Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:15])[N:10]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:17]=[CH:16][C:5]3[CH2:6][CH2:7][CH2:8][C:9](=[O:15])[N:10]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1C(=O)CCCc2ccc(N)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(C)c1Nc1nc(Nc2ccc3c(c2)N(CCOC)C(=O)CCC3)ncc1Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A microwave vessel was charged with 8-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (51.3 mg, 0.219 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide (56.8 mg, 0.182 mmol), 10-camphorsulfonic acid (4.2 mg, 0.018 mmol) and isopropyl alcohol (2.0 mL) and heated at 120° C. for 60 minutes in a microwave reactor (sealed vessel). The reaction mixture was quenched with a slurry of saturated, aqueous NaHCO3 and stirred for 2 h. This mixture was diluted with water (10 mL) and extracted into DCM. The organic layer was dried by passing through a funnel filled with Na2SO4, and the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 25% EtOAc/hexane→80% EtOAc gradient). The appropriate fractions were combined, evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (50.0 mg, 54%) as a white powder that had the following properties: mp: 185-187° C.; LC/MS (ESI+): 509 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.30-9.17 (m, 2H), 8.29 (br s, 1H), 8.13 (s, 1H), 7.45-7.38 (m, 2H), 7.35 (m, 1H), 7.30-7.18 (m, 2H), 6.92 (d, J=7.9, 1H), 4.05 (br s, 2H), 3.28 (br s, 2H), 3.09 (s, 3H), 2.70 (d, 3H, J=4.3), 2.55 (m, 2H) 2.25 (2, 3H), 2.20-1.80 (series of m, 4H).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4](=[NH:7])[NH:5][NH2:6].[Br:8][C:9]1[C:10]([O:18][CH2:19][CH3:20])=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)[CH:12]=O.Cl>O.C(O)C>[Br:8][C:9]1[C:10]([O:18][CH2:19][CH3:20])=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)[CH:12]=[N:2][NH:3][C:4]([NH:5][N:6]=[CH:12][C:11]1[CH:14]=[C:15]([Br:17])[CH:16]=[C:9]([Br:8])[C:10]=1[O:18][CH2:19][CH3:20])=[NH:7]
Reactant: CCOc1c(Br)cc(Br)cc1C=O
Reactant: N=C(NN)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOc1c(Br)cc(Br)cc1C=NNC(=N)NN=Cc1cc(Br)cc(Br)c1OCC
Temperature: 20 °C

Procedure:
A mixture was prepared by dissolving 7.9 grams (0.063 mole) of diaminoguanidine, hydrochloride in 60 milliliters of lukewarm water and this mixture was added to a solution of 38.2 grams (0.125 mole) of 3,5-dibromo-2-ethoxybenzaldehyde dissolved in 500 milliliters of ethanol. To this mixture was added a solution of 8 milliliters of concentrated hydrochloric acid in 80 milliliters of ethanol. The mixture was heated at the reflux temperature for 10 minutes and thereafter cooled to 20° C. The solid 1,3-bis[(3,5-dibromo-2-ethoxybenzylidene)amino]guanidine, hydrochloride product was recovered by filtration under reduced pressure, washed with ethanol and dried. The product was recovered in a yield of 20 grams (45 percent of theoretical) and melted at 188°-190° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]([O:14][CH:15]([O:20][CH2:21][CH3:22])[CH2:16][CH2:17][CH2:18][NH2:19])[CH3:13].NCCN1CCNCC1>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:5]([O:4][C:2](=[O:3])[NH:19][CH2:18][CH2:17][CH2:16][CH:15]([O:14][CH2:12][CH3:13])[O:20][CH2:21][CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(CCCN)OCC
Reactant: O=C(Cl)OCc1ccccc1
Agent: NCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(CCCNC(=O)OCc1ccccc1)OCC
Reaction time: 0.83 h

Procedure:
Three portions of benzyl chloroformate (260 ml) in dichloromethane (170 ml) were added sequentially over 1 h 40 min to a vigorously stirred mixture of 4-aminobutyraldehyde diethyl acetal (910 ml) in dichloromethane (3 l) and aqueous sodium carbonate (1M, 3 l). Stirring was continued for 50 min until gas evolution ceased. N-(2-aminoethyl)piperazine (40 ml) was added and stirring was continued for 1 h 15 min. The layers were separated and the organic layer was washed with aqueous citric acid (1M, 3.8 l) and saturated aqueous sodium bicarbonate (2 l), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a yellow oil (1.6kg). T.l.c. (Ether) Rf 0.5.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:33])[C@H:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)[O:17][NH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=O)[C:41]([OH:43])=[O:42])[N:39]=1.O.Cl>CN(C)C=O>[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:18]/[O:17][C@H:16]([C:15]([O:14][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)/[C:41]([OH:43])=[O:42])[N:39]=1
Reactant: CC(=O)Oc1ccc([C@H](ON)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1ccc([C@H](O/N=C(\C(=O)O)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To an ice-cooled solution of the product obtained in Step 4 (20.3 g) in dimethylformamide (60 ml) was added 2-(2-amino-4-thiazolyl)glyoxylic acid (7.8 g). the mixture was allowed to stand until it reached room temperature, and stirred overnight. The reaction mixture was then poured into ice-cooled water (400 ml), and the pH of the resulting mixture was adjusted to 2.0 with 1 N hydrochloric acid. The mixture was extracted twice with ethyl acetate (500 ml). The combined organic layer was washed with brine (200 ml) and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure and the residue was dissolved in a small amount of chloroform. This solution was added dropwise to ether. The formed crystals were collected by filtration and washed with ether, giving 22.3 g of the objective compound as pale yellow crystals.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]cc(CCC(=O)O)c1C
Yield: 42.9 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (190 mg), 163 mg of 6-methoxy-2-oxindole, and 2 drops of piperidine in 2 mL of ethanol were heated to 90° C. for 3 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 140 mg of the title compound (43%) as a brown solid.
Reaction SMILES: Br.Br.[NH2:3][CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[C:6]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[N:5]1.C(N(CC)CC)C.[C:44]1([N:50]=[C:51]=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH:24]([N:15]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:13](=[O:14])[CH2:12][N:9]1[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[C:6]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[N:5][CH:4]([NH:3][C:51]([NH:50][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:52])[C:10]1=[O:11])([CH3:26])[CH3:25]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(N)N=C(c3cccnc3)c3ccccc32)C(C)C)cc1
Reactant: O=C=Nc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)Nc3ccccc3)N=C(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
According to process A, a solution of 175 mg of 2-(3-amino-2-oxo-5-pyridin-3-yl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide dihydrobromide (0.283 mmol), prepared as in Intermediate 31, in 3 mL of methylene chloride was treated with 98.5 μL of triethylamine (0.706 mmol) and 33.8 μL of phenyl isocyanate (0.311 mmol). After stirring under nitrogen for 20 min., the reaction mixture was diluted with methylene chloride and washed with aqueous potassium carbonate (5% w/v). The phases were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue. The residue was triturated with 5 mL of acetonitrile and the resulting slurry was heated to reflux under nitrogen. After stirring for 20 min., the slurry was cooled to ambient temperature, filtered and washed with cold acetonitrile. The product was combined again with 3 mL of acetonitrile and brought to reflux. After stirring for 30 min., the slurry was cooled to ambient temperature, filtered and washed with cold acetonitrile. The product was dried under high vacuum to provide 95 mg of the title compound as a white crystalline solid. 