Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]3=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>C1COCC1.CO>[CH:1]1([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]3=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccc3ccccc3c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC1CCc2ccc3ccccc3c21
Reaction time: 6 h

Procedure:
A 12.36 g portion of benzindanone (63 mmole) was dissolved in 300 ml of THF and 150 ml of methanol, and 3.6 g (95 mmole) of sodium borohydride was added at room temperature. After stirring the mixture for 6 hours, the reaction was terminated with dilute hydrochloric acid, and extracted with hexane (100 ml X 2) and ether (100 ml×2). Two stereoisomers of benzindanol were obtained. The crude product was used for the next reaction without purification.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=3)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(OC2CCN(C3CCCC3)CC2)cc1
Solvent: CO
Product: Nc1ccc(OC2CCN(C3CCCC3)CC2)cc1
Yield: 85.8 %

Procedure:
1-cyclopentyl-4-(4-nitrophenoxy)piperidine (1.30 g) was dissolved in methanol, and the target compound (1.0 g, 86%) was obtained as a light brown solid by catalytic reduction using a palladium charcoal catalyst.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1>S(=O)(=O)(O)O.O>[Br:5][C:6]1[CH:7]=[C:8]([Br:12])[CH:9]=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: Brc1cccc(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Add drop wise fuming nitric acid (101.40 mL) to a solution of 1,3-dibromo benzene (102.51 mL) in concentrated sulfuric acid (322.79 mL) and water (62.39 mL) at 0° C. Warm to RT and stir for 12 h. Pour the reaction on ice-water (1500 mL). Filter the resulting yellow solid under vacuum and dry to afford 178.46 g of the title compound. MS (ES+): m/z=281 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:5]1)(=[O:3])[CH3:2].[Br:19]Br>C(O)(=O)C.ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:19])=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)N1CC(CCS(C)(=O)=O)c2ccccc21
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)N1CC(CCS(C)(=O)=O)c2cc(Br)ccc21

Procedure:
Bromination was done by treatment of 19a with bromine in a mixture of acetic acid and dichloromethane. The compound was an oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[CH2:18][CH:10]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:18][CH:10]([OH:9])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: c1ccc(CC2CO2)cc1
Solvent: CO
Product: OC(CNc1ccc(Br)cc1)Cc1ccccc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A mixture of 4-bromoaniline (1.75 g, 0.0102 mol) and 2,3-epoxy-propylbenzene (1.77 g, 0.0132 mol) in methanol (40 mL) was heated at reflux for 16 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield 1-(4-bromoanilino)-3-phenyl-2-propanol (2.2 g, 0.00719 mol) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(OCC)(=O)C.[H][H]>C(O)C.[Pt](=O)=O>[F:1][C:2]1[C:3]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[CH:4][CH:5]=[C:6]([NH2:8])[CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-n2cccn2)c(F)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2cccn2)c(F)c1

Procedure:
A solution of 1-(2-fluoro-4-nitrophenyl)-1H-pyrazole (3 g, 14.5 mmol) and platinum(IV) oxide (100 mg) in ethanol (100 ml) with ethyl acetate (100 ml) was reduced under 40 psi hydrogen for 30 min, then filtered and the solvent removed, to give 5-fluoro-4-(pyrazol-1-yl)phenylamine as a colourless oil: MS (ES+) m/z 178 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(O)c2)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(OCc3ccccc3)c2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl 5,6-dihydro-4-(3-hydroxyphenyl)pyridine-1(2H)-carboxylate (crude, 100 mg) and potassium carbonate (300 mg) in DMF was added benzyl bromide (60 μL) at room temperature. The resulting mixture was stirred at 80° C. for 16 h. The mixture was cooled down, diluted with ethyl acetate, washed with water, brine, dried and concentrated. The product (60 mg) was purified by combiflash using hexane/ethyl acetate (max. EtOAc 10%) to afford tert-butyl 4-(3-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate which was then converted to the final compound using procedures analogous to those for example 1. MS(ESI): (M+H)+=462.2
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:37])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:37][C:23]1[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Yield: 93.6 %

