Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.CC([O-])(C)C.[K+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.CCOC(C)=O>CN(C=O)C.O>[Cl:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([O:8][C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:21]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cc(Cl)ncn2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
Add 5-aminopyridin-2-ol (500 mg, 4.545 mmol), t-BuOK (555 mg, 4.545 mmol) in DMF (20 mL), stir at 25° C. for 30 min. Cool to 0° C., add slowly 4,6-dichloropyrimidine (614 mg, 4.13 mmol). Stir the reaction under N2 for 1 hr. TLC (EtOAc:PE=1:1) shows the reaction is complete. Cool the mixture to 0° C., add water (20 mL), extract with EtOAc (20 mL×2). Combine the organic layers; wash with brine, dry over anhydrous Na2SO4. Filter and concentrate under reduced pressure to give crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (650 mg, 70.8%). MS: (M+1): 223.1.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[C:14]2[CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[C:14]2[CH2:27][C:28]1[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=1
Reactant: [H][H]
Reactant: COc1cc(Cc2nccc3c(OCc4ccccc4)cc(OCc4ccccc4)cc23)cc(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc(Cc2nccc3c(O)cc(O)cc23)cc(OC)c1OC
Yield: 95.5 %

Procedure:
0.2 g of 5.7-dibenzyloxy-1-(3,4,5-trimethoxybenzyl)-isoquinoline is dissolved in 250 ml of ethanol, and 0.05 g ot 10% palladium-carbon is added thereto. The mixture is shaken at 25° C in a hydrogen atmosphere. After the hydrogen uptake is completed, the catalyst is removed by filtration. The filtrate is evaporated to remove solvent. 0.125 g of 5,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-isoquinoline is thereby obtained as a crude product. Yield: 95% M.p. 270° - 275° C (decomp.) (recrystallized from ethanol).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Br:22][C:23]1[C:24](Cl)=[C:25]([C:31](=[O:38])[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[C:26]([CH3:30])=[N:27][C:28]=1[CH3:29]>CC#N>[Br:22][C:23]1[C:24]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[C:25]([C:31](=[O:38])[C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33])[C:26]([CH3:30])=[N:27][C:28]=1[CH3:29]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(c3ccccc3)CC2)c1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
To a solution of 4-phenylpiperidine (1.25 g, 7.75 mmol) and DIEA (4.1 mL, 23.3 mmol) in anhydrous CH3CN (40 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.59 g, 7.75 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; concentrated, and charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-oxoacetate 2.63 g (74%). 1H NMR (500 MHz, DMSO-d6) δ 7.34-7.31 (m, 2H), 7.25-7.20 (m, 3H), 5.11-5.06 (m, 1H), 3.50 (br. s, 2H), 2.94 (br. s, 2H), 2.68-2.63 (m, 1H), 2.63 (s, 3H), 2.13 (s, 3H), 1.81-1.78 (m, 2H), 1.60 (br. s, 2H), 1.26 (d, J=6.2 Hz, 6H). UPLC (M+H)=461.05.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH2:18]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH3:19].Cl.N1C=CC=CC=1.C(OCCO)C>>[CH2:18]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[CH:22][CH:21]=1)[CH3:19]
Reactant: CCc1ccc(N)cc1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: CCc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)cc1
Temperature: 139 °C
Yield: 97.5 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.14 ml (1.1 mmol) of 4-ethylaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 1 hour; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.325 g (97.5%) of the desired product as light cream crystals. MP 248-250° C.; : mass spectrum (electrospray, m/e,): 333.1462.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:41]1[S:45][C:44]([S:46]([NH2:49])(=[O:48])=[O:47])=[CH:43][CH:42]=1>>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:41]2[S:45][C:44]([S:46]([NH2:49])(=[O:48])=[O:47])=[CH:43][CH:42]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccc(S(N)(=O)=O)s2)o1
Yield: 75 %

Procedure:
The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (54 mg, 0.081 mmol) and 5-bromothiophene-2-sulfonamide following General Procedure A. Flash chromatography (10-20% EtOAc/hexanes) yielded the title compound as a white solid (33 mg, 75%): 1H NMR (CDCl3, 500 MHz) δ 7.68 (d, 1H, J=4.0 Hz), 7.36-7.33 (m, 3H), 7.29 (d, 1H, J=3.5 Hz), 7.26-7.23 (m, 3H), 5.29 (s, 2H), 4.89 (t, 1H, J=6.0 Hz), 2.67 (t, 2H, J=7.5 Hz), 2.02-1.95 (m, 2H), 1.74-1.59 (m, 2H), 1.40-1.38 (m, 6H), 0.97 (s, 9H), 0.17 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 166.2, 145.2, 143.2, 142.5, 136.4, 132.7, 128.8, 128.7, 126.0, 124.2, 123.8, 68.9, 36.7, 36.3, 31.8, 29.6, 26.1, 26.1, 25.5, 18.6, −4.5, −4.7.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([OH:10])CCC.[CH3:11][CH2:12][CH2:13][CH2:14]CC>>[CH3:4][C:3](=[CH:2][CH2:1][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][OH:10]
Reactant: [Li]CCCC
Reactant: CCCCO
Reactant: CCCCCC
Product: CCCCCC=C(C)CO
Yield: 73 %

