Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]([O:11][CH2:12][CH2:13][NH2:14])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.ClC1C=C(Cl)C(Cl)=CC=1[CH:24]([F:32])[CH2:25][N:26]([N:30]=[O:31])[C:27](=O)[O-:28].C(Cl)(Cl)Cl.C(OCC)(=O)C>N1C=CC=CC=1>[F:32][CH2:24][CH2:25][N:26]([N:30]=[O:31])[C:27]([NH:14][CH2:13][CH2:12][O:11][C:3]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:10])=[O:28]
Reactant: O=NN(CC(F)c1cc(Cl)c(Cl)cc1Cl)C(=O)[O-]
Reactant: NCCOC(=O)c1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=NN(CCF)C(=O)NCCOC(=O)c1cccnc1

Procedure:
A solution of 2-aminoethyl nicotinate dihydrochloride (1.5 g, 6.3 mmol) and 2,4,5-trichlorophenyl-N-(2-fluoroethyl)-N-nitrosocarbamate (2.18 g, 6.9 mmol) in 50 mL of pyridine was stirred under nitrogen at room temperature for 24 hours. The reaction was monitored by thin layer chromatography (silica, 1:1 chloroform/ethyl acetate, Rf 0.25). The solvent was removed in vacuo and the residue was chromatographed on a silica gel column by eluting, first with benzene to remove unreacted nitrosocarbamate and trichlorophenol, and then with chloroform to elute the desired product. The compound (1.56 g, 87.4%) melted at 75°-77° C. and was characterized by the structural formula: ##STR154##
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11](I)=[C:10]([S:13][CH3:14])[N:9]=[C:8]([NH2:15])[N:7]=1.[C:16](#[N:19])[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:15][C:8]1[N:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:11](/[CH:18]=[CH:17]/[C:16]#[N:19])=[C:10]([S:13][CH3:14])[N:9]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1I
Reactant: C=CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CSc1nc(N)nc(-c2ccco2)c1/C=C/C#N

Procedure:
From 4-furan-2-yl-5-iodo-6-methylsulfanyl-pyrimidin-2-ylamine, acrylonitrile, bis(triphenylphosphine)palladium(II) chloride and cesium carbonate in dioxane. EI-MS m/e (%): 258 (M+, 76), 241 ([M—NH3]+, 100), 150 (56), 114 (32).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:22][CH3:23])[CH2:27]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCNCC1CCNC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)C1
Yield: 43.9 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-ethylaminomethylpyrrolidine (100 mg), DBU (110 mg) and anhydrous acetonitrile (3 ml) was refluxed for 6 hours. After cooling, the resulting precipitate was collected by filtration and recrystallized from methanol to give the title compound (120 mg) as colorless prisms, mp 217°-219° C.
Reaction SMILES: N.[C:2]([O:6][C:7]([C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C[N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CS(C)=O>[C:2]([O:6][C:7]([C:9]1([C:14]([NH2:18])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(C(=O)O)CCCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C1(C(N)=O)CCCC1
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of 2 M methanolic ammonia (3.3 mL) was added to a stirred solution of 1-(tert-butoxycarbonyl)cyclopentanecarboxylic acid (1.0 g, 4.36 mmol), TEA (3.65 mL, 0.0262 mol), and TBTU (1.61 g, 5 mmol) in DMSO (5 mL) at 22° C. After stirring for 1 hr the solution was poured into ice cold water. The mixture was extracted with ethyl acetate. The extract was washed with brine (2×), dried over MgSO4 and concentrated to leave a colorless solid. Recrystallization from ethyl acetate-hexanes afforded 1-(tert-butoxycarbonyl)cyclopentanecarboxamide (660 mg, 66%). TFA (2.5 mL) was added to a stirred solution of the amide (445 g) in methylene chloride (2.5 mL). The solution was stirred for 1 hr at 22° C. and then concentrated to an oil. Trituration with diethyl ether afforded the TFA salt of 1-aminocyclopentanecarboxamide as a colorless solid. Coupling of the amine with, 13-cyclohexyl-6,7-dihydro-6-oxo-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid afforded the titled compound. MS m/z 486 (MH+); 1H NMR (300 MHz, DMSO-D6) δ ppm 1.09–2.29 (m, 8 H) 2.42–2.56 (m, 2 H) 2.86 (s, 1 H) 4.61 (s, 1 H) 4.97–5.17 (m, 1 H) 6.73 (s, 1 H) 7.03 (s, 1 H) 7.29 (d, J=7.68 Hz, 1 H) 7.38 (t, J=7.50 Hz, 1 H) 7.50 (t, J=7.50 Hz, 2 H) 7.61 (d, J=9.51 Hz, 1 H) 7.88 (d, J=8.78 Hz, 1 H) 8.28 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[C:13][Si](C)(C)C)[CH:7]=1)([CH3:5])[C:3]#[N:4].[OH2:18].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][C:2]([C:6]1[CH:7]=[C:8]2[C:9](=[CH:10][CH:11]=1)[C:19](=[O:18])[CH2:13][CH2:12]2)([CH3:5])[C:3]#[N:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C#N)c1cccc(C#C[Si](C)(C)C)c1
Reactant: O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc2c(c1)CCC2=O
Temperature: 160 °C