1H NMR (300 MHz, d6-DMSO) -- =9.06 (b, 1H), 8.68 (m, 2H), 7.93 (d, 1H, J=8.0), 7.72 (m, 1H), 7.53 (m, 3H), 7.37 (m, 4H), 7.26 (m, 4H), 7.07 (m, 2H), 6.94 (m, 1H), 5.31 (d, 1H, J=8.3), 4.72 (m, 1H), 4.29 (d, 1H, J=16.4), 4.16 (d, 1H, J=16.4), 3.81 (s, 3H), 0.96 (d, 6H, J=6.1); MS (ESI) [M+H]+ =577.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[CH2:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].O>CN(C=O)C>[C:3]1([O:13][CH2:15][CH2:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Oc1cccc2ccccc12
Reactant: O[C@@H](CCCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@@H](CCOc1cccc2ccccc12)c1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a mixture of 8 ml of DMF and 0.44 g of 60% sodium hydride in mineral oil at 5° C. in an ice bath was added dropwise a solution of 1.44 g of 1-naphthol in 8 ml of DMF. The reaction mixture was stirred at 5° C. for two hours and a solution of 1.71 g of (S)-(-)-3-chloro-1-phenyl-1-propanol in 5 ml of DMF was added. After stirring overnight at room temperature, the reaction mixture was poured into 150 ml of water and extracted with ethyl acetate (3×50 ml). The combined extracts were combined and washed with water and 1N sodium hydroxide solution and dried over sodium sulfate. Yield: 2.56 g (92%). The crude product can be recrystallized from 95:5 hexane/ethyl acetate to give 1.5 g (54%) of purified (S)-(+)-3-(1-naphthalenyloxy)-1-phenyl-1-propanol, mp 76°-78° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([I:11])[CH:5]=1)=[O:3].[OH-].[Na+].O.Cl[C:16]([CH3:20])([CH3:19])[C:17]#[CH:18]>C1(C)C(C)=CC=CC=1>[C:2]([C:4]1[CH:5]=[C:6]([I:11])[C:7]2[O:10][C:16]([CH3:20])([CH3:19])[CH:17]=[CH:18][C:8]=2[CH:9]=1)(=[O:3])[CH3:1]
Reactant: C#CC(C)(C)Cl
Reactant: CC(=O)c1ccc(O)c(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(=O)c1cc(I)c2c(c1)C=CC(C)(C)O2
Temperature: 90 °C
Yield: 46.8 %

Procedure:
A mixture of 4-hydroxy-3-iodoacetophenone (5.24 g), 40% sodium hydroxide solution (4.8 ml), water (19 ml), xylene (11 ml) and 3-chloro-3-methylbut-1-yne (4.1 g) was heated to 90° C. for 3 hrs. The mixture was cooled and extracted with ether, and the ether extracts were washed with 2N sodium hydroxide solution, water and brine and dried over anhydrous sodium sulphate. The ethereal solution was filtered and evaporated, and the xylene solution that remained was refluxed for 16 hrs. The solution was evaporated and the residue chromatographed on silica gel using 10% ethyl acetate in hexane to give 6-acetyl-8-iodo-2,2-dimethyl-2H-1-benzopyran as a colourless solid (3.07 g), m.p. 102° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.C(N(CC)CC)C.[CH2:24]([N:29]=[C:30]=[O:31])[CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)(Cl)Cl>[CH3:15][C:14]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:4][NH:3][C:30]([NH:29][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31]
Reactant: Cc1c(CN)[nH]c2ccccc2c1=O
Reactant: CCCCCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCNC(=O)NCc1[nH]c2ccccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (160 mg) in chloroform (5 mL) were sequentially added triethylamine (0.26 mL) and pentyl isocyanate (0.09 mL), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 1-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]-3-pentylurea (117 mg).
