Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[N:13]1([NH2:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(Cl)Cl>[N:13]1([NH:19][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: NN1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NN1CCOCC1
Temperature: 25 °C

Procedure:
Using the adapted Tozer procedure of Example 1, NEt3 (2.8 mL) and methanesulfonyl chloride Compound 1i (2.3 g, 20.0 mmol) were added to a solution of morpholin-4-ylamine Compound 11a (2.1 g, 20.0 mmol) in 20 mL of CH2Cl2 at 0° C. under a N2 atmosphere. The mixture was stirred and warmed to ambient temperature over a 2 hr period, then the reaction was quenched with water (10 mL). The organic layer was diluted with CH2Cl2 (60 mL) and washed with water and brine, separated and dried with anhydrous Na2SO4, then filtered and concentrated in vacuo to afford N-morpholin-4-yl-methanesulfonamide Compound 11b as an oil.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:29])[NH:12][C@H:13]([C:17]1[NH:26][C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([Cl:28])=[CH:22][CH:23]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:9])([CH3:8])[CH3:7].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([O:10][C:11](=[O:29])[NH:12][C@H:13]([C:17]1[N:26]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([Cl:28])=[CH:22][CH:23]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:8])([CH3:9])[CH3:7]
Reactant: BrCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer and nitrogen inlet, was charged with 50 mL of DMF, 3.50 g (10 mmol) of (S)-[1-(7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (the compound of Formula 202 prepared, e.g., as described in Example 3.2), 1.34 mL of benzyl bromide (98%), and 3.04 g of potassium carbonate. The mixture was stirred at room temperature overnight. TLC (hexanes/ethyl acetate 7:3) indicated complete reaction. The mixture was transferred into a Erlenmeyer flask and mixed with 100 mL of water. To the stirring mixture was then added hexanes, 50 mL. The formed white solid was collected by filtration to afford the title compound of Formula 203 (S)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (also corresponding to Formula 107). The layers were separated and the organic was concentrated to dryness. The residue was chromatographed to afford an additional yield of the title compound. 1HNMR (300 MHz, DMSO-d6) δ (ppm)8.15(d,1H), 7.65(S,1H), 7.60(d,1H), 7.40–7.20(m,5H), 5.75(d,1H), 5.15(d,1H), 4.40(t,1H), 2.25(m,1H), 1.40–1.15(m,10H), 0.08(d, 3H), 0.35(d,3H).
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:14])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Br:15])=[CH:9][CH:8]=1)[CH:3]([F:4])[F:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(OC(F)(F)C(F)F)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)C(F)(F)Oc1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(1,1,2,2-tetrafluoroethoxy)toluene (6.73 g, 32.3 mmol), N-bromosuccinimide (5.75 g, 32.3 mmol) and 2,2-azobis(isobutyronitrile) (0.2 g) in carbon tetrachloride (30 ml) was heated under reflux for 0.5 hr. After cooling the reaction solution to room temperature, the white precipitate as removed by filtration and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was evaporated under reduced pressure to give a crude product of 4-(1,1,2,2-tetrafluoroethoxy)benzyl bromide as a pale-yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[N:8][CH2:7]1)=[O:5])[CH3:2].O>C1C=CC=CC=1.O=[Mn]=O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN=C(CN2C(=O)c3ccccc3C2=O)c2c(OC)cc(OC)cc21
Agent: O=[Mn]=O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1cnc(CN2C(=O)c3ccccc3C2=O)c2c(OC)cc(OC)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
Silica gel (5 g) and MnO2 (4.60 g, 52.9 mmol) were ground to a homogenous consistency and the mixture was added to a solution of 1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6,8-dimethoxy-3,4-dihydro-isoquinoline-4-carboxylic acid ethyl ester (Note 1) (1.39 g, 3.53 mmol) in 180 mL of benzene. The reaction flask, equipped with a Dean-Stark trap and a condenser, was then heated to 100° C., with azeotropic removal of water (18 ml). After 4 hours, the reaction was cooled to room temperature and filtered through a plug of celite, rinsing with 3% MeOH in DCM. The filtrate was concentrated to give 1.30 g (94%) of 1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester as a white solid. H1-NMR (CDCl3): δ, 8.85 (s, 1H), 8.07 (d, 111, J=2.1 Hz), 7.92 (m, 2H), 7.75 (m, 2H), 6.62 (d, 1H, J=2.4 Hz), 5.62 (s, 2H), 4.36 (q, 2H, J=7.4), 4.03 and 3.98 (s, 3H each), 1.36 (t, 3H, J=6.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[N:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:15])[N:6]=[CH:5]2
Reactant: Oc1ncc2cc(Br)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncc2cc(Br)ccc2n1

