Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[O:15][CH2:14][CH2:13][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1

Procedure:
33.03 g (200 mmol) of 4-nitroacetophenone, 12.30 mL (220 mmol) of ethylene glycol, and 1.00 g (5 mmol) of p-toluenesulfonic acid are placed in 250 mL of toluene, then refluxed for 16 hours using the water separator. Then the reaction mixture is cooled and extracted with water. The organic phase is dried and evaporated to dryness. The residue is extracted with diisopropyl ether and suction filtered. Yield: 34.45 g (82%).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[OH:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=1.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37](/[C:40](/[CH3:44])=[CH:41]/[CH2:42]O)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1>C1COCC1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:42]/[CH:41]=[C:40](/[C:37]2[CH:38]=[CH:39][C:34]([C:31]3[CH:30]=[CH:29][C:28]([Br:27])=[CH:33][CH:32]=3)=[CH:35][CH:36]=2)\[CH3:44])[CH:16]=1)[CH3:26]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: C/C(=C\CO)c1ccc(-c2ccc(Br)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(OC/C=C(\C)c2ccc(-c3ccc(Br)cc3)cc2)c1
Reaction time: 16 h
Yield: 51.6 %

Procedure:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (353 mg, 1.4 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.4 mL, 1.4 mmol), ethyl 3-hydroxyphenylacetate (120 mg, 0.7 mmol) and (E)-3-(4′-bromo-biphenyl-4-yl)-but-2-en-1-ol (200 mg, 0.7 mmol) in dry THF (10 ml), the mixture stirred for 16 h, filtered and concentrated in vacuo. The crude product was then purified by column chromatography on silica (eluent: 20% ethyl acetate in heptane) to give 168 mg (44%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:16]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([Cl:18])=[N:7][C:6]=2[CH:16]=1
Reactant: O=C1Nc2cc(Cl)ccc2Oc2cscc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: ClC1=Nc2cc(Cl)ccc2Oc2cscc21

Procedure:
A 4.0 g. portion of 7-chloro-thieno[3,4-b][1,5]benzoxazepin-10(9H)-one (Example 4) and 4.0 g. of phosphorus pentachloride in 100 ml. of dry toluene are refluxed for 41/2 hours concentrated and triturated with toluene, giving 7,10-dichlorothieno[3,4-b][1,5]benzoxazepine.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]([OH:31])=[O:30])=[C:24]2[C:28]=1[O:27][CH2:26][CH2:25]2.Cl>C(O)C.O>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:29]([OH:31])=[O:30])=[C:24]4[C:28]=3[O:27][CH2:26][CH2:25]4)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: Nc1ccc(C(=O)O)c2c1OCC2
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Yield: 65.1 %

Procedure:
(7R)-2-Chloro-7-ethyl-8-isopropyl-5-methyl-7H-pteridin-6-one 22d (82 mg, 3.07 mmol) and 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid 22e (500 mg, 2.80 mmol) were dissolved in 34 mL of the mixture solvent of ethanol and water (V/V=1:2.4) followed by the addition of 0.4 mL of concentrated hydrochloric acid. The reaction solution was heated to reflux for 15 hours and cooled down resulting in the formation of precipitate. The precipitate was filtered to obtain the title compound 7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 22f (0.75 g, yield: 65.0%) as a white solid.
Reaction SMILES: I[CH2:2][CH3:3].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][C:26]([CH3:27])=[C:21]3[NH:20][C:19]2=[O:28])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][C:26]([CH3:27])=[C:21]3[N:20]([CH2:2][CH3:3])[C:19]2=[O:28])=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCI
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C)c21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Iodoethane (0.289 ml) was added to a mixture of 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (998 mg) and cesium carbonate (1.96 g) in DMF (10 mL) at room temperature. The mixture was stirred at 50° C. for 4 h. The mixture was diluted with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15%-30% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (801 mg) as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7].CN(C)C=O.N1C=CN=C1.Cl[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22]>O>[CH2:21]([Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[O:1][CH2:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7])[CH3:22]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCCCC(=O)CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)CO[Si](CC)(CC)CC

Procedure:
To a solution of the crude 1-hydroxy-hexan-2-one (prepared in Example 1) in 80 ml. of dimethylformamide at 0° C. is added with stirring, 40.8 g. of imidazole and 45.21 g. of chlorotriethylsilane. The mixture is stirred at 0° C. for 5 minutes and then at room temperature overnight, then poured into cold water and extracted with petroleum ether. The petroleum ether solution is washed with water, then saturated sodium bicarbonate solution and then dried over magnesium sulfate. The solvent is removed and the residue is distilled. The fraction boiling at 95°-103° C. (0.7 mm.) is collected giving the desired product as a cloudy colorless liquid.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](F)[CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:10]=1[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][NH2:37]>CS(C)=O.O>[CH2:29]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[C:10]([F:28])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:37][CH3:36])[CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Fc1cc(-c2c[nH]nc2-c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)ccn1
Reactant: CN
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(-c2c[nH]nc2-c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)ccn1

