Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:29]=[CH:28][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[C:21]([CH3:27])[N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[CH2:32]([NH2:43])[C:33]1[CH:42]=[CH:41][C:38]([O:39][CH3:40])=[C:35]([O:36][CH3:37])[CH:34]=1.C(N(CC)CC)C>CN1CCCC1=O.O.CO.C(Cl)Cl>[CH3:37][O:36][C:35]1[CH:34]=[C:33]([CH:42]=[CH:41][C:38]=1[O:39][CH3:40])[CH2:32][NH:43][C:7]1[N:29]=[CH:28][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:25])[CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(OS(=O)(=O)C(F)(F)F)cc2OCC3)n(C(C)C)n1
Reactant: COc1ccc(CN)cc1OC
Solvent: CO
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2cc3c(cn2)-c2nc(-c4nc(C)nn4C(C)C)cn2CCO3)cc1OC
Temperature: 120 °C
Yield: 23.5 %

Procedure:
2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl trifluoromethanesulfonate (790 mg, 1.7 mmol) was dissolved in N-methylpyrrolidinone (11 mL) and treated with veratrylamine (1.0 mL, 6.9 mmol) and triethylamine (1.9 mL, 14 mmol). The reaction mixture was heated at 120° C. overnight. The mixture was diluted with water and 20% MeOH in DCM and the layers separated. The aqueous phase was extracted into DCM/MeOH (3×), dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford N-(3,4-dimethoxybenzyl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-amine as a light yellow solid (190 mg, 23%). 1H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 7.75 (s, 1H), 6.95 (d, J=1.5 Hz, 1H), 6.92 (s, 1H), 6.88 (s, 1H), 6.02 (s, 1H), 5.85 (hept, J=6.6 Hz, 1H), 4.65 (s, 1H), 4.50-4.36 (m, 6H), 3.73 (s, 6H), 2.24 (s, 3H), 1.44 (d, J=6.6 Hz, 6H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([C:20]3[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=3)[C:25]([O:27][CH3:28])=[O:26])=[O:19])=[N:16][CH:17]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:35]I.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:35])[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([C:20]3[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=3)[C:25]([O:27][CH3:28])=[O:26])=[O:19])=[N:16][CH:17]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COC(=O)c1cc(C(=O)c2ncc3ccc(NC(=O)OC(C)(C)C)cn23)ccc1[N+](=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)c2ncc3ccc(N(C)C(=O)OC(C)(C)C)cn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
540 mg (1.23 mmol) of methyl 5-({6-[(tertbutoxycarbonyl)amino]imidazo[1,5-a]pyridin-3-yl}carbonyl)-2-nitrobenzoate in 10 ml of dimethylformamide are added to 53.9 mg (1.35 mmol) of sodium hydride (60% dispersion in oil) in 2 ml of dimethylformamide, the mixture is stirred at ambient temperature for 30 minutes, then 84 μl (1.35 mmol) of methyl iodide are added and the mixture is left stirring at ambient temperature overnight. The mixture is acidified to pH=4 with an aqueous potassium hydrogensulfate solution and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. The product is purified by filtration through a bed of silica, elution being carried out with dichloromethane. 475 mg of an orange-colored powder are obtained. Melting point: 55° C.; 1H NMR (d6-DMSO): 1.46 (9H, s), 3.33 (3H, s), 3.92 (3H, s), 7.57 (1H, d), 7.98 (1H, s), 8.06 (1H, d), 8.25 (1H, d), 8.68 (1H, d), 8.76 (1H, s), 9.77 (1H, s)
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:19](=[O:22])[CH:20]=[CH2:21])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: C=CC(=O)Cl
Reactant: NCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of freshly prepared 4-nitrobenzylamine (3.8 g) in dry dichloromethane (100 ml) containing triethylamine (3.5 ml) was added dropwise to acryloyl chloride (2.2 ml) in dry dichloromethane (100 ml), over 20 min during which time the temperature was kept between -15° and -7°. The reaction mixture was stirred at this temperature for 0.5 h. and then allowed to reach room temperature over a period of 1.25 h. The resulting solution was washed with 2N hydrochloric acid (50 ml), water (50 ml), aqueous 8% sodium bicarbonate solution, and water (50 ml), dried (MgSO4) and evaporated to dryness to afford a solid (3.89 g). This which was triturated with cyclohexane (about 400 ml) to give the title compound as a powder (3.654 g) m.p. 119°-121°.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:8]([NH2:17])[N:7]=[C:6]([NH2:18])[N:5]=1)=O.C(O)C.Cl.[NH2:23][OH:24].C([O-])(=O)C.[Na+]>O>[CH3:1][C:2](=[N:23][OH:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:8]([NH2:17])[N:7]=[C:6]([NH2:18])[N:5]=1