Procedure:
2-Methyl-2-(3-trimethylsilanylethynylphenyl)-propionitrile (4.00 g, 16.6 mmol) was added to a mixture of THF (35 mL), TEA (4.82 mL, 34.6 mmol), water (3.12 mL, 173 mmol), [Rh(COD)Cl]2 (83 mg, 1681 μmol) and triphenylphosphine (1.81 g, 6.90 mmol) in a stainless steel autoclave. The reactor was sealed and flushed with carbon monoxide, and then it was pressurized with carbon monoxide (500 psi). The stirred mixture was heated at 160° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was concentrated to a black residue and chromatographed on silica gel with 20-40% ethyl acetate in hexane. Obtained 2-methyl-2-(1-oxo-indan-5-yl)-propionitrile (2.71 g, 82%) as a brown solid. MS (DCI/NH3) m/z: 200.0 [M+H]+. 1H NMR (DMSO-d6) δ: 1.73 (s, 6H), 2.65 (m, 2H), 3.14 (m, 2H), 7.60 (dd, 1H), 7.68 (d, 1H), 7.74 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28](C)(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:32]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Product: CC(C)(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384 substituting 2-(3,4-difluorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 310 mg, 38%). mp 173-175° C. 1H NMR (300 MHz, DMSO-d6) δ 0.8 (s, 9H), 3.3 (s, 3H), 4.1 (s, 2H), 7.51 (m, 3H), 7.6 (m, 1H), 7.85 (m, 3H), 7.95 (d, J=9 Hz, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 450 (M+H)+, 467 (M+NH4)+. Anal. calc. for C21H21F2N3O4S: C, 56.12; H, 4.71; N, 9.35. Found, C, 55.83; H, 4.73; N, 9.08.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:4]=[N:3]1.C1C(=O)N([Br:21])C(=O)C1>>[Br:21][C:9]1[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:8]=1
Reactant: Cn1cc(-c2ccc(N)nc2)cn1
Reactant: O=C1CCC(=O)N1Br
Product: Cn1cc(-c2cnc(N)c(Br)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine(380 mg, 2.18 mmol) acetonitrile(30 mL) solution at 0° C. was added NBS (388 mg, 2.18 mmol) and the reaction mixture was stirred at 0° C. for 30 min, then at room temperature for additional 40 min. The reaction mixture was then concentrated, redissolved in methanol, to it was added solid LiOH (80 mg), sonicated and concentrated, the residue was triturated with water (2×5 mL), and the supernatants were discarded. the residue was dried under high vacuum, then triturated with EtOAc (2×8 mL), and the supernatants were collected, combined, and concentrated and the light brown residue was obtained as crude 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine. LCMS (m/z): 253.0/255.0 (MH+), 0.38 min.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=[CH:6][C:5]=2[CH:16]=O.[C:18]([O:24][CH:25]([CH3:27])[CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=O.[NH2:28]/[C:29](/[CH3:33])=[CH:30]\[C:31]#[N:32].C(O)(=O)C>CC(O)C>[C:31]([C:30]1[CH:16]([C:5]2[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:19]([C:18]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[C:20]([CH3:22])[NH:28][C:29]=1[CH3:33])#[N:32]
Reactant: C/C(N)=C/C#N
Reactant: Cc1cc(=O)c2c([N+](=O)[O-])ccc(C=O)c2o1
Reactant: CC(=O)CC(=O)OC(C)C
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc([N+](=O)[O-])c3c(=O)cc(C)oc23)C(C(=O)OC(C)C)=C(C)N1

