Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[CH:4][N:3]=1.[C:9](=[O:12])([O-])[O-].[K+].[K+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([N:5]1[C:6](=[O:8])[CH:7]=[C:2]([O:12][CH2:9][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=[CH:4]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(O)ncn1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2)ncn1Cc1ccccc1

Procedure:
4,6-dihydroxypyrimidine (25.0 g, 0.223 mol) and potassium carbonate (65.1 g, 0.471 mol) are combined in 0.5 L anhydrous dimethylformamide. Benzyl chloride (55.7 g, 0.439 mol) is added dropwise over 30 minutes with stirring. After 4 h the solution is filtered, and the filtrate concentrated in vacuo. The residue is washed with acetonitrile, and the product is collected as a white solid by filtration (44.6 g, 68%). 1H-NMR (400 MHz, DMSO-d6) δ 8.06 (m, 2 H), 7.61 (quartet, J=8.45 Hz, 1H), 7.30 (t, J=10.37 Hz, 1H), 7.12, (t, J=8.45 Hz, 1H), 7.09 (d, J=5.06 Hz, 2H), 5.14 (s, 2H). LC/MS tr=5.29 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 293 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[C:15]([F:32])=[CH:16][C:17]3[O:22][CH2:21][C:20](=S)[N:19]([CH:24]([C:26](OCC)=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:34][NH2:35]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([O:13][C:14]2[CH:31]=[C:18]3[C:17](=[CH:16][C:15]=2[F:32])[O:22][CH2:21][C:20]2[N:19]3[CH:24]([CH3:25])[C:26](=[O:27])[NH:34][N:35]=2)([CH3:12])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C)N1C(=S)COc2cc(F)c(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2COc3cc(F)c(OC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 45.9 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-7-fluoro-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.080 g, 0.171 mmol) in EtOH (5 mL) was added hydrazine hydrate (0.085 g, 1.707 mmol) and the mixture was heated to reflux for 2 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by preparative TLC (eluting with 30% EtOAc in petroleum ether) to give 3-(7-fluoro-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.033 g, 46%) as a white solid. LC/MS (Table 1, Method 2) Rt=1.144 min.; MS m/z: 421 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:12]=[CH:11][O:10][CH:9]=2)=[CH:6][N:5]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:4]=1)#[N:2].[Br:25]N1C(=O)CCC1=O.CCOCC.O>O1CCCC1>[Br:25][C:9]1[O:10][CH:11]=[CH:12][C:8]=1[C:7]1[C:3]([C:1]#[N:2])=[N:4][N:5]([C:13]2[C:14]([Cl:24])=[CH:15][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:17][C:18]=2[Cl:19])[CH:6]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1ccoc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1ccoc1Br
Reaction time: 24 h

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(furan-3-yl)pyrazole (0.19 g) in tetrahydrofuran (5 ml) was added portionwise N-bromosuccinimide (0.093 g). The mixture was left at room temperature for 24 hours and then poured into ether (15 ml) and water (15 ml). The layers were separated and the organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with hexane:dichloromethane (1:1). Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 111° C.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[CH:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][N:28]=[C:27]2[O:36][C:37]1[C:38]([F:44])=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40]>C1COCC1>[F:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([O:36][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[C:38]=2[F:44])=[O:21])[CH:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3F)c2cc1OC
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)on4)c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 36 h
Yield: 42.3 %

