Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:17])[CH2:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH3:4]>O1CCOCC1.COC(C)(C)C>[CH2:3]([O:5][C:6](=[O:17])[CH:7]([Br:1])[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH3:4]
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)c1ccccc1C
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: CCOC(=O)C(Br)C(=O)c1ccccc1C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Bromine (1.65 g, 10.3 mmol, 1.03 equiv) was added drop-wise to a stirred solution of 3-oxo-3-o-tolyl-propionic acid ethyl ester (2.06 g, 10.0 mmol, 1.0 equiv) in 1,4-dioxane (25 mL) at ambient temperature. The mixture was stirred for 1 hour and then diluted with tert-butyl methyl ether (50 mL). The resultant solution was washed sequentially with water, aqueous potassium carbonate solution and saturated aqueous sodium chloride solution. The collected organic was dried over magnesium sulphate, filtered, and concentrated under vacuum to afford 2.74 g (96%) of 2-bromo-3-oxo-3-o-tolyl-propionic acid ethyl ester as a dark brown residue. 1H NMR (400 MHz, CDCl3) δ: 7.66 (d, 1H), 7.46-7.37 (m, 1H), 7.28 (m, 2H), 5.62 (s, 1H), 4.29-4.22 (q, 2H), 2.52 (s, 3H), 1.28-1.19 (t, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:33]([F:36])([F:35])[F:34])=[C:16]([CH2:20][O:21][CH:22]4[CH2:25][N:24]([C:26]([NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]4)[CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.ClCC1C=CC(C2C(C(F)(F)F)=C(COC3C[N:55](C(NC(C)(C)C)=O)[CH2:54]3)C=CC=2)=CC=1.CN1CCNCC1>>[CH3:54][N:55]1[CH2:3][CH2:2][N:1]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:15]([C:33]([F:35])([F:34])[F:36])=[C:16]([CH2:20][O:21][CH:22]4[CH2:23][N:24]([C:26]([NH:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:25]4)[CH:17]=[CH:18][CH:19]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(CN4CCOCC4)cc3)c2C(F)(F)F)C1
Reactant: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(CCl)cc3)c2C(F)(F)F)C1
Agent: CN1CCNCC1
Product: CN1CCN(Cc2ccc(-c3cccc(COC4CN(C(=O)NC(C)(C)C)C4)c3C(F)(F)F)cc2)CC1
Yield: 67 %

Procedure:
3-[4-(4-methyl-piperazin-1-ylmethyl)phenyl-2-(trifluoromethyl)phenyl]methoxy-N-(tert-butyl)azetidine-1-carboxamide (211) was prepared using the procedure given in Example 146 for compound 196, starting from compound 195 and N-methylpiperazine. Purification through an SCX-2 cartridge afforded the title compound as a white solid (32 mg, 67% yield).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=O.[H][H].[NH3:13]>[Ni]>[OH:10][C:8]1[CH:9]=[C:4]([CH:2]([NH2:13])[CH3:1])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(=O)c1cccc(O)c1
Reactant: N
Agent: [Ni]
Product: CC(N)c1cccc(O)c1
Temperature: 77.5 °C
Reaction time: 6 h

