Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:6]1[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(C(F)(F)F)cc(=O)[nH]1
Solvent: CN(C)c1ccccc1
Product: Cc1nc(Cl)cc(C(F)(F)F)n1
Yield: 91 %

Procedure:
2-Methyl-6-trifluoromethyl-4H-pyrimidin-4-one of Example 4 (2.00 g, 11.2 mmol) was mixed with phosphorus oxychloride (10 mL) and N,N-dimethylaniline (2 mL), and refluxed for 3 h. The dark solution was poured into crushed ice and extracted with Et2O. The organic layer was washed with H2O (twice), dried over Na2SO4, then evaporated to dryness to afford 2.00 g (91%) of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[CH:20]([CH3:21])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.ClC1C=CC2C3C(=CNC=3)CN=C(C3C=CC=CC=3F)C=2C=1>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: CC1N=CC2=C1c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Agent: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Product: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
The preparation of 8-chloro-6-(2-fluorophenyl)-1-methyl-1H,4H-pyrrolo[3,4-d][2]benzazepine was conducted in the same manner as the preparation of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine to give colorless prisms, mp 226°-227°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH3:10])=[O:8].S.[Na].BrC[C:20]([OH:22])=[O:21]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH2:10][C:20]([OH:22])=[O:21])=[O:8]
Reactant: O=C(O)CBr
Reactant: COC(=O)C(c1cccs1)c1cccs1
Agent: S
Agent: [Na]
Solvent: CO
Product: O=C(O)COC(=O)C(c1cccs1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a well stirred solution of methyl dithiophenylacetate (16.2 grams, 0.089 mole) in methanol (50 mL) was added anhydrous sodium hydrogen sulfide (5.6 grams, 0.10 mole). The mixture was stirred overnight at room temperature, and the solvent removed in vacuo. The solid salt thus obained was taken up in tetrahydrofuran (125 mL). To the solution was added bromoacetic acid (12.4 grams, 0.089 mole). The resulting mixture was stirred for 2 hours at room temperature, and the solvent removed in vacuo. The resulting solid was taken up in 5% (w/v) aqueous sodium bicarbonate, then washed twice with chloroform. The aqueous layer was acidified by the addition of concentration HCl and then extracted three times into diethyl ether. The combined ethereal extracts were dried over anhydrous Na2SO4. The solvent was then finally removed in vacuo to afford carboxymethyl dithiophenylacetate, an orange solid, in 94.5% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:15]([OH:17])=[O:16])=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].IC.[C:22](=O)(O)[O-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:22])[C:9]1[S:10][C:11]([C:15]([OH:17])=[O:16])=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nc(N(C)C(=O)OC(C)(C)C)sc1C(=O)O
Temperature: 25 °C

Procedure:
To a stirred solution of 2-(tert-butoxycarbonylamino)-4-methylthiazole-5-carboxylic acid (0.13 g, 0.50 mmol) in N,N-dimethylformamide (2.5 mL) at 0° C. was added sodium hydride (0.044 g, 1.10 mmol, 60% dispersed in mineral oil). The resultant mixture was stirred at 0° C. for 40 min, followed by the dropwise addition of iodomethane (31.2 mL, 0.50 mmol). The resultant solution was allowed to warm to ambient temperature over 18 h, followed by the addition of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (50/50 to 100/0) to afford 2-(tert-butoxycarbonyl(methyl)amino)-4-methylthiazole-5-carboxylic acid (0.070 g, 0.26 mmol).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].O.[C:16]1(C)[CH:21]=CC(S(O)(=O)=O)=C[CH:17]=1.C1(C)C=CC=CC=1.CCCO>O>[CH2:17]([O:4][C:3](=[O:5])[C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)=[O:1])[CH2:16][CH3:21]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOc1ccc(C(=O)C(=O)O)cc1
Solvent: CCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOC(=O)C(=O)c1ccc(OCC)cc1

Procedure:
10.4 g (50 mmol) of α-oxo-4-ethoxyphenylacetic acid (Bandyopahyay et al., J. Ind. Chem. Soc. 66(4), 239, 1989) and 1.0 g of p-toluenesulfonic acid-monohydrate are refluxed into a mixture of 100 ml of toluene and 50 ml of N-propanol while in a water separator until no more water separates out. Then, it is concentrated by evaporation in a vacuum, the residue is dispersed between ethyl acetate and sodium bicarbonate solution, the organic phase is dried on magnesium sulfate, filtered and concentrated by evaporation.
