Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH:24](=[N:2][CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(N)CC
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(CC)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A solution of the product from step (a) (149.6 g), magnesium sulphate (74.3 g), and triethylamine (246 ml) in dichloromethane (1500 ml) was stirred at room temperature under nitrogen and benzaldehyde (94.9 g, Aldrich) was added dropwise. The mixture was stirred at room temperature for 3 hours then filtered. The filtrate was concentrated, triturated in diethyl ether, filtered and concentrated to yield the desired product as a yellow oil (174 g). 1H NMR consistent with the proposed structure.
Reaction SMILES: [C:1]([CH:3]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4]1)#[N:2].[Cl:12][CH2:13][C:14]([N:16]=[C:17]=[O:18])=[O:15]>C(OCC)C>[Cl:12][CH2:13][C:14]([NH:16][C:17]([N:4]1[CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:3]1[C:1]#[N:2])=[O:18])=[O:15]
Reactant: N#CC1NC1c1ccccc1
Reactant: O=C=NC(=O)CCl
Solvent: CCOCC
Product: N#CC1C(c2ccccc2)N1C(=O)NC(=O)CCl

Procedure:
1 g. Crude 2-cyano-3-phenyl-aziridine is dissolved in 25 ml. anhydrous diethyl ether. A solution of 0.83 g. chloroacetyl isocyanate in 3.5 ml. diethyl ether is added thereto dropwise, while stirring, and the reaction mixture is further stirred for 1 hour at ambient temperature. The precipitate obtained is then filtered off with suction, washed with diethyl ether and dried in a vacuum. There is thus obtained 1.24 g. 1-(N-chloroacetyl-carbamoyl)-2-cyano3-phenyl-aziridine; m.p. 153°-158°-165° C. According to the NMR spectrum, the product is an isomeric mixture containing about 30% of the trans form and about 70% of the cis form.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][C:15]=2[O:14]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH2:18][N:1]3[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]3)=[CH:16][C:15]=2[O:14]1
Reactant: CCOC(=O)CC1CCNCC1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CC1CCN(Cc2ccc3c(c2)OCO3)CC1
Yield: 85.1 %

Procedure:
A mixture of ethyl piperidine-4-acetate (0.34 g, 2.0 mmol), 3,4-methylenedioxybenzyl chloride (0.34 g, 2.0 mmol), sodium carbonate (1.0 g) and sodium iodide (0.10 g) in acetonitrile (30 ml) was heated under reflux for 16 hours and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on SiO2 using dichloromethane plus 0-20% ethyl acetate as eluant. Appropriate fractions were combined and evaporated to give the title compound (0.52 g) as a colourless oil which was characterised by its 1H-NMR spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:15][C:14]([CH3:16])([CH3:17])[CH2:13][CH:12]([F:20])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCc2nc3cc(Br)ccc3c(=O)n2C1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(F)c2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To a solution of 3-bromo-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (0.1 g, 0.327 mmol, 1 equiv) in DMF (5 mL), Selectfluor (0.12 g, 0.327 mmol, 1 eq) was added. The reaction mixture was heated to 90° C. and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL), dried over Na2SO4. After filtration and concentration, 80 mg of the desired product was obtained, which was directly used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4Cl)cc23)CC1
Yield: 19.8 %

