Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][NH:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:26])[CH3:25].Cl>N1C=CC=CC=1>[C:24]([N:14]([CH2:13][CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc(NCCOc2cccc3ccccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)N(CCOc1cccc2ccccc12)c1ccc(C(=O)O)cc1

Procedure:
A solution of 6.14 g. of 4-[2-(1-naphthyloxy)ethylamino]benzoic acid and 20 ml. of acetyl chloride in 50 ml. pyridine is warmed on a steam-bath for 8 hours. The dark solution is then poured into 370 ml. of 2 N hydrochloric acid. The resulting solution is then extracted several times with methylene chloride. The residue from evaporation of this extract is crystallized from acetonitrile giving a white solid, m.p. 182°-183° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: COc1cc(F)ccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1c(C(=O)O)ccc(F)c1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
To 4-fluoro-2-methoxybenzoic acid (0.96 g) was added concentrated sulfuric acid (6 mL) under ice-cooling, and the mixture was stirred for 15 minutes. To the mixture was added concentrated nitric acid (0.6 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added ice, and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To the residue was added a mixed solvent (n-hexane/ethyl acetate=2/1), and the insoluble material was collected by filtration, and dried under reduced pressure to give the title compound (0.78 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH3:12][C:13]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O.P(=O)(O)(O)O>O>[CH3:12][C:13]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:14]=1[CH:15]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:9][CH2:10][NH:11]1
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: COc1cccc(CCN)c1
Agent: O=P(O)(O)O
Solvent: O
Product: COc1ccc2c(c1)CCNC2c1ccc(C)cc1C
Temperature: 37 °C
Yield: 54.6 %

Procedure:
3-Methoxyphenylethylamine (1.51 g) and 2,4-dimethylbenzaldehyde (1.34 g) were mixed together. Phosphoric acid, 85%, (20 mL) was added then the reaction was warmed to 37° C. for 60 h. The reaction was cooled, poured into water (300 mL) then washed with diethyl ether (2×50 mL). The aqueous layer was diluted to 700 mL with water, made basic (pH=10) by the slow addition of sodium hydroxide, and then extracted with diethyl ether (2×150 mL). The organic extracts were dried and evaporated. The resulting residue was purified by silica gel chromatography (eluant: ethyl acetate-hexane, gradient from 1:1 to 100% ethyl acetate) to give the title compound (1.458 g). MS: 268.2 (MH+); HPLC tR: 1.71 min (method D); TLC Rf: 0.21 (ethyl acetate); 1H NMR (DMSO-d6): 6.96 (s, 1H), 6.86 (s, 2H), 6.67 (d, 1H, J=2.3 Hz), 6.59 (dd, 1H, J=2.5, 8.5 Hz), 6.44 (d, 1H, J=8.5 Hz), 5.07 (s, 1H), 3.69 (s, 3H), 3.03-3.11 (m, 1H), 2.82-2.89 (m, 2H), 2.63-2.77 (m, 1H), 2.26 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[Na]>C(O)C>[CH:3]1([CH2:2][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: c1c[nH]cn1
Reactant: BrCC1CCCCC1
Agent: [Na]
Solvent: CCO
Product: c1cn(CC2CCCCC2)cn1

Procedure:
Bromomethylcyclohexane (39.8 g; 0.225 mole) was added dropwise to a refluxing solution of imidazole (13.6 g; 0.2 mole) and sodium (4.6 g; 0.2 mole) in absolute ethanol (100 ml). After addition the reaction mixture was heated under reflux for a further 5 hours. After this period the mixture was cooled and the solvent evaporated under reduced pressure. The residue was taken up in water (150 ml), washed with ether (50 ml) and extracted with chloroform (3×50 ml). The combined chloroform extracts were dried over anhydrous magnesium sulphate and evaporated under reduced pressure to leave a residual yellow oil as crude product which was purified to give the product as a colourless oil b.p. 86°-90° C./0.2 mmHg. The product solidified on cooling, m.p. 25° to 30° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-:14].[K+].[K+].[Mn]([O-])(=O)(=O)=O.[K+]>O>[Cl:1][C:2]1[C:3]2[C:12](=[O:14])[NH:11][S:8](=[O:9])(=[O:10])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(N)(=O)=O
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C1NS(=O)(=O)c2cccc(Cl)c21