Procedure:
32 mg (0.137 mmol) of 2-methyl-5-nitro-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 19.7 mg (0.137 mmol) of isopropyl acetoacetate, 11.26 mg (0.137 mmol) of 3-aminocrotononitrile and 8.24 mg (0.137 mmol) of acetic acid in 3 ml of 2-propanol and heated under reflux under argon for 6 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 13 mg (22.3% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18].C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:25][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(CCN2CCN(c3ccc([N+](=O)[O-])cc3Cl)CC2)cc1

Procedure:
The title compound, m.p. 102°-4°, was prepared similarly to the procedure of Example 1(A) from 1-(2-chloro-4-nitrophenyl)piperazine (1.2 g), 4-nitrophenethyl bromide (1.15 g) and sodium bicarbonate (0.85 g). The yield of the title compound was 0.37 g (from ethyl acetate), m.p. 100°-102°. A second batch had an m.p. of 102°-4° (from ethyl acetate/methanol)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:15]([OH:16])=[N:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10]=2[CH:11]=1.[Br:19]Br.CCOC(C)=O.C([O-])(O)=O.[Na+]>CC(O)=O.ClCCl.[Zn]>[Br:19][C:12]1[C:8]2[NH:9][C:10]3[CH:11]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=[CH:5][C:6]=3[C:7]=2[C:15]([OH:16])=[N:14][CH:13]=1
Reactant: BrBr
Reactant: Oc1nccc2[nH]c3cc(C(F)(F)F)ccc3c12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1ncc(Br)c2[nH]c3cc(C(F)(F)F)ccc3c12
Reaction time: 0.17 h

Procedure:
To a suspension of 7-(trifluoromethyl)-5H-pyrido[4,3-b]indol-1-ol in AcOH (0.3 M) in a cold water bath was added a solution (0.3 M) of Br2 (1 equiv) in dichloromethane to provide a homogeneous mixture. After standing at room temperature a precipitate formed, and Zn powder (excess) was added at 0° C. After a period of 10 min, the reaction mixture was poured over EtOAc and saturated NaHCO3. The organic phase was separated, dried over Na2SO4 and evaporated. The resulting solid was suspended in ether and hexanes, and was then collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][C:10]1[N:19]=[C:18](Cl)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:9][C:10]1[N:19]=[C:18]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Nc1ccccc1F
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1Nc1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a mixture of 2-fluoroaniline (232 mg), 2,4-dichloroquinazoline (400 mg) and N,N-dimethylformamide (4 mL), potassium carbonate (430 mg) was added and stirred at room temperature for 8 hours. The reaction mixture was diluted with water (40 mL), and the precipitated solid was collected by filtration and purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1-3:1) to give 2-chloro-N-(2-fluorophenyl)quinazoline-4-amine (0.22 g) as a light-yellow solid.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[N:4]=[C:5]([CH:13]2[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[C:7]=12>CC(O)CC>[NH2:1][C:8]1[C:7]2[N:6]([C:5]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:4][C:3]=2[Br:2])[CH:11]=[CH:10][N:9]=1
Reactant: CC1(O)CC(c2nc(Br)c3c(Cl)nccn23)C1
Reactant: N
Solvent: CCC(C)O
Product: CC1(O)CC(c2nc(Br)c3c(N)nccn23)C1
Temperature: 90 °C

