Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.CC1C=CC(C2[O:21]C=CN=2)=CC=1>>[O:10]1[CH:11]=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH:1]=[O:21])=[CH:7][CH:6]=2)=[N:9]1
Reactant: Cc1ccc(-c2ncco2)cc1
Reactant: Cc1ccc(-c2ccon2)cc1
Product: O=Cc1ccc(-c2ccon2)cc1

Procedure:
The title compound is prepared by a procedure analogous to Step B of Reference Example 73 by substituting 3-(4-methylphenyl)isoxazole (prepared as described in J. Organomet. Chem. 1966, 6, 598) for the 2-(4-methylphenyl)oxazole of Step B of Reference Example 73. MS 174 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:21](O)=O)[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(OC1C=CC(S(N[C@H]2CCC[C@H]2[C:44]([NH:46][OH:47])=[O:45])(=O)=O)=CC=1)C#CC>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][C@H:16]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:21]2[C:44]([NH:46][OH:47])=[O:45])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)O)CCCC2)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@H]2CCC[C@H]2C(=O)NO)cc1
Product: CC#CCOc1ccc(S(=O)(=O)N[C@H]2CCCC[C@H]2C(=O)NO)cc1
Yield: 63.5 %

Procedure:
(1R,2S)-2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}aminocyclopentanecarboxylic acid (0.506 g, 1.5 mmol) was converted to (1R, 2S)-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxycyclopentanecarboxamide (0.28 g) as described in Example 21 to give an off-white solid (0.185 g), mp 140-145° C. Electrospray Mass Spec 353.4 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].[Li]CCCC.[CH2:13]1[O:15][CH2:14]1>C(OCC)C>[CH2:1]([C:3]1[S:4][C:5]([CH2:14][CH2:13][OH:15])=[CH:6][CH:7]=1)[CH3:2]
Reactant: C1CO1
Reactant: CCc1cccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCc1ccc(CCO)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-ethylthiophene (2 g, 17.85 mmol, 1 eq) in anhydrous diethyl ether at 0° C. was added n-BuLi (8.6 mL, 21.4 mmol, 2.5 M in hexanes, 1.2 eq) over 15 minutes. The mixture was stirred at room temperature for 30 minutes. After cooling to 0° C., a solution of ethylene oxide (1.1 mL, 21.4 mmol, 1.2 eq) in anhydrous ether was added. After stirring at 0° C. for 3 hr, the reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10]([NH:22][S:23]([C:26]2[S:27][C:28](Br)=[CH:29][CH:30]=2)(=[O:25])=[O:24])([N:19]([CH3:21])[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10]([NH:22][S:23]([C:26]2[S:27][C:28]([C:36]3[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=3)=[CH:29][CH:30]=2)(=[O:25])=[O:24])([N:19]([CH3:21])[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C1(NS(=O)(=O)c2ccc(Br)s2)CN(C(=O)OC(C)(C)C)CCc2ccccc21
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)C1(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CN(C(=O)OC(C)(C)C)CCc2ccccc21
Temperature: 60 °C

Procedure:
A solution of the bromo intermediate D6 (0.2 g, 0.00037 moles), 4-chlorophenylboronic acid (0.070 g, 0.00045 moles), K2CO3 (2M solution, 1 ml), ethanol (1 ml) and toluene (2 ml) at room temperature was degassed by bubbling argon through the solution for 10 minutes. Pd(PPh3)4 (0.1 g, 0.000086 moles) was added and the mixture heated at 60° C. under argon for 24 hours. Upon cooling the mixture was partitioned between water and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate (×3) and the combined organic phase washed with water, brine then dried over anhydrous MgSO4. The solution was evaporated to dryness then purified by chromatography over silica eluting, with hexane up to 50% EtOAc/hexane, affording the title compound D8 as a off white foam, which was used directly in the next step. M-H 563.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C:11](=[O:17])[CH2:10][CH2:9]2.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>COCCOC>[CH3:16][O:15][C:14]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2=[O:17])=[CH:7][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cc2c(cc1OCCCBr)CCC2=O
Reactant: C1CCNC1
Solvent: COCCOC
Product: COc1cc2c(cc1OCCCN1CCCC1)CCC2=O