Procedure:
Beginning with 2.0 gm (8.8 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 1.9 gm (9.7 mMol) 2-chloro-4-fluorobenzoyl chloride, 0.67 gm (19.8%) of the title compound were recovered as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:17](Cl)=[O:18].S1C=CC=C1C(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:17](=[O:18])[C:16]2[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=[C:14]([C:13]([F:12])([F:27])[F:28])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
4-Fluoro-3-nitro-phenylamine was reacted with 3,5-bis-trifluoromethyl-benzoyl chloride according to the procedure of Example 256a substituting 3,5-bis-trifluoromethyl-benzoyl chloride for thiophene-2-carbonyl chloride to provide N-(4-Fluoro-3-nitro-phenyl)-3,5-bis-trifluoromethyl-benzamide which was then reacted according to the procedures of Examples 256b and 256c to provide the title product.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]>CS(C)=O.[Cu]Br>[Br:7][C:8]1[CH:9]=[C:10]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH:11]=[CH:12][CH:13]=1
Reactant: Brc1cccc(I)c1
Reactant: O=C1CCCN1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C1CCCN1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
To a flask charged with Cs2CO3 (4.74 g), Copper(I) bromide (99 mg), and ethyl-2-cyclohexanone-carboxylate (248 mg) was added 3 mL of DMSO under an argon atmosphere. 1-bromo-3-iodobenzene (2.0 g) was added followed by a solution of 2-pyrrolidinone (715 mg) in 3 mL of DMSO. The reaction mixture was stirred at rt for 16 h and then heated to 90° C. for 24 h. The mixture was filtered over celite, concentrated and purified by flash chromatography (65:35 hexanes:ethyl acetate) to afford 983 mg of 1-(3-Bromo-phenyl)-pyrrolidin-2-one as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](Cl)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
15.6 Grams (0.1 mol) of 4-hydroxy-2-fluorobenzoic acid was dissolved in 140 ml of dichloromethane. To the mixture were consecutively added 16 ml of triethylamine, 0.1 g (0.11 mol) of n-decanoic acid chloride and 0.97 (0.0079 mol) of dimethylaminopyridine, and the mixture was stirred at room temperature for a whole day. 10% Hydrochloric acid in an amount of 50 ml was added, and the mixture was subjected to extraction with 100 ml of ether three times. The organic layer was washed with a sodium chloride aqueous solution three times and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was washed with 400 ml of hexane to give 25.5 g of the intended product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[C:18]1(/[C:24](/[C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:25]/[CH2:26][CH2:27][CH2:28][CH2:29]I)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:18]1(/[C:24](/[C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:25]/[CH2:26][CH2:27][CH2:28][CH2:29][CH:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[C:12]([O:14][CH3:15])=[O:13])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ICCCC/C=C(/c1ccccc1)c1cccnc1
Reactant: COC(=O)CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(CCCC/C=C(/c1ccccc1)c1cccnc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
Methyl p-methylphenylsulfonylacetate (0.43 g, 2 mmole) was dissolved in dimethylformamide, and after the solution was cooled to 0° C. under argon, sodium hydride (0.1 g) was added, followed by stirring for 10 minutes. A solution of (Z)-6-phenyl-6-(3-pyridyl)-1-iodo-5-hexene (0.8 g) in dimethylformamide (4 ml) was added to the reaction solution, and the reaction was carried out at room temperature for 3 hours. After the completion of the reaction, water (30 ml) was added, and the product was extracted with ethyl acetate. Working up in the usual procedure, the resulting product was chromatographed on silica gel, and development was effected with isopropyl ether:ethyl acetate (1:1) to yield methyl (Z)-8-phenyl-8-(3-pyridyl)-2-(p-methylphenylsulfonyl)-7-octenoate (1-c) (0.6 g, 61%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][O:13][C:12]3[C:15]4[C:20]([C:21]([OH:24])=[C:22]([CH3:23])[C:11]2=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:25][C:26]([F:32])([F:31])[S:27]([O-])(=[O:29])=[O:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:25][C:26]([F:32])([F:31])[S:27]([O:24][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12]2[O:13][CH2:14][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:11]=2[C:22]=1[CH3:23])(=[O:29])=[O:28]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: Cc1c2c(c3ccccc3c1O)OCC2c1ccc(C(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1c2c(c3ccccc3c1OS(=O)(=O)C(F)(F)F)OCC2c1ccc(C(C)C)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-ol obtained in Reference Example 252 (2.60 g, 8.17 mmol) and 4-dimethylaminopyridine (2.0 g, 16.3 mmol) in pyridine (30 mL) was added anhydrous trifluoromethanesulfonate (1.51 mL, 9.00 mmol) at room temperature at 0° C., and the mixture was stirred at 50° C. for 8 hours. Water was added to the reaction solution to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 1 N hydrochloric acid and a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 2.8 g (yield 76%) of the title compound. Oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:20]>C1(C)C=CC=CC=1>[Cl:20][C:7]1[N:6]=[N:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: FC(F)(F)c1cccc(-c2cc(Cl)cnn2)c1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(-c2cc(Cl)c(Cl)nn2)c1
Yield: 76 %