Procedure:
To a solution of dibenzyl-{2,4-difluoro-3-[4-(2-fluoro-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-amine (400 mg, 0.849 mmol) in DMSO (4.24 mL), a 40% methyl amine solution in water (3.5 mL) was added. The mixture was irradiated in the microwave oven at 120° C. for one hour and then poured into water and extracted with ethyl acetate. The organic layer was washed three times with saturated aqueous NaHCO3 and once with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduce pressure and the crude product was used in the following step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[CH2:24][N:15]1[C:16]([CH3:19])([CH3:20])[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:22])[CH:12]=2)[C:14]1=[O:21]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: COc1ccc(CBr)cc1OC
Product: COc1ccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)cc1OC
Yield: 67 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 4-(bromomethyl)-1,2-dimethoxybenzene. Yield 67%, white solid. 1H NMR (DMSO-d6, 400 MHz): .s, 6H), 2.16 (s, 3H), 2.42 (s, 3H), 3.72 (s, 3H), 3.73 (s, 3H), 4.49 (s, 2H), 5.20 (s, 2H) 6.92 (m, 2H), 7.00 (d, J=2.0 Hz, 1H), 7.83 (d, J=0.4 Hz, 1H), 8.20 (d, J=0.4 Hz, 1H). MS 454 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an 1050 of 0.08 μM.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH3+:15])[CH3:14])=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3].C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[C:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]([NH:15][C:45]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:46])[CH3:14])=[CH:11][CH:12]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H]([NH3+])c1ccc(OC(C)(C)C)cc1
Agent: [Cl-]
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(OC(C)(C)C)cc3)cc12

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with (S)-1-(4-(tert-butoxy)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 574 [M+1]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[N:12]1([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Reactant: C1CNCCN1
Solvent: O
Product: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Temperature: 100 °C
Yield: 96.1 %

Procedure:
A mixture of 4-fluorobenzenesulfonamide (6.95 g) and piperazine (17.1 g) in 30 mL of water is heated at 100° C. overnight. The solid is then collected, washed with water and toluene, and dried under reduced pressure to give 9.2 g of 4-(piperazin-1-yl)benzenesulfonamide; mp 219-221° C.; ms m/z 241; IR (mineral oil) 1160, 822, 1332, 608, 1593, 1137 cm-1. 1H NMR (DMSOd6) δ 2.81, 3.17, 2.3, 7.01, 7.07, 7.61.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:6][CH:5]=1.[OH-].[Na+].O.Cl>CO>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][N:6]=1)=[O:19]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)O)cn1
Yield: 105.5 %

Procedure:
To a solution of 6-(2-methylbenzoylamino)nicotinic acid methyl ester (2.1 g) in methanol (30 ml) is added 5% aqueous sodium hydroxide solution (24 ml), and the mixture is refluxed for two hours. To the reaction solution is added water, and the mixture is made weak acidic with 1N aqueous hydrochloric acid solution, and then, extracted with diethyl ether. The extract is dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent to give 6-(2-methylbenzoylamino)nicotinic acid (2.1 g) as white powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[F:25])[CH3:2].[C:26](#N)C.O>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24][CH3:26])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[F:25])[CH3:2]
Reactant: CC#N
Reactant: CCc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1F
Solvent: O
Product: CCc1ccc(COc2ccnn2-c2cc(C(=O)OC)ccn2)cc1F

