Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:13]2[CH2:18][CH2:17][N:16]([C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:13]2[CH2:14][CH2:15][N:16]([C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]3[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N(c2ccccc2)C2CCN([C@@H]3CCCC[C@@H]3c3ccccc3)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(c1ccc(O)cc1)N(c1ccccc1)C1CCN([C@@H]2CCCC[C@@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
A solution of (+/−)-4-methoxy-N-phenyl-N-[cis-1-(2-phenyl-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide (0.047 g, 0.090 mmol) in dichloromethane (2 ml) was cooled to −78° C. Boron tribromide IM in dichloromethane (0.30 ml, 0.30 mmol) was added dropwise at this temperature. The mixture was then warmed to room temperature and stirred for 5 hours. The reaction was quenched with sodium hydroxyde 1N and extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated. The residue was purified via flash chromatography on silica gel (dichloromethane/methanol/ammonia 110:10:1), yielding the title compound (0.029 mg, 63%) as an off-white solid, MS (ISP): m/e=491.3 (M+H+).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:42])[NH:24][C:25]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([N:36]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH3:37])=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:38]([N:36]([CH3:37])[C:29]1[C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:25]2[NH:24][C:23](=[O:42])[CH2:22][C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)=[N:27][C:26]=2[CH:28]=1)[CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c1)=N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(N)(=O)=O)c3)c1)=N2

Procedure:
) The title compound was prepared from the above described 3′-[8-(isobutyl-methyl-amino)-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (250 mg) and TFA (5 mL) according to the general procedure I step 2. Obtained as a light yellow solid (69 mg, 25%). MS (ISN) 543.5 [(M−H)−]; mp 232° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([Si:13]([CH3:19])([CH3:18])[O:14][CH2:15][C:16]#[CH:17])([CH3:12])([CH3:11])[CH3:10]>[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:17]#[C:16][CH2:15][O:14][Si:13]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:18])[CH3:19])=[CH:4][N:3]=1
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Reactant: Nc1cnc(Br)cn1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)OCC#Cc1cnc(N)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
2-Amino-5-bromopyrazine (1.50 g, 8.6 mmol) was dissolved in anhydrous, deoxygenated DMF (24.5 mL) with triethylamine (10.5 mL). Copper(I) iodide (0.33 g, 1.7 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.61 g, 0.51 mmol) and tert-butyldimethyl(prop-2-ynyloxy)silane (1.90 g, 11.2 mmol) were added and the solution was stirred overnight at 60° C., then cooled and partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried (Na2SO4) and evaporated. The residue was purified by silica chromatography to give 2-amino-5-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)pyrazine (2.06 g, 91%) as a brown solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:16]([C:18]#[N:19])[Na].CC(O)=O>C(Cl)Cl>[C:13]([C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:18]([NH2:19])=[O:16])[CH2:3][CH2:2]2)=[CH:12][CH:11]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: N#CO[Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CCN(C(N)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 111.4 %

Procedure:
1-(4-Piperazin-1-yl-phenyl)-ethanone (500 mg, 2.45 mmol) was dissolved in DCM (20 ml) and NaOCN (318.6 mg, 4.90 mmol) and AcOH (0.28 ml, 4.90 mmol) were added to the resulting solution. The mixture was stirred at room temperature for 36 h and the resulting precipitate was filtered off, washed with DCM and water to give 675 mg of 4-(4-acetyl-phenyl)-piperazine-1-carboxylic acid amide (crude compound was used without further purification in the next step).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:10])[CH2:5]2.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:10])[CH2:5]2
Reactant: O=C1Cc2cc(Br)ccc21
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: OC1(c2ccccc2)Cc2cc(Br)ccc21
Yield: 75 %

