Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([NH:10][C:11](=[O:29])[CH2:12][C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:17][CH:18]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.C(OCCl)C.[CH3:35][Si:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][O:39][CH2:40]Cl>C1COCC1>[Br:3][C:4]1[C:5]([N:10]([CH2:40][O:39][CH2:38][CH2:37][Si:36]([CH3:43])([CH3:42])[CH3:35])[C:11](=[O:29])[CH2:12][C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:17][CH:18]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(CC1=CCN(C(=O)OCc2ccccc2)CC1)Nc1ncccc1Br
Agent: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN(C(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1)c1ncccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 117 mg, 4.88 mol) was added in portions over 10 min to a solution of benzyl 4-{2-[(3-bromopyridin-2-yl)amino]-2-oxoethyl}-3,6-dihydropyridine-1(2H)-carboxylate (1.91 g, 4.43 mol) in THF (15 mL) at 0° C. After 0.5 h, 2-trimethylsilyl)ethoxymethyl chloride (0.861 mL, 4.88 mol) was then added slowly, keeping the temperature of the reaction mixture below 10° C. After 4 h, sodium hydride (60 mg) and 2-(trimethylsilyl)ethoxymethyl chloride (0.45 ml) were added and the reaction allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 40 to 70% ethyl acetate: hexanes to give the title compound (1.51 g). MS: m/z=560.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12](=[O:22])[CH:13]([CH:20]=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]>>[CH2:9]([O:11][C:12](=[O:22])[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][NH:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:10]
Reactant: Cc1cccnc1N
Reactant: CCOC(=O)CC(C=O)C(=O)OCC
Product: CCOC(=O)CC(=CNc1ncccc1C)C(=O)OCC
Reaction time: 8 h
Yield: 65 %

Procedure:
10.8 g. (0.1 mole) of 3-methyl-2-amino-pyridine are admixed with 20.2 g. (0.1 mole) of 2-formyl-succinic acid diethyl ester. The reaction mixture warms up to 40°-50° C. The mixture is stirred for an hour, whereupon it is allowed to stand at room temperature overnight. The α-(ethoxycarbonyl-methyl)-β-(3-methyl-2-pyridyl-amino)-acrylic acid ethyl ester thus obtained is recrystallized from 50% aqueous ethanol. Yield: 65-70%, m.p.: 62° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[N+:27]([O-])=O)[C:19]2=[O:30])=[N:2]1.[Cl-].[NH4+].O>C(OCC)(=O)C.CCCCCC.[Fe]>[NH2:27][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[CH2:26][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1/[CH:11]=[CH:10]/[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=1)[C:19]2=[O:30]
Reactant: O=C1c2cccc([N+](=O)[O-])c2CN1c1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: Nc1cccc2c1CN(c1ccccc1/C=C/c1n[nH]c3ccccc13)C2=O
Yield: 19.5 %

Procedure:
To a solution of (E)-2-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}-4-nitro-2,3-dihydroisoindol-1-one (54 mg, 0.14 mmol) obtained in Step 1 in ethanol/water (2/1, 3.3 mL), ammonium chloride (40 mg, 0.75 mmol) and iron (38 mg, 0.68 mmol) were added, followed by heating under reflux for 4.0 hours under nitrogen atomosphere. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10) and crystallized from hexane/ethyl acetate (1/1) to obtain Compound 216 (10 mg, 20%).
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)#N.N([O-])=[O:18].[Na+].[OH2:21]>S(=O)(=O)(O)O.[OH-].[Na+]>[C:1]([C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)([OH:18])=[O:21]
Reactant: N#Cc1c2ccccc2nc2ccccc12
Reactant: O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c2ccccc2nc2ccccc12
Temperature: 100 °C

Procedure:
Part of the product of the above procedure, that is, 9-cyano acridine (4 g) is dissolved in sulphuric acid containing 10% by weight of distilled water (total volume equals 40 cm3). The mixture thus obtained is heated at a temperature of 100° C. for 2 hours after which time sodium nitrite (10.7 g) is added slowly with continuous stirring. The resulting mixture is heated at 100° C. for 2 hours then poured into cold, distilled water (650 cm3) The solid material which precipitates at this stage is isolated by filtration and allowed to dissolve in the minimum quantity of one molar sodium hydroxide solution; the solution thus obtained is filtered and the filtrate made slightly acidic by the addition of a 50%, by volume, solution of sulphuric acid in water. The 9-carboxy-acridine so formed is then dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]2[C:14]([OH:21])=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:11]=2[N:10]=1.O=S(Cl)Cl.[CH3:26]O>>[CH3:26][O:19][C:18]([C:17]1[C:11]2[N:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[NH:13][C:12]=2[C:14]([OH:21])=[CH:15][CH:16]=1)=[O:20]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3F)nc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3F)nc12
Temperature: 25 °C
Yield: 84 %