Procedure:
A mixture of 16.4 gm (80 mmols) of 3-chloro-2-methyl-benzene sulfonamide, 14 gm (100 mmols) of potassium carbonate, 33.2 gm (210 mmols) of potassium permanganate and 350 ml of water was refluxed for 1 hour. The reaction mixture was filtered while still hot, and the filter cake was washed with hot water. The combined filtrates were acidified with concentrated aqueous hydrochloric acid and cooled. The resulting crystals were suction-filtered off, washed with water and dried.
Reaction SMILES: [C:1]1([C:7]2[C:12]3[CH2:13][CH:14]([CH2:16][NH2:17])[O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[NH:17][CH2:16][CH:14]1[CH2:13][C:12]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=[CH:10][C:11]=2[O:15]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2c(cccc2-c2ccccc2)O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2c(cccc2-c2ccccc2)O1)OCc1ccccc1
Yield: 70.3 %

Procedure:
Treatment of (±)-(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (0.622 g, 2.38 mmol) with diisopropylethylamine (0.447 g, 3.57 mmol) and benzyl chloroformate (0.462 g, 2.62 mmol) generally according to the procedure described for Intermediate 12 provided 0.601 g (70%) of (±)-benzyl(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a white solid. mp 132-134° C.; Anal. calcd. for C23H21NO3: C, 76.86H, 5.89; N, 3.90. Found: C, 75.98H, 5.80; N, 3.72. Chiral HPLC separation of (±)-benzyl(4-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OD, ethanol:water 15:85) provided two fractions. Fraction 1 (Rt=6.651 min Chiralcel OD, ethanol:water 1:3); Fraction 2 (Rt=7.395 min, Chiralcel OD, ethanol:water 1:3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.P(Br)(Br)[Br:11].O>C(Cl)(Cl)Cl>[Br:11][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1]
Reactant: OCc1ccncc1F
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1cnccc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
To a solution of (3-fluoropyridin-4-yl)methanol (910 mg, 7.2 mmol) in anhydrous chloroform (25 mL) was added dropwise a solution of phosphorus tribromide (675 μL, 7.2 mmol) in anhydrous chloroform (10 mL) at 0° C. The mixture was stirred for 3 hours at room temperature. Water was added and extracted 3 times with dichloromethane. The organic phase was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, 4-(bromomethyl)-3-fluoropyridine was obtained (260 mg, 19% yield) and used in the next step without further purification; 1H NMR (400 MHz, MeOd4): δ 0.81 (s, 2H), 8.25 (t, J=6.4 Hz, 1H). 8.76 (d, J=5.9 Hz, 1H), 9.05 (d, J=3.5 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH:25]=[CH2:26]>>[CH2:26]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[CH2:25][CH:24]=[CH2:23]
Reactant: C=CCCBr
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: C=CCCN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 143 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4-bromobut-1-ene and conditions outlined in procedure V. LCMS: 356 [M+H]; Rt=0.88 min.
Reaction SMILES: [N:1]1([CH2:7][C:8](=[CH2:12])[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([Cl:49])[CH:43]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Cl:49][C:44]1[CH:43]=[C:42]([NH:41][C:32]2[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([NH:28][C:9](=[O:11])[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH2:12])[CH:30]=3)[N:35]=[CH:34][C:33]=2[C:39]#[N:40])[CH:47]=[CH:46][C:45]=1[F:48]
Reactant: C=C(CN1CCOCC1)C(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: C=C(CN1CCOCC1)C(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
Partially dissolved 1.37 g (8.00 mmol) 2-morpholin-4ylmethyl-2-propenoic acid in 50 ml ThF and chilled to 0° C. under N2. Added 1.06 ml (9.6 mmol) N-methylmorpholine and 833 μl (6.4 mmol) isobutyl chloroformate. Stirred at 0° C. for 1 hour and added a solution of 1.00 g (3.20 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)-amino]-3-quinolinecarbonitrile in 5 ml pyridine. Stirred overnight at 25° C. Poured onto a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried organic layer with brine and sodium sulfate, and stripped solvent to a small volume. Loaded onto a column of silica gel, eluted with 1% methanol/ethyl acetate, stripped solvent from desired fractions and dried under vacuum, giving 139 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=465.8, 468.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)([CH3:8])[NH:6][CH:7]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+]>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[CH2:10]([O:17][C:7]1[C:2]([Br:1])=[CH:3][CH:4]=[C:5]([CH3:8])[N:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(Cl)C=CC(Br)=CN1
Reactant: OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(Br)c(OCc2ccccc2)n1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
step 1—A mixture of 5-bromo-2-chloro-2-picoline (4.855 g, 23.51 mmol), benzyl alcohol (2.60 mL, 25.12 mmol), KOH (2.93 g, 52.32 mmol), and 18-crown-6 ether (0.34 g, 1.29 mmol) in toluene (30 mL) was refluxed overnight. The reaction was cooled to RT, diluted with ice water and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with 2% EtOAc/hexanes to afford 5.006 g (78%) of 2-benzyloxy-3-bromo-6-methyl-pyridine (58) as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Si:36]([O:43][C@@H:44]1[CH2:49][C@@H:48]([OH:50])[CH2:47][N:46]([C:51]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:52])[CH2:45]1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].[C:61](O)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C1COCC1>[C:61]([O:50][C@H:48]1[CH2:49][C@@H:44]([O:43][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:45][N:46]([C:51]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:52])[CH2:47]1)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Reactant: O=C(O)c1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
To a stirring 0° C. solution of triphenylphosphine (1.2 equiv) in 23 mL of THF was added di-tert-butyl azodicarboxylate (1.2 equiv). The mixture was stirred at 0° C. for 10 minutes. Then a solution of (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-hydroxypiperidine-1-carboxylate (1.0 equiv) in 11 mL of THF was added and stirred for 20 minutes at 0° C. Benzoic acid (1.2 equiv) was then added and the reaction mixture was allowed to slowly warm to rt. After 16 hours the reaction mixture was concentrated in vacuo then diluted with EtOAc and washed with water then brine. The organic layer was dried with Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:8) to yield (3S,5R)-benzyl 3-(benzoyloxy)-5-(tert-butyl-dimethylsilyloxy)piperidine-1-carboxylate (77%). LC/MS (m/z): 470.2 (MH+), HPLC Rt=6.05 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]([CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[C:22](=[O:38])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH:31]=[CH:30]2)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][N:21]([CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)[C:22](=[O:38])[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH:31]=[CH:30]2)=[O:17])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Solvent: c1ccncc1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Yield: 5.7 %