Procedure:
A mixture of 5-(3-bromo-propoxy)-6-methoxy-indan-1-one (Intermediate J) (2.0 g, 0.0066 mole) and pyrrolidine (1.7 mL, 0.02 mole) was stirred in 50 mL of DME (1,2-Dimethoxyethane) at room temperature overnight under Argon. The reaction was quenched with water (150 mL) and made acidic with 1 N HCl (50 mL). The water solution was washed with ethyl acetate, made basic with 3N NaOH (25 mL) and extracted with ethyl acetate. After washing with brine and drying over sodium sulfate, the solvent was removed in vacuo to yield the title compound. MS m/z 290 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][CH2:23][C:24]4(C)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:31])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[CH3:32][C:33]1([CH:38]=O)[O:37][CH2:36][CH2:35][O:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[Cl:31][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][CH2:23][CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:32][C:33]3([CH3:38])[O:37][CH2:36][CH2:35][O:34]3)[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: CC1(C=O)OCCO1
Reactant: CC1(CNc2nc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)ccc2F)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(CN[C@H]2CC[C@H](Nc3cc(-c4ccc(F)c(NCC5CCOCC5)n4)c(Cl)cn3)CC2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N2′-(trans-4-aminocyclohexyl)-5′-chloro-5-fluoro-N6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (21 mg, 0.048 mmol) in DCM (1.0 ml) was added 2-methyl-1,3-dioxolane-2-carbaldehyde (synthesized following the procedure reported in Org. Lett., 2009, 11, 3542-3545), sodium triacetoxyborohydride (20.51 mg, 0.097 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC and lyophilized to give 12 mg off-white powder of the title compound as its TFA salt. LCMS (m/z): 534.1 (MH+), retention time=0.62 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:19]=[N:20][C:21]([CH:25]3[CH2:27][CH2:26]3)=[C:22]([Cl:24])[CH:23]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:19]=[N:20][C:21]([CH:25]3[CH2:27][CH2:26]3)=[C:22]([Cl:24])[CH:23]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of tert-butyl 5-chloro-4-(((5-chloro-6-cyclopropylpyridin-3-yl)oxy)methyl)-2-fluorobenzoate (Preparation 26, 1.24 g, 3.01 mmol) in dichloromethane (22 mL) was added TFA (10.0 mL, 0.02 mol). The mixture was stirred under nitrogen at room temperature for 18 hours. Additional TFA (2.50 mL, 32.0 mmol) was added and stirring continued for 3 hours. The reaction mixture was evaporated under reduced pressure and the resulting residue dissolved in EtOAc (25 mL) and washed with 2M aqueous solution of HCl (25 mL). The resulting solid was filtered to afford the title compound (1.4 g, crude quant.) which was used with no further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[CH:26](O)[CH3:27].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[CH:26]([O:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH3:27]
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Reactant: CC(O)c1c(F)cccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc2c(OC(C)c3c(F)cccc3F)cc(C)cn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.50 g (23.5 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 87A, 4.46 g (28.2 mmol) of 1-(2,6-difluorophenyl)ethanol, 5.35 ml (27.0 mmol) of diisopropyl azodicarboxylate and 7.08 g (27.0 mmol) of triphenylphosphine were dissolved in 141 ml of THF, and the mixture was stirred at RT for 2 h. 0.70 ml (3.5 mmol) of diisopropyl azodicarboxylate and 0.62 g (2.3 mmol) of triphenylphosphine were added to the reaction mixture, and the reaction solution was stirred at RT for 1 h. The precipitated solid was filtered off and dried under high vacuum. This gave 4.6 g (52.8% of theory; purity 100%) of the title compound. The filtrate was concentrated and purified twice by silica gel chromatography (cyclohexane:ethyl acetate gradient=from 8:1 to 4:1). All product-containing fractions were re-purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave another 2.16 g (25% of theory) of the target compound.
Reaction SMILES: C(OC([N:8]1[CH2:27][CH2:26][CH2:25][C:10]2([N:13]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH:11]2[CH3:24])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([N:13]1[C:10]2([CH2:25][CH2:26][CH2:27][NH:8][CH2:9]2)[CH:11]([CH3:24])[CH2:12]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1CN(C(=O)OCc2ccccc2)C12CCCN(C(=O)OC(C)(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC1CN(C(=O)OCc2ccccc2)C12CCCNC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of an optically-active compound of 3-methyl-1,6-diazaspiro[3,5]nonane-1,6-dicarboxylic acid 1-benzyl ester 6-tert-butyl ester (5.54 g) in chloroform (83 ml) cooled to 4° C. was added a solution of trifluoroacetic acid/chloroform (28 ml/55 ml), and the mixture was warmed to room temperature and stirred for additional 2 hours. The reaction mixture was cooled to 4° C., and thereto was added 4M aqueous sodium hydroxide solution (90 ml). The mixture was basified to be pH 9 to 10, and extracted with chloroform/methanol (4/1, 60 ml×2) twice. The combined organic layer was sequentially washed with 5% aqueous sodium bicarbonate solution, 10% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol/28% ammonia water=90/10/1) to give the titled compound (2.20 g).
Reaction SMILES: [NH:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][C:2]1=[O:11].[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH:16]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][N:4]1[C@@H:5]2[C@H:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:1][C:2](=[O:11])[CH2:3]1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: O=C1CN[C@H]2CCCC[C@@H]2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CN2CC(=O)N[C@H]3CCCC[C@@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.3 %

