium(II) dimer (0.215 g, 0.22 mmol) and (αS,αS)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(R,R)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphine]ferrocene (=Mandyphos SL-M004-2) (0.50 g, 0.47 mmol) in degassed ethanol (15 ml). The solution is degassed using vacuum and a pressure of 20 bar hydrogen is applied. The mixture is stirred at 25° C. for 15 h. The vessel is then purged with nitrogen. The solvent is removed in vacuo. The resulting solid is dried overnight at 50° C. under 1-50 mbar vacuum to afford the title compound [Ratio 2(i-a): 2(i-b) 7:93, as determined by HPLC analysis].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[O:10]1[CH:16]2[CH:11]1[C:12]([CH3:29])([CH3:28])[O:13][C:14]1[CH:20]=[CH:19][C:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[CH:17][C:15]=12.O>CS(C)=O>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C@@H:16]1[C:15]2[CH:17]=[C:18]([S:21]([C:24]([F:25])([F:27])[F:26])(=[O:23])=[O:22])[CH:19]=[CH:20][C:14]=2[O:13][C:12]([CH3:28])([CH3:29])[C@H:11]1[OH:10]
Reactant: Oc1ccccn1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](n2ccccc2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.5 %

Procedure:
105 mg of 2-hydroxypyridine were added to a suspension of 48 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in anhydrous dimethyl sulfoxide, and the resulting mixture was stirred at room temperature for 15 minutes. At the end of this time, 309 mg of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-2H-1-benzopyran (prepared as described in Preparation 8) were added under an atmosphere of nitrogen and at room temperature to the mixture. The mixture was then stirred at room temperature for 24 hours, after which it was poured into water and extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order; it was then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of ethyl acetate and cyclohexane as the eluent, to afford 95 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1I.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1B(O)O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[O:19][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: CCSc1ccc(I)c(Cl)c1
Product: CCSc1ccc(-c2cc(Cl)ccc2OCc2ccccc2)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and the product from example 16 step (ii). Yield 3.64 g
Reaction SMILES: Cl[C:2]1[N:3]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].[CH2:26](I)[CH3:27].O>CN(C)C=O>[Cl:18][C:14]1[C:15]([O:17][CH2:26][CH3:27])=[CH:16][C:11]([N:3]2[CH:2]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)=[N:4]2)=[C:12]([F:19])[CH:13]=1
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-n2cc3c(n2)CCCC3)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Into a solution of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole (0.9 g) in dimethylformamide (10 ml), there was added potassium carbonate (0.25 g) and ethyl iodide (1 g), and the mixture was stirred for 60° C. for 3 hours. After cooling, water was added to the reaction mixture, followed by extraction with ether. The ether layer was washed with water twice, dried and concentrated. The residue was crystallized from hexane to give 0.2 g of 3-chloro-2-(4-chloro-2-fluoro-5-ethoxyphenyl-4,5,6,7-tetrahydro-2H-indazole (Compound No. 1). m.p., 85.1° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C@@H:5]([NH:9][C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C:6]([OH:8])=O.N=C=N.Cl.[CH3:31][O:32][C:33](=[O:36])[CH2:34][NH2:35].C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:16]1[C:15]2[CH:14]([CH2:13][O:12][C:10]([NH:9][C@@H:5]([C:6]([NH:35][CH2:34][C:33]([O:32][CH3:31])=[O:36])=[O:8])[CH2:4][CH2:3][CH2:2][CH3:1])=[O:11])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CN
Reactant: CCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Agent: N=C=N
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of fmoc-D-Nle-OH (10 g, 28.3 mmol, Novabiochem) and PS-carbodiimide (33 g, 42.45 mmol, 1.28 mmol/g, Argonaut Technologies Inc.) in dichloromethane (250 mL) was stirred at room temperature for 0.5 h. Then, glycine methyl ester hydrochloride (5.3 g, 42.45 mmol, Aldrich), HOAt (3.8 g, 28.3 mmol, Perseptive Biosystems) and diisopropylethylamine (16 mL, 84.9 mmol, Aldrich) were added and the mixture was stirred at room temperature for 16 h. The mixture was filtered and the resin was washed with dichloromethane (2×70 mL). The filtrate was concentrated in vacuo and the residue was purified by column chromatography, eluting with EtOAc/hexane (1:2) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 425 (M+1).
Reaction SMILES: [N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[O:6][CH2:5][CH2:4][N:3]3[C:2]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:1]2[C:11]3=[C:12]4[C:7](=[CH:8][CH:9]=[CH:10]3)[O:6][CH2:5][CH2:4][N:3]4[C:2]2=[N:13][S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[CH:26][CH:27]=1
Reactant: O=S(=O)(Nc1nc2cccc3c2n1CCO3)c1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(N=c1n(Cc2ccc(C(F)(F)F)cc2)c2cccc3c2n1CCO3)c1ccccc1
Temperature: 120 °C