Procedure:
2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (1.70 mg, 5.86 mmol) obtained in step 3 was dissolved in methanol, SOCl2 (8.2 ml, 112 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO3. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel chromatography to obtain the title compound (1.50 mg, 1.64 mmol) in a yield of 84%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Si]([O:41][NH2:42])(C(C)(C)C)(C)C.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:42][OH:41])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: N#Cc1ccc(-c2ccc(OCCCCC(=O)O)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(OCCCCC(=O)NO)cc2)cc1
Reaction time: 2 h
Yield: 45.5 %

Procedure:
To a solution in THF (13 mL) of 5-(4-(4-cyanophenyl)phenoxy)pentanoic acid (0.50 g, 1.7 mmol), prepared as in step 1, was added DMF (10 μL, 0.13 mmol), and oxalyl chloride (0.16 mL, 1.9 mmol) and the reaction mixture was stirred for 2 hours. A solution in THF (2 mL) of O-tert-butyldimethylsilylhydroxylamine (0.30 g, 2.0 mmol) and triethylamine (0.25 mL, 1.8 mmol) was added dropwise via syringe and the reaction mixture was stirred for 3.5 hours. The reaction mixture was quenched with methanol and concentrated in vacuo. The residue was partitioned between aqueous 1M NaOH and ethyl ether, and the aqueous phase was extracted with ethyl ether. The aqueous phase was taken to pH 2 with concentrated HCl and extracted three times with dichloromethane. The combined dichloromethane extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate gave 5-[4-(4-cyanophenyl)phenoxy]pentanohydroxamic acid (0.24 g) as a white solid. mp 141.8°-142.6° C. 1H NMR (DMSO-d6) δ 1.59-1.84 (c, 4H), 2.03 (t, 2H, J=7.5 Hz), 4.03 (t, 2H, J=6 Hz), 7.06 (d, 2H, J=9 Hz), 7.69 (s, 1H), 7.72 (s, 1H), 7.81-7.92 (c, 4H), 8.71 (s, 1H), 10.39 (s, 1H). IR (KBr) 3200, 3030, 3010, 2860, 2240, 1630, 1600, 1540, 1520, 1490, 1470, 1460, 1390, 1290, 1250, 1180, 1110, 980, 850, 820, 630, 580, 530 cm-1. MS (DCI/NH3) 294 (M-16), 311 (M+H)+, 328 (M+NH4)+. Anal. Calcd for C18H18N2O3 : C, 69.66; H, 5.85; N, 9.03. Found: C, 69.54; H, 5.73; N, 8.99.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[NH2:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=1)([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)OC)cc1