Procedure:
A mixture of phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (prepared as described in Example 162A steps 1 and 2) (211 mg, 0.714 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (prepared as described in Example 265A steps 1 through 3) (150 mg, 0.475 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 36 h. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification via silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded 1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea (104 mg, 42%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.96 (brs, 1H), 8.87 (brs, 1H), 8.58 (s, 1H), 8.08 (m, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.27 (m, 1H), 7.15 (m, 1H), 6.81 (s, 1H), 4.66 (d, J=47 Hz, 4H), 4.01 (s, 6H), 1.34 (s, 3H); LC-MS (ESI) m/z 518 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:15]=[C:14]([C:16]([NH:18][NH2:19])=O)[S:13][CH:12]=2)=[O:9])[CH:3]=1.C[N:21]([CH3:25])[C:22](=O)[CH3:23].[CH3:26]N(C)C=O.C1(N)CC1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:15]=[C:14]([C:16]3[N:21]([CH:22]4[CH2:26][CH2:23]4)[CH:25]=[N:19][N:18]=3)[S:13][CH:12]=2)=[O:9])[CH:3]=1
Reactant: CN(C)C=O
Reactant: NNC(=O)c1cc(NC(=O)c2cc(Br)ccn2)cs1
Reactant: CC(=O)N(C)C
Agent: NC1CC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(Nc1csc(-c2nncn2C2CC2)c1)c1cc(Br)ccn1
Temperature: 145 °C
Reaction time: 0.08 h
Yield: 49.8 %

Procedure:
The 4-bromo-N-(5-(hydrazinecarbonyl)thiophen-3-yl)picolinamide (600 mg, 1.8 mmol) and toluene (9 mL) were added to a sealable vial, N,N-dimethylformamide N,N-dimethylacetamide (600 μL, 4.5 mmol) was added and the reaction was stirred for 5 minutes. Cyclopropyl amine (490 μL, 7.2 mmol), and acetic acid (100 μL, 1.8 mmol) were added and the reaction was heated in a microwave reactor at 145° C. for 30 minutes. The solvent was removed under reduced pressure, and the product, 4-bromo-N-(5-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiophen-3-yl)picolinamide 350 mg (50%), was isolated by precipitation from acetonitrile/methanol. Alternatively, the reaction mixture may be purified by flash chromatography. M+1=390.1
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[La+3:5].[N+:6]([O-:9])([O-:8])=[O:7].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Ba+2:18].[N+]([O-])([O-])=O>O>[N+:1]([O-:4])([O-:3])=[O:2].[Ba+2:18].[N+:6]([O-:9])([O-:8])=[O:7].[La:5].[Ba:18]
Reactant: [La+3]
Agent: O=[N+]([O-])[O-]
Agent: [Ba+2]
Solvent: O
Product: [Ba]
Product: [La]

Procedure:
A barium nitrate solution is prepared by dissolving 159.9 g Ba(NO3)2 in 1,650 ml of H2O. Lanthanum nitrate, in the amount of 264.9 g La(NO3)2.6H2O is dissolved in the barium nitrate solution by mixing vigorously to yield a barium-lanthanum solution, to which is added to 3,000 g of high surface area gamma alumina powder. The solution and powder are thoroughly mixed in a sigma blade mixer for 30 minutes.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1>CN(C)C=O.C(Cl)Cl>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:7])[CH3:8].[N:52]1[CH:53]=[CH:54][C:49]([CH2:48][CH2:47][NH-:46])=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: NCCc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Product: [NH-]CCc1ccncc1
Reaction time: 0.25 h

Procedure:
Fmoc-Asp(t-Bu)-OH (Bachem Bioscience) (9.04 g, 22 mmoles) and dicyclohexylcarbodiimide (4.12 g, 20 mmoles) were dissolved in dimethylformamide/methylene chloride (1:5; 50 ml) and cooled in an ice bath. The mixture was stirred for 15 minutes and 4-(2-amino-ethyl)-pyridine (2.44 g, 20 mmoles) was added. The combined reaction mixture was stirred overnight and the precipitate was filtered. The filtrate was evaporated to dryness. The residue was redissolved in ethyl acetate (300 ml) and washed with saturated sodium bicarbonate solution (3 times), 0.5 N HCl (2 times) and water. The organic layer was dried over sodium sulfate, filtered and the filtrate was evaporated to dryness. The residue was treated with 20% diethylamine/methylene chloride (50 ml) for 1.5 hours, and the reaction mixture was evaporated to dryness and used without further purification.
Reaction SMILES: C[O:2][CH:3]1[CH:7]=[CH:6][CH:5](OC)[O:4]1.CO.O.NN.N1[CH:20]=[CH:19][CH:18]=[CH:17]N=1>O.C(O)(=O)C>[CH3:17][C:18]1[O:2][C:3]([CH2:7][CH2:6][CH2:5][OH:4])=[CH:20][CH:19]=1
Reactant: c1ccnnc1
Reactant: COC1C=CC(OC)O1
Agent: NN
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(CCCO)o1
Temperature: 25 °C