Procedure:
A mixture of 1000 ml of methanolic ammonia, 100 g of 3-hydroxyacetophenone, 25 g of molecular sieves and 10 g of Raney nickel was taken in an autoclave flask at 0-5° C. The autoclave flask was then closed and stirred for 6 h at 75-80° C. without applying hydrogen gas pressure. The reaction mass was further hydrogenated at 75-80° C. by applying 15-20 kg/cm2 pressure of hydrogen gas and the reaction mixture was allowed to stir while maintaining the same conditions of temperature and pressure for 18-22 h. After the completion of the reaction, the reaction mixture was cooled to room temperature and filtered through hyflo bed. The hyflo bed was washed with 200 ml methanol and the solvent distilled off, under reduced pressure at a temperature of 60° C. The reaction mass was cooled to 0-5° C. and stirred for 1 h to obtain a slurry. The solid thus obtained was filtered, washed with ethyl acetate and dried to obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:26]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:26])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 5-allyl-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol (0.59 g, 1.63 mmol) (from Example 18, Step D, supra) in acetone (175 mL) was added K2CO3 (0.68 g, 4.91 mmol) and methyl iodide (2.32 g, 16.4 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 3 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:3:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-chloro-4-fluoro-phenyl)-amine as an off white solid. (Yield 0.29 g, 48%).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([OH:10])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:22][C:23]1[C:24]([F:48])=[CH:25][C:26]([Cl:47])=[C:27]([CH:46]=1)[O:28][C:29]1[CH:43]=[CH:42][C:32]2[N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[S:35][C:31]=2[C:30]=1[C:44]#[N:45]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([NH:22][C:23]1[CH:46]=[C:27]([O:28][C:29]2[CH:43]=[CH:42][C:32]3[N:33]=[C:34]([NH:36][C:37]([CH:39]4[CH2:41][CH2:40]4)=[O:38])[S:35][C:31]=3[C:30]=2[C:44]#[N:45])[C:26]([Cl:47])=[CH:25][C:24]=1[F:48])=[O:10]
Reactant: Cn1ncc(C(=O)O)c1Br
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ncc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c(Cl)cc2F)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
To a solution of 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid (68 mg, 0.331 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (35 μL, 0.408 mmol) and N,N-dimethylformamide (5 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1 mL). N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (90 mg, 0.223 mmol) produced in Example 23(vi) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (7 mL) and saturated brine (7 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (34 mg, 26%) as a white powder.
Reaction SMILES: C(C(NC(C1C=C(F)C=CC=1S[S:20][N:21]([C:30](=[O:38])[C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][CH:32]=1)[CH:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=O)CC(C)C)(O)=O.BrBr>C(#N)C.ClCCl>[CH3:28][CH:27]([CH3:29])[CH2:26][C@H:22]([N:21]1[C:30](=[O:38])[C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[S:20]1)[C:23]([OH:25])=[O:24]
Reactant: CC(C)CC(NC(=O)c1cc(F)ccc1SSN(C(=O)c1cccc(F)c1)C(CC(C)C)C(=O)O)C(=O)O
Agent: BrBr
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)C[C@@H](C(=O)O)n1sc2ccc(F)cc2c1=O
Yield: 137.3 %

Procedure:
Following the general method of Example 3, a slurry of {s-(R*,R*)]-2-{-[2-(1-carboxy-3-methylbutylcarbamoyl)-4-fluorophenyldisulfanyl]-5-fluorobenzoylamino}-4-methyl-pentanoic acid (2.1 g, 3.6 mmol) (from Preparation 21) in 8 mL acetonitrile and 25 mL dichloromethane was treated with bromine (0.7 g, 4.4 mmol) in 15 mL dichloromethane. The crude compound was recrystallized from methanol/water to afford 1.4 g of the title compound, mp 161°-162° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.C([Si](C)(C)[O:44][CH:45]1[CH2:48][CH:47]([N:49]2[CH:53]=[C:52](B3OC(C)(C)C(C)(C)O3)[CH:51]=[N:50]2)[CH2:46]1)(C)(C)C>>[OH:44][CH:45]1[CH2:48][CH:47]([N:49]2[CH:53]=[C:52]([C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9]4[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]5[CH:21]=[CH:22][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:33][CH:34]=5)[N:10]=4)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=3)[CH:51]=[N:50]2)[CH2:46]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Reactant: CC1(C)OB(c2cnn(C3CC(O[Si](C)(C)C(C)(C)C)C3)c2)OC1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(C5CC(O)C5)c4)cc3C(=O)NC)n2)cc1)OCC
Temperature: 25 °C

Procedure:
The title compound was prepared using the procedure from Example 97 with Diethyl (4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and 1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Compound 100A). After Suzuki reaction and SPE pre-purification, dried material was dissolved in DCM and 1.0 M HCl in ether was added. The mixture was stirred at room temperature for half an hour. The crude was sent to MDP for purification. MS (ES+): m/z 674.34 (100) [MH+]; HPLC: tR=0.94 min (UPLC, purity).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[CH3:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]12[C:44]2[C:35](=[CH:36][C:37]3[O:42][CH2:41][CH2:40][O:39][C:38]=3[CH:43]=2)[O:34][CH2:33]1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[CH3:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[C:27](=[O:32])[C:26]12[C:44]2[C:35](=[CH:36][C:37]3[O:42][CH2:41][CH2:40][O:39][C:38]=3[CH:43]=2)[O:34][CH2:33]1
Reactant: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2
Reactant: FC(F)(F)c1cccnc1CCl
Agent: BrCC1CCCCO1
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2Cc1ncccc1C(F)(F)F