Procedure:
To a stirred and cooled suspension of N-tert-butyl-3-[6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonamide (example 287) (0.239 g, 0.455 mmol) in dichloromethane (1.5 mL) was added TFA (10 mL) and the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.200 g, 94%). MS (ISP) 470.3 [(M+H)+]; mp>250° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:20]>C(Cl)Cl.O1CCOCC1>[ClH:20].[Br:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCCCBr)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: BrCCCCOC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.47 g (7.35 mmol) 4-(4-Bromo-butoxy)-piperidin-1-carboxylic acid tert-butyl ester in 10 ml of CH2Cl2 was added 20 ml of 4N HCl in dioxane. The reaction-mixture was stirred for 2 h at RT and then concentrated under reduced pressure. The crude residue was suspended several times with Et2O and then dried in vacuo to yield 1.78 g (quantitative) of 4-(4-Brom-butoxy)-piperidine hydrogen chloride, MS: 236 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[B:8](OC(C)C)([O:13]C(C)C)[O:9]C(C)C.N#N.[Li]CCCC.CCCCCC.Cl>C1COCC1>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([B:8]([OH:13])[OH:9])[CH:3]=1
Reactant: Cc1cc(Br)cs1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)cs1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-2-methylthiophene (300 mg, 1.69 mmol) and triisopropyl borate (486 μL, 2.12 mmol) were dissolved in THF (1 mL) and the solution was vacuumed and filled with N2 3 times. The solution was cooled to −70° C. using an acetone/dry ice bath. 2.5 M of n-BuLi in hexane (1.0 mL, 2.54 mmol) was added drop wise and the mixture was stirred for an additional 30 minutes while the temperature was held at −70° C. The reaction mixture was allowed to warm up to −20° C. and 2 mL of 3 N HCl was added. When the mixture was warmed up to room temperature, two layers were separated. The water layer was neutralized to about pH 7, using 5 N NaOH. Both layers were extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na2SO4. The material was not further purified and was used directly in the next step. MS (ESI): 143.05 [M+H]+; HPLC tR=1.30 min (HPLC: Anayltical—2 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[C:13](Cl)(=[O:15])[CH3:14]>O1CCCC1>[F:12][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][C:13](=[O:15])[CH3:14])[CH:3]=1)[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: CC(=O)Cl
Reactant: Nc1cc(F)cc2c1NC(=O)C2
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(F)cc2c1NC(=O)C2
Temperature: 0 °C
Yield: 96.1 %

Procedure:
A stirred solution of 7-amino-5-fluoro-1,3-dihydro-indol-2-one (1.0 g, 6 mmol) obtained from Example 4 in 30 ml of tetrahydrofuran was added with tirethylamine (1.3 ml, 9 mmol). The solution was cooled down to 0° C. in an ice-water bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. The resulting mixture was heated to reflux for 1.5 hours and cooled until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-acetamide (1.2 g, 96%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.C(N(CC)CC)C.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>ClCCl>[CH2:19]([S:21]([NH:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])(=[O:23])=[O:22])[CH3:20]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N[C@@H](CC(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A stirred solution of 3.0 g of H-Leu-OMe.HCl in 30 mL of dichloromethane was adjusted to pH 8 using triethylamine and cooled at 0° C. Then 3.2 mL of ethanesulfonyl chloride and 2.3 mL of triethylamine were added. After stirring for 16 h at room temperature the reaction mixture was washed successively with 0.5 N hydrochloric acid, water and aqueous 5% sodium hydrogencarbonate and concentrated. The crude product was purified by chromatography on silica gel (eluent: dichloromethane/methanol=9/1 v/v) to yield 3.3 g of EtSO2-Leu-OMe.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][OH:8].[H-].[Na+].[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[NH:13]1
Reactant: CN1CCC[C@@H]1CO
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1CON1C=CC=C(Cl)N1
Temperature: 0 °C
Yield: 41.7 %

Procedure:
(R)-1-Methyl-2-pyrrolidinemethanol (300 mg, 2.61 mmol) was dissolved in anhydrous THF and cooled to 0° C. with stirring. NaH (80% dispersion in mineral oil, 0.082 g, 2.9 mmol) was added and the mixture was slowly warmed to room temperature with stirring. After 30 minutes a THF solution of 3,6-dichloropyridazine (0.41 g, 2.74 mmol) was added to the mixture via syringe. The reaction was stirred for 48 hours. The solvent was then evaporated in vacuo and the mixture diluted with chloroform, washed with saturated NaHCO3 and then with brine. The organic layer was dried over MgSO4. The resulting crude material was purified by flash chromatography (10% MeOH/CHCl3) to give 0.25 g (42% yield) of the title compound as a cream colored solid. MS (DCI/NH3) m/e 228 (M+H)+. [α]25D =+32° (c=1, MeOH).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[Br-].[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:11])=[O:10]>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]([OH:11])=[O:10])=[CH:2]1
Reactant: O=C(O)CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccsc1
Agent: [Br-]
Product: O=C(O)CCCCCCCC=Cc1ccsc1