Reactant: NO
Reactant: CC(=O)c1nc(N)nc(N)c1-c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1nc(N)nc(N)c1-c1ccc(Cl)cc1

Procedure:
[2,6-Diamino-5-(p-chlorophenyl)-4-pyrimidinyl] methyl ketone (2.6 g.) was dissolved in 30 ml. of ethanol and hydroxylamine, hydrochloride (1.5 g.) and sodium acetate (2.5 g.) in 25 ml. of water was added and the mixture refluxed for 5 hours. After cooling a white precipitate separated; it was recrystallized from methanol to give 1.5 g. of the title product, m.p. 256°-259°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][O:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ncccc2C(F)(F)F)cn1
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Heat a mixture of 2-chloro-3-trifluoromethylpyridine (37 g, 0.2 mol), 2-methoxypyridine-5-boronic acid (32 g, 0.21 mol), tetrakis(triphenylphosphine) palladium(0) (9 g, 7 mmol) and 2M potassium carbonate (150 mL) in toluene (500 mL) under a nitrogen atmosphere, at 90° C. for 8 hours. Cool the reaction mixture and separate the layers. Extract the aqueous layer with ethyl acetate (2×250 mL) and wash the combined organics with 4M sodium hydroxide (250 mL), water (250 mL), and brine (250 mL). Dry (MgSO4) and concentrate under reduced pressure. Purify the oil by flash chromatography on silica gel (50% ether/50% hexane) to give the title compound (48.2 g, 95%) as a colorless oil.
Reaction SMILES: C(O[C:4](=[O:14])[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH:6]O)C.[NH:15]([C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[NH2:16].[H-].[Na+].Cl>C(O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[C:4](=[O:14])[N:15]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:16][CH:6]=2)[CH:9]=1
Reactant: CCOC(=O)C(=CO)c1cccnc1
Reactant: NNc1ncccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(-c2cccnc2)c[nH]n1-c1ncccn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
193 mg (1 mmol) of the compound from Example 2A and 116 mg (1.05 mmol) 2-hydrazinopyrimidine are initially introduced into 2 ml anhydrous ethanol under argon and the mixture is stirred at RT for 20 h. 40 mg (1 mmol) sodium hydride suspension (60% strength in paraffin oil) are then added in portions, a significant clouding of the reaction solution developing. The mixture is subsequently stirred at RT for 10 min. 1 ml 1 M hydrochloric acid is then added to the dark reaction mixture, a precipitate separating out. The precipitate is filtered off with suction and the residue is washed with water (2×1 ml) and dried in vacuo. 173 mg (72% of th.) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=1.[C:24](Cl)(=[O:29])[CH2:25][C:26](Cl)=[O:27].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C1COCC1>[C:19]([O:18][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[NH:1][C:26](=[O:27])[CH2:25][C:24]2=[O:29])=[CH:11][CH:12]=1)=[O:23])([CH3:20])([CH3:22])[CH3:21]
Reactant: Cc1cccc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)c1N
Reactant: O=C(Cl)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc2c1NC(=O)CC(=O)N2c1ccc(NC(=O)OC(C)(C)C)cc1
Yield: 33.3 %

Procedure:
tert-Butyl 4-(2-amino-3-methylphenylamino)phenylcarbamate (294 mg, 0.938 m mmol) was dissolved in THF (30 mL), and then the solution was added dropwise with malonyl chloride (91 μL, 0.938 mmol) under ice cooling. After the disappearance of the starting materials was confirmed, the reaction mixture was added with aqueous sodium hydrogencarbonate, and ethyl acetate, and the organic layer was separated. The organic layer was washed with brine and water, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=100/1) to obtain the title compound (119 mg, yield 33%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[OH-:17].[Na+]>O1CCOCC1>[NH2:1][C:2]1[NH:3][C:4](=[O:17])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: [OH-]