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, (5′-methyl-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (62%) as a colorless solid: mp 137-139° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J=4.6 Hz, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.57-7.50 (m, 1H), 7.02-6.94 (m, 2H), 6.72 (d, J=7.9 Hz, 1H), 6.47 (s, 1H), 6.40 (s, 1H), 5.29-5.03 (ABq, 2H), 4.76-4.64 (ABq, 2H), 4.18-4.06 (m, 4H), 2.18 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 155.0, 153.0, 152.9, 144.5, 140.9, 138.2, 135.5 (q, 4J=5.31 Hz), 132.5, 132.5, 129.3, 124.5, 124.4 (q, 1J=273.6 Hz), 123.5 (q, 2J=32.3 Hz), 123.5, 122.2, 112.3, 109.3, 99.1, 79.7, 64.7, 64.1, 57.8, 42.4 (q, J=3.1 Hz), 21.0; MS (ES+) m/z 469.0 (M+1).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[CH2:8]([NH:14][C:1](=[O:7])[CH:2]=[CH:3][C:4]([OH:6])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCN
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: CCCCCCNC(=O)C=CC(=O)O
Reaction time: 2 h

Procedure:
Maleic anhydride (39.4 g, 0.40 mol) was partly dissolved in toluene (1 l) to form a milky suspension. N-hexylamine (53 ml, 0.40 mol) was diluted with toluene (500 ml) and added dropwise over a period of 1.5 h. After 2 h, the reaction mixture was filtered and the title compound was obtained as a white solid (76.4 g, 96%) after drying for 16 h in a vacuum oven at 40° C.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]1([CH3:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:25]([OH:27])[CH3:26]>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.O>[CH3:24][C:18]1[CH:23]=[CH:22][C:21]([C:3]2[CH:8]=[C:7]3[C:6]([CH2:9][CH2:26][C:25]3=[O:27])=[CH:5][CH:4]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: CCO
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C(=O)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, a mixture of 6—(trifluoromethanesulfoxy)-1-indanone (11.5 g), 4-methylphenyl borate (6.69 g), potassium carbonate (11.3 g), toluene (400 ml), ethanol (40 ml) and water (40 ml) was stirred at room temperature for 30 minutes, and to the mixture was added tetrakis(triphenylphosphine)palladium (1.42 g). The mixture was refluxed for 17 hours and cooled to room temperature. The organic layer was separated, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/toluene=1/10) and recrystallized from ethyl acetate-hexane to give 6—(4-methylphenyl)-1-indanone (5.20 g) as pale brown crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][Si:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:7])[CH3:6].[NH3:16]>>[NH2:16][CH2:2][CH2:3][O:4][Si:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:7])[CH3:6]
Reactant: C[Si](C)(CCc1ccccc1)OCCCl
Reactant: N
Product: C[Si](C)(CCc1ccccc1)OCCN

Procedure:
reacting said (chloromethyl) phenylethyldimethylmethoxysilane with ammonia under heat and pressure, and distilling the reaction mixture to yield (aminomethyl) phenylethyldimethylmethoxysilane.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4]CC1.[N+]([O-])(O)=O.[O:12]=O.[C:14]([OH:17])(=[O:16])[CH3:15]>[N+]([O-])([O-])=O.[Mn+2].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Co+2].[N+]([O-])([O-])=O>[C:1]([OH:7])(=[O:12])[CH2:6][CH2:5][CH2:4][CH2:15][C:14]([OH:17])=[O:16]
Reactant: O=C1CCCCC1
Reactant: CC(=O)O
Reactant: O=O
Agent: [Co+2]
Agent: [Mn+2]
Agent: O=[N+]([O-])[O-]
Solvent: O=[N+]([O-])O
Product: O=C(O)CCCCC(=O)O