Procedure:
A 35% ammonia solution (132 ml, 2.9 moles) was added to a suspension of 3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (22.0 g, 0.06463 mol) in 2-butanol (81 ml). The mixture was heated at 90° C. in a pressure vessel for 15 hr then concentrated to ˜130 ml, cooled to room temperature and the solid collected by filtration. This material was washed with water (3×22 mL) and dried at 40° C. under vacuum. To afford the desired product. 1H NMR (DMSO-d6, 400 MHz): δ 7.5 (d, 1H), 7.0 (d, 1H), 6.6 (bs, 2H), 5.1 (s, 1H), 3.4 (pentet, 1H), 2.3-2.4 (m, 4H) and 1.4 (s, 3H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:19][C:20]2[C:25]([C:26](=[O:28])[CH:27]=1)=[C:24]([O:29][CH3:30])[CH:23]=[C:22]([O:31][CH3:32])[C:21]=2[C@@H:33]1[CH2:37][CH2:36][N:35]([CH3:38])[C@H:34]1[CH2:39][OH:40].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:19][C:20]2[C:25]([C:26](=[O:28])[CH:27]=1)=[C:24]([O:29][CH3:30])[CH:23]=[C:22]([O:31][CH3:32])[C:21]=2[C@@H:33]1[CH2:37][CH2:36][N:35]([CH3:38])[C@H:34]1[CH:39]=[O:40]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dimethyl sulfoxide (1.8 mL, 25.3 mmol) in methylene chloride (20 mL) was added to a stirred solution of oxalyl chloride (840 μL, 9.84 mmol) in dry methylene chloride (120 mL) dropwise at −50° C. The reaction mixture was stirred for 30 min. Compound of example 7, (2.0 g, 4.65 mmol) in methylene chloride (20 mL) was added dropwise to the reaction mixture. The resulting mixture was further stirred for 30 min. Triethylamine was added dropwise at −50° C. and the reaction mixture was warmed to room temperature and basified with NaHCO3 solution (10 mL). Reaction mixture was extracted with methylene chloride, organic layer was washed with water, brine and dried (anhydrous Na2SO4) to afford the title compound.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([O:24]C)[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[N:13]=[CH:12][CH:11]=[CH:10]2.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([OH:24])[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: COc1cc2cccnc2c(OC)c1-c1ccccc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1-c1c(O)cc2cccnc2c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 7.7 %

Procedure:
At −78° C., 1N BBr3 in CH2Cl2 (1.5 ml, 1.5 mmol) was added to 6,8-dimethoxy-7-o-tolylquinoline (0.10 g, 0.36 mmol) in CH2Cl2 (5 ml), and the mixture was warmed to room temperature and stirred for 6 h. The solution was poured into ice-water and neutralized with saturated NaHCO3 solution. The mixture was extracted with ethyl acetate, and the organic phase was dried with Na2SO4. Purification of the residue by HPLC gave 6,8-dihydroxy-7-o-tolylquinoline (7 mg) as a white powder.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[CH:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:1][C:3]3[CH:18]=[CH:17][C:6]([O:7][C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=4)=[CH:5][CH:4]=3)[CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: C1CCC(N2CCNCC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCN(C4CCCCC4)CC3)cc2)nc1
Yield: 32.6 %

Procedure:
Using a method similar to Example 334, using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.299 g, 1.23 mmol), 1-cyclohexyl-piperazine (0.208 g, 1.24 mmol), and sodium borohydride (0.107 g, 2.83 mmol) in methanol (12 mL) provides 0.158 g (32%) of the title compound as a white solid (chromatography solvent: 20:1→10:1 methylene chloride:methanol). High resolution mass spectrum (electrospray): m/z calc for C23H31N4O2 395.2447, found 395.2461; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.0 Hz), 8.30 (dd, 1H, J=2.4, 8.8 Hz), 7.48-7.43 (m, 2H), 7.18-7.13 (m, 2H), 7.04 (d, 1H, J=8.3 Hz), 3.61 (s, 2H), 2.82-2.53 (m, 8H), 2.39-2.29 (m, 1H), 2.03-1.96 (m, 2H), 1.91-1.83 (m, 2H), 1.73-1.66 (m, 1H), 1.40-1.15 (m, 5H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10](O)=O)=[O:7])(C)(C)C.[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:20](C(Cl)=O)=[CH:19][CH:18]=1.[C:32]1([NH2:39])[C:33]([NH2:38])=[CH:34][CH:35]=[CH:36][CH:37]=1>>[C:26]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:27]=[CH:28][C:29]([C:6]([N:8]2[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]2[C:10]2[NH:39][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:38]=2)=[O:7])=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccc1N
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=C1C[C@@H](c2nc3ccccc3[nH]2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, [1,1′-biphenyl]-4-carbonyl chloride, and 1,2-benzenedi-amine the title compound was obtained in 73% purity by LC/MS. MS(ESI+): m/z=380.4.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1.[NH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23](F)[C:20]=1[C:21]#[N:22]>>[NH2:18][C:19]1[C:20]([C:21]#[N:22])=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1
Reactant: O=C(NC1CCC(CO)CC1)c1ccncc1
Reactant: N#Cc1c(N)cccc1F
Product: N#Cc1c(N)cccc1OCC1CCC(NC(=O)c2ccncc2)CC1