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccco2)nc(N)[nH]c1=O
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a stirred solution of 4.2 g (18.1 mmol) 2-amino-4-(2-furyl)-6-(methylthio)-pyrimidine-5-carbonitrile in 50 ml dioxane was added 50 ml (100 mmol) 2M sodium hydroxide solution and the mixture heated at reflux for 16 h. The reaction mixture was then concentrated in vacuo and the residue resuspended in 300 ml ethyl acetate and the mixture stirred for 30 minutes. The resulting crystals were collected by filtration and dried in vacuo. They were then dissolved in 150 ml water and the mixture neutralised with 1M hydrochloric acid. The resulting crystals were collected by filtration and washed with water to afford 3.3 g (90%) 2-amino-4-furan-2-yl-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile as an off-white crystalline solid. ES-MS m/e (%): 201 ([M—H]−, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:24])[CH:11]([NH:16]C(OC(C)(C)C)=O)[CH2:12][CH:13]=[CH:14][CH2:15][CH:8]2[CH2:7][CH2:6]1)=[O:4]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:24])[C@@H:11]([NH2:16])[CH2:12][CH:13]=[CH:14][CH2:15][C@@H:8]2[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC2CC=CCC(NC(=O)OC(C)(C)C)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@H]2CC=CC[C@H](N)C(=O)N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
6-tert-butoxycarbonylamino-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid methyl ester, 7, (3.46 g, 10.2 mmol) is treated with a solution of 1:1 trifluoroacetic acid/CH2Cl2 (50 mL) and allowed to stir for 2 hours at room temperature after which the solution is concentrated in vacuo and the resulting residue purified over silica (5% methanol/methylene chloride) to afford 2.43 g (100% yield) of the desired product as dark orange crystals. 1H NMR (CDCl3): δ 8.11 (bs, 2H), 5.76 (m, 2H), 4.66 (dd, J=9.3, 6.0 Hz, 1H), 4.50 (dd, J=8.7, 3.6, 1H), 4.21 (m, 1H), 3.68 (s, 3H), 2.95 (m, 1H), 2.73 (dt, J=15.3, 6.0, 1H), 2.43 (m, 2H), 2.15 (m, 2H), 1.94 (m, 2H). 13C NMR (CDCl3): δ 172.3, 168.5, 127.1, 60.7, 58.7, 52.3, 51.9, 32.7, 32.6, 31.2, 27.3. ESI MS 239.12 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:38])([CH3:37])[C:9]([N:11]1[CH2:14][CH:13]([C:15]2[CH:36]=[CH:35][C:18]3[C:19]4[N:20]=[C:21]([C:27]5[N:28]([CH:32]([CH3:34])[CH3:33])[N:29]=[CH:30][N:31]=5)[S:22][C:23]=4[CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[CH2:12]1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]([CH3:38])([CH3:37])[C:9]([N:11]1[CH2:12][CH:13]([C:15]2[CH:36]=[CH:35][C:18]3[C:19]4[N:20]=[C:21]([C:27]5[N:28]([CH:32]([CH3:34])[CH3:33])[N:29]=[CH:30][N:31]=5)[S:22][C:23]=4[CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[CH2:14]1)=[O:10]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C(C)(C)NC(=O)OC(C)(C)C)C3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C(C)(C)N)C3)ccc1-2
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of (2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (203 mg, 0.36 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred for 1 hour then concentrated in vacuo. The residual solid was triturated with ether, filtered off and air-dried before being dissolved in DCM. The organic solution was washed (aqueous saturated sodium bicarbonate solution, followed by water and then brine), dried (MgSO4) and concentrated in vacuo. The residue was freeze-dried from MeOH/H2O to give 469 as a white solid (116 mg, 71%). LCMS: RT=8.13 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 8.30 (1 H, d, J=8.19 Hz), 8.06 (1 H, s), 7.18 (1 H, dd, J=8.24, 1.86 Hz), 7.00 (1 H, d, J=1.82 Hz), 5.82-5.74 (1 H, m), 4.79 (1 H, s), 4.42 (1 H, s), 4.33 (2 H, t, J=5.13 Hz), 4.19 (1 H, s), 3.77-3.70 (2 H, m), 3.39 (2 H, t, J=5.02 Hz), 1.74 (2 H, s), 1.50 (6 H, d, J=6.59 Hz), 1.17 (6 H, s)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17]C)=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[CH3:19][N:20](C=O)C>C(Cl)Cl.[C-]#N.[C-]#N.[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:19]([C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)#[N:20]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(Br)cc2cc(OC)ccc12
