Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]([O:27][CH3:28])[C:11]1[C:16]([O:17][CH2:18][O:19][CH3:20])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=[CH:13][C:12]=1[CH2:25][OH:26].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(OCC)(=O)C>[CH3:29][S:30]([O:26][CH2:25][C:12]1[CH:13]=[CH:14][C:15]([C:21]([F:22])([F:23])[F:24])=[C:16]([O:17][CH2:18][O:19][CH3:20])[C:11]=1[CH:10]([O:9][CH3:8])[O:27][CH3:28])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCOc1c(C(F)(F)F)ccc(COS(C)(=O)=O)c1C(OC)OC
Reaction time: 0.5 h

Procedure:
Triethylamine (2.74 ml, 19.7 mmol) was added to a solution of [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (5.09 g, 16.4 mmol) obtained in Example (6-6) in ethyl acetate (50 ml). After methanesulfonyl chloride (1.33 ml, 17.2 mmol) was added dropwise to the mixture under ice-cooling, the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was filtered through Celite. The filtrate was successively washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. n-Hexane was added to the residue obtained by removing the solvent under reduced pressure. The precipitated crystals were filtered to give 2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl methanesulfonate as a pale yellow compound (5.37 g, yield: 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]2[CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[CH:4][CH:3]=1>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH2:12][NH:11][CH2:10][CH:9]2[CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[CH:4][CH:3]=1
Reactant: CCC(CC)C1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(Cl)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CCC(CC)C1CNCC(OCc2ccc3ccccc3c2)C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
40 mg (0.08 mmol) of tert-butyl (3SR,4RS,5RS)-4-(4-chloro-phenyl)-3-(1-ethyl-propyl)-5-(naphthalen-2-ylmethoxy)-piperidine-carboxylate were dissolved in 5 ml of dry methylene chloride and treated with 35 mg (0.16 mmol) of anhydrous zinc bromide in an analogous manner to the procedure described by A. Mann et al. in Synth. Comm. 19(18), 3139-3142 (1989). The reaction mixture was stirred at room temperature for 5 hours. For the working-up, the reaction mixture was evaporated under reduced pressure and the crude product obtained was purified by chromatography on silica gel using a 90:10:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained 28 mg (86% of theory) of (3SR,4RS,5RS)-4-(4-chloro-phenyl)-3-(1-ethyl-propyl)-5-(naphthalen-2-ylmethoxy)-piperidine as a colourless oil; MS: 422 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 45.4 %