Procedure:
Reaction of 3-thiophenecarboxaldehyde with (8-carboxy-octyl)-triphenyl-phosphonium bromide, in analogy with example 34, step 2, produced 10-(thiophen-3-yl)-dec-9-enoic acid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:35]=[CH:36][CH:37]=1)[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:19]([CH3:22])=[N:20][N:21]=3)[C:13]=2[CH:12]=[C:11]1[C:23]1[CH:27]=[CH:26][N:25]([C:28]2([CH2:32][C:33]#[N:34])[CH2:31][NH:30][CH2:29]2)[N:24]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:30]1[CH2:31][C:28]([CH2:32][C:33]#[N:34])([N:25]2[CH:26]=[CH:27][C:23]([C:11]3[N:10]([CH2:9][C:8]4[CH:35]=[CH:36][CH:37]=[C:6]([Cl:5])[CH:7]=4)[C:14]4[CH:15]=[CH:16][C:17]5[N:18]([C:19]([CH3:22])=[N:20][N:21]=5)[C:13]=4[CH:12]=3)=[N:24]2)[CH2:29]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3cccc(Cl)c3)n12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(CC#N)(n2ccc(-c3cc4c(ccc5nnc(C)n54)n3Cc3cccc(Cl)c3)n2)C1
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
Acetyl chloride (1.1 μL, 0.016 mmol, Aldrich) in DCM (0.35 mL) was added to (3-{3-[6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl]-1H-pyrazol-1-yl}azetidin-3-yl)acetonitrile (6.0 mg, 0.013 mmol, from Step 1). Triethylamine (3.7 μL, 0.026 mmol) was then added and the reaction was stirred for 10 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product (4.0 mg, 61%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:9]([C:10](=[O:12])[N:11]=1)=[CH:8][C:7]([I:13])=[CH:6][CH:5]=2.[NH:14]1[CH2:19][CH2:18][C:17]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[O:20]2)[CH2:16][CH2:15]1>CN1C(=O)CCC1>[I:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[O:20]3)[CH2:16][CH2:15]1)=[N:11][C:10]2=[O:12]
Reactant: O=c1nc(Cl)[nH]c2ccc(I)cc12
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Solvent: CN1CCCC1=O
Product: O=C1OC2(CCN(c3nc(=O)c4cc(I)ccc4[nH]3)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Stir 2-chloro-6-iodo-1H-quinazolin-4-one (75 mg) and spiro[isobenzofuran-1,4′-piperidin]-3-one (100 mg) in NMP (2 mL) at 110° C. for 6 h. Cool the mixture and pour in ice-water (20 mL). After stirring for 5 min, filter the precipitate and wash with MeOH to obtain 1′-(6-iodo-1H-quinazolin-4-on-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]2[NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=3[N:21]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.CC1C=CC(S(O[CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]2)(=O)=O)=CC=1>>[NH2:20][C:16]1[C:15]2[N:21]=[C:12]([S:11][C:3]3[C:2]([Br:1])=[CH:10][C:6]4[O:7][CH2:8][O:9][C:5]=4[CH:4]=3)[N:13]([CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]3)[C:14]=2[CH:19]=[CH:18][N:17]=1
Reactant: CC(=O)N1CCC(CCOS(=O)(=O)c2ccc(C)cc2)CC1
Reactant: Nc1nccc2[nH]c(Sc3cc4c(cc3Br)OCO4)nc12
Product: CC(=O)N1CCC(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)nccc32)CC1

Procedure:
The title compound was prepared by a similar procedure described for step 7 of example 1 using 2-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-1H-imidazo[4,5-c]pyridin-4-amine and 2-(1-acetylpiperidin-4-yl)ethyl 4-methylbenzenesulfonate. 1H NMR (DMSO-d6) δ; 7.70 (d, J=6.0 Hz, 1H), 7.38 (s, 1H), 6.79 (d, J=6.0 Hz, 1H), 6.66 (s, 1H), 6.42 (s, 2H), 6.07 (s, 2H), 4.30 (brd, J=13.2 Hz, 1H), 4.20 (t, J=7.2 Hz, 2H), 3.74 (brd, J=13.2 Hz, 1H), 2.89 (t, J=13.6 Hz, 1H), 2.40 (t, J=13.6 Hz, 1H), 1.96 (s, 3H), 1.66 (m, 2H), 1.56-1.51 (m, 2H), 1.43 (m, 1H), 1.08 (m, 1H), 0.94 (m, 1H); LC-MS [M+H]+ 518.09.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CO.[OH-].[Na+].Cl>O>[CH3:8][C:6]1[CH:5]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3cc(C)cc(C)c3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2cc(C)cc(C)c2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.9 %