Procedure:
A solution of 6-bromoquinazolin-2-ol (31) (6.0 g, 26.7 mmol) in POCl3 (80 mL) was refluxed at 110° C. for 5 hours. An aliquot of the reaction mixture was analyzed by LCMS and indicated that the reaction had proceeded to completion. Most of POCl3 was removed under reduced pressure, and the residue was added dropwise to ice water (500 mL). The resulting precipitate was collected via filtration as a yellow solid (3.5 g, 54%). MS (ES+) C8H4BrClN2 requires: 242. Found: 243, 245 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].[CH2:22]([NH:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]([N:28]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:14])=[CH:15][CH:16]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:2]
Reactant: CCCCCCNCCc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCN(CCc1ccccc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy} acetic acid (0.110 g, 0.37 mmol) in methylene chloride (3.7 mL) were added N-hexyl-2-phenylethylamine (0.080 g, 0.39 mmol) and DMAP (0.045 g, 0.37 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.071 g, 0.37 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (25 mL), and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL) and brine (25 mL), dried over Na2SO4, and concentrated in vacuo.
Reaction SMILES: [Br-].[CH3:2][C:3]([CH3:15])=[CH:4][CH2:5][N+:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:14])[CH3:13])[CH:7]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH3:2][CH:3]([CH3:15])[CH:4]=[CH:5][N:6]1[CH2:11][CH2:10][CH2:9][C:8]([C:12]([CH3:13])=[O:14])=[CH:7]1
Reactant: [H][H]
Reactant: CC(=O)c1ccc[n+](CC=C(C)C)c1
Agent: [Pd]
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C1=CN(C=CC(C)C)CCC1