Procedure:
A mixture of 2-butylbenzimidazole (2.6 g), the bromomethyl compound (C) (5.0 g) and potassium carbonate (1.55 g) in N,N-dimethylformamide (DMF) (40 ml) was heated at 100° C. for 3 hours. Dichloromethane (200 ml) was added and insoluble material was removed by filtration. The filtrate was concentrated and the residue purified by flash chromatography, eluting with triethylamine/ethyl acetate/hexane (1:40:60 v/v), to give methyl 4'-[2-butyl-1H-benzimidazol-1-yl)methyl]biphenyl-2-carboxylate (A) as a clear oil (2.7 g); NMR (CDCl3): 0.95(t,3H), 1.45(m,2H), 2.9(t,2H), 3.6(s,3H), 5.4(s,2H), 7.2(d,2H), 7.2-7.6 (complex m,3H), 7.8(m,2H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:25]2[CH:30]=[C:29]([CH3:31])[C:28]([OH:32])=[C:27]([CH3:33])[CH:26]=2)([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:8]1=[O:34].[CH3:39]O>C1COCC1>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]2([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH3:39])=[C:27]([CH3:33])[CH:26]=3)[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][C:5]3[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=3[Cl:3])[C:8]2=[O:34])=[CH:21][CH:20]=1
Reactant: Cc1cc(C2(c3ccc([N+](=O)[O-])cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc(C)c1O
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(C)cc(C2(c3ccc(N)cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolve nickelous chloride (36 mg, 0.15 mmol) in methanol (3 mL). Add sodium borohydride (17 mg) followed 1-(2-chloro-benzyl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-3-(4-nitro-phenyl)-1,3-dihydro-indol-2-one (152 mg, 0.3 mmol) in THF (3 mL). Add additional sodium borohydride and stir at room temperature for 30 min. Concentrate to dryness and partition the resulting residue in water/ethyl acetate. Separate and extract aqueous with ethyl acetate (2×). Wash combined organic portions with brine and then dry (MgSO4), filter and concentrate in vacuo to give 145 mg of residue. Purify by flash chromatography (gradient of 10% EtOAc/hexanes to 50% EtOAc/hexanes) to give 97 mg (67%) of the title compound as a white foam. MS (ES): m/z=483 (M+1); 1H NMR(DMSO-d6): δ9.99 (s, 1H), 7.53 (m, 3H), 7.36-7.24 (m, 4H), 7.10 (t, J=8 Hz, 1H), 6.95 (m, 2H), 6.85 (m, 4H), 6.52 (d, J=8.5 Hz), 5.19 (bs, 2H), 5.06 (s, 2H) 3.65 (s, 3H), 2.16 (s, 6H).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].CCCCCC>C1COCC1>[CH3:27][S:28]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 7.7 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (2 g, 7.78 mmol) in THF (25 mL) was cooled to −78° C. followed by dropwise addition of LDA (1.8 M in THF, 8.8 mL, 15.56 mmol) and was stirred at the same temperature for 45 minutes followed by addition of methanesulfonyl chloride (1.3 g, 11.67 mmol) at −78° C. The temperature of the reaction was slowly raised to rt and left to stir for 6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 30% EtOAc:hexane to obtain the product as an orange viscous liquid (0.20 g, 8.0% yield). MS: 336.18 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=3)[CH:39]=[CH:40][C:41]=2[OH:42])=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:42][C:41]2[CH:40]=[CH:39][C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:50])([F:51])[F:52])[CH:44]=3)=[CH:37][C:36]=2[C:33]2[CH:34]=[CH:35][N:30]=[N:31][CH:32]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4cccc(C(F)(F)F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 16, 219 mg, 0.474 mmol) and 3-pyridazin-4-yl-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 3, 150 mg, 0.474 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (196 mg, 1.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with a 1M aqueous solution of sodium hydroxide whereupon a precipitate formed. The solid was collected by filtration, washed with water and freeze dried to afford the title compound as a solid (266 mg, 74%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15]([C:17]1[N:18]([CH3:40])[C:19]([CH2:38][CH3:39])=[C:20]([C:36]#[N:37])[C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH2:35])=[CH:24][CH:23]=1)=[O:16])[CH3:13].[CH:41]([S:44](Cl)(=[O:46])=[O:45])([CH3:43])[CH3:42].O>C(Cl)Cl>[CH2:12]([O:14][C:15]([C:17]1[N:18]([CH3:40])[C:19]([CH2:38][CH3:39])=[C:20]([C:36]#[N:37])[C:21]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][S:44]([CH:41]([CH3:43])[CH3:42])(=[O:46])=[O:45])=[CH:26][CH:27]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1c(-c2ccc(Oc3ccccc3N)cc2)c(C#N)c(CC)n1C
Reactant: CC(C)S(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(-c2ccc(Oc3ccccc3NS(=O)(=O)C(C)C)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Add DBU (0.29 mL, 1.92 mmol) to 3-[4-(2-amino-phenoxy)-phenyl]-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.25 g, 0.64 mmol, prepared in example E-95) in methylene chloride at room temperature with stirring. After 10 minutes, cool to 0° C. and add isopropyl-sulfonylchloride (0.11 mL, 0.96 mmol). Stir the reaction mixture at 0° C. for 30 minutes and then at room temperature for 2-6 hours. Then pour the reaction mixture into water and extract with methylene chloride. Combine the organic extracts, wash with 1N HCl, water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with acetonitrile:methylene chloride to provide the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1>C(O)C>[Cl:11][C:10]1[C:5]([NH:2][NH2:3])=[N:6][CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncc(C(F)(F)F)cc1Cl
Temperature: 20 °C