Procedure:
To a solution of N-(3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-benzenesulfonamide (125 mg, 0.40 mmol) in DMF (2.5 mL) was added 1-bromomethyl-4-trifluoromethyl-benzene (190 mg, 0.80 mmol) and potassium carbonate (55 mg). The resulting mixture was heated to 120° C. in a microwave reactor for 1 h and then diluted with EtOAc, washed with H2O and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield N-[1-(4-trifluoromethyl-benzyl)-3,4-dihydro-1H-5-oxa-1,2a-diaza-acenaphthylen-2-ylidene]-benzenesulfonamide (2nd compound to elute off the column); which was further purified by HPLC (reverse phase C-18 column, 45-100% acetonitrile/water containing 0.05% trifluoroacetic acid) to yield N-[1-(4-trifluoromethyl-benzyl)-3,4-dihydro-1H-5-oxa-1,2a-diaza-acenaphthylen-2-ylidene]-benzenesulfonamide trifluoroacetic acid salt. MS 474 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CO)c2c1cc([N+](=O)[O-])c1ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)c2c1cc([N+](=O)[O-])c1ccccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
A stirred solution of 3-(tert-butyloxycarbonyl)-1-(hydroxymethyl)-5-nitro-1,2-dihydro-3H-benz[e]indole (12) (450 mg, 1.31 mmol) in pyridine (1.3 mL) was treated dropwise at -5° C. with methanesulfonyl chloride (0.121 mL, 1.57 mmol) and then stirred at 20° C. for 2 h. The mixture was diluted with water then cooled and the resulting solid collected, washed with water and dried. This product was dissolved in CH2Cl2 and the solution was filtered through a short column of silica gel, eluting with further CH2Cl2. The resulting product was triturated with iPr2O/petroleum ether to give 3-(tert-butyloxycarbonyl)-1-[(methanesulfonyloxy)methyl]-5-nitro-1,2-dihydro-3H-benz[e]indole (494 mg, 89%), mp 147° C. (dec.). 1H NMR [(CD3)2SO] δ 8.75 (br s, 1 H, H-4), 8.32 (d, J=8.5 Hz, 1 H, H-6), 8.12 (d, J=8.2 Hz, 1 H, H-9), 7.77-7.63 (m, 2 H, H-7, 8), 4.54 (dd, J=10.0, 3.7 Hz, 1 H, H-2), 4.43 (dd, J=10.0, 6.4 Hz, 1 H, H-2), 4.42-4.33 (m, 1 H, H-1), 4.25 (t, J=10.3 Hz, 1 H, CHHO), 4.14 (dd, J=11.4, 2.5 Hz, 1 H, CHHO), 3.11 (s, 3 H, SO2CH3), 1.56 (s, 9 H, C(CH3)3). Anal. Calculated for C19H22N2O7S: C, 54.0; H, 5.3; N, 6.6; S, 7.6. Found: C, 54.3; H, 5.4; N, 6.9; S, 7.4%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].ClC(Cl)(Cl)[C:12]([N:14]=C=O)=[O:13].N>C(#N)C.CO>[NH2:14][C:12]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])=[O:13]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: NC(=O)c1ccsc1N
Agent: N
Solvent: CO
Solvent: CC#N
Product: NC(=O)Nc1sccc1C(N)=O
Reaction time: 0.17 h

Procedure:
2-Amino-3-thiophenecarboxamide (0.44 g) was suspended in acetonitrile (25 ml) and trichloroacetylisocyanate (0.2 ml) added dropwise with stirring over 10 minutes. Stirring was continued for a further 3 h at room temperature and then a solution of ammonia in methanol (10 ml of a 2M solution) was added and stirring continued for a further 2 h. The solvent was evaporated and the residue treated with water. The resultant solid was filtered off and washed with more water. Trituration with ether gave the title urea (0.2 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]2[C:26]([C:27]([O-:29])=[O:28])=[C:25]([CH2:30][CH3:31])[N:24]=[CH:23][N:22]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10].CI>CC(CC)=O>[CH2:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]2[C:26]([C:27]([O:29][CH3:1])=[O:28])=[C:25]([CH2:30][CH3:31])[N:24]=[CH:23][N:22]=2)=[CH:16][CH:17]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ccc(CCNc2ncnc(CC)c2C(=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CCCCOc1ccc(CCNc2ncnc(CC)c2C(=O)OC)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
Potassium carbonate (0.27 g, 1.95 mmol) was added to a solution of 4-(2-(4-butoxyphenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate acid (0.34 g, 0.99 mmol) in ethyl methyl ketone (20 ml), and methyl iodide (0.42 g, 2.96 mmol) was added. After stirring at 65° C. for 3 hours, the mixture was cooled to room temperature. The resulting solid was filtered off and the solvent was evaporated. The reside was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired methyl 4-(2-(4-butoxyphenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.26 g, 73%).
Reaction SMILES: Br[C:2]1[C:22]([NH2:23])=[CH:21][C:5]2[O:6][CH2:7][CH2:8][CH:9]3[CH2:18][C:13]4([O:17][CH2:16][CH2:15][O:14]4)[CH2:12][CH2:11][C:10]3([CH2:19][CH3:20])[C:4]=2[CH:3]=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].COCCOC.CB1OB(C)OB(C)O1>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>[CH2:19]([C:10]12[CH2:11][CH2:12][C:13]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:18][CH:9]1[CH2:8][CH2:7][O:6][C:5]1[CH:21]=[C:22]([NH2:23])[C:2]([CH3:24])=[CH:3][C:4]2=1)[CH3:20]
Reactant: CCC12CCC3(CC1CCOc1cc(N)c(Br)cc12)OCCO3
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCC12CCC3(CC1CCOc1cc(N)c(C)cc12)OCCO3
Temperature: 90 °C
Yield: 74.9 %