Procedure:
5-Chloro-3-[3-(trifluoromethyl)phenyl]pyridazine, 1-oxide (27 g, 0.098 mole, Compound No. 70) and POCl3 (16.9 g, 0.11 mole) were heated to 105° C. in toluene (250 mL) under N2 for 18 h. The solvent was then removed in vacuo and the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered through silica gel and evaporated in vacuo. The crude solid was recrystallized from cyclohexane/ethyl acetate to give 3,4-dichloro-6-[3-(trifluoromethyl)phenyl]pyridazine (21.57 g, 76% yield, Compound No. 47) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][C:11]#[N:12])=[N:8][O:9][C:5]=2[CH:4]=1.[ClH:15].[NH2:16][OH:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[ClH:15].[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][C:11](=[N:16][OH:17])[NH2:12])=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(CC#N)noc2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(CC(N)=NO)noc2c1
Reaction time: 8 h
Yield: 58.4 %

Procedure:
In ethanol (30 ml) was dissolved 6-methoxy-1,2-benzisoxazole-3-acetonitrile (1 g) and thereto was added a solution of hydroxylamine hydrochloride (0.7 g) and sodium carbonate (0.8 g) in water (5 ml) under stirring. After stirring for 4 hours, the mixture was allowed to stand at room temperature overnight. The precipitated crystallines were separated by filtration and added to ethanol containing 20 % of hydrochloric acid. The mixture was stirred for 2 hours and thereto was added ether. The precipitated crystallines were separated by filtration and recrystallized from ethanol-ether to give the desired compound (0.8 g). m.p. 185° to 187°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:15][NH:16][CH2:17]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=C(c2cc(F)cc(F)c2)C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=C1CNC1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 210 mg (0.623 mmol) of tert-butyl 3-[1(3,5-difluorophenyl)-2,2-dimethylpropylidene]azetidine-1-carboxylate in 1 mL of CH2Cl2, was added 1.5 mL of TFA followed by stirring for 1 h at rt. The reaction mixture was concentrated and washed with ether to afford the title compound as white solid; Mass Spectrum: m/e=238 (M+1).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[OH:11].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[O:16]1[CH2:15][CH:14]1[CH2:12][O:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[S:1]1
Reactant: ClCC1CO1
Reactant: OC1CCc2ccccc2S1
Product: c1ccc2c(c1)CCC(OCC1CO1)S2
Yield: 65 %

Procedure:
The procedure of Step A of Example 1 is followed, starting from 1.72 g (10.34 mmol) of thiochromanol and 7.653 g (82.72 mmol) of epichlorohydrin. 1.5 g (6.721 mmol) of 2,3-epoxypropoxythiochroman are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][C:5]([NH2:17])=[C:4]([N+:18]([O-])=O)[CH:3]=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CO.[Zn]>[NH2:17][C:5]1[CH:6]=[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:2]([F:1])=[CH:3][C:4]=1[NH:18][C:33](=[O:34])[O:35][CH2:36][CH3:37]
Reactant: Nc1cc(NCc2ccc(F)cc2)c(F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1cc(F)c(NCc2ccc(F)cc2)cc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.2 %