Procedure:
To methyl 4-[(2-{1-[5-(3,5-dimethylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.015 mmol, 6.5 mg), methanol (1 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.077 mL) was added at room temperature. After 20 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.077 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was recovered by filtration and dried to give the desired product as a yellow solid (1.7 mg, yield 27%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1.[CH3:19]I>C1COCC1>[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:19])[CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Clc1nccc(-c2c[nH]c3ccccc23)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
NaH (1.707 g, 42.68 mmol, 40% dispersion in mineral oil) was added in small portions to a cooled (0° C.) mixture of 3-(2-chloropyrimidin-4-yl)-1H-indole (Intermediate 131, 8.168 g, 35.57 mmol) in THF (250 mL). The resulting mixture was stirred at 0° C. for 0.5 h and then CH3I (2.67 mL, 42.68 mmol) was added and the mixture stirred at 0° C. for a further 3 h. The reaction was quenched by the addition of sat. NaHCO3 (25 mL). The mixture was then diluted with EtOAc (100 mL), and the resulting solution was washed with sat. NaHCO3 (50 mL), water (50 mL) and sat. brine (50 mL). The organic solution was then concentrated in vacuo. Purification by FCC, eluting with 0-20% CH3OH in CH2Cl2 gave the title compound (8.35 g, 96%) as a pale yellow solid; 1H NMR: 3.90 (3H, s), 7.30 (2H, pd), 7.54-7.60 (1H, m), 7.82 (1H, d), 8.38-8.44 (1H, m), 8.49 (1H, s), 8.53 (1H, d); m/z: ES+ MH+ 1244.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:25]([F:24])[CH:26]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: Cc1ccc(C(=O)Cl)cc1F
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(OCCN3CCOCC3)c(-c3c(Cl)cnn3C)c2)cc1F
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To a solution of 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (0.040 g, 0.12 mmol) in CH2Cl2 (1.8 mL) was added 3-fluoro-4-methylbenzoyl chloride (0.025 mL, 0.14 mmol) and trietylamine (0.022 mL, 0.15 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.0096 g, 14%). LCMS m/z (%) 473 (M+H35Cl, 100), 475 (M+H 37Cl, 27). 1H NMR (400 MHz, DMSO-d6) δ: 10.31 (s, 1H), 7.96 (dd, J=2.6, 11.6 Hz, 1H), 7.76-7.72 (m, 3H), 7.67 (s, 1H), 7.49-7.44 (m, 1H), 7.30 (d, J=9.1 Hz, 1H), 4.48-4.44 (m, 1H), 4.38-4.30 (m, 1H), 3.66 (s, 3H), 4.00-2.90 (m, 10H), 2.32 (s, 3H).
Reaction SMILES: C([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=3)[CH:11]=2)[C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4]1)C.[CH:26]1C=CC(C2C=CC=CC=2)=C[CH:27]=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[F:21][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=1)[NH:3][CH:4]=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:6]2=[O:22]
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3cc(C)nc(C)c3)cc21
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O

Procedure:
Preparation of 1-ethyl-6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid was then carried out by refluxing the EMME adduct of Example 4B in Dowtherm A to produce ethyl 6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylate (Example 4C), ethylating the compound of Example 4C by heating it with ethyl iodide in dimethylformamide in the presence of anhydrous potassium carbonate to produce ethyl 1-ethyl-6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylate (Example 4D) and hydrolyzing the compound of Example 4D by refluxing it in aqueous sodium hydroxide solution containing methanol to produce 1-ethyl 6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid (Example 4E).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10]CC2C=CC=CC=2)[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4]>C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: COC(=O)C1CC(OCc2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(O)CN1C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
4-Benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (500 mg, 1.49 mmol) was taken up in ethyl acetate in a Paar vessel. The solution was flushed with argon and Pd/C (200 mg) was added to the vessel. The argon atmosphere was replaced by hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen atmosphere was replaced by argon and the solution was filtered through a celite pad. The pad was washed twice with ethyl acetate. The solvent was removed under reduced pressure. The product was used without further purification. Yield 350.98 mg. C11H19NO5 MS m/e=246.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:5](Cl)=[O:6])[CH2:4][CH2:3]1.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1([C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[O:6])[CH2:4][CH2:3]1
Reactant: CC1(C(=O)Cl)CC1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C(=O)n2ccnc2)CC1
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of 1-methylcyclopropylcarbonyl chloride (11.8 g) in toluene (15 ml) was added dropwise to a solution of imidazole (13.6 g) in tetrahydrofuran (100 ml) whilst maintaining the temperature below 25° C. The mixture was stirred for 3 hours and filtered. The filtrate was evaporated to dryness to give 1-(1-methylcyclopropylcarbonyl)-imidazole (13.6 g) as a white solid, mp 34°-35° C.