Procedure:
To 10 ml of pyridine were added 0.9 g of 3-nitrobenzaldehyde and 2.7 g of N-(2-acetoacetoxyethyl)-N-cyclohexyl-4-(6-carbostyriloxy)butyramide, and the mixture was heated at 90°-100° C. for 20 hours. After cooling the reaction mixture was extracted with chloroform, and the chloroform layer was washed with a saturated aqueous solution of potassium hydrogensulfate and with a saturated aqueous solution of sodium chloride, then was dried with anhydrous magnesium sulfate. After being concentrated, the residue was purified by a silica gen column chromatography (eluant: chloroform/methanol=100/1), then the eluate was dried under vacuum condition to yield 0.2 g of N-{2-[2-(3-nitrobenzyliden)acetoacetoxy]ethyl}-N-cyclohexyl-4-(6-carbostyriloxy)butyramide in the form a brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][CH2:12]3)[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1.[OH-].[K+].CC(O)C>O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:7](=[O:10])[N:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCC(n2c(=O)n(C)c3cc(Cl)ccc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cn1c(=O)n(C2CCNCC2)c2ccc(Cl)cc21

Procedure:
A mixture of 12.8 parts of ethyl 4-(5-chloro-1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)-1-piperidinecarboxylate, 20 parts of potassium hydroxide, 128 parts of 2-propanol and 2.5 parts of water is stirred and refluxed overnight. The reaction mixture is cooled and evaporated. Water is added to the residue and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding 5-chloro-1,3-dihydro-3-methyl-1-(4-piperidinyl)-2H-benzimidazol-2-one; mp. 200.9° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[CH3:10].C(N(CC)CC)C.[CH:18](OCC)=[O:19]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH:18]=[O:19])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CN)ccc1Br
Reactant: CCOC=O
Solvent: CCN(CC)CC
Product: Cc1cc(CNC=O)ccc1Br

Procedure:
To a solution of 4-bromo-3-methyl-benzylamine (Example 10.1) (15.11 g) in ethyl formate (150 ml) was added triethylamine (1.5 ml) at ambient temperature. The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was concentrated and the residue was triturated with diisopropyl ether/heptane (1:1) (100 ml) to give N-(4-bromo-3-methyl-benzyl)-formamide (14.04 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.49 (m, 1H), 7.16 (s, 1H), 6.97 (m, 1H), 5.85 (s, 1H), 4.42 (m, 2H), 2.39 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.Cl.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH:21]1[C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:23]3[CH2:24][CH2:25][NH:20][CH:21]([C:26]([O:28][CH3:29])=[O:27])[CH2:22]3)=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Reactant: COC(=O)C1CNCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(C(=O)C2=Cc3cc(OC)c(OC)cc3CCC2)CCN1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 81.6 %