Procedure:
Using 3-Bromobicyclo[4.2.0]octa-1,3,5-triene-7-one (3) (2.0 g, 10.1 mmol), diethyl ether (20 ml), phenyl magnesium bromide (3M in diethyl ether, 3.4 ml, 10.1 mmol) afforded 3-Bromo-7-phenyl-bicyclo[4.2.0]octa-1,3,5-triene-7-ol (4a) as a pale yellow oil (2.1 g, GC-MS: M+=274, M−=276, 75% yield, isolated as a mixture of isomers).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:16])[CH3:2].[CH:18]1([S:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH:29]=O)(=[O:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH:18]1([S:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH2:29][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[C:7]=2[CH3:16])(=[O:25])=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=Cc1ccccc1S(=O)(=O)C1CCCCC1
Reactant: CCOC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)C2CCCCC2)c2cc(F)ccc21
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a stirred solution of [5-fluoro-2-methyl-1H-indol-1-yl]acetic acid ethyl ester (0.85 g, 3.62 mmol) at room temperature in dichloromethane (20 mL) was added 2-(cyclohexylsulfonyl)benzaldehyde (1.00 g, 3.97 mmol) followed by triethylsilane (2.9 mL, 18.3 mmol). TFA (0.85 mL, 11.0 mmol) was then added dropwise over 15 minutes, and after the addition was complete, the resulting mixture was stirred for 2 hours. Saturated aqueous NaHCO3 was then added to the solution, and the separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting solid was purified by trituration with light petroleum then recrystallised from an ethyl acetate/hexanes mixture to afford ethyl 2-(3-(2-(cyclohexylsulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetate (0.875 g, 1.86 mmol, 51%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)[N:18]=[CH:19][N:20]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Oc2ccc(Nc3cc(NC4CCNC4)ncn3)cc2)cc1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a stirred solution of tert-butyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyrrolidin-1-carboxylate (0.1 g, 0.2 mmol) in dry CH2Cl2 (2.0 mL) at 0° C. was added CF3COOH (2 mL, 20 vol.) and the reaction mixture was kept at this temperature for 30 min. It was allowed to come to rt and stir at this temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was quenched with water (2 mL), basified with NaHCO3 solution, and was extracted with ethyl acetate (2×8 mL). The combined ethyl acetate extract was washed with water (2 mL) and brine (2 mL), was dried over Na2SO4 and was concentrated under reduced pressure to give N4-(4-phenoxyphenyl)-N6-(pyrrolidin-3-yl)pyrimidine-4,6-diamine (0.025 g, 32.4%) as a light a brown solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7]C(=O)C)[CH2:3][CH2:2]1.[OH-].[K+].Br[C:14]1([CH3:20])[CH2:19][CH2:18][O:17][C:15]1=[O:16].C(Cl)(=O)C>CC(O)C>[CH3:20][C:14]1([S:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:19][CH2:18][O:17][C:15]1=[O:16]
Reactant: CC(=O)SC1CCOCC1
Reactant: CC1(Br)CCOC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(=O)Cl
Product: CC1(SC2CCOCC2)CCOC1=O
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To thioacetic acid S-(tetrahydro-pyran-4-yl)ester (4.25 g; 26.5 mmol) in 2-proponal (20 mL) was added KOH (36.4 mL of a 0.8 M solution in 2-propanol; 29.2 mmol). The mixture was stirred 30 minutes and α-bromo-α-methyl-γ-butyrolactone (3.00 mL; 26.5 mmol) was added dropwise. The mixture was stirred 2 hours, quenched with acetyl chloride (0.62 mL; 8.75 mmol) and the volatiles removed in vacuo. The residue was diluted with ether and filtered. Removal of the volatiles in vacuo provided a residue which was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. The product-rich fractions were concentrated in vacuo to provide 2.65 g of the desired product. 1H NMR (CDCl3) δ 4.45 (m, 1H), 4.29 (dt, 1H), 3.89 (m, 2H), 3.48 (dq, 2H), 3.20 (m, 1H), 2.33 (m, 1H), 2.21 (m, 1H), 1.95 (m, 1H), 1.88 (m, 1H), 1.86 (m, 2H), 1.65 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12]C(O)=O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:16])[CH:8]=2)[N:3]=1.[S:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][NH:20][CH2:19][CH2:18]1>C(O)CCC.ClCCl>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:16])[CH:8]=2)[N:3]=[C:2]([N:20]2[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:17][CH2:18][CH2:19]2)[CH:11]=1
Reactant: Cc1ccc2nc(Cl)cc(CC(=O)O)c2c1
Reactant: c1ccc2c(c1)CNCCS2
Solvent: CCCCO
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)cc(C)c2c1
Temperature: 160 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
A solution of (2-chloro-6-methylquinolin-4-yl)acetic acid (118 mg, 0.5 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine (247 mg, 1.5 mmol) in n-butanol (0.2 mL) was heated with stirring in a sealed 0.5 mL of microwave process vial for 2 hours at 160° C. After being cooled to room temperature, the reaction mixture was diluted with dichloromethane (50 mL), washed with a saturated aqueous solution of sodium carbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20-30% ethyl acetate in petroleum ether) to afford 100 mg of the desired product (yield was 62%). MS (ESI+) [(M+H)+] 321.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+]>CCO.O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([CH:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:22])=[O:3])[CH2:7][CH2:8]2)=[O:21])=[CH:18][CH:17]=1
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccc(OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of [4-(4-methoxy-benzoyl)-piperidin-1-yl]-acetic acid ethyl ester (11.7 g, 38 mmol, 1 eq.) in 154 mL of EtOH was added a solution of NaOH (3.07 g, 77 mmol, 2 eq.) in 154 mL of H2O. The resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was concentrated and treated with 1 N HCl to pH 5. The resulting mixture was freeze dried using lyophilizer to remove H2O. The resulting yellow solids were washed with dichloromethane/methanol and filtered off NaCl. The filtrate was concentrated to give the title compound as a white solid (11 g, 38 mmol). Exact mass calculated for C15H20N1O4 278.1. MS (ESI) m/z 278.8 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2([NH:13][C:14]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)=[O:15])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.F[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[C:33]([F:36])([F:35])[F:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CC(C)=O>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([O:1][C:2]2[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]3([NH:13][C:14]([C:16]4[CH:21]=[N:20][CH:19]=[N:18][CH:17]=4)=[O:15])[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)=[C:26]([C:33]([F:34])([F:35])[F:36])[CH:27]=1)#[N:30]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(NC1(C(=O)NCc2ccc(O)cc2)CC1)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cncnc4)CC3)cc2)c(C(F)(F)F)c1
Yield: 82 %