Procedure:
A hexane solution of n-butyllithium (2.1 mmol) was cooled to 0° C. under an argon atmosphere, and a hexane solution of n-butanol (74 mg; 1.0 mmol) was added dropwise thereto and stirred. A hexane solution of 3-methyl-3,4-epoxybutene-1 (84.4 mg; 1.0 mmol) was further added thereto, and after the addition was completed, the reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour, followed by the usual work up. Removal of the solvent and distillation of the residue gave 104 mg of 2-methyl-2-octen-1-ol (yield, 73%). NMR spectrum and gas chromatographic analysis (Golay column, PEG 20M, 45 m, at 140° ) showed that the resulting product contained none of 3-methyl-1-octen-4-ol, 2-methyl-2-vinylhexen-1-ol, 3-methyl-1-octen-3-ol, etc. The Z/E ratio of 2-methyl-2-octen-1-ol was 97.2/2.8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1C=CC=CC=1.C(N(CC)CC)C.[CH2:31]([OH:34])[C:32]#[CH:33]>Cl.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.[Cu](I)I>[OH:34][CH2:31][C:32]#[C:33][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCO
Reactant: O=S(=O)(Nc1ccccc1)c1cccc(Br)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccccc1)c1cccc(C#CCO)c1
Yield: 64.2 %

Procedure:
A mixture of 3-bromo-N-phenyl-benzenesulfonamide (52a) (1.0 g, 3.2 mmol), benzene (2.4 ml), tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.34 mmol), copper iodide (0.032 g, 0.16 mmol), triethylamine (2.4 ml, 17.2 mmol), and propargyl alcohol (1.0 ml, 17.2 mmol)) was refluxed under argon for 30 min. The reaction mixture was diluted with 5% HCl (50 ml) and product was extracted with ethyl acetate (50 ml). The extract was washed successively with 5% NaHCO3, water and dried (Na2SO4). The solvents were removed under reduced pressure and the product was purified on silica gel with ethyl acetate-hexane (1:1, v/v) as eluent. The title compound (0.59 g, 64%) was obtained as an oil. 1H NMR (DMSO-d6, HMDSO) δ: 4.29 (2H, d, J=6.0 Hz, CH2); 5.36 (1H, t, J=6.0 Hz, OH); 6.94-7.32 (5H, m, C6H5); 7.35-7.91 (4H, m, C6H4); 10.32 (1H, s, NH).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:10]=2[C:11]2[C:12]([O:30][CH3:31])=[CH:13][C:14]([O:26][CH2:27][CH2:28][CH3:29])=[C:15]([N+:23]([O-])=O)[C:16]=2[C:17]3=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Cl:34][Sn]Cl>>[ClH:34].[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:10]=2[C:11]2[C:12]([O:30][CH3:31])=[CH:13][C:14]([O:26][CH2:27][CH2:28][CH3:29])=[C:15]([NH2:23])[C:16]=2[C:17]3=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Sn]Cl
Reactant: CCCOc1cc(OC)c2c(c1[N+](=O)[O-])C(=O)c1cccc(OCCN3CCCC3)c1-2
Solvent: O
Product: CCCOc1cc(OC)c2c(c1N)C(=O)c1cccc(OCCN3CCCC3)c1-2
Product: Cl
Yield: 33 %

Procedure:
5-(2-Pyrrolidinyl-ethoxy)-4-methoxy-2-propoxy-1-nitro-fluoren-9-one (0.30 g, 0.7 mmol) and stannous chloride dihydrate (1.0 g, 0.7 mmol) are reacted as described in Example 9A to give the title compound (0.10 g, 33%). m.p. 122°-124° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:11])=[CH:5][C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].[OH-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.Cl>CC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:10][S:7]([C:6]2[CH:5]=[C:4]([CH3:11])[S:3][C:2]=2[CH3:1])(=[O:9])=[O:8])=[O:23])=[CH:17][CH:16]=1
Reactant: Cc1cc(S(N)(=O)=O)c(C)s1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1cc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)c(C)s1