Procedure:
Under nitrogen with stirring 5-methyl-2- 3- 2, 6-dimethyl-4-(2-methyl-tetrazol-5-yl) phenoxy!-propyl!-2,5-dimethoxy-2,5-dihydrofuran (820 mg, 1.8 mmol), 0.8 mL of methanol, and 1.5 mL of 1% aqueous acetic acid solution were combined at room temperature, refluxed for 10 min, and then cooled to room temperature. To the above solution was added hydrazine hydrate (0.26 mL) over a 2 min period, and the mixture was allowed to reflux for 1 h, and cooled to room temperature. The mixture was diluted with water, the aqueous layer was extracted with methylene chloride, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford 180 mg (29 %) of 3,methyl-6- 3- 2,6-dimethyl-4-(2-methyltetrazol-5-yl)-phenoxy!propyl !-pyridazine (Formula I; R1, R2 =3,5-dimethyl, R3 =6-methyl, R4 =hydrogen, R5 =2-methyltetrazol-5-yl), m.p. 114°-115° C.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[C:2]([C:3](=[CH:14][N:15]([CH3:17])[CH3:16])[C:4]#[N:5])(=[O:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)c1ccccc1
Yield: 8 %

Procedure:
A solution of 3-oxo-3-phenylpropanenitrile (1.0 equiv.) in 1,1-dimethoxy-N,N-dimethylmethanamine (2.2 M) was stirred at 50° C. under nitrogen overnight. After reaction completion, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to afford 2-benzoyl-3-(dimethylamino)acrylonitrile (8% yield) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 7.83 (s, 1H), 7.61-7.60 (m, 2H), 7.52-7.50 (m, 1H), 7.47-7.45 (m, 2H), 3.37 (s, 3H), 3.28 (s, 3H); MS (ESI) m/z=201.2 [M+1]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si](C)(C)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH2:25]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=O)[CH:26]=[CH2:27]>C1COCC1>[CH2:25]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=[CH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:26]=[CH2:27]
Reactant: C=CCC1CCCCC1=O
Reactant: CC(C)(C)OC(=O)C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCC1CCCCC1=CC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
To a solution of diisopropylamine (6.60 mL, 46.6 mmol) in THF (200 mL) at −10° C., was added a solution 2.22M of n-butyllithium (20.4 mL, 44.4 mmol). The solution was stirred 15 min at −10° C., cooled down to −78° C. and tert-butyl 2-trimethylsilylacetate (9.7 mL, 44.4 mmol) in 1 mL of THF was added dropwise. The solution was stirred 15 min at −78° C., and 2-allylcyclohexanone (3.3 mL, 22.2 mmol) was added dropwise. The reaction mixture was stirred 1 h at −78° C. and 3 h at −25° C. It was then quenched with saturated NH4Cl, extracted with ethylacetate, washed with brine, dried and concentrated. Purification by flash chromatography (cyclohexane) gave tert-butyl 2-(2-allylcyclohexylidene)acetate (5.06 g, 96%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) 5.62 (1H, m), 5.41 (1H, s), 4.89 (2H, m), 3.83 (1H, m), 2.16 (3H, m), 1.90 (1H, m), 1.73 (1H, m), 1.61 (1H, m), 1.47-1.22 (4H, m), 1.36 (9H, s).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][C:32]=4[F:41])=[C:24]3[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C.CO.ClCCl>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:41][C:32]1[CH:33]=[C:34]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=[CH:36][C:31]=1[O:30][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:21]([CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[N:22]=[CH:23][C:24]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)c(F)c1
Yield: 90 %