Procedure:
The title compound was prepared from 2-[5-[(4-ethyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 96) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.67 (2H, q, J=7.6 Hz), 3.97 (3H, s), 5.20 (2H, s), 5.75 (1H, d, J=1.6 Hz), 7.12-7.23 (3H, m), 7.58 (1H, d, J=2.0 Hz), 7.78 (1H, dd, J=1.6, 5.2 Hz), 8.34 (1H, s), 8.71 (1H, d, J=5.2 Hz). LCMS (mobile phase: 30%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=3.783 min. [M+H] Calc'd for C19H18FN3O3, 356; Found, 356.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[N:12]=[C:13]([C:16]#[N:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:8]2[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:11]3[N:12]=[C:13]([C:16]#[N:17])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:20][CH:21]=1
Reactant: N#Cc1ncc2cc(Cc3ccc(CO)cc3)n(C3CCCCC3)c2n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ncc2cc(Cc3ccc(CBr)cc3)n(C3CCCCC3)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a solution of 7-cyclohexyl-6-(4-hydroxymethyl-benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.43 mmol) in CH2Cl2 (5 ml), triphenylphosphine (0.47 mmol) and carbontetrabromide (0.47 mmol) are added at 0° C. under nitrogen. The reaction mixture is stirred at 0° C. for 1 h and at room temperature for 1 h. The crude product is applied to a column of silica gel, which is eluted with following solvents: n-hexane:AcOEt=10:1 (v/v), n-hexane:AcOEt=8:1 (v/v) and n-hexane:AcOEt=5:1 (v/v). The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 73.9%, Rf=0.72 (n-hexane:AcOEt=1:1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH:24]S(O)(=O)=O.[OH-].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]([NH2:20])=[O:24])[CH:13]=[CH:12][N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2nccc(-c3cccc(C#N)c3)n2)cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(-c2nccc(-c3cccc(C(N)=O)c3)n2)cc1
Temperature: 70 °C
Yield: 98 %

Procedure:
A mixture of 3-[2-(4-isopropyl-phenyl)-pyrimidin-4-yl]-benzonitrile (50 mg, 0.167 mmol) and aq. H2SO4 (257 μL, 0.65 M) is heated to 70° C. for 12 h. The mixture is cooled and adjusted to pH 7 with aq. sodium hydroxide (1 M). The mixture is partitioned between water and ethyl acetate, and the organic layer is washed with satd. aq. sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to afford the title compound as a white crystalline solid (52 mg, 98%), m.p. 167-169° C. 1H NMR (300 MHz, acetone-d6): δ 8.91 (1H, d, J=6 Hz), 8.87 (1H, t, J=2 Hz), 8.54 (2H, d, J=9 Hz), 8.52 (1H, ddd, J=8, 2, 1 Hz), 8.15 (1H, ddd, J=8, 2, 1 Hz), 7.93 (1H, d, J=6 Hz), 7.80 (1H, br s), 7.68 (1H, t, J=8 Hz), 7.41 (2H, d, J=9 Hz), 6.96 (1H, br s), 3.01 (1H, heptet, J=7 Hz), 1.30 (6H, d, J=7 Hz). 13C NMR (acetone-d6): δ 205.9, 168.4, 164.8, 163.4, 159.0, 152.4, 137.8, 136.2, 135.9, 130.6 (2C), 129.7, 128.9, 127.2 (2C), 126.8, 115.4, 34.7, 24.1 (2C). MS (ES+): m/e 319 (25), 318 (100).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][N:11]([CH:13]2[CH2:32][N:17]3[C:18]4[C:23]([C:24]([CH2:25][C:26]([O:28]CCC)=[O:27])=[C:16]3[CH2:15][CH2:14]2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.CO>[CH2:1]([C:8]1[N:9]=[N:10][N:11]([CH:13]2[CH2:32][N:17]3[C:18]4[C:23]([C:24]([CH2:25][C:26]([OH:28])=[O:27])=[C:16]3[CH2:15][CH2:14]2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(n1cc(Cc3ccccc3)nn1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(Cc3ccccc3)nn1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of propyl [7-(4-benzyl-1H-1,2,3-triazol-1-yl)-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl]acetate (1 eq) in THF/MeOH (2:1, 0.1M) at room temperature was added a 2M solution of potassium hydroxide (10 eq) The reaction mixture was stirred at room temperature for 2 h then quenched by adding HCl 10% until acidic pH and diluted with dichloromethane (DCM). Filtration through a phase separator followed by evaporation afforded the desired product as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1 H), 8.05 (s, 1 H), 7.46 (d, 1 H), 7.40 (d, 1 H), 7.34-7.17 (m, 5 H), 7.12-7.00 (m, 2 H), 5.35-5.18 (m, 1 H), 4.67 (dd, 1 H), 4.32 (dd, 1 H), 4.02 (s, 2 H), 3.69-3.50 (m, 2 H), 3.07-2.92 (m, 2 H), 2.52-2.30 (m, 2 H). MS (+ESI) m/z: 387.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:19]([NH2:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)=O)=[N:6][CH:7]=1.[CH3:21][NH:22][S:23](Cl)(=[O:25])=[O:24].[BH4-].[Na+]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:10]3[CH:11]=[CH:12][C:13]4[C:18](=[N:17][CH:16]=[CH:15][CH:14]=4)[C:19]=3[NH:20][S:23](=[O:25])(=[O:24])[N:22]2[CH3:21])=[N:6][CH:7]=1
Reactant: Nc1c(C(=O)c2ccc(F)cn2)ccc2cccnc12
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)cn2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 6.9 %