Reaction SMILES: N#N.[C:3]1(=[O:8])[CH2:7][CH2:6][CH:5]=[CH:4]1.[CH2:9]([N:16]([CH2:22]OC)[CH2:17][Si](C)(C)C)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(Cl)Cl.COC(C)(C)C.FC(F)(F)C(O)=O>[CH2:9]([N:16]1[CH2:22][CH:4]2[C:3](=[O:8])[CH2:7][CH2:6][CH:5]2[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1C=CCC1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: COC(C)(C)C
Product: O=C1CCC2CN(Cc3ccccc3)CC12
Reaction time: 4 h
Yield: 774.1 %

Procedure:
A 3-neck, 1-L round bottom flask equipped with an addition funnel, internal thermometer, and N2 inlet at RT was charged with cyclopentenone (16.48 g, 0.20 mol) in 0.5 L of CH2Cl2. Benzyl(methoxymethyl)trimethylsilylmethylamine (5.0 grams, 21 mmol) and trifluoroacetic acid (TFA) (1.07 mL, 13.9 mmol) were added. To this mixture was added additional benzyl(methoxymethyl)-trimethylsilylmethylamine (40 g, 0.168 mol) dropwise via addition funnel over 1 hour with the reaction temperature being maintained below 25° C. (water bath). After the addition was complete, the mixture was stirred for 4 h. The mixture was washed with 1×100 mL 10% Na2CO3. The layers were separated and the organic layer was washed with 1×100 mL 23% NaCl. The organic extract was concentrated under reduced-pressure to give an oil. The oil was redissolved in methyl-t-butyl ether (250 mL) and extracted into 1M H3PO4 (200 mL). The aqueous layer was basified with 50% NaOH to pH 12. The product was extracted with methyl-t-butyl ether (250 mL). The layers were separated and the organic layer was washed with 23% NaCl. The layers were separated. The organic layer was charged with acetonitrile (50 mL) and silica gel (10 gms). The mixture was stirred 5 minutes and filtered through a silica gel pad (10 grams). The filtrate was concentrated to give the title compound (35.0 grams, 81.4% of theory), which was carried on to the next step without further purification. MS (ESI/APCl) m/z 216 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:12](=[O:14])[CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CC(=O)OCCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(CCCCOC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
Compound 3 was prepared by following a previously reported method. {Santra, 2004 #6} Briefly, diethyl malonate 1 (10 g, 62.5 mmol). 4-bromobutyl acetate 2 (15.84 g, 81.3 mmol) were placed in a round bottom flask containing acetonitrile (120 mL) and stirred for 2 min at room temperature. Then to this, we added potassium carbonate (34.5 g, 250.1 mmol) and refluxed for 36 h. Next, the mixture was filtered and the filtrate was concentrated to obtain a yellow liquid. This was extracted with ethyl acetate, and washed with water. The organic layers were combined and dried over Na2SO4, and purified by column chromatography using 4% ethyl acetate in petroleum ether as the eluent.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([Si](C)(C)C)[S:4][C:3]=1[C:11]1[S:12][C:13]([Si](C)(C)C)=[CH:14][C:15]=1Br.C([Li])CCC.[CH3:26][CH:27]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:28][CH2:29][Si:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(Cl)Cl.O>O1CCCC1.CCCCCC>[CH3:26][CH:27]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:43])[CH3:44])[CH2:28][CH2:29][Si:30]1([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:11]2[S:12][CH:13]=[CH:14][C:15]1=2
Reactant: CCCCCC[Si](Cl)(Cl)CCC(C)CCCC(C)C
Reactant: C[Si](C)(C)c1cc(Br)c(-c2sc([Si](C)(C)C)cc2Br)s1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC[Si]1(CCC(C)CCCC(C)C)c2ccsc2-c2sccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
3,3′-dibromo-5,5′-bis(trimethylsilyl)-2,2′-bithiophene (Compound G4, synthesized in accordance with WO 2010/136353, 11.4 g, 24.3 mmol) was placed in a 500 mL four-necked flask in a nitrogen atmosphere, and dissolved in tetrahydrofuran (200 mL). This was cooled to −78° C., and a solution of n-butyl lithium in hexane (KANTO CHEMICAL CO., INC., 1.59 M, 32.1 mL) was added dropwise. After about 20 minutes of agitation, the 3,7-dimethyloctyl-n-hexyl-dichlorosilane (Compound G18, 9.5 g) synthesized in Synthesis Example B15 was added dropwise. The temperature was raised gradually to room temperature over the course of about 2 hours, water was added, and the product