Procedure:
To a solution of 60 mL of hydrazine monohydrate in 380 mL of ethanol was added 81 g (0.38 mole) of 2,3-dichloro-5-trifluoromethylpyridine during a period of 25 minutes. At the end of the addition the temperature had risen to 37° C. This mixture was heated to reflux and maintained at reflux for approximately 15 hours. The solvent was evaporated under reduced pressure, leaving a wet slurry that was immediately recrystallized from boiling ethanol/water (5:2). The mixture was cooled to 20° C. and then filtered. The filter cake was air-dried, yielding approximately 60 g of 3-chloro-5-trifluoromethylpyrid-2-ylhydrazine. The NMR spectrum was consistent with the assigned structure. This reaction was repeated to obtain additional material for subsequent reactions.
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([O:17][CH2:18][C:19]#[CH:20])[CH:14]=[CH:13][C:11]=2[N:12]=1)(=[O:7])=[O:6].N>CO>[CH2:18]([O:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([S:5]([NH2:4])(=[O:7])=[O:6])[S:9][C:10]=2[CH:16]=1)[C:19]#[CH:20]
Reactant: C#CCOc1ccc2nc(S(=O)(=O)N=CN(C)C)sc2c1
Agent: N
Solvent: CO
Product: C#CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
To a 500 mL round bottomed flask equipped with a magnetic stir bar, rubber septum, and argon inlet was placed 2 (9 g, 27.8 mmol) and 200 mL of ammonia in methanol (7 N). The mixture was stirred at rt for 24 h. The solution was bubbled with air for 1 h and filtered. The filtrate was acidified with concentrated HCl to pH=2 and concentrated and dried. This solid was again treated with ammonia methanol solution (7 N, 200 mL) for 24 h at rt. The solution was bubbled with air for 1 h and filtered. The filtrate was added concentrated HCl to pH=2 and concentrated. It was filtered and the solid was washed with cooled water and dried to afford compound 3 as a yellow solid (5.2 g, 70%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=2)[CH:10]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Nc1cncc(-c2cccnc2)n1
Reaction time: 16 h
Yield: 85.9 %

Procedure:
An oven dried resealable Schlenk tube was charged with 6-chloropyrazin-2-amine (0.73 g, 5.71 mmol), 3-pyridineboronic acid (0.91 g, 7.42 mmol), dioxane (50 mL) and a 2M aqueous solution of cesium carbonate (8.5 mL, 17.13 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (290 mg, 0.35 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 90° C. oil bath. After 16 h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (845 mg, 86%) as a solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([C:12]([O-])=O)[C:8]([O:10][CH3:11])=[O:9].C(NCC)C.C=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](=[CH2:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(Cc1cccs1)C(=O)[O-]
Agent: C=O
Solvent: CCNCC
Product: C=C(Cc1cccs1)C(=O)OC
Yield: 75.4 %

Procedure:
11.8 g of monomethyl 2-thienylmethylmalonate, 5.8 ml of diethylamine and 5.0 ml of 36% aqueous formaldehyde solution are stirred under argon at R.T. for 1 h. The water is subsequently removed in vacuo, and the residue is chromatographed. 7.6 g of the title compound are obtained as a colorless liquid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:22]4[NH:21][C:20]5C(=[CH:16][CH:17]=[CH:18][CH:19]=5)C=4C[CH2:12][N:11]3[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C[C:31]([CH3:34])([O-:33])[CH3:32].[K+].O=O>CN(C=O)C>[CH2:23]([N:11]1[CH2:12][C:34]2[C:31](=[O:33])[C:32]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[NH:21][C:22]=2[CH:10]1[C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)[O-]
Reactant: c1ccc(CN2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)cc1
Agent: O=O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)CCO3)N(Cc1ccccc1)C2
Reaction time: 1.5 h

Procedure:
1-(2,3-Dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline (prepared as in Example 2) (3.10 g, 8.15 mmol) was dissolved in dry DMF (20 mL). Potassium t-butoxide (2.29 g, 20.38 mmol) was added, followed by oxygen, bubbled in via syringe needle. The solution was stirred for 1.5 h. To the reaction mixture was added a solution of HCl in ether (10 mL, 2M) and the solution dripped into rapidly stirring water. The resulting suspension was stirred overnight. A brown solid was filtered off and washed with water. The filtrate was neutralized with 1N NaOH, resulting in a yellow precipitate. The solid was filtered, washed with water, dried briefly, and partially dissolved in THF/methanol. The precipitate solid was filtered and washed with ether to yield the product as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([CH3:40])[CH2:38][OH:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH:37]([CH3:40])[CH2:38][OH:39])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(CN)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: CC(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-2-methyl-1-propanol using methods similar to Example 563 to provide an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89 (d, J=6.95 Hz, 3 H), 1.52-1.65 (m, 4 H), 1.79-1.88 (m, 1 H), 2.03 (t, J=6.00 Hz, 2 H), 3.20-3.47 (m, 6 H), 3.51 (t, J=6.00 Hz, 2 H), 4.16 (s, 2 H), 4.40 (t, J=6.11 Hz, 2 H), 4.64 (s, 1 H), 7.11-7.17 (m, 2 H), 7.38-7.43 (m, 2 H), 8.20 (d, J=1.47 Hz, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.38 (t, J=5.90 Hz, 1 H), 17.24 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.C(N(CC)CC)C.[N-]=C=O>CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:2]2[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]=2[OH:8])=[O:18])=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C1CCCC(=O)C1
Agent: [N-]=C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCCC(O)=C1C(=O)Nc1ccc(Cl)cc1