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:23])=[C:12]([C:14]3[C:15]([C:21]#[N:22])=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:13]=2)OC1.Br[C:26]1[N:30]2[N:31]=[CH:32][C:33]([C:35]([F:38])([CH3:37])[CH3:36])=[N:34][C:29]2=[N:28][CH:27]=1.CCOC(C)=O.CCCC(C)C>>[F:20][C:17]1[CH:16]=[C:15]([C:21]#[N:22])[C:14]([C:12]2[CH:13]=[C:8]([C:26]3[N:30]4[N:31]=[CH:32][C:33]([C:35]([F:38])([CH3:36])[CH3:37])=[N:34][C:29]4=[N:28][CH:27]=3)[CH:9]=[CH:10][C:11]=2[F:23])=[CH:19][CH:18]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Reactant: CC(C)(F)c1cnn2c(Br)cnc2n1
Solvent: CCOC(C)=O
Solvent: CCCC(C)C
Product: CC(C)(F)c1cnn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3)cnc2n1

Procedure:
5′-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-4,2′-difluorobiphenyl-2-carbonitrile was coupled to 7-bromo-3-(1-fluoro-1-methylethyl)imidazo[1,2-b][1,2,4]triazine in 77% yield using a similar procedure to that described in Example C, step f, to give a yellow solid: mp 156-159° C. (EtOAc-isohexane); 1H NMR (400 MHz, CDCl3) δ 1.84 (6H, d, J 22.0 Hz), 7.36-7.46 (2H, m), 7.54 (1H, dd, J7.8, 2.7 Hz), 7.57-7.60 (1H, m), 8.10-8.16 (2H, m), 8.30 (1H, s), 8.79 (1H, d, J 1.2 Hz); MS (ES+) m/z 394 [M+H]+. Anal. Found: C, 64.07; H, 3.66; N, 17.60%. Required for C21H14F3N5: C, 64.12; H, 3.59; N, 17.80%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH2:18])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[Cl:24][C:25]1[CH:30]=[C:29](Cl)[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1>C(O)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:18][C:29]3[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=[C:25]([Cl:24])[CH:30]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3cc(Cl)ncc3[N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (5.2 g, 21.0 mmol) in ethanol (60 mL) and THF (15 mL) was added NaHCO3 (5.3 g, 63.0 mmol) followed by the product of Example 1, Step 3 (4.05 g, 21.0 mmol), and the reaction mixture was stirred overnight rt. The reaction mixture was concentrated then taken up in EtOAc and H2O extracted with EtOAc, the organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude material was crystallized from EtOAc/hexane to give the title compound as a yellow solid. MS (ES+) m/e 406 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[CH2:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:15]([NH:23][CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCC(O)(CCCl)c1ccccc1
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(O)(CCNCCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A mixture of 1-chloro-3-phenyl-hex-5-en-3-ol (500 mg, 2.38 mmol), phenethylamine (348 mg, 2.862.24 mmol), and K2CO3 (643 mg, 4.76 mmol) in anhydrous CH3CN (10 mL) were stirred at rt under N2. Then the solution was refluxing at 80-90° C. overnight. The solid was filtered, and the filtrate was condensed under reduced pressure to give the residue, which was purified by preparative TLC to afford 1-phenethylamino-3-phenyl-hex-5-en-3-ol (320 mg, 45%). 1H NMR (CDCl3): 2.07-2.15 (m, 1H), 2.28-2.39 (m, 1H), 2.51-2.69 (m, 3H), 2.81 (m, 1H), 2.90-3.01 (m, 3H), 3.09 (m, 1H), 5.04 (m, 2H), 5.47-5.58 (m, 1H), 7.17-7.38 (m, 11H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].CC(C)([O-])C.[K+].[C:18](OCC)(=O)[C:19]([O:21]CC)=[O:20]>>[F:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][C:18]([C:19]([OH:21])=[O:20])=[CH:1][C:2](=[O:3])[C:4]=2[CH:9]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(F)ccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)c1cc(=O)c2cc(F)ccc2o1

Procedure:
5-Fluoro-2-hydroxyacetophenone (II) was treated with potassium tertiary butoxide and diethyl oxalate to give 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (III) according to Reaction 1 as given below by a known process (JP 2218675).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])=[O:4].C(Cl)(=O)O.[CH3:25][NH2:26]>O1CCCC1.C(N(CC)CC)C>[CH3:25][NH:26][C:12](=[O:14])[CH2:11][NH:10][C:8](=[O:9])[C:7]1[CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1
Reactant: COC(=O)c1cc(C(=O)NCC(=O)O)cc([N+](=O)[O-])c1
Reactant: CN
Agent: O=C(O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)CNC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