Procedure:
1-(3-methyl-2-butenyl)-3-acetyl-pyridinium bromide (27.0 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in ethyl alcohol (50 ml) over 5% palladium on carbon (5 g) was hydrogenated at room temperature and pressure until two molar equivalents of hydrogen was taken up. The catalyst was removed by filtration and the filtrate concentrated at reduced pressure. The semi-solid residue was diluted with diethyl ether (75 ml), the solid removed by filtration and the filtrate concentrated under reduced pressure to leave a pale oil which solidified on standing. Recrystallisation from ethanol/water gave the product, methyl 1-(3-methylbutenyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (4) as a pale yellow crystalline solid m.p. 76°-78° C.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].N#N.[OH-].[Na+].[CH2:17](Cl)[CH:18]=[CH2:19]>O.CC(O)C>[CH3:12][O:11][C:1]1[CH:10]=[C:6]([CH2:7][CH:8]=[CH2:9])[CH:5]=[CH:4][C:2]=1[O:3][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: C=CCCl
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: C=CCOc1ccc(CC=C)cc1OC
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
A multi-necked round bottom flask equipped with mechanical stirrer, thermometer, reflux condenser and dropping funnel was charged with 150 g of eugenol, 400 ml of 2-propanol and a gentle flow of N2 was introduced. A 40% NaOH solution (43.9 g NaOH, 1.1 mole in 66 g H2O) was added slowly to the externally cooled reaction vessel at a rate to maintain the internal temperature below 35° C. The mixture was stirred for 10 minutes and 113 ml (1.38 mole) of allyl chloride was added to the flask and heated to maintain a gentle reflux for 1 hour, at which time the reaction was complete (GC analysis). The flask was charged with 300 ml water. A Dean-Stark Trap and steam bath were used to azeotropically remove the 2-propanol. The distillation ceased when the temperature reached 94° C. and after cooling, 300 ml of hexane was added and the water layer separated. The organic layer was washed with water until the pH of the water wash was neutral, the layer was then dried over MgSO4, filtered and the solvent removed under vacuum. The product was vacuum distilled to yield 155 g (84%) of a pale yellow 3-[2-methoxy-4-(2-propenyl)phenoxy]propene.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH2:28].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:13][C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:28][CH2:27][CH:26]([O:29][CH3:30])[O:25][CH3:24])[N:3]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:5]=1
Reactant: COC(CN)OC
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)nc1NCC(OC)OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A mixture of methyl [4,6-dichloro-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (2.0 g, 5.6 mmol), aminoacetaldehyde dimethylacetal (0.68 g, 6.5 mmol) and diisopropylethylamine (1.5 mL, 8.4 mmol) in 1,4-dioxane (50 mL) was stirred at 80° C. for 2 hours. The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extracts were washed with aq NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative MPLC (silica gel, hexane:ethyl acetate, 2/1) to give methyl [4-chloro-6-[(2,2-dimethoxyethyl)amino]-2-(4-nitrobenzyl)pyrimidin-5-yl]-acetate (1.89 g, 79%) as a gray solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH3:21])[CH:14]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-].[Li+].[Cl-]>C1COCC1.CO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([CH:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:23])=[O:3])[CH2:7][CH2:8]2)=[O:22])=[CH:14][C:15]=1[CH3:21]
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccc(OC)c(C)c2)CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1C
Temperature: -78 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To a stirred solution of [4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-acetic acid ethyl ester (0.19 g, 0.60 mmol) in 6 mL of THF and 2 mL of MeOH, was added LiOH (0.13 g, 3.0 mmol in 3 mL of water). After 1.5 hours at ambient temperature the solvent was removed in vacuo, then diluted with 20 mL of water (pH 14). The residue was treated with 12 mL of 1N HCl (pH 4), frozen at −78° C. then lyophilized for 24 hours to yield the title product (0.17 g, 0.54 mmol, 90%) with LiCl salt. MS (ESI) m/z 291.8 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.58 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4](Cl)[N:3]=1.[Na].[CH2:11]([OH:14])[CH2:12][OH:13]>O>[NH2:1][C:2]1[N:3]=[C:4]([O:13][CH2:12][CH2:11][OH:14])[CH:5]=[C:6]([NH2:8])[N:7]=1
Reactant: OCCO
Reactant: Nc1cc(Cl)nc(N)n1
Agent: [Na]
Solvent: O
Product: Nc1cc(OCCO)nc(N)n1
Temperature: 80 °C
Yield: 47 %