Procedure:
A solution of 100 mg (0.32 mmol) of pyrimidin-5-carboxylic acid[1-(4-hydroxy-benzylcarbamoyl)-cyclopropyl]-amide, 60.5 mg (0.32 mmol) of 4-fluoro-3-trifluoromethyl-benzonitrile and 110 mg (0.8 mmol) of potassium carbonate in 5 mL DMF was stirred for two hours at 110° C. After cooling the mixture was diluted with approx. 3 mL acetone, filtered and evaporated down. The crude product thus obtained was purified by column chromatography (reversed phase).
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:29])[C:3]=1[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15](O)=[O:16])[CH:13]=2)[NH:8][CH:7]=1)=[O:5].[CH2:30]([NH2:32])[CH3:31].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>O1CCCC1.O>[CH2:30]([NH:32][C:15]([C:12]1[CH:13]=[C:14]2[C:6]([C:4](=[O:5])[C:3]3[C:18]([F:29])=[CH:19][CH:20]=[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:24])=[O:25])[C:2]=3[F:1])=[CH:7][NH:8][C:9]2=[N:10][CH:11]=1)=[O:16])[CH3:31]
Reactant: CCN
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C(=O)O)cc23)c1F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C(=O)NCC)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To 3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (P-1559, 38.0 mg, 0.090 mmol) in tetrahydrofuran (2.3 mL) was added a solution of ethylamine (2.0 M in tetrahydrofuran, 0.20 mL), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (80.0 mg, 0.17 mmol) and triethylamine (0.30 mL, 2.2 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred overnight at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give the compound as a white solid (P-1630, 13.2 mg, 33%). MS (ESI) [M−H+]−=449.0.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:8](=[O:23])[C:7]3=[CH:24][N:25](S(C4C=CC(C)=CC=4)(=O)=O)[C:5]([C:6]=23)=[N:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:20]([CH3:21])[CH3:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:8](=[O:23])[C:7]3=[CH:24][NH:25][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(F)cnc42)CN([C@@H](C(=O)OC(C)(C)C)C(C)C)C3=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](C(=O)OC(C)(C)C)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60.4 %

Procedure:
To a stirred solution of (R)-tert-butyl 2-(6-fluoro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoate (933 mg, 1.860 mmol) in MeOH (4 mL) was added aqueous NaOH (1N, 2 mL). The reaction mixture was stirred at 25° C. for 40 min. The reaction was partitioned between DCM and brine. The organics were dried over MgSO4 and concentrated. Purification by silica column chromatography (MeOH/DCM, 0-5%) afforded the title compound as a yellow oil (0.39 g, 60.4%). [M+H] calc'd for C18H22FN3O3, 348; found, 348.5.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH:10]=[C:9]2[CH:20]=[O:21].[CH2:27]([Mg]Br)[CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH:10]=[C:9]2[C:20](=[O:21])[CH2:27][CH3:28]
Reactant: CC[Mg]Br
Reactant: N#CCCCn1cc(C=O)c2cc(OCc3c(Cl)cccc3Cl)ccc21
Solvent: C1CCOC1
Product: CCC(=O)c1cn(CCCC#N)c2ccc(OCc3c(Cl)cccc3Cl)cc12
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a flame dried flask was added a solution of 4-[5-(2,6-dichlorobenzyloxy)-3-formyl-indol-1-yl]butyronitrile (0.23 g, 0.59 mmol) in THF (10 mL) and cooled to −78° C. To this solution ethyl magnesium bromide (1.0M in THF, 0.65 mL, 0.65 mmol) was added via dropwise addition. The reaction was stirred at −78° C. for 3 h then warmed to room temperature slowly. After stirring at room temperature for 18 h, the reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over Na2SO4. Purification by flash column chromatography (silica gel, ethyl acetate/hexane) afforded three products, one of which was identified by NMR, IR and LC-MS as the ketone 4-[5-( 2,6-dichlorobenzyloxy)-3-propionyl-indol-1-yl]butyronitrile (0.034 g, 14%). MS(ES) m/e 415.0 [M+H]+. None of the expected secondary alcohol was recovered.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[CH2:32][NH2:33])=[CH:27][CH:26]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:33][CH2:32][CH:31]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)[C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)=[O:18])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: NCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: O=C(NCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid was coupled with 2,2-bis-(4-chloro-phenyl)-ethylamine as in EXAMPLE 1, Part C. HPLC: RT=11.40 min. MS (ESI−): mass calcd. for C27H19Cl3N4O3S2, 616.00; m/z found, 615/617 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.49 (s, 1H), 8.36 (dd, J=7.1, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 7.72 (dd, J=8.8, 7.0, 1H), 7.68 (d, J=1.8, 1H), 7.34-7.30 (m, 4H), 7.18-7.13 (m, 4H), 6.89 (d, J=8.4, 1H), 6.86 (dd, J=8.4, 1.8, 1H), 5.87 (br t, J=5.6, 1H), 4.24 (t, J=8.0, 1H), 3.95 (dd, J=7.9, 5.9, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:10][OH:11].Cl.[OH-].[K+].O>CO.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:10][OH:11]
Reactant: O=Cc1cccc(I)c1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: ONCc1cccc(I)c1