Procedure:
To a stirred solution of compound 3 (0.400 g, 1.40 mmol, 1.00 equiv) in methanol (10 mL) was added zinc powder (0.470 g, 7.10 mmol, 5.00 equiv) followed by ammonium chloride solution (0.380 g, 9.10 mmol, 5.00 equiv) drop wise. After being stirred for 5 h at RT, DIPEA (0.155 g, 1.54 mmol, 1.10 equiv) and ethyl chloroformate (0.151 g, 1.40 mmol, 1.00 equiv) were added to reaction mixture at 0° C. and the stirring was continued for another 3 h at RT. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (25 mL) and Extracted with EtOAc (2×75 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 1:4) to afford to compound 3A (0.100 g, 21.0%) as brown solid. TLC: 40% EtOAc/Hexane (Rf: 0.50); 1HNMR (400 MHz, DMSO-d6): δ 8.27 (br s, 1H), 7.39-7.34 (m, 2H), 7.12 (t, J=8.8 Hz, 2H), 6.81-6.78 (m, 1H), 5.93 (d, J=9.2 Hz, 1H), 5.79 (t, J=6.4 Hz, 1H), 4.42 (s, 2H), 4.22 (d, J=6.0 Hz, 2H), 4.03 (q, J=6.8 Hz, 2H), 1.19 (t, J=6.8 Hz, 3H); LC-MS: m/z=322 (M++1) at RT 3.54 (95.8% purity); UPLC purity: 98.8%
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][CH:20]([C:23]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](=[O:36])[C:26]2=[CH:37][CH:38]=[CH:39][N:25]2[N:24]=1)[CH2:21][CH3:22].[C:40]1(=O)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>ClCCCl>[CH2:29]([N:28]1[C:27](=[O:36])[C:26]2=[CH:37][CH:38]=[CH:39][N:25]2[N:24]=[C:23]1[CH:20]([NH:19][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:21][CH3:22])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
Acetic acid (65 μl, 0.95 mmol) and sodium triacetoxyborohydride (200 mg, 0.95 mmol) were added to a solution of 2-(1-amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 26, 180 mg, 0.64 mmol) and cyclohexanone (62 mg, 0.64 mmol) in 1,2-dichloroethane (5 mL). The mixture was stirred for 4 h at room temperature concentrated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, dried (MgSO4) and concentrated to give the title compound (211 mg, 91%) as a white solid: 1H NMR (DMSO-d6) δ 0.69–1.19 (m, 10H), 1.38–1.89 (m, 6H), 1.99 (m, 1H), 3.63 (m, 1H), 4.82 (m, 1H), 5.80 (m, 1H), 6.55 (s, 1H), 7.06 (s, 1), 7.15 (m, 2H), 7.22–7.35 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:10]=[C:9]([C:16]([O:18]CC4C=CC=CC=4)=[O:17])[C:8]4[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:7]=4[C:6]=3[C:5]=2[CH:4]=1>CN(C=O)C.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]4[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:7]=4[C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c3cc(C(=O)OCc4ccccc4)c4c(c3c2c1)C(=O)NC4=O
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3cc(C(=O)O)c4c(c3c2c1)C(=O)NC4=O
Reaction time: 2 h