Procedure:
A solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (2.14 g) in dichloromethane (20 ml) is added dropwise, taking 40 minutes while stirring at 0° C., to a mixture of methyl piperazine-2-carboxylate hydrochloride (1.75 g), triethylamine (3.2 g) and dichloromethane (40 ml). The reaction mixture is poured into ice-water and shaken. The organic layer is separated and subjected to distillation under reduced pressure. The residue is dissolved in 1N-HCl (20 ml) and washed with ethyl acetate. The aqueous layer is separated and then neutralized with sodium hydrogencarbonate, followed by extraction with dichloromethane. The organic layer is dried, and the solvent is distilled off. Crystals obtained from the residue are recrystallized from ethyl acetate - hexane to afford methyl 4-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)piperazine-2carboxylate as colorless needles (2.45 g), m.p. 103-104° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.[O:16]=[C:17]1[CH2:22][N:21]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19][N:18]1[C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(#N)C>[O:16]=[C:17]1[CH2:22][N:21]([C:23](=[O:28])[C:24]([F:26])([F:25])[F:27])[CH2:20][CH2:19][N:18]1[C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)(=[O:37])=[O:36])=[CH:33][CH:34]=1
Reactant: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccncn1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Nc2ccncn2)cc1
Yield: 43.1 %

Procedure:
Synthesized according to general procedure 12, method B. The reaction was set up with 4-aminopyrimidine (0.26 g, 2.16 mmol), anhydrous acetonitrile (10 mL), DABCO (0.24 gm, 2.16 mmol) and 4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonyl chloride (0.80 g, 2.16 mmol). The dark oil was purified via silica gel chromatography using 5% MeOH in CH2Cl2 followed by a second purification on silica gel using 80% methanol in dichloromethane to obtain the desired sulfonamide as a white solid (0.43 g, 0.93 mmol, 47% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=439.3; tR=2.3 min
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:22]([CH3:24])([CH3:23])[CH2:21][NH:20][CH:19]=[C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:14]=3[NH:15][C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35](Cl)=[O:36]>>[CH2:28]([O:27][C:25]([C:18]1[C:14]2[NH:15][C:16]3[CH:17]=[C:9]([N:8]([CH2:30][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=[CH:11][C:12]=3[C:13]=2[C:22]([CH3:24])([CH3:23])[CH2:21][N:20]([C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:40]([F:41])=[CH:32][CH:33]=2)[CH:19]=1)=[O:26])[CH3:29]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCOC(=O)C1=CNCC(C)(C)c2c1[nH]c1cc(N(C)Cc3ccccc3)ccc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(N(Cc3ccccc3)Cc3ccccc3)ccc21

Procedure:
In a manner similar to Example 2A, but using ethyl 8-(benzyl(methyl)amino)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 3,4-difluorobenzoyl chloride, the following compound was prepared:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2c(F)cccc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1c(F)cccc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
Cis-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.404 g, 6.27 mmol) was dissolved in MeOH (21 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.251 g, 6.27 mmol) dissolved in water (2.100 mL) was added over 8 min. After 20 min with stirring, hydroxylamine (50% by weight in water, 0.384 mL, 6.27 mmol) was added over 6 minutes and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (32.3 mL, 193.76 mmol) and the mixture continued to stir at 80° C. for 25 min. The solvent was evaporated and the crude mixture was redissolved in DCM/water. The organic phase was dried and concentrated. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-20% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.232 g, 55.8%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.94-2.04 (m, 2H), 2.08-2.16 (m, 2H), 2.63-2.73 (m, 1H), 2.81-2.91 (m, 1H), 2.98-3.09 (m, 1H), 3.24-3.37 (m, 4H), 3.88-3.99 (m, 1H), 4.41-4.54 (m, 1H), 5.81 (s, 1H), 6.82-6.92 (m, 2H), 7.16-7.26 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([O:14][CH2:15][C:16](O)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([O:14][CH2:15][C:16]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: C1COCCN1
Product: O=C(COCc1ccccc1)N1CCOCC1
Yield: 90 %

Procedure:
Using the mixed anhydride procedure described in Example 2, morpholine was coupled to benzyloxyacetic acid to give the desired product in 90% yield.