Procedure:
A mixture of (4aS,8aS)-octahydroquinoxalin-2(1H)-one (8.82 g, 57.19 mmol), 2,4-dimethoxybenzaldehyde (9.50 g, 57.19 mmol), and sodium triacetoxyborohydride (36.31 g, 171.57 mmol) in 1% HOAc in CH2Cl2 (250 mL) was stirred at room temperature for 16 h. The mixture was neutralized with saturated aqueous NaHCO3 solution (200 mL). The organic layer was separated and washed with H2O (100 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0% to 100% 90:9:1 CH2Cl2/CH3OH/NH4OH in CH2Cl2) afforded (4aS,8aS)-4-(2,4-dimethoxybenzyl)octahydroquinoxalin-2(1H)-one (1.10 g, 11.1% over two steps). 1H NMR and MS consistent.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1.Br[C:25]1[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[F:23][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:25]3[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(OCC)c3)nc12
Product: CCOc1cccc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(N)(=O)=O)s4)c3n2)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.19) (313 g, 1.0 mmol) and commercially available 5-bromothiophene-2-sulfonamide (315 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (160 mg, 34%). MS (ISP) 489.2 [(M+NH4)+]; mp 214° C.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][C@@H:15]1[CH2:19][N:18]([C:20](=[O:33])[C:21]2[CH:26]=[C:25]3[O:27][CH2:28][O:29][C:24]3=[CH:23][C:22]=2[N+:30]([O-:32])=[O:31])[C@@H:17]([C:34]([OH:36])=[O:35])[CH2:16]1>CC(C)=O.O>[O:14]=[C:15]1[CH2:19][N:18]([C:20](=[O:33])[C:21]2[CH:26]=[C:25]3[O:27][CH2:28][O:29][C:24]3=[CH:23][C:22]=2[N+:30]([O-:32])=[O:31])[CH:17]([C:34]([OH:36])=[O:35])[CH2:16]1
Reactant: O=C(O)[C@H]1C[C@H](O)CN1C(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC(C(=O)O)N(C(=O)c2cc3c(cc2[N+](=O)[O-])OCO3)C1
Reaction time: 2 h