was extracted with hexane. The organic layer was washed with water, dried over sodium sulfate, and concentrated by filtration. The resulting oily substance was dissolved in chloroform (40 mL) and hexane (80 mL), trifluoroacetic acid (3.6 mL) was added, and the mixture was agitated for about 10 minutes at room temperature. Saturated sodium bicarbonate solution was added to the reaction solution, which was extracted with hexane and then concentrated under reduced pressure. The resulting yellow oily substance was dissolved in hexane, and subjected to silica gel column chromatography (solvent: hexane) to obtain the target 4-(3,7-dimethyloctyl)-4-n-hexyldithieno[3,2-b:2′,3′-d]silole (Compound G19, 8.2 g, yield 81%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:12][NH:13][C:14]2[O:15][C:16]3[CH:22]=[C:21]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30](=[O:33])[NH:31][CH3:32])[CH:25]=4)[CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].C1COCC1>CO>[CH3:32][NH:31][C:30]([C:26]1[CH:25]=[C:24]([O:23][C:21]2[CH:20]=[CH:19][C:17]3[N:18]=[C:14]([NH:13][CH2:12][C:6]4([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)[O:15][C:16]=3[CH:22]=2)[CH:29]=[CH:28][N:27]=1)=[O:33]
Reactant: CCOC(=O)C1(CNc2nc3ccc(Oc4ccnc(C(=O)NC)c4)cc3o2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Oc2ccc3nc(NCC4(C(=O)O)CCCCC4)oc3c2)ccn1

Procedure:
1-{[6-(2-Methylcarbamoyl-pyridin-4-yloxy)-benzooxazol-2-ylamino]methyl}-cyclohexanecarboxylic acid ethyl ester (1 eq) was dissolved in 3 M sodium hydroxide (20 eq); THF and methanol were added to homogenize the solution. The mixture was allowed to react at room temperature overnight. The solvents were removed. The crude product was brought to a pH of 4 with 1 N HCl, then to pH of 7 with saturated aqueous sodium bicarbonate. This solution was saturated with solid sodium chloride then extracted three times with ethyl acetate. The combined organic extracts were washed once with brine, dried with anhydrous sodium sulfate, filtered and concentrated. The product was purified by silica gel column in isopropanol and dichloromethane (50%) MH+=425.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C@@H:11]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:19]([N:29]=[N+:30]=[N-:31])[C@@H:18]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:17][C@H:12]1[O:13]C(=O)C)(=O)C>CO.O>[N:29]([C@H:19]1[C@@H:18]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:17][CH:12]([OH:13])[C@H:11]([OH:10])[C@H:20]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N+:30]=[N-:31]
Reactant: CC(=O)O[C@@H]1O[C@H](COCc2ccccc2)[C@H](N=[N+]=[N-])[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=N[C@@H]1[C@H](OCc2ccccc2)[C@@H](O)C(O)O[C@@H]1COCc1ccccc1
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
Potassium carbonate (0.600 g, 4.34 mmol, 3.99 equiv) was added to a solution of diacetate 222 (0.511 g, 1.09 mmol, 1.00 equiv) in methanol (50 mL) and water (5 mL). After 1.5 h, the yellow solution was decanted from the undissolved potassium carbonate and concentrated to about 4 mL and then diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The aqueous layer was extracted with dichloromethane (2×10 mL) and the combined organic layers were dried with magnesium sulfate and purified by silica gel chromatography (ethyl acetate) to afford 223 (0.353 g, 0.917 mmol, 84% yield) as a yellow oil (1:1 α:β). Rf=0.17, 014 (hexane/ethyl acetate 1:1); 1H NMR (400 MHz, CDCl3) δ 7.43-7.27 (m, 20H), 5.28 (d, J=3.8, 1H), 4.78 (d, J=11.5, 1H), 4.78 (d, J=11.5, 1H), 4.67 (d, J=11.5, 1H), 4.68 (d, J=11.5, 1H), 4.58 (d, J=11.9, 1H), 4.56 (d, J=11.9, 1H), 4.52 (d, J=11.9, 1H), 4.51 (d, J=11.9, 1H), 4.51 (d, J=7.7, 1H), 4.21 (td, J=6.5, 1.1, 1H), 4.02 (dd, J=3.4, 1.3, 1H), 3.99 (dd, J=9.9, 3.8, 2H), 3.85 (dd, J=9.7, 3.5, 1H), 3.73 (dd, J=9.5, 7.7, 1H), 3.69-3.51 (m, 6H); 13C NMR (126 MHz, CDCl3) δ 137.62, 137.50, 137.48, 128.67, 128.59, 128.16, 128.13, 128.10, 128.09, 128.07, 128.02, 128.00, 97.08, 92.50, 80.85, 78.06, 73.64, 73.61, 72.63, 72.51, 72.14, 71.82, 69.25, 68.76, 68.68, 67.38, 60.27, 59.49; FTIR (neat film) 3401.3, 3032.4, 2921.6, 2105.6, 1454.4, 1367.2, 1279.3, 1095.8, 1028.3, 738.1, 698.0 cm−1; HRMS (ESI) m/z: Calcd for C20H23N3O5Na (M+Na+) 408.1535, found 408.1535.