Procedure:
The procedure of Example 4B was followed with 2,5-dimethyl-3-thiophenesulfonamide (1.73 g, 9.06 mmole), acetone (10 ml), 1N NaOH (9.1 ml), 4-chlorophenyl isocyanate (1.39 g, 9.0 mmole), 1N HCl (9.1 ml). The aqueous layer was extracted with two 100 ml aliquots of ethyl acetate, which were combined and washed with 50 ml of water. The organic layer was then dried over Na2SO4. The solvent was removed and the residue chromatographed using a mixture of 4% methanol/methylene chloride as the eluent over a 50 mm silica gel column. The solvent was removed to provide the named product.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:18][NH:17][CH2:16][CH2:15][N:14]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[O:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.C1C2C(COC([N:58]=[C:59]=[S:60])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[CH:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:18][N:17]([C:59](=[S:60])[NH2:58])[CH2:16][CH2:15][N:14]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[O:12])=[CH:32][CH:33]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc(CNC(=O)[C@H]2CNCCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(CNC(=O)[C@H]2CN(C(N)=S)CCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of the compound (506 mg) obtained in Example 1 in chloroform (5 ml) was added, with stirring at room temperature, triethylamine (167 μl), and 9-fluorenylmethoxycarbonyl isothiocyanate (281 mg) was added. After stirring overnight at room temperature, piperidine (198 μl) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, and purified by column chromatography (3% methanol/chloroform) to give the title compound (442 mg).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[CH:17][N:16]([C:19]3[N:24]=[C:23](SC#N)[C:22]([N+:28]([O-:30])=[O:29])=[CH:21][N:20]=3)[C:15]=2[CH:31]=1.Cl.[C:33]([O:37][C:38](=[O:42])[C@@H:39]([CH3:41])[NH2:40])([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[CH:17][N:16]([C:19]3[N:24]=[C:23]([NH:40][C@H:39]([CH3:41])[C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:42])[C:22]([N+:28]([O-:30])=[O:29])=[CH:21][N:20]=3)[C:15]=2[CH:31]=1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: N#CSc1nc(-n2cnc3ccc(Cl)cc32)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H](Nc1nc(-n2cnc3ccc(Cl)cc32)ncc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
Diisopropylethylamine (2.6 mL) was added to a mixture of 6-chloro-1-(5-nitro-4-thiocyanatopyrimidin-2-yl)-1H-benzo[d]imidazole (1.66 g, 5 mmol) and D-alanine t-butyl ester hydrochloride (1.1 g, Chem-Impex Int.) in THF (50 mL). The combined mixture was stirred at RT overnight, partitioned between ethyl acetate and water then separated. The aqueous layer was extracted once again with ethyl acetate and the combined organics were concentrated and purified by column chromatography. Elution with DCM and 0.5% MeOH in DCM provided the above compound (0.58 g), MH+=419, 421.
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5](B(O)O)=[CH:4][N:3]=1.Br[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[NH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:23][C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)[N:3]=[CH:4][C:5]=2[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:10]=1
Reactant: Brc1ncccn1
Reactant: Cc1ccc2c(B(O)O)cnc(Cl)c2n1
Reactant: Cc1nc(N)cs1
Product: Cc1ccc2c(-c3ncccn3)cnc(Nc3csc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=335.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-2-methyl-[1,7]naphthyridine-5-boronic acid (Example L), 2-bromopyrimidine and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14](OC(=O)C)(=O)[CH3:15]>>[CH3:14][C:15]1[O:5][C:4](=[O:6])[C:3]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1

Procedure:
In certain embodiments, the solvent in step (a) (i.e., reacting 2-amino-6-nitrobenzoic acid with acetic anhydride in a solvent to form 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one) is a carboxylic acid ester. In certain embodiments, the solvent in step (a) is isopropyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[C:10]([CH3:15])=[N:11][O:12][C:13]=2[CH3:14])[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:4]([C:23](=O)[CH3:24])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[C:10]([CH3:15])=[N:11][O:12][C:13]=2[CH3:14])[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:4]([CH:23]([NH2:32])[CH3:24])[CH:3]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(-c2c(C)noc2C)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1c(C)c(Cl)cc(C(C)N)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 87 %