Procedure:
A solution of 21 g. of methyl 16-bromohexadecanoate and 20 g. of ethyl 4-aminobenzoate in 150 ml. of hexamethylphosphoramide is stirred at 120° C. for 20 horus, cooled, diluted with water and filtered. A methylene chloride solution of the solid is dried over anhydrous magnesium sulfate, clarified with activated charcoal, and filtered through silica gel. The filtrate is evaporated and the residue crystallized from acetonitrile to yield ethyl 4-(15-carbomethoxypentadecylamino)benzoate as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:20][CH3:21])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=2)[C:6]1=[O:22].[Li]CCCC.[F:36][C:37]([F:45])([F:44])[C:38]([C:40]([F:43])([F:42])[F:41])=[O:39]>C1COCC1>[F:36][C:37]([F:45])([F:44])[C:38]([C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:20][CH3:21])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=2)[C:6]1=[O:22])([OH:39])[C:40]([F:43])([F:42])[F:41]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: COc1cc2c(cc1N1CCOCC1)CC(Cc1cc(C(F)(F)F)ccc1Cl)C2=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1cc(C(F)(F)F)ccc1C(O)(C(F)(F)F)C(F)(F)F)C2=O
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
To a stirred solution of 2-(2-chloro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 269 (0.1 g, 0.226 mmol) in dry THF, cooled to 0° C., n-BuLi (0.021 g, 0.339 mmol) was added drop wise and the solution stirred for 10 min. Then hexafluoroacetone 244 (0.10 g, 0.453 mmol) was added to the reaction and stirred for another 2 h. After completion of the reaction, it was quenched with saturated ammonium chloride solution. The organic layer was separated and aqueous phase was extracted again with diethyl ether, the combined organic layer was dried over sodium sulphate and concentrated to get the crude 270, which was purified through 100-200 mesh silica gel by eluting with 15% ethyl acetate in hexane to give 20 mg of compound 2-(2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 270.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:17])=[C:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[H][H]>[Pd].C(O)(=O)C.CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH3:17])[CH:12]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2=C(C)c3ccc(OC)cc3C3CCCCC23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C2C(C)c3ccc(OC)cc3C3CCCCC32)cc1
Reaction time: 18 h
Yield: 92.5 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-9-methyl-1,2,3,4,4a,10a-hexahydro-phenanthrene (0.116 g, 0.347 mmol), Pd-Black (14.7 mg, 0.139 mmol) and acetic acid/methanol/tetrahydrofuran (1.0 mL, 10.0 mL, 3.0 mL) at 50 psi Hydrogen pressure. After 18 hours, filter off the Pd catalyst over celite eluting with ethyl acetate. Concentrate and flash chromatograph with 0% to 10% ethyl acetate/hexanes to yield the titled compound (0.108 g, 93%) as a clear oil. TLC Rf=0.30 in 5:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.26 (d, 1H, J=8.4 Hz), 7.03 (m, 3H), 6.83 (m, 3H), 3.90 (s, 3H), 3.83 (s, 3H), 3.36 (m, 2H), 3.12 (m, 1H), 2.52 (m, 1H), 2.35 (m, 1H), 1.87 (m, 1H), 1.51 (m, 4H), 1.30 (m, 2H), 1.18 (d, 3H, J=6.6 Hz).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[C:18](Cl)(=O)[C:19]1[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.Cl>C1COCC1>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: NC(=O)c1ccccc1N
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Temperature: 10 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a cooled (0-5° C.) mixture of anthranilamide (350 g, 2.57 mol) and triethylamine (286 g, 2.83 mol) in THF (2.5 L) was added dropwise o-anisoyl chloride (437 g, 2.57 mol) while maintaining the temperature between 0-20° C. The resulting suspension was stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue was washed several times with water. The wet residue was suspended in 2 M aq. NaOH (13 L), and the mixture was heated to reflux. After 20 minutes a clear solution was obtained. After 1 h of reflux the clear solution was cooled in an ice water bath and then acidified to pH 6 with conc. aq. HCl. The suspension was filtered, and the residue was washed thoroughly with water. The white solid was dried by azeotropic distillation with toluene. 2-(2-Methoxyphenyl)quinazolin-4(3H)-one (567 g) was obtained in 82%. 1H-NMR (200 MHz, Me2SO-d6): δ 3.90 (s, 3 H), 7.20 (m, 2 H), 7.60 (t, 2 H), 7.85 (m, 3 H), 8.20 (d, 1 H), 12.20 (s, 1 H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:16])[CH:8]=[CH:7][C:6]([C:9]([NH:11][CH2:12][C:13](=[O:15])[CH3:14])=[O:10])=[CH:5][CH:4]=1.I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[C:13]([CH:12]([NH:11][C:9]([C:6]1[CH:5]=[CH:4][C:3]([CH3:16])=[CH:8][CH:7]=1)=[O:10])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([CH3:31])([CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:15])[CH3:14]
Reactant: CCOC(=O)C(C)(C)OCCCCCCI
Reactant: CC(=O)CNC(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)OCCCCCCC(NC(=O)c1ccc(C)cc1)C(C)=O
Yield: 73 %