Reaction SMILES: [C:1]([Si:5]([CH3:40])([CH3:39])[O:6][C@H:7]1[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13]2[N:12]=[C:11]([C:19]([CH3:21])=[CH2:20])[C:10]([C:22]3[C:23]([C:30]([F:33])([F:32])[F:31])=[CH:24][CH:25]=[C:26]([CH:28]=[O:29])[CH:27]=3)=[C:9]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[C:8]1=2)([CH3:4])([CH3:3])[CH3:2].[H-].[NH4+].[Li].Cl>O1CCCC1.C(OC(=O)C)C>[C:1]([Si:5]([CH3:39])([CH3:40])[O:6][C@H:7]1[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13]2[N:12]=[C:11]([C:19]([CH3:21])=[CH2:20])[C:10]([C:22]3[C:23]([C:30]([F:31])([F:32])[F:33])=[CH:24][CH:25]=[C:26]([CH2:28][OH:29])[CH:27]=3)=[C:9]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[C:8]1=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)c1nc2c(c(C3CCCC3)c1-c1cc(C=O)ccc1C(F)(F)F)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: Cl
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)c1nc2c(c(C3CCCC3)c1-c1cc(CO)ccc1C(F)(F)F)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
125 mg 5-(S)-[5-(tert-Butyl-dimethyl-silanyloxy)-4-cyclopentyl-2-isopropenyl-7,7-dimethyl-5,6,7,8-tetrahydro-quinolin-3-yl]-(4-trifluoromethyl-phenyl)-methanone are dissolved in 10 ml tetrahydrofurane cooled to 0° C. and mixed with 890 μl of a 1 M solution of lithium ammonium hydride in tetrahydrofurane. The mixture is stirred for 2 h, diluted with ethylacetate and mixed with 890 μl of a 1 M hydrochloric acid. Then the mixture is dried with magnesium sulphate, the solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 95:5 to 70:30).
Reaction SMILES: [CH2:1]([S:7][CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:9](Cl)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:20][C:21]1[C:22]([S:30][CH3:31])=[N:23][C:24]([CH3:29])=[CH:25][C:26]=1[S:27][CH3:28]>C(Cl)Cl.N1C=CC=CC=1>[CH3:31][S:30][C:22]1[C:21]([NH:20][C:9](=[O:10])[CH:8]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:26]([S:27][CH3:28])[CH:25]=[C:24]([CH3:29])[N:23]=1
Reactant: CCCCCCCCC(SCCCCCC)C(=O)Cl
Reactant: CSc1cc(C)nc(SC)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCC(SCCCCCC)C(=O)Nc1c(SC)cc(C)nc1SC
Temperature: 5 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A solution of 4.19 g (13.7 mmol) 2-hexylthiodecanoyl chloride, prepared according to Example 4A, in 15 ml methylene chloride was added dropwise with stirring under nitrogen to a solution of 2.75 g (13.7 mmol) 3-amino-2,4-bis(methylthio)-6-methylpyridine in 30 ml pyridine cooled to 5° C. The reaction mixture was stirred at room temperature under nitrogen overnight. Methylene chloride (250 ml) was then added to the reaction mixture and the resulting solution was washed with 3×50 ml 3N aqueous hydrochloric acid solution, 2×50 ml water, 1×50 ml saturated aqueous sodium bicarbonate solution and 1×50 ml brine. The methylene chloride solution was dried over anhydrous sodium sulfate, filtered and concentrated to dryness in vacuo. The solid residue (6.5 g) was recrystallized from petroleum ether to yield 4.7 g of the title compound, m.p. 75°-76.5° C. (72.8% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)CC3C=CC(OC)=CC=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][CH:38]([NH:41]C(=O)OC(C)(C)C)[CH2:37][CH2:36]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:41][CH:38]1[CH2:37][CH2:36][N:35]([C:3]2[C:2]([Cl:1])=[C:7]([NH:8][C:9]3[N:14]=[C:13]([NH:15][CH:25]4[CH2:27][CH2:26]4)[C:12]4=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]4[N:10]=3)[CH:6]=[C:5]([C:33]#[N:34])[CH:4]=2)[CH2:40][CH2:39]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(NC(=O)OC(C)(C)C)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCC(N)CC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45 %

Procedure:
To a round bottom flask charged with tert-butyl (1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (I12C) (0.517 g, 0.773 mmol) in dichloromethane (5.15 ml) was added anisole (1.688 ml, 15.45 mmol), followed by the slow addition of trifluoroacetic acid (2.381 ml, 30.9 mmol). The reaction mixture was stirred at room temperature 2 d. The reaction mixture was warmed to 45° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. After cooling to room temperature, 25 mL 2 N ammonia/methanol was added and a white solid crashed out of solution. The slurry was stirred for 30 min and the solid was isolated by vacuum filtration washing with cold methanol. 2-((3-(4-Aminopiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (0.1563 g) was isolated as a white solid. Material used as is in subsequent transformations.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.Br.[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: C[C@@H]1CCCN1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.8 %

Procedure:
A suspension of Example 1C (0.19 g, 0.55 mmol), (2R)-2-methylpyrrolidine hydrobromide (0.17 g, 1.0 mmol) and sodium carbonate (0.23 g, 2.2 mmol) in acetonitrile (0.4 mL) was heated to 50° C. with stirring for 48 hours. The reaction was cooled to ambient temperature, diluted with acetonitrile and centrifuged. The supernatant liquid was removed and the solids washed with acetonitrile. The combined liquids were concentrated under reduced pressure and the residue chromatographed by reverse phase HPLC with aqueous CF3CO2H/acetonitrile to give the titled compound (0.065 g, 34%). 1H NMR (300 MHz, CD3OD) δ7.88 (m, 1H), 7.71 (m, 4H), 7.50 (m, 2H), 6.82 (s, 1H), 3.72-3.9 (m, 2H), 3.58 (m, 1H), 3.25-3.5 (m, 4H), 2.48 (m, 1H), 2.05-2.2 (m, 2H), 1.75 (m, 1H), 1.50 (d, J=6 Hz, 3H); MS (DCI) m/z 331 (M+H)+;
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:19]=3)[N:14]=2)[CH:12]=1)=[O:7])C.O>C1COCC1>[O:23]=[C:21]1[C:20]2[C:15](=[CH:16][C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:18][CH:19]=2)[N:14]=[C:13]([N:11]2[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]2)[NH:22]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Potassium hydroxide (37.4 mg, 0.666 mmol) was added to a mixture of 1-(4-oxo-7-phenyl-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (48.0 mg, 0.133 mmol), water (0.8 mL) and THF (0.8 mL). The mixture was stirred for 16 h at 23° C. The reaction mixture was concentrated under reduced pressure to remove the THF and the aqueous residue was acidified to pH 2 with 1M aq. HCl. The resulting precipitate was collected by filtration to provide the titled compound (42.0 mg, 85%). MS (ESI): mass calcd. for C18H12N4O3, 332.1; m/z found, 333.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.45 (d, J=0.8 Hz, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.78-7.72 (m, 2H), 7.62 (d, J=1.5 Hz, 1H), 7.55 (d, J=0.8 Hz, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.41-7.36 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[S:5][C:6]=1[C:7](=[O:16])[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15].[NH2:27][CH2:28][C:29]1([N:33]([CH3:35])[CH3:34])[CH2:32][CH2:31][CH2:30]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:27][CH2:28][C:29]3([N:33]([CH3:35])[CH3:34])[CH2:32][CH2:31][CH2:30]3)=[O:24])=[CH:25][CH:26]=2)[S:5][C:6]=1[C:7](=[O:16])[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15]
Reactant: Nc1nc(Nc2ccc(C(=O)O)cc2)sc1C(=O)c1c(F)cccc1F
Reactant: CN(C)C1(CN)CCC1
Product: CN(C)C1(CNC(=O)c2ccc(Nc3nc(N)c(C(=O)c4c(F)cccc4F)s3)cc2)CCC1
Yield: 61 %

Procedure:
The title compound was prepared in a manner similar to Step 3 in Method A; from coupling 4-[4-amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3) and 1-(aminomethyl)-N,N-dimethylcyclobutanamine (Yang et al., Eur. J. Med. Chem. 31, 231-239 (1996)) to afford a yellow amorphous powder in 61% yield.
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:11]([O:16][CH3:15])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Cc1cc2nc(N)c(Cl)nc2cc1C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc2cc(C)c(C)cc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To 2-amino-3-chloro-6,7-dimethyl quinoxaline (2.59 g, 12.5 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (4.05 g, 18.7 mmol) in methanol was added at room temperature and stirred further at room temperature for 1 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 2.38 g of the titled compound (yield, 94%).