Procedure:
A mixture of 1-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3′-fluoro-5-methylbiphenyl-2-yl]ethanone (40 mg, 0.11 mmol), ammonium acetate (86 mg, 1.1 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.28 mL, 0.28 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to give the desired product (35 mg, 87%). LCMS calculated for C20H21ClFN2O (M+H)+: m/z=359.1. found: 359.1.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(C(C)C)CC)(C)C.[Cl:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[CH:29][C:30]([NH2:34])=[N:31]2)=[CH:26][CH:25]=1>>[NH2:34][C:30]1[CH:29]=[C:28]([N:35]2[CH2:36][CH2:37][N:38]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH2:39][CH2:40]2)[C:27]2[C:32](=[CH:33][C:24]([Cl:23])=[CH:25][CH:26]=2)[N:31]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 78, 7-chloro-4-aminoqunoline, p-nitrophenyl chloroformate, diisopropylethyl amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. LC-MS: 427 (M++1). 1H NMR (DMSO-d6) δ 3.0–3.2 (m, 4H), 3.6–3.9 (m, 4H), 6.2–6.3 (s, 1H), 6.4–6.6 (s, H), 7.05–7.2 (m, 1H), 7.35–7.4 (m, 1H), 7.4–7.5 (d, 2H), 7.7–7.8 (d, 1H), 8.2–8.35 (d, 2H).
Reaction SMILES: Br[C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([S:17]([CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:19])=[O:18])[CH2:12]2)=[N:4][C:5](SC)=[N:6][CH:7]=1.C[Si](C)(C)CCOC[N:30]1[C:34]2=[N:35][CH:36]=[C:37]([Sn](C)(C)C)[N:38]=[C:33]2[CH:32]=[CH:31]1>>[CH3:22][CH:21]([CH3:23])[CH2:20][S:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:11]([NH:10][C:3]2[C:2]([C:37]3[N:38]=[C:33]4[CH:32]=[CH:31][NH:30][C:34]4=[N:35][CH:36]=3)=[CH:7][N:6]=[CH:5][N:4]=2)[CH2:12]1)(=[O:19])=[O:18]
Reactant: C[Si](C)(C)CCOCn1ccc2nc([Sn](C)(C)C)cnc21
Reactant: CSc1ncc(Br)c(N[C@H]2CCCN(S(=O)(=O)CC(C)C)C2)n1
Product: CC(C)CS(=O)(=O)N1CCC[C@H](Nc2ncncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
Starting with (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-[(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-amine from above and 5-(2-trimethylsilanyl-ethoxymethyl)-2-trimethylstannanyl-5H-pyrrolo[2,3-b]pyrazine described in step 3 of Example 76, and using similar synthetic procedures of steps 4-5 described herein from Example 76, gave [(S)-1-(2-methyl-propane-1-sulfonyl)-piperidin-3-yl]-[5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-amine. MS (ES+): 416.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]1(=[O:21])[O:16][C:14](=[O:15])[C@H:13]2[CH2:17][CH:18]=[CH:19][CH2:20][C@@H:12]12>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:9][CH3:10])[C:11]([C@H:12]1[CH2:20][CH:19]=[CH:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:21]
Reactant: COc1ccccc1OC
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Product: COc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1OC

Procedure:
Prepared from 1,2-dimethoxybenzene and cis-1,2,3,6-tetrahydrophthalic anhydride as described for compound A. M.p. 110°-112° C.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=3)[CH:13]=2)=[CH:38][CH:37]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.88-0.99 (m, 6H), 1.57 (ddd, J=13.33, 6.85, 6.72 Hz, 1H), 1.77 (ddd, J=13.88, 7.21, 7.03 Hz, 1H), 2.02-2.11 (m, 1H), 3.80 (t, J=7.70 Hz, 1H), 7.11-7.20 (m, 3H), 7.51-7.65 (m, 4H), 7.68-7.73 (m, 4H); Calcd for C25H22F4O2 (M+Na) 453.16, Found 453.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:28][CH2:29]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccccc2C)CC1
Yield: 84 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 84%). 1H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H), 2.50 (s, 3H), 2.89-3.09 (m, 4H), 3.68-3.88 (m, 4H), 4.14 (s, 3H), 6.99-7.78 (m, 7H), 7.76 (d, J=8.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.Br[CH2:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[N:16]([CH2:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: O=c1[nH]nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Reactant: Cc1nc(C(F)(F)F)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 55 °C
Yield: 77.6 %

Procedure:
To a stirred solution of 8-bromo-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1.00 g, 3.08 mmol) in DMF (12 mL) at room temperature under argon was added 3-(bromomethyl)-2-methyl-6-(trifluoromethyl)pyridine (861 mg, 3.39 mmol), followed by K2CO3 (1278 mg, 9.24 mmol). The resulting suspension was warmed to 55° C. for 8 h. After cooling the reaction mixture to room temperature, most of the solvent was removed under reduced pressure. The residue was diluted with water (˜20 mL) and shaken vigorously. A solid formed and was filtered, washed with water and air-dried. The crude product was purified by automated silica gel chromatography (eluted with EtOAc/hexanes) to obtain 1.19 g (71% yield) of title compound as a tan amorphous solid. HPLC/MS: retention time=3.90 min, [M+H]+=497.