Procedure:
A 500 mL round-bottom flask equipped with air cooled reflux condenser outfitted with a nitrogen inlet adapter was charged with rac-(7aR,11aS)-2-bromo-11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (87, R2=Ethyl) (9.14 g, 23.9 mmol), bis(triphenylphosphine)palladium(II) chloride (0.839 g, 1.20 mmol) and Cs2CO3 (23.4 g, 71.7 mmol), and then DME (180 mL), water (60 mL) and trimethylboroxine (6.67 mL, 47.8 mmol) were added. The reaction mixture was heated to about 90° C. for about 15 h. The reaction was allowed to cool to rt and then it was partitioned between EtOAc (350 mL) and water (200 mL). After separating the layers, the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phases were then washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on silica gel (330 g, eluted with 0% to 50% EtOAc in heptane). Collection and concentration of the appropriate fractions gave rac-(7aR,11aS)-11a-ethyl-2-methyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (88, R2=Ethyl) (5.68 g, 74.8%) containing about 20% of a minor regioisomer. The material was used directly in Step #5 without further purification. LC/MS, method 3, 2.26 min, MS m/z 318 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH3:13])=[N:10][CH:9]=1.[Br:14]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:11]1[S:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][N:10]=1
Reactant: Cc1ncc(-c2ccccc2Cl)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccccc1-c1cnc(CBr)s1
Temperature: 25 °C

Procedure:
180 mg (0.86 mmol) of the compound from Example 75A together with 229 mg (1.29 mmol) of N-bromosuccinimide and 14 mg (0.09 mmol) of 2,2′-azobis-2-methylpropanenitrile in 5 ml of carbon tetrachloride were heated under reflux for 8 h. For work-up, the reaction mixture was cooled to RT, and 10 ml of dichloromethane were added. The mixture was washed with 5 ml of water, and the aqueous phase was re-extracted twice with in each case 5 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 66 mg (27% of theory) of the target compound.
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[CH:9]=[C:8]([CH3:10])O[CH:6]=[C:5]1[O:11][CH2:12][C:13]([OH:15])=[O:14]>O>[CH3:1][N:2]1[C:8]([CH3:10])=[CH:9][C:4](=[O:3])[C:5]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6]1
Reactant: CN
Reactant: Cc1cc(=O)c(OCC(=O)O)co1
Solvent: O
Product: Cc1cc(=O)c(OCC(=O)O)cn1C
Reaction time: 3 h

Procedure:
To a stirred solution of 40% aqueous methylamine (9.0 ml) and water (9.0 ml) was added 2-(4-oxo-6-methyl-4H-pyran-3-yloxy)acetic acid (6.0 g) in small portions at room temperature. The mixture was stirred at the same temperature for 3 hours and concentrated. To the residue was added water (5 ml) and the mixture was adjusted to pH 3. The resulting precipitates were collected and washed with water to give crystals of 2-(1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yloxy)acetic acid (1.53 g), mp 240° to 242° C. The filtrate and the washings were combined together and adsorbed on Amberlite IRA-400 (Tradename, prepared by Rohm and Haas Co.) and eluted with water and then 0.3 N hydrochloric acid. The hydrochloric acid fraction was concentrated and dried to give crystals (3.7 g) of 2-(1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yloxy)acetic acid hydrochloride. The hydrochloride was dissolved in a small amount of water and the solution was adjusted to pH 3. The resulting crystals were collected by filtration and washed with water to give an additional amount of the same product (2.2 g) as obtained above.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[CH2:2][CH2:3][CH2:4][C:5]([O:7]C)=O.[CH3:12][NH:13][CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1.Cl>>[CH3:12][N:13]([C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]([O:10][CH3:11])=[O:9])[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1
Reactant: COC(=O)CCCC(=O)OC
Reactant: CNCCc1c[nH]c2ccccc12
Agent: Cl
Product: COC(=O)CCCC(=O)N(C)CCc1c[nH]c2ccccc12
Temperature: 150 °C
Yield: 74.8 %

Procedure:
8.0 g of dimethyl glutarate were added to 8.70 g of N-methyl-tryptamine (i.e., 3-(2-methylaminoethyl)-indole), and the mixture was heated at 150° C. under reduced pressure for 2 hours. After the reaction was completed, the mixture was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, successively. The washed extract was dried and evaporated under reduced pressure to remove solvent. The residue thus obtained was recrystallized from a mixture of ethyl acetate and n-hexane. 11.3 g of N-methyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-methyl-4-methoxycarbonylbutanamido)ethyl]-indole) were thereby obtained. M.p. 101°-102° C. Yield: 70%