Procedure:
15 ml of Jones reagent (aqueous chromic and sulfuric acid solution) are added dropwise to a solution of 8 g (0.025 mole) of trans-4-hydroxy-1-(4,5-methylenedioxy-2-nitrobenzoyl)pyrrolidine-2-carboxylic acid obtained in Example 1, in 500 ml of acetone. The reaction mixture is stirred for 2 hours. The acetone is removed under vacuum. The residue obtained is taken up in water. The precipitate is separated, dried and recrystallized in a V/V mixture of methanol and petroleum ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[N:6]([C:7]2[S:8][C:9]3[CH2:15][CH2:14][O:13][C:12]4[CH:16]=[C:17]([CH:20]5[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]5)[CH:18]=[CH:19][C:11]=4[C:10]=3[N:33]=2)[C:5](=[O:34])[NH:4][C:3]1=[O:35]>FC(F)(F)C(O)=O.ClCCl>[NH:23]1[CH2:22][CH2:21][CH:20]([C:17]2[CH:18]=[CH:19][C:11]3[C:10]4[N:33]=[C:7]([N:6]5[C:2]([CH3:36])([CH3:1])[C:3](=[O:35])[NH:4][C:5]5=[O:34])[S:8][C:9]=4[CH2:15][CH2:14][O:13][C:12]=3[CH:16]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCCc2sc(N4C(=O)NC(=O)C4(C)C)nc2-3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Yield: 30 %

Procedure:
tert-Butyl 4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-tetrahydropyridine-1(2H)-carboxylate was stirred in 50% trifluoroacetic acid in dichloromethane to give 514. Yield 30%. MS(ESI+): 413.2. 1H NMR (500 MHz, DMSO) δ 8.23 (s, 1H), 8.17 (d, J=8.2, 1H), 7.02 (d, J=8.2, 1H), 6.85 (d, J=1.6, 1H), 4.30 (t, J=4.9, 2H), 3.22-3.20 (m, 3H), 2.88 (t, J=11.2, 2H), 2.75 (t, J=12.0, 1H), 1.89 (d, J=12.5, 2H), 1.67 (d, J=12.9, 7H)
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36]CC)=[O:35]>CN(C=O)C>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([O:17][CH2:33][C:34]([OH:36])=[O:35])([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(OCC(=O)O)c2cccnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.1 %

Procedure:
To a solution of 1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol (200 mg, 0.597 mmol) in DMF (5 mL) was added potassium carbonate (412 mg, 2.98 mmol). After stirring for 5 min at RT, ethyl bromoacetate (200 mg, 1.19 mmol) was added into the reaction mixture, which was stirred at RT for 2 h. The progress of reaction was monitored by LCMS. The reaction was quenched with water and extracted with EtOAc. The aqueous layer was concentrated and residue was purified by reverse HPLC to yield 2-((1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-yl)oxy)acetic acid (80 mg). The resulting racemate was purified and resolved by chiral preparative HPLC. 1H NMR (CD3OD, freebase) δ (ppm): 8.5 (d, 1H), 8.36 (s, 1H), 7.8 (dd, 1H), 7.31 (m, 1H), 7.19 (s, 1H), 7.1 (d, 1H), 6.88 (d, 1H), 4.86 (m, 1H), 4.58 (s, 1H), 4.32 (d, 1H), 4.25 (m, 2H), 3.94 (m, 2H), 3.8 (m, 1H), 3.35 (s, 3H), 3.2 (m, 1H), 3.0 (m, 1H), 2.36 (s, 3H), 1.69 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1CCOC.[F:24][C:25]1[CH:30]=[C:29]([CH:31]([CH3:35])[C:32](Cl)=[O:33])[CH:28]=[CH:27][C:26]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[CH:31]([C:29]3[CH:28]=[CH:27][C:26]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[C:25]([F:24])[CH:30]=3)[CH3:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C(=O)Cl)c1ccc(-c2ccccc2)c(F)c1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CC(C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21)c1ccc(-c2ccccc2)c(F)c1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-(2-fluoro-4-biphenylyl)propionyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-(2-fluoro-4-biphenylyl)propanamide as a white powder, m.p. 76.1-79.9° C. 1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.03 (m, 2H), 7.62 (d, J=8.3 Hz, 1H), 7.49-7.14 (m, 10H), 6.59 (broad s, 2H), 4.58 (t, J=6.9 Hz, 2H), 3.59 (q, J=7.0 Hz, 1H), 3.09 (pentet, J=6.7 Hz, 2H), 1.82 (m, 2H), 1.45 (m, 2H), 1.30 (d, J=7.0 Hz, 3H); MS (EI) m/e 481.2268 (481.2278 calcd for C29H28FN5O).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:11]2[C:6](=[C:7](OC)[CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH3:25][O-:26].[Na+]>CO>[CH3:25][O:26][CH2:3][C:4]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: C[O-]
Reactant: COc1cccc2c(NCc3ccccc3C)cc(CCl)nc12
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cc(NCc2ccccc2C)c2ccccc2n1