Procedure:
3-Iodobenzaldehyde prepared above (8.1 g, 34.9 mmol) was dissolved in 50 mL MeOH and 20 mL THF. After addition of H2NOH.HCl (10 mL H2O) and 6N KOH, an additional 20 mL H2O, 10 mL THF, and 10 mL MeOH were added. The product was recovered as a white solid (7.96 g, 91.6%, 92% desired product). mp: 63.0-70.0° C. IR (film): 3256, 3056, 2857, 1591, 1564, 1470, 1420, 1063, 995, 777. 1H-NMR (400 MHz, CDCl3): δ 7.73 (t, 1H, J=1.6, C6-H), 7.63 (dt, 1H, J=7.9, 1.3, C5-H), 7.31 (d, 1H, J=7.6, C7-H), 7.09 (t, 1H, J=7.8, C6-H), 5.5 (br s, 1H, C1-NHOH), 5.1 (br s, 1H, C1-NHOH), 3.98 (s, 2H, C1-H2). 13C-NMR (100 MHz, CDCl3): δ 139.9,137.9, 136.6, 130.2, 128.2, 94.4, 57.4. EI-MS m/z (rel int): 249 (M+, 65), 217 ([M−NHOH]+, 100). CI-MS (NH3) m/z (rel int): 284 ([M+2NH3+H]+, 28), 267 ([M+NH4]+, 100), 250 ([M+H]+, 45).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([C@@H:9]([NH2:16])[CH2:10][C:11]3[N:12]=[CH:13][NH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[C:29]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30])[C:23](O)=[O:24].ClCl>ClCCl.CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([C@@H:9]([NH:16][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:28]([C:29]([N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[O:30])=[C:20]([CH3:19])[CH:21]=3)[CH2:10][C:11]3[N:12]=[CH:13][NH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: N[C@@H](Cc1c[nH]cn1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](Cc2c[nH]cn2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 55 %

Procedure:
Prepared analogously to Example 10d from (S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-(1H-imidazol-4-yl)ethylamine and 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid. Yield: 55% of theory. Rf value: 0.72 (silica gel; dichloromethane/methanol=4:1); C25H25ClN6O2 (476.97); mass spectrum: (M+H)+=477/479 (chlorine isotope).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Br[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][N:14]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:23]([O:25][CH3:26])=[O:24])[C:13]2=[O:31]>>[CH3:30][C:29]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[N:14]1[C:13](=[O:31])[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([N:6]3[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]3)[CH:11]=2)[N:16]=[CH:15]1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(Br)cc3c2=O)c1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2ccc3ncn(-c4cc(C(=O)OC)ccc4C)c(=O)c3c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting material N-ethylpiperazine was reacted with methyl 3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate to give methyl 4-methyl-3-[6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoate; NMR Spectrum: (DMSOd6) 1.05 (t, 3H), 2.17 (s, 3H), 2.40 (m, 2H), 2.53 (m, 4H), 3.29 (m, 4H), 3.87 (s, 3H), 7.48 (s, 1H), 7.63 (m, 3H), 7.97 (s, 1H), 8.02 (d, 1H), 8.10 (d, 1H); Mass Spectrum: M+H+ 407.