Procedure:
28.9 g (0.20 mol) of 2,4-diamino-6-chloropyrimidine was added to a solution of 4.6 g (0.20 mol) of sodium in 124 ml of ethylene glycol and heated to 80° C. for 44 h while stirring was performed. After termination of the reaction, the solution was diluted with 300 ml of water and extracted with tert-butyl methyl ether (5×200 ml). The combined organic phases were discarded; a precipitate precipitated out of the aqueous phases. The precipitate was washed with water; after drying, 2-[(2,6-diaminopyrimidin-4-yl)oxy]ethan-1-ol (16.1 g, 47%) was obtained as a light-beige solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[CH2:20][CH2:19][CH2:18]2)=[CH2:14].[C:26]1([C:32]2[O:36][N:35]=[C:34]([C:37](F)=[O:38])[C:33]=2[C:40]([F:43])([F:42])[F:41])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:26]1([C:32]2[O:36][N:35]=[C:34]([C:37]([CH:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([CH:13]=[CH2:14])[CH:16]=4)[C:21]3=[O:25])=[O:38])[C:33]=2[C:40]([F:42])([F:43])[F:41])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(F)c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C=Cc1ccc2c(c1)CCCC2=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)CCC(C(=O)c1noc(-c3ccccc3)c1C(F)(F)F)C2=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
To a heat gun dried 100 mL 2-necked flask was added diisopropylamine (0.910 mL, 6.39 mmol) under a nitrogen atmosphere followed by THF (5 mL). The flask was cooled to 0° C. and n-BuLi (2.55 mL, 6.39 mmol) was added dropwise over a period of 2 min. The contents were stirred at 0° C. for 20 min., cooled to −78° C. and 6-vinyl-3,4-dihydronaphthalen-1(2H)-one (I-1B, 1 g, 5.81 mmol) dissolved in 2 mL of THF was added dropwise over a period of 3 min. The pale yellow reaction mixture was stirred at −78° C. for 20 min. Then 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (I-14, 1.505 g, 5.81 mmol) dissolved in 2 mL of THF was added dropwise over a period of 2 min. The reaction mixture was stirred at −78° C. for 20 min, bought to room temperature and stirred at room temperature for 10 min. The reaction mixture was quenched with 1N HCl (5 mL) and extracted into EtOAc (20 mL). The aqueous layer was re-extracted with EtOAc (10 mL). The combined organic layers were dried over sodium sulfate concentrated and purified by column chromatography using an ISCO setup (80 g, RediSep® silica gel column). The desired fractions were collected and concentrated to yield 2-(5-phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl)-6-vinyl-3,4-dihydronaphthalen-1(2H)-one (1.55 g, 3.77 mmol, 64.9% yield) as a yellow solid. LC/MS M+1=412.12.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)/[C:10](=[CH:13]/[N:14](C)C)/[CH2:9][CH2:8][O:7][C:6]=2[CH:17]=1.Cl.Cl.[NH2:20]N>C(O)(C)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[C:10]([CH2:9][CH2:8][O:7][C:6]=2[CH:17]=1)=[CH:13][NH:14][N:20]=3
Reactant: NN
Reactant: CN(C)/C=C1\CCOc2cc(Br)ccc2C1=O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Brc1ccc2c(c1)OCCc1c[nH]nc1-2
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a suspension of 8-bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one (5.32 g, 17.9 mmol) in isopropyl alcohol (50 mL) was added powdered hydrazine dihydrochloride (3.77 g, 35.9 mmol) at room temperature, then the mixture stirred for 2 h. The reaction mixture was diluted with water (20 mL) and then heated at 100° C. for 2 h before cooling to room temperature. The reaction mixture was concentrated in vacuo to remove the volatile solvent. The resulting suspension was filtered and the filtrate washed with water and dried under vacuum at 40° C. to yield 8-Bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene as a pale yellow solid (4.28 g, 90%). 1H NMR δ (ppm) (DMSO-d): 8.07 (1H, d, J=8.52 Hz), 7.64 (1H, s), 7.30-7.24 (1H, m), 7.21 (1H, d, J=2.07 Hz), 4.24 (2H, dd, J=5.63, 4.50 Hz), 3.00 (2H, t, J=5.09 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br)#[N:2].Cl.[CH3:12][CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:14].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:14][CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:6][C:5]2[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])[CH2:26][CH2:27]1)[CH3:12]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)Oc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1ccccc1N1CCN(Cc2cccc(C#N)c2)CC1

Procedure:
A solution of 3-cyanobenzyl bromide (10.0 g, 0.051 mol), commercially available from Aldrich Chemical, and acetonitrile (250 mL) was added to a mixture of N-[2-(methylethoxy)phenyl]piperazine hydrochloride (13.10 g, 0.051 mol, prepared according to Martin, G. E., et al, J. Med. Chem., 1989, 32, 1052), K2CO3 (21.15 g, 0.153 mol) and acetonitrile (250 mL) and the resulting mixture was stirred at reflux under nitrogen for 6.75 hours. The reaction was cooled, concentrated to dryness, and the residue partitioned between CH2Cl2 and aqueous NaHCO3. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated to give a gummy residue. This material was chromatographed on silica gel (CH3OH:CH2Cl2 /2:98 eluant) to produce 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzonitrile as a yellow gum, 10.86 g. A solution of this material (10.36 g, 0.031 mol) and anhydrous ether (500 mL) was added dropwise to a slurry of LiAIH4 (1.17 g, 0.031 mol) in anhydrous ether (500 mL) under N2 at room temperature. The reaction was stirred at reflux for 5.5 hours at which point additional LiAlH4 (1.17 g, 0.031 mol) was added. After stirring at reflux for 12 hours, the reaction was cooled in an ice bath and treated slowly with H2O (100 mL), 20% aqueous NAOH (100 mL), and H2O (100 mL) in that order, followed by extraction with diethyl ether. The ether layer was separated, dried over anhydrous Na2SO4, filtered, and evaporated to give 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzyl amine as a pale yellow gum, 8.07 g.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12].[CH3:14][O:15][C:16](=[O:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])O.[Na+]>CC(=O)CC>[CH3:14][O:15][C:16]([C:17]1[C:3]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=2[CH3:12])=[CH:2][N:19]2[C:18]=1[CH:23]=[CH:22][CH:21]=[CH:20]2)=[O:24]
Reactant: COC(=O)Cc1ccccn1
Reactant: Cc1c(F)cccc1CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Product: COC(=O)c1c(Cc2cccc(F)c2C)cn2ccccc12
Yield: 61.3 %