Procedure:
800 mg (=2.2 mmol) of 2-chloromethyl-8-methoxy-4(2-methylbenz-ylamino)quinoline hydrochloride were refluxed with 1.2 g (=22 mmol) of sodium methylate in 30 ml of absolute methanol for 5 hours The mixture was concentrated in a rotary evaporator, ethyl acetate was added, and the mixture was extracted several times with K2CO3 solution. The residue after drying over Na2SO4 and removal of the solvent was recrystallized from ethanol 200 mg (=28%) of 8-methoxy..2-methoxymethyl-4-(2-methylbenzylamino)quinoline of melting point 194-195° C. were obtained
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][C:16]4[CH2:20][CH2:21][C:22](=O)[CH2:23][C:15]=4[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:27]1([CH2:26][NH:25][CH:22]2[CH2:23][C:15]3[C:14]4[CH:13]=[CH:12][N:11]([S:8]([C:5]5[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=5)(=[O:10])=[O:9])[C:19]=4[CH:18]=[CH:17][C:16]=3[CH2:20][CH2:21]2)[CH2:29][CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)CCC(=O)C4)cc1
Reactant: NCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)CCC(NCC2CC2)C4)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-[(4-methylphenyl)sulfonyl]-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-one (2.0 g) in CH2Cl2 is treated sequentially with aminomethylcyclopropane ((0.630 g, 1.5 eq.) and sodium triacetoxyborohydride (1.6 g, 1.3 eq.), stirred at room temperature for 16 h, quenched with 1N NaOH and extracted with CH2Cl2. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give the title product, 2.2 g, identified by NMR and mass spectral analyses.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][NH:10][C:11]=3[CH:12]=[C:4]2[O:3][CH2:2]1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CC(O)C>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[N:10]1[C:11]2[CH:12]=[C:4]3[O:3][CH2:2][O:1][C:5]3=[CH:6][C:7]=2[CH2:8][CH2:9]1
Reactant: c1c2c(cc3c1OCO3)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cc5c(cc43)OCO5)c2cc1OC
Yield: 93 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 93% yield from 6,7-dihydro-5H-[1,3]dioxolo[4,5-f]indole (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 225°-228° C. (dec); LC-MS: 352 (MH+); anal. RP18-HPLC RT: 3.91 min.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11](N(OC)C)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH:11]=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CON(C)C(=O)/C=C/c1ccc(F)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C/C=C/c1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
(E)-3-(3,4-Difluorophenyl)-N-methoxy-N-methyl-prop-2-enamide (100 mg, 0.440 mmol) is dissolved in dry tetrahydrofuran under inert atmosphere and the resulting solution is cooled to −78° C. A solution of diisobutylaluminum hydride in toluene (1M, 1100 μl, 1.100 mmol) is slowly added and the resulting mixture is stirred for 1 h at −78° C. The reaction is allowed to warm up to room temperature and is stirred for 1 h at this temperature. The reaction mixture is concentrated under reduced pressure and the crude product is purified by flash column chromatography on silica gel (heptane/ethyl acetate 0 to 50% as eluent) to afford the desired product as white oil (56 mg, 0.333 mmol, 76% yield).