Procedure:
A 20% solution of trifluoroacetic acid in dichloromethane (12 mL) was added to a solution of 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 60; 520 mg, 1.06 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature until TLC (6% methanol/dichloromethane) showed that all of the starting material had reacted. Volatiles were evaporated. Ether (5 mL) was added, and the solvents were evaporated again. The resulting white semi-solid was held under vacuum, then triturated with ether and held under vacuum again to give 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine trifluoroacetate salt (479 mg, 90%) as a white powder. A portion of this material (200 mg, 0.4 mmol) was taken up in anhydrous dichloromethane (5 mL) with diisopropylethylamine (210 μL, 1.2 mmol) and the resulting suspension was cooled to about 0° C. Ethyl chloroformate (57 μL, 0.6 mmol) was added, and the reaction mixture was stirred at 0° C. for 2 min and then at room temperature for 30 min. Water (5 mL) was added, and the layers were separated. The organic layer was washed with brine, dried (sodium sulfate), filtered, evaporated, and purified on a 4 g Isco column, eluting with 0-10% methanol/dichloromethane, to give 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid ethyl ester (140 mg, 77%). 1H NMR (300 MHz, DMSO-d6) δ 1.19 (t, 3H, J=7.1 Hz), 1.95-2.06 (m, 4H), 3.05-3.14 (m, 2H), 4.02-4.16 (m, 4H), 4.98-5.07 (m, 1H), 7.82 (dd, 1H, J=7.1, 8.5 Hz), 7.89 (dd, 1H, J=1.8, 8.8 Hz), 8.06 (dd, 1H, J=2.0, 9.5 Hz), 8.50 (s, 1H), 8.56 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8](=[O:34])[C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-])=O)=[CH:18][C:17]=2[CH3:26])[CH:12]=[CH:11][C:10]=1[O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>[Pd].CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8](=[O:34])[C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:17]([CH3:26])=[CH:18][C:19]([NH2:23])=[CH:20][C:21]=2[CH3:22])[CH:12]=[CH:11][C:10]=1[O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]
Reactant: COCCOCOC(=O)c1cc(Oc2c(C)cc([N+](=O)[O-])cc2C)ccc1OCOCCOC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCOCOC(=O)c1cc(Oc2c(C)cc(N)cc2C)ccc1OCOCCOC
Reaction time: 3 h