Procedure:
The compound of step 1 (3.89 g, 15.88 mmol), pyridin-2-ylacetic acid methyl ester (1.65 g, 10.92 mmol) and sodium hydrogencarbonate (4.59 g, 54.60 mmol) in butan-2-one (43 ml) were heated under reflux for 24 h. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel chromatography (HEP/EA) to give 1.99 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2S[CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([OH:25])=[O:24].Cl[C:27]1[C:36](=O)[C:35]2[C:30](=CC=CC=2)/[C:29](=N/S(C2C=CC3C(=CC=CC=3)C=2)(=O)=O)/[CH:28]=1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][C:18]3[C:36](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:35]=2)(=[O:14])=[O:15])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc3ccccc3c2)c2ccccc21
Product: O=C(O)CSc1cc(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2c1O

Procedure:
5.2.59 2-(1-hydroxy-4-(naphthalene-2-sulfonamido)naphthalen-2-ylthio)acetic acid (14q) was prepared according to the procedure of procedure B for 10a except using (E)-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)naphthalene-2-sulfonamide (12f), which afforded the title compound 64.3 mg (73.5%) as a white solid, m.p.: 185-187° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[C:8]([C:10]2[N:14]=[CH:13][NH:12][N:11]=2)=[O:9])[CH2:3][CH2:2]1.[H-].[Na+].CI.[C:31](=O)([O-])O.[Na+]>CN(C=O)C>[CH3:31][N:12]1[CH:13]=[N:14][C:10]([C:8]([N:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:24])[F:25])[CH:17]=2)=[O:9])=[N:11]1
Reactant: O=C([O-])O
Reactant: O=C(c1nc[nH]n1)N(Cc1cccc(OC(F)(F)F)c1)C1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)C2CCOCC2)n1
Reaction time: 0.17 h

Procedure:
To a solution of N-(tetrahydro-2H-pyran-4-yl)-N-[3-(trifluoromethoxy)benzyl]-1H-1,2,4-triazole-3-carboxamide (138 mg) in DMF (2 mL), sodium hydride (60%, 18 mg) was added and the resulting mixture was stirred for 10 minutes; thereafter, methyl iodide (35 μL) was added and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography (NH silica gel cartridge; hexane/ethyl acetate=1:0 to 1:3) to give the titled compound (75 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6](=[O:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([CH:17]=2)[O:13][CH2:14][CH:15]=O)[C:4](=[O:20])[N:3]1[CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.[NH2:33][CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1>>[CH3:19][O:18][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[C:6](=[O:7])[C:2]([CH3:1])([CH3:32])[N:3]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)[C:4]2=[O:20])=[CH:17][C:12]=1[O:13][CH2:14][CH2:15][NH:33][CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1
Reactant: COc1ccc(N2C(=O)N(Cc3ccnc4ccccc34)C(C)(C)C2=O)cc1OCC=O
Reactant: CN1CCC(N)CC1
Product: COc1ccc(N2C(=O)N(Cc3ccnc4ccccc34)C(C)(C)C2=O)cc1OCCNC1CCN(C)CC1

Procedure:
The title compound was prepared in analogy to example 51e by using 100 mg [5-(4,4-dimethyl-2,5-dioxo-3-quinolin-4-ylmethyl-imidazolidin-1-yl)-2-methoxy-phenoxy]-acetaldehyde as starting material and 4-amino-1-methylpiperidine instead of morpholine.