Procedure:
A solution containing 25 mmol of cyclohexanone, 0.5 mmol of manganese(II) nitrate, 0.5 mmol of cobalt(II) nitrate and 1.5 mmol of nitric acid in 25 ml of acetic acid was stirred for 5 h at 40° C. in an oxygen atmosphere under ambient pressure. Subsequently, the acetic acid was distilled off. The residue was found to consist mainly of adipic acid with some glutaric acid and a small amount of unreacted starting material. The conversion of cyclo-hexanone was found to be 97.5%, the selectivity of the oxidation to adipic acid being 93.4%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].S(OC)(O[CH3:14])(=O)=O.Cl>[OH-].[K+]>[Cl:1][C:2]1[C:7]([O:8][CH3:14])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9]
Reactant: COS(=O)(=O)OC
Reactant: Oc1cccc(O)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1cccc(O)c1Cl
Temperature: 100 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To an aqueous solution (100 mL) of potassium hydroxide (11.0 g) was added 2-chlorobenzene-1,3-diol (22.8 g). Then, dimethyl sulfate (19.9 g) was slowly added to the reaction mixture while keeping the reaction mixture at 10° C. to 20° C., and the mixture was stirred at 100° C. for 2 days. The reaction mixture was acidified with 2N hydrochloric acid, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (18.0 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[N:7]=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: [N-]=[N+]=NCCc1cc2ccccc2cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To a solution of 3-(2-azidoethyl)isoquinoline (Description 112; 5.6 g, 28.3 mmol) in anhydrous tetrahydrofuran (50 ml) was added triphenylphosphine (14.85 g, 56.6 mmol) and water (0.509 ml, 28.3 mmol), and the resulting mixture stirred at room temperature overnight. The mixture was loaded directly onto a Bond-elut SCX cartridge and eluted with methanol until TLC indicated complete elution of triphenylphosphine. The product was then eluted with 2.0M ammonia in methanol. The basic fractions were collected and evaporated to give the title compound (2.7 g, 55%).
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[CH3:16][O:17]C1C=C2C(=CC=1)CC(=O)CC2.IC>>[CH3:16][O:17][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:3]=1)[C:10]([CH3:13])([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Solvent: CI
Product: COc1ccc2c(c1)CCC(=O)C2(C)C

Procedure:
Under the same conditions as the method for synthesizing Compound A2, the title compound was prepared from 6-methoxy-3,4-dihydro-1H-naphthalen-2-one and iodomethane.
Reaction SMILES: [Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.Br[C:22]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][C:22]2([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][CH2:23]2)=[N:5][N:6]=1
Reactant: Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Reactant: CCOC(=O)C1(Br)CCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(Sc2nnc(Br)n2-c2ccc(C3CC3)c3ccccc23)CCC1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (100 mg, 0.289 mmol), ethyl 1-bromocyclobutanecarboxylate (47 μL, 0.289 mmol) and diisopropylethylamine (151 μL, 0.866 mmol) in DMF (1 mL) was heated at 60° C. for 4 days. After cooling to room temperature, the mixture was concentrated and partitioned between dichloromethane (15 mL) and HCl (1N aqueous, 15 mL). The aqueous layer was extracted with dichloromethane (2×15 mL) and the combined organic extracts dried over sodium sulfate, concentrated and purified by column chromatography (40% EtOAc/hexanes) to provide ethyl 1-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)cyclobutanecarboxylate as a light yellow sticky foam (75 mg, 55% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:15]1[C:14]2[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[N:2]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)sc1N
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cccnc1
Product: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 3-cyanopyridine and 2-amino-5-trifluoromethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[O:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[OH:21])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([O:21][C:15]2[C:14]([O:12][CH3:13])=[CH:19][CH:18]=[CH:17][C:16]=2[F:20])=[N:3][CH:4]=1
Reactant: COc1cccc(F)c1O
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(F)c1Oc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 2-bromo-5-chloro-3-nitropyridine (2.37 g, 10 mmol) was dissolved in 40 mL DMF was added of 2-methoxyl-6-fluorophenol (1.7 g 11.9 mmol) was added into the solution followed by potassium carbonate (2.76, 20 mmol). The mixture was stirred at room temperature for 5 h, then poured into ice water (200 mL). The precipitate was filtered and dried under high vacuum to provide 5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-3-nitro-pyridine.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3]([Cl:5])=[O:4].[Cl:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26]CNC)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:32])[CH:9]=1.[CH2:33]([N:35](CC)[CH2:36]C)C>C(Cl)Cl>[ClH:5].[Cl:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:1][N:2]([CH3:6])[C:3]([N:35]([CH3:36])[CH3:33])=[O:4])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:32])[CH:9]=1
Reactant: CNCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Reactant: CN(C)C(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN(C)C(=O)N(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.3 %

Procedure:
Dimethylcarbamyl chloride (38 μl, 0.42 mmol) was added to a solution of 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylaminoethoxy)quinazoline (150 mg, 0.4 mmol), (prepared as described for the starting material in Example 60), and triethylamine (61 μl, 0.44 mmol) in methylene chloride (4 ml). The mixture was stirred for 2.5 hours at ambient temperature, the resulting precipitate was collected by filtration and washed with ether. The solid was purified by column chromatography, eluting with methylene chloride/methanol (92/8). The purified product was dissolved in methylene chloride/methanol (1/1), 2.9M ethereal hydrogen chloride (1 ml) was added and the volatiles were removed by evaporation. The residue was triturated with ether and the solid product collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N′, N′, N-trimethylureido)ethoxy)quinazoline hydrochloride (80 mg, 41%).