Procedure:
A solution of benzyl 9-methoxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylate (2.00 g), prepared as in example 3, in DMF/MeOH (4:1) (50 mL) containing 5% Pd-C (0.50 g) was hydrogenated at 60 psi for 2 h (Parr apparatus). The solution was filtered through a plug of Celite, which was washed 6 times with neat DMF followed by MeOH (several cycles). The combined filtrate and washings were concentrated to dryness in vacuo and the residue was slurried with diethyl ether to give the 9-methoxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylic acid (5) as a greenish solid. The reaction was repeated 5 times on this scale to and the products were combined to give 9-methoxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylic acid, (8.1 g, 84%). A portion of the product was purified by adsorption onto silica, followed by chromatography on silica, eluting with EtOAc. The product was triturated with diethyl ether to give 9-methoxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylic acid as an orange solid; mp>300° C. 1H NMR δ [(CD3)2SO] 12.15 (s, 1H), 8.42 (d, J=2.5 Hz, 1H), 7.97 (s, 1H), 7.57 (d, J=8.8 Hz, 1H0, 7.25 (dd, J=8.8, 2.5 Hz, 1H), 3.82 (s, 3H), 3.40 (br, 2H). Found: C, 58.69; H, 3.55; N, 8.40. C16H10N2O5,H2O requires C, 58.54; H, 3.68; N, 8.53.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]=[C:8]([C:13]3[CH:14]=[C:15]([S:23]([N:26]4[CH2:30][CH2:29][C@@H:28]([N:31]([CH3:33])[CH3:32])[CH2:27]4)(=[O:25])=[O:24])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:7][C:6]=2[C:5]2=[CH:34][N:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[N:36]=[C:4]2[N:3]=1.[Cl:46][C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][C:54]=1[O:55][CH3:56])[CH2:50][NH2:51].Cl.CCN(C(C)C)C(C)C>CCCCO>[CH3:32][N:31]([CH3:33])[C@@H:28]1[CH2:29][CH2:30][N:26]([S:23]([C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH3:22])=[C:13]([C:8]3[NH:7][C:6]4[C:5]5[C:4](=[N:36][N:35]([CH2:37][C:38]6[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=6)[CH:34]=5)[N:3]=[C:2]([NH:51][CH2:50][C:49]5[CH:52]=[CH:53][C:54]([O:55][CH3:56])=[C:47]([Cl:46])[CH:48]=5)[C:11]=4[C:10](=[O:12])[N:9]=3)[CH:14]=2)(=[O:25])=[O:24])[CH2:27]1
Reactant: CCCOc1ccc(S(=O)(=O)N2CC[C@@H](N(C)C)C2)cc1-c1nc(=O)c2c(Cl)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1
Reactant: COc1ccc(CN)cc1Cl
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(S(=O)(=O)N2CC[C@@H](N(C)C)C2)cc1-c1nc(=O)c2c(NCc3ccc(OC)c(Cl)c3)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1

Procedure:
A mixture of (3R)-1-[[3-(5-Chloro-4,8-dihydro-8-[(4-methoxyphenyl)methyl]-4-oxo-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-yl)-4-propoxyphenyl]sulfonyl]-3-(dimethylamino)pyrrolidine (39 mg, 0.06 mmol), 3-chloro-4-methoxybenzylamine.HCl (25 mg, 0.12 mmol) and DIEA (78 mg, 0.6 mmol) in n-BuOH was heated at 125° C. under nitrogen for 4 h. The reaction mixture was concentrated and the residue was chromatographed (silica gel, 5% MeOH in DCM) to give the desired product (42.6 mg) as a yellow solid. LC: 4.36′ (Gradient 1); MH+: 787.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]([O:12][CH:13]=[CH2:14])(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].O>CO.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[C:6]([O:12][CH:13]=[CH:14][CH2:4][CH:3]([CH3:5])[CH:2]=[CH2:1])(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C=COC(=O)C(C)(C)C
Reactant: C=CC(=C)C
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: CO
Product: C=CC(C)CC=COC(=O)C(C)(C)C
Temperature: 100 °C

Procedure:
(Benzene)ruthenium dichloride dimer (14 mg, 0.056 mmol Ru), silver triflate (20 mg, 0.078 mmol) and 2,2-methylenebis(4-phenyl-2-oxazoline) (17.8 mg, 0.058 mmol) were dissolved in 2 ml of methanol. To the mixed solution were added isoprene (2 ml) and vinyl pivalate (1 ml) and the mixture was stirred under heat at 100° C. for 10 hours. The resulting product was poured into water and the separated organic layer was subjected to a GLC analysis. As a result, it was confirmed that a co-dimer was produced with the conversion rate being 72% and the ratio of an isomer being 4:1.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:37][N:36]([CH3:38])[S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:34])=[O:35]
Reactant: CN(C)S(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)S(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N,N-dimethyl-benzenesulfonamide [CAS 6274-18-6; commercially available] according to general procedure II. Light yellow solid. MS (ISP) 540.4 [(M+H)+]; mp 197° C.