Procedure:
A solution containing 8.5 parts of cyclohexane-1,3-dione, 11.5 parts of p-chlorophenylisocyanate and 7.6 parts of triethylamine in 200 parts of acetone is stirred and refluxed for two hours. The infrared spectrum then shows no isocyanate (band at 2270 cm-1). The solution is concentrated under reduced pressure to about 50 parts, with separation of a few crystals, and poured with stirring into 500 parts of 2-normal hydrochloric acid. The precipitated solid is collected by filtration and dried. The resulting solid is mixed with chloroform, 250 parts by volume, and filtered from 6.5 parts of insoluble by-product. Removal of chloroform from the filtrate leaves a light pink solid which is crystallized from alcohol to give 6.7 parts of nearly white solid, melting point 113°C.-114°C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:24][B:23](B2OC(C)(C)C(C)(C)O2)[O:22]1.C([O-])(=O)C.[K+]>O1CCOCC1>[O:19]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[N:9]1[CH2:8][C:5]1[N:6]=[CH:7][C:2]([B:23]([OH:24])[OH:22])=[CH:3][CH:4]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Br)cn1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(B(O)O)cn1
Temperature: 70 °C
Yield: 99.3 %

Procedure:
To a mixture of 2-((5-bromopyridin-2-yl)methyl)isoindoline-1,3-dione (317 mg, 1.000 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (381 mg, 1.499 mmol) in dioxane (10 mL) at rt under nitrogen was added potassium acetate (294 mg, 3.00 mmol), followed by PdCl2(dppf)-CH2Cl2Adduct (82 mg, 0.100 mmol). At this time, the reaction mixture was heated to 70° C. under nitrogen for 5 hr. After cooling to rt, the solvent was removed on the rotovap and the residue was taken up in EtOAc (30 ml). The mixture was filtered through celite and the filter cake was thoroughly washed with EtOAc. The EtOAc filtrate was concentrated to afford (6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)boronic acid (280 mg, 0.993 mmol, 99% yield) as a brown oil. This material was used as is in the next step. MS (ES+) m/z: 283.1 (M+H); LC retention time: 0.54 min (analytical LCMS Method B).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>>[N:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[NH:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Product: NC(=O)c1cccc2c(NCc3cccc(Nc4ccc5ccccc5n4)c3)ncnc12

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Chloro-quinoline at 120° C.:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][C:12](=O)[CH:13]([F:15])[F:14])[CH3:10]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][CH2:12][CH:13]([F:15])[F:14])[CH3:10]
Reactant: CC(NC(=O)C(F)F)c1ccc(F)cc1Br
Solvent: C1CCOC1
Product: CC(NCC(F)F)c1ccc(F)cc1Br
Reaction time: 1 h
Yield: 93.6 %

Procedure:
Add borane-THF complex (10.69 mL, 10.7 mmol) to a solution of N-(1-(2-bromo-4-fluorophenyl)ethyl)-2,2-difluoroacetamide (1.06 g, 3.56 mmol) in THF (3 mL). Reflux the mixture for 17 h. Quench with hydrochloric acid (5 N, 8 mL). Stir the solution for 1 h. Add saturated NaHCO3. Dilute the mixture with DCM, wash with water and aqueous saturated sodium chloride. Separate the organic layer and dry over sodium sulfate. Filter and concentrate in vacuo to give the title compound (0.94 g, 93%). MS (ES) m/z 282 [M+1]+.
Reaction SMILES: Cl[C:2]#[C:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13].S(=O)(=O)(O)[OH:17]>FC(F)(F)C(O)=O>[F:13][C:12]([F:15])([F:14])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[O:5][CH2:4][CH2:3][C:2]2=[O:17]
Reactant: FC(F)(F)c1ccccc1OCC#CCl
Reactant: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCOc2c1cccc2C(F)(F)F
Temperature: 0 °C
Yield: 32.4 %

Procedure:
A solution of Example 18A (24.1 g, 103 mmol) and sulfuric acid (12 mL, 225 mmol) in trifluoroacetic acid (200 mL) was stirred at room temperature for 3 days. The reaction mixture was poured into ice-water and extracted with dichloromethane (2×200 mL). The organic layers were combined, washed with a saturated aqueous NaHCO3 solution (200 mL), dried (MgSO4), filtered, and concentrated. Silica gel chromatography (15% EtOAc/hexanes) gave the title compound (7.21 g, 33.4 mmol, 32%). MS (DCI/NH3) m/z 216 (M+NH4—H2O)+.