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)c1cc(C#N)cc2cc(OC)ccc12
Yield: 88 %

Procedure:
A solution of ethyl 3-bromo-6-methoxy-1-naphthoate (Wrobel, et al; J. Med. Chem. 34, 2504 (1991) (206 mg, 0.66 mmol), Zn(CN)2, and tetrakis(triphenylphosphine) palladium (36 mg, 0.031 mmol) in DMF (12 mL) was stirred at 80° C. for 1 h. The mixture was diluted with DCM, washed with water, dried (MgSO4), filtered and concentrated to a yellow precipitate, and purified by chromatography (5% EtOAc in hexanes) to afford methyl 3-cyano-6-methoxy-1-naphthoate as a white powder (150 mg, 0.588 mmol, 88%). The ester was saponified by stirring in 2% water in THF with 1.5 equivalents of LiOH at 80° C. for 3 h to afford the title compound. 1H NMR (CDCl3) δ 8.99 (d, J=9.6, 1H), 8.33 (s, 1H), 7.45 (dd, J=9.3, 2.7, 1H), 7.26 (s, 1H), 7.22 (d, J=2.4, 1H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.COC1CCC(C(O)=O)CC1.Cl.ClC1C(NCC2C=C3C(C=CC(C4C=CC=CC=4)=N3)=CC=2)=NC=CN=1.[Cl:50][C:51]1[C:52]([CH:57]([C:69]2[CH:78]=[C:77]3[C:72]([CH:73]=[CH:74][C:75]([C:79]4[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=4)=[N:76]3)=[CH:71][CH:70]=2)[NH:58][C:59]([CH:61]2[CH2:66][CH2:65][CH:64]([O:67][CH3:68])[CH2:63][CH2:62]2)=O)=[N:53][CH:54]=[CH:55][N:56]=1.O=P(Cl)(Cl)Cl>CCOC(C)=O.C(#N)C.CN(C=O)C>[Cl:50][C:51]1[C:52]2[N:53]([C:59]([CH:61]3[CH2:66][CH2:65][CH:64]([O:67][CH3:68])[CH2:63][CH2:62]3)=[N:58][C:57]=2[C:69]2[CH:78]=[C:77]3[C:72]([CH:73]=[CH:74][C:75]([C:79]4[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=4)=[N:76]3)=[CH:71][CH:70]=2)[CH:54]=[CH:55][N:56]=1
Reactant: COC1CCC(C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)CC1
Agent: COC1CCC(C(=O)O)CC1
Agent: Cl
Agent: Clc1nccnc1NCc1ccc2ccc(-c3ccccc3)nc2c1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COC1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A round bottom flask, charged with carbonyldiimidazole (252.2 mg, 1.55 mmol) and 4-methoxy-cyclohexanecarboxylic acid (mixture of cis/trans isomers) (242.9 mg, 1.54 mmol) was evacuated and filled with nitrogen. THF (15 mL) was added and the reaction mixture was stirred at 60° C. for 16 h. (3-Chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methylamine hydrochloride salt (500 mg, 1.10 mmol) was then added and stirring was continued at 60° C. for another 20 h. After cooled to rt, the reaction mixture was diluted with 20 mL of EtOAc and washed with sat. NaHCO3 (3×30 mL) followed by brine (3×30 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (60% EtOAc in hexane→100% EtOAc). N-[(3-Chloropyrazin-2-yl)(2-phenyl-quinolin-7-yl)-methyl]-4-methoxycyclohexanccarboxamide was obtained as a yellow solid. To a solution of N-[(3-chloropyrazin-2-yl)(2-phenyl-quinolin-7-yl)-methyl]-4-methoxycyclohexanecarboxamide (440 mg, 0.91 mmol) in acetonitrile (20 mL) was added POCl3 (0.17 mL, 1.69 mmol) and DMF (0.3 mL). This mixture was heated to 55° C. under N2 for 2 h, concentrated under reduced pressure, and quenched with 2N NH3 in 2-propanol to pH 9. 2-Propanol was removed under reduced pressure and the residue was dissolved in dichloromethane (50 mL) and water (30 mL). Layers were separated and the organic phase was washed with brine and dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (2%→6% CH3CN in dichloromethane) to afford the individual cis-isomer and trans-isomers:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([F:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1.[Cl-].[Na+].O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH:21]=[O:22])[CH:12]([F:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)C(F)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.6 %

Procedure:
NaH (55-65%; 44 mg; 1.09 mmol; 1.2 eq.) was added to a solution of 3-fluoro-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (200 mg; 0.91 mmol; 1 eq.) in THF (15 mL) and the resulting mixture was stirred at room temperature for 15 minutes whereupon 2-fluoro-benzaldehyde (113 mg; 0.91 mmol; 1 eq.) was added dropwise. The reaction mixture was stirred at room temperature for 15 hours then at 60° C. for a further 4 hours. NaH (44 mg; 1.09 mmol; 1.2 eq.) was added and the resulting mixture was stirred at 60° C. for 2 hours. The solution was diluted with brine extracted with EA (2×). The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (DCM then EtOAc) afforded the title compound (196 mg, 66%) as a yellow oil.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9]([N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH2:7][N:6]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N+:2]=[N-:3].O.NN>CO>[NH2:10][C@H:9]1[CH2:8][CH2:7][N:6]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[C@@H:5]1[CH2:4][N:1]=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N2C(=O)c3ccccc3C2=O)[C@H]1CN=[N+]=[N-]
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of the compound 6 (493 mg) in methanol (13 mL), hydrazine monohydrate (339 mg) was added. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was concentrated and then added dichloromethane. The appeared solid was collected by filtration and then the residue was concentrated and obtained the title compound (245 mg) having the following physical properties.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]=2[CH:15]=1)(=[O:5])[CH3:4]>C(Cl)Cl.C(O)(=O)C>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]=2[CH:15]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccc2sc(=O)[nH]c2c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc2sc(=O)[nH]c2c1
Yield: 58.8 %

Procedure:
Bromine (2.4 g) was added to the solution of 5-acetyl-2-benzothiazolinone (2.9 g) in a mixture of methylene chloride (60 ml) and acetic acid (10 ml) at 32° C. to 35° C. with stirring and the mixture was stirred at the same temperature for an hour. The resulting precipitate was collected by filtration, washed with methylene chloride and dried over phosphorus pentoxide to give 5-bromoacetyl-2-benzothiazolinone (2.4 g). mp 249° C. (dec.)
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][OH:22]>>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][O:22][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CN(C)CCO
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Product: CN(C)CCOC(=O)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
(2-Dimethylaminoethyl)-p-benzoylbenzoate was prepared from para-benzoylbenzoic acid chloride and 2-dimethylaminoethanol. The structure of the product was confirmed by the presence of carbonyl absorption bands in the infrared spectrum at 1670 and 1725 cm-1. When added at 4% by weight loading to the test solution described in Example 3, a cure rate of 40 ft./min./lamp was observed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:31])([CH3:30])[CH2:20][CH:21]([NH:22]C(OC(C)(C)C)=O)[C:15]2=[CH:14][C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:5]([O:7][CH3:8])=[O:6].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][CH:21]1[C:15]2[C:16](=[N:17][C:12]([C:11]3[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=3[Cl:1])=[C:13]([C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[CH:14]=2)[O:18][C:19]([CH3:31])([CH3:30])[CH2:20]1
Reactant: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(NC(=O)OC(C)(C)C)CC(C)(C)O3)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(N)CC(C)(C)O3)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 315 (200 mg, 0.36 mmol) in 5.0 mL of CH2Cl2 was added 500 μL of TFA. After stirring at rt for 16 h, the reaction mixture was concentrated. The amine TFA salt was taken onto next step without further purification.
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[H-].[Na+].[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:18]2[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=2)=[CH:8][CH:7]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
To a solution of DMSO (50 mL) of p-fluorophenol (3.6 g) was added NaH (1.3 g/60% in oil) at room temperature, which was stirred for 15 minutes at room temperature. 5-Nitro-furan-2-carbaldehyde (5.0 g) was then added thereto, which was stirred for 40 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The solvent was evaporated from the organic layer under a reduced pressure, and the residue was purified by silica gel chromatography (heptane:ethyl acetate=2:1) to obtain 5-(4-fluoro-phenoxy)-furan-2-carbaldehyde (1.6 g).