Process 2: 8.5 g. (0.03 mole) of N-(3-metoxycarbonyl-5-nitrobenzoyl-glycine (VIa) dissolved in 130 ml. of absolute tetrahydrofuran, is cooled to -15° C., after the addition of 4.2 ml. of triethylamine, and mixed under agitation with 3 ml. of the ethyl ester of chlorocarbonic acid. The reaction mixture is agitated for about 10 minutes at -10° to -5° C., and a solution of 2.8 ml. of methylamine in 20 ml. of absolute tetrahydrofuran, cooled to -15° C., is gradually added thereto dropwise under agitation. Then, the mixture is stirred for another 30 minutes at -15° C. and subsequently overnight at room temperature; the triethylamine hydrochloride is filtered off, the filtrate concentrated under vacuum, and the residue recrystallized from acetonitrile; yield 4.6 g. m.p. 173°-174° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[C:9]([CH3:26])=[CH:10][C:11]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]3[C:16]=2[CH2:15][CH2:14][CH2:13]3)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](O)=[O:38])=[CH:32][CH:31]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([C:4]2[CH:5]=[C:6]([CH:27]=[CH:28][C:3]=2[O:2][CH3:1])[O:7][C:8]2[C:9]([CH3:26])=[CH:10][C:11]([NH:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]3[C:16]=2[CH2:15][CH2:14][CH2:13]3)=[O:38])=[CH:32][CH:31]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(OC)cc2)c2c1CCC2
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(OC)c(C(=O)Cc3ccc(F)cc3)c2)c2c1CCC2
Yield: 54.6 %

Procedure:
Ethyl N-[7-(4-methoxyphenoxy)-6-methylindan-4-yl]malonamate (100 mg) and 4-fluorophenylacetic acid (60 mg) were dissolved in dichloromethane (261 μL). To the solution was added dropwise trifluoromethanesulfonic anhydride (66 μL) at room temperature with stirring. The mixture was stirred at room temperature for 15 hours. Adding water, the reaction mixture was extracted with diethyl ether. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (74 mg).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1F.[NH2:15][CH2:16][CH:17]([NH2:19])[CH3:18].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:18][CH:17]1[CH2:16][NH:15][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=2[C:3](=[O:14])[NH:19]1
Reactant: CC(N)CN
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CNc2cccc([N+](=O)[O-])c2C(=O)N1
Yield: 66.6 %

Procedure:
A solution of 2-fluoro-6-nitrobenzoic acid methyl ester (500 mg, 2.51 mmol) in 1,4-dioxane (3 mL) was treated with 1,2-diaminopropane (0.186 mL, 2.51 mmol) and diisopropylethylamine (0.874 mL, 2.51 mmol). The reaction was irradiated at 140° C. for 20 minutes. The reaction mixture was then reduced en vacuo and purified by flash column chromatography (0% ethyl acetate/hexanes-100% ethyl acetate/hexanes) to afford 370 mg of 3-Methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and 2-Methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (mixture of regioisomers) as a yellow oil.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])/[CH:2]=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].CO[CH2:13][N:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([N:14]1[CH2:15][CH:3]([C:4]([O:6][CH3:7])=[O:5])[CH:2]([C:1]([O:9][CH3:10])=[O:8])[CH2:13]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)/C=C\C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(Cc2ccccc2)CC1C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.02 %

Procedure:
To a solution of dimethyl maleate (4.00 g) in CH2Cl2 (100 mL) was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.2 eq) followed by a solution of TFA in CH2Cl2 (0.1 eq, 1 M) dropwise at 0° C. under N2. The reaction mixture was heated to room temperature and stirred for 6 h, washed with water followed by brine. The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 3:1 (v/v) PE/EA) to yield the title compound (6.62 g, 86.02%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 278 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.70-2.75 (m, 2H), 3.12-3.17 (m, 1H), 3.30-3.33 (m, 2H), 3.66 (s, 6H), 7.24-7.31 (m, 5H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:14][O:13][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N+:1]([O-:20])=[CH:2][CH:3]=[CH:4]2)=[O:12]
Reactant: COC(=O)c1ccc2ncccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(ccc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of methyl quinoline-6-carboxylate from above in DCM (10 mL) was added 3-chlorobenzoperoxoic acid (1.991 g, 11.54 mmol). The reaction was stirred 21 h at rt. The mixture was then diluted with saturated aqueous NaHCO3 (40 mL), and the mixture was extracted with DCM (2×30 mL). The organic layers were combined, washed with saturated aqueous NaCl (40 mL), dried (MgSO4), and concentrated. The N-oxide was isolated as an orange solid which was used without purification in the next step.