Procedure:
In a similar fashion using route 27 general procedure 70, 7-[(5-fluoropyridin-2-yl)carbonyl]-8-aminoquinoline (Intermediate 373) (648 mg, 2.4 mmol), N-methylsulfamoyl chloride (Intermediate 213) (942 mg, 7.2 mmol) and NaBH4 (92 mg, 2.4 mmol) in pyridine (10 ml) gave the title compound (57 mg, 2.2%) after purification by preparative HPLC (acidic conditions).
Reaction SMILES: I[CH3:2].[Mg].[Cl:4][CH2:5][CH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CCOCC>[Cl:4][CH2:5][CH2:6][CH2:7][C:8]([OH:14])([CH3:2])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(=O)CCCCl
Reactant: CI
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC(C)(O)CCCCl
Temperature: 0 °C

Procedure:
The Grignard reagent prepared from iodomethane (14.2 g., 0.1 mole) and magnesium (2.4 g., 0.1 mole) in ether solution is added, dropwise to an ether solution of 1-chloro-4-nonanone (Example A, Step 1) (17.6 g., 0.1 mole). The reaction is refluxed gently for 3 hours then cooled and poured carefully into ice water (300 ml.). The ether layer is separated, washed with brine, and dried over sodium sulfate. Removal of the ether in vacuo gives 1-chloro-4-hydroxy-4-methylnonane as an oil. The tertiary alcohol is dissolved in pyridine and treated with one molar equivalent of acetic anhydride at 60°-80° for 8-16 hours to give 1-chloro-4-acetoxy-4-methylnonane as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH:28]([CH3:30])[CH3:29])[C:3]1[C:4]([C:17]2[O:18][CH:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH:28]([CH3:30])[CH3:29])[C:3]1[C:4]([C:17]2[O:18][CH:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3occc3-c3ccccc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1occc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(3-phenylfuran-2-yl)quinoxaline-6-carboxylate (140 mg, 0.35 mmol) in methanol (35 mL) and water (2.0 mL) was added sodium hydroxide (55 mg, 1.38 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 4 with HCl (3N). The solids were collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(3-phenylfuran-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid (100 mg, 74%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:15][Si:14]([CH3:17])([CH3:16])[C:12]#[C:13][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc2cnccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2cnccc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
To a solution of 6-bromoisoquinoline (2.0 g, 9.6 mmol) (commercially available from Gateway Chemical Technology, Inc.) in 45 mL of Et3N was added PdCl2(PPh3)2 (0.34 g, 0.48 mmol) and copper(I) iodide (0.27 g, 1.4 mmol). The mixture was degassed by bubbling nitrogen through the mixture for 1 minute. Ethynyltrimethylsilane (2.7 mL, 19 mmol) was added. The mixture was heated to 50° C. After 1 hour, the solvent was removed by rotary evaporation and the residue was purified by flash chromatography on silica gel (5% to 30% EtOAc/hexanes), affording 6-(2-(trimethylsilyl)ethynyl)isoquinoline (2.2 g, 100% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17][C:18]2[CH:19]=[C:20]([NH2:25])[CH:21]=[CH:22][C:23]=2[CH3:24])[CH:3]=1.[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=2)[C:35](O)=[O:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17][C:18]2[CH:19]=[C:20]([NH:25][C:35](=[O:36])[C:34]3[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=[C:32]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:33]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])[CH:3]=1
Reactant: Cc1ccc(N)cc1Nc1nc2ccccc2n1-c1cc(N)ncn1
Reactant: O=C(O)c1cc(N2CCOCC2)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1Nc1nc2ccccc2n1-c1cc(N)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N3-[1-(6-amino-pyrimidin-4-yl)-1H-benzoimidazol-2-yl]-4-methyl-benzene-1,3-diamine (10.0 mg, 0.030 mmol), 3-morpholin-4-yl-5-trifluoromethyl-benzoic acid (10 mg, 0.036 mmol), and DIEA (21 μL, 0.12 mmol) in DMF (2 mL) is added HATU (13 mg, 0.033 m mol). After stirring for 1 hour at room temperature, the solvent is removed under vacuum. The residue is dissolved in DMSO (1 mL). The resulting solution is subjected to purification by reverse-phase LC-MS to yield the title compound.