Procedure:
A suspension (70 ml) of 1.81 g of 60.% sodium hydride in N,N-dimethylformamide was cooled to −18° C. with ice-sodium chloride bath, and 21 ml of a solution of 8.67 g of 1-(p-toluoylamino)-2-propanone in N,N-dimethylformamide was added slowly. After 1-hour-stirring, 21 ml of a solution of 14.10 g of ethyl 2-(6-iodohexyloxy)-2-methylpropionate in N,N-dimethylformamide was added dropwise slowly. The bath was removed and the mixture was stirred for additional 18 hours at room temperature. The reaction solution was, after addition of ice-cold water, extracted with ethyl acetate, washed with water and brine sequentially, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=3:1) to provide 12.20 g of the objective compound as yellow crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(OCC)(=O)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[N:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]2[CH:31]=[CH:30][C:27]3[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=3[N:33]=2)[CH2:7][CH2:6]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCn2c(=O)cnc3c(F)cc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)cnc5c(F)cc(F)cc54)CC3)nc2N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a solution of 1-[2-(4-aminopiperidin-1-yl)ethyl]-5,7-difluoroquinoxalin-2(1H)-one (Intermediate 192, 0.158 g) in methanol (10 mL) were added 3 Å molecular sieve power (0.15 g) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (92 mg). After 2 hours at reflux, the reaction was cooled to 0° C. and NaBH(OAc)3 (0.19 g) was added. The reaction was allowed to warm to room temperature and was stirred overnight. It was diluted with ethyl acetate, filtered, washed with saturated solutions of Na2CO3 and brine, dried over sodium sulfate and concentrated. Chromatography on silica gel with 0-20% methanol in dichloromethane. Fractions containing product were collected, concentrated, dissolved in a minimum of CH2Cl2, precipitated with diethyl ether, and filtered to yield 104 mg of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([O:43][CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:38][C:37]=1[CH3:53].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:51][C:45]([CH3:52])([CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH2:44][O:43][C:39]1[CH:40]=[C:41]([CH3:42])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:37]([CH3:53])[CH:38]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OCC(C)(C)CS(C)(=O)=O)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC(C)(C)CS(C)(=O)=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-bromo-5-(2,2-dimethyl-3-(methylsulfonyl)propoxy)-1,3-dimethylbenzene following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.81 min; Mass spectrum (ESI+): m/z=611 [M+H]+.
Reaction SMILES: Br[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].C([O-])([O-])=O.[K+].[K+].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2[C:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30](=[O:38])(=[O:37])[NH:29][N:28]=1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CC#N.O.C(Cl)Cl>[C:44]([O:43][C:41](=[O:42])[CH2:40][N:22]1[C:23]2[C:19](=[CH:18][C:17]([F:16])=[CH:25][CH:24]=2)[C:20]([C:27]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30](=[O:37])(=[O:38])[N:29]([CH:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH3:3])[N:28]=2)=[C:21]1[CH3:26])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(Br)c1ccccc1
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: Cc1c(C2=NN(C(C)c3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(1-Bromoethyl)benzene (9 mL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]3[O:19][CH2:18][CH2:17][C:16]=3[CH:20]=1)[N:6]=[CH:5]2.[ClH:21]>CC#N>[OH2:19].[ClH:21].[ClH:21].[O:19]1[C:15]2[CH:14]=[CH:13][C:12]([C:7]3[N:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:2](=[NH:1])[CH3:11])[CH:3]=4)[N:8]=3)=[CH:20][C:16]=2[CH2:17][CH2:18]1.[O:19]1[C:15]2[CH:14]=[CH:13][C:12]([C:7]3[N:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:5](=[NH:6])[CH3:4])[CH:3]=4)[N:8]=3)=[CH:20][C:16]=2[CH2:17][CH2:18]1.[ClH:21].[ClH:21]
Reactant: Nc1ccc2nc(-c3ccc4c(c3)CCO4)ncc2c1
Agent: Cl
Solvent: CC#N
Product: CC(=N)Nc1ccc2nc(-c3ccc4c(c3)CCO4)ncc2c1
Product: O
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A suspension of 6-amino-2-(2,3-dihydro-5-benzofuryl)-quinazoline (1.4 g, 0.0053 mol) in MeCN (50 ml) was satured with HCl at 0° C. and stirred at r.t. for 24 hrs. The precipitated was filtered and triturated with acetone/methanol. The light yellow solid was filtered and dried in vacuum at 40° C. to give the titled compound, 1.3 g, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:31][NH:32][CH3:33]>C1COCC1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:32]([CH3:33])[CH3:31])=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Reactant: CNC
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N(C)C)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and 2.0 M dimethylamine in THF. LCMS (M+H)+=475.0/477.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]=[C:22]1[CH:27]=[C:26]([C:28](O)=[O:29])[CH:25]=[CH:24][NH:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:26]3[CH:25]=[CH:24][NH:23][C:22](=[O:21])[CH:27]=3)=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1cc[nH]c(=O)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cc[nH]c(=O)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1,2-dihydro-2-oxo-4-pyridinecarboxylic acid, as starting materials, MS (LC/MS): 424.0 (M+H).