Procedure:
A mixture of the title A compound, 5-(2,6-dimethyl-4-nitrophenoxy)-2-(2-methoxyethoxymethoxy)benzoic acid 2-methoxyethoxymethyl ester (3.2 g, 6.68 mmol) and palladium on activated carbon (10 wt. %; 320 mg) in 50 mL of EtOAc is stirred under hydrogen atmosphere (H2, 1 atm) for 3 h. The catalyst is removed by vacuum filtration through celite, washed with EtOAc, and the combined filtrate and washings are concentrated and dried under vacuum to give 5-(4-amino-2,6-dimethylphenoxy)-2-(2-methoxyethoxymethoxy)benzoic acid 2-methoxyethoxymethyl ester: NMR (CDCl3) 2.07 (s, 6H), 3.37 (s, 3H), 3.40 (s, 3H), 3.52-3.62 (m, 4H), 3.83-3.92 (m, 4H), 5.26 (s, 2H), 5.52 (s, 2H), 6.60 (s, 2H), 6.80 (dd, 1H, J=8.3, 3), 7.13 (d, 1H, J=8.3), 7.24 (d, 1H, J=3).
Reaction SMILES: Cl.CO[C:4](=[NH:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[C:15]([O:19][C:20]([NH:22][NH2:23])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(O)C>[C:15]([O:19][C:20]([NH:22][NH:23][C:4](=[NH:14])[C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=N)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NNC(=N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-nitro-benzimidic acid methyl ester hydrochloride (500 mg, 2.31 mmol) in ethanol (8 mL), hydrazinecarboxylic acid tert-butyl ester (305 mg, 2.31 mmol) was added followed by triethylamine. The mixture was stirred at rt over night. The solvent was removed and the residue was suspended in methylene chloride (10 mL). The mixture was filtered and the filtrate was concentrated to about 4 mL and loaded on a 20 g silica gel column. Eluting with 40-90% EtOAc/Hexanes on an ISCO machine gave a yellow solid. 410 mg. Which was directly used for the next step.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:22]2[CH2:21][CH2:20][N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])=[CH:30][CH:29]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccc(F)cc3)C2=O)CC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 4-fluorobenzyl bromide, to give the desired product as a white solid (69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][C:18]([CH2:27][CH2:28][OH:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:30])[CH:10]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40].O>C(Cl)Cl>[CH3:38][S:39]([O:29][CH2:28][CH2:27][C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:17][C:16](=[O:30])[N:15]([C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:14]=[CH:13][CH:12]=2)[CH2:20][CH2:19]1)(=[O:41])=[O:40]
Reactant: O=C1OC(CCO)(c2ccccc2)CCN1c1cccc(-c2ccc(F)cc2F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.49 mmol) in dry CH2Cl2 (4 mL) was added Et3N (0.234 mL, 1.46 mmol) at 0˜−5° C. A solution of methanesulfonyl chloride (67 mg, 0.59 mmol) in dry CH2Cl2 (1 mL) was added dropwise at the same temperature. After addition, the mixture was allowed to warm to rt gradually. When the reaction was complete, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with 10% aq citric acid, satd aq NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl methanesulfonate (230 mg, 97%), which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[NH2:30][C:31]1[C:39]2[O:38][CH:37]=[C:36]([Cl:40])[C:35]=2[CH:34]=[CH:33][CH:32]=1>>[ClH:1].[ClH:40].[Cl:40][C:36]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([NH:30][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:9][C:10]=4[O:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:5]=[CH:4][N:3]=3)[C:39]=2[O:38][CH:37]=1
Reactant: Nc1cccc2c(Cl)coc12
Reactant: CN1CCN(CCCOc2cc(OC3CCOCC3)c3c(Cl)ncnc3c2)CC1
Product: CN1CCN(CCCOc2cc(OC3CCOCC3)c3c(Nc4cccc5c(Cl)coc45)ncnc3c2)CC1
Product: Cl

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-7-[3-(4-methylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline was reacted with 7-amino-3-chlorobenzofuran to give the title compound, a portion of which was treated with a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was evaporated to give the free base; NMR Spectrum: (CDCl3) 2.07 (m, 2H), 2.1 (m, 2H), 2.25 (m, 2H), 2.27 (s, 3H), 2.35–2.68 (m, 10H), 3.6 (t, 2H), 4.0–4.2 (m, 4H), 4.75 (m, 1H), 6.52 (s, 1H), 6.85 (s, 1H), 7.35 (m, 2H), 7.65 (s, 1H), 8.6 (s, 1H), 8.7 (d, 1H), 10.3 (s, 1H); Mass Spectrum: M+H+ 522 and 524.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:19])[CH:11]=[CH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[S:30]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][NH:9][C:10](=[O:19])[CH:11]=[CH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:2][CH2:3]1)(=[O:31])=[O:32]
Reactant: O=C(C=Cc1cccnc1)NCCN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCN1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1

Procedure:
Batch size: 8.0 g (22.6 mmol) N-(2-(piperazin-1-yl)-ethyl]-3-pyridin-3-yl-acrylamide.trihydrochloride (substance 317 as a trihydrochloride), 13 ml (92.7 mmol) TEA and 5.6 g (24.9 mmol) naphthalin-2-sulfonic acid chloride in 180 ml absolute dichloromethane.