Procedure:
Prepared as in Example 22b from N-(4-(Hydroxymethyl)cyclohexyl)isonicotinamide (Example 108c) and 2-amino-6-fluorobenzonitrile as a colorless oil (6%). MS 351 (MH+).
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[C:5]1([NH:11][C:12](=[S:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)C.ICC>ClCCl>[CH2:2]([S:19][C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:11][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:3]
Reactant: CC[O-]
Reactant: S=C(Nc1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCI
Solvent: ClCCl
Solvent: CCO
Product: CCSC(=Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
First, 3.2 g of sodium ethoxide, 10 g of N-phenylthiobenzamide, and 60 mL of ethanol were put in a 300 mL three-neck flask, and this mixed solution was stirred at room temperature for 1 hour. Then, 3.7 mL of iodoethane was added to this mixed solution, and heated and stirred at 60° C. for 6 hours to be reacted. After the reaction, ethanol was distilled off under a reduced pressure to give a brown oily substance. This oily substance was dissolved in dichloromethane, and washed with water and then a saturated aqueous solution of sodium hydrogen carbonate. After the washing, anhydrous magnesium sulfate was added to the resulting organic layer for drying. The resulting mixture was subjected to gravity filtration, and the filtrate was concentrated, so that N-[(ethylsulfanyl)phenylmethylidene]aniline was prepared (a brown oily substance, crude yield: 110%). The synthetic scheme of Step 1 is shown by (a-5).
Reaction SMILES: [Pb:1]=O.[C:3]([O-:6])(=[O:5])[CH3:4].[NH4+]>>[C:3]([O-:6])(=[O:5])[CH3:4].[Pb+2:1].[C:3]([O-:6])(=[O:5])[CH3:4]
Reactant: O=[Pb]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: [Pb+2]

Procedure:
After the calcination step 15, the impure lead monoxide and other impurities are subjected to an acid ammonium acetate leach at 21 to form a solution of lead acetate and an insoluble residue. The lead acetate solution is separated from the solids at 22. The solids, comprising an antimonial lead gangue is removed at 23 for smelting. The lead acetate solution is treated with ammonium hydroxide at 24 to precipitate lead hydroxide with the concurrent formation of an ammonium acetate solution. After separation of insoluble lead hydroxide from the solution at 25, the lead hydroxide is dehydrated by heating at 26 to form a pure PbO product at 27.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([NH2:8])[CH3:7].[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[Na]>CO>[CH2:6]([NH:8][CH:12]1[CH2:13][CH2:14][O:9][CH2:10][CH2:11]1)[CH3:7]
Reactant: CCN
Reactant: O=C1CCOCC1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Product: CCNC1CCOCC1
Reaction time: 16 h

Procedure:
At 0° C. and with efficient cooling, 51 g (0.5 mol) of conc. sulfuric acid were added dropwise to a solution of 105 g (2.3 mol) of ethylamine in 0.5 l of methanol. 50 g (0.5 mol) of tetrahydro-2H-pyran-4-one and 18.8 g (0.3 mol) of sodium cyanoborhydride were then added successively. After 16 hours at room temperature, the methanol was distilled off, an excess of 10% strength aqueous sodium hydroxide solution was added and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed neutral with water, dried over magnesium sulfate and filtered and the residue was distilled. Bp. 76-82° C. (20 mbar), yield 24 g. 1H NMR (250 MHz, in CDCl3): δ=0.86 (s, 1H), 1.13 (t, 3H), 1.40 (dq, 2H), 1.84 (m, 2H), 2.68 (m, 3H), 3.40 (dt, 2H), 3.98 (m, 2H).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)#[N:2].[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([O-:23])=[O:18].[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][NH2+:7][CH2:6][CH2:5]1)#[N:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Solvent: ClCCl
Product: N#CC=C1CC[NH2+]CC1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(cyanomethylene)piperidine-1-carboxylate (5.0 g, 22 mmol) was dissolved in DCM (75.0 mL). TFA (8.7 mL, 112 mmol) was added, and the resulting mixture was allowed to stir at ambient temperature for 2 hours. The mixture was concentrated in vacuo to afford the title compound.