Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=3)[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]5[O:31][C:32]([C:35]([F:38])([F:36])[F:37])=[N:33][N:34]=5)[CH:28]=4)[N:23]=[CH:22][N:21]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: Nc1ccc2c(cnn2Cc2ccccc2F)c1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: Fc1ccccc1Cn1ncc2cc(Nc3ncnc4ccc(-c5nnc(C(F)(F)F)o5)cc34)ccc21

Procedure:
The title compound was prepared according to Procedure A from 1-(2-fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.79(1H, bs), 9.53(1H, s), 8.89(1H, s), 8.77(1H, dd), 8.21(1H, s), 8.11(1H, m), 8.10(1H, d), 7.84(1H, d), 7.70(1H, dd), 7.37(1H, m), 7.24 (1H, m), 7.18 (2H, m), 5.76(2H, s); m/z (M+1+) 506.
Reaction SMILES: C([C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=O.[C:21](O)(=O)[CH2:22][C:23]([OH:25])=[O:24].N1CCCCC1.Cl>N1C=CC=CC=1>[C:23](/[CH:22]=[CH:21]/[C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)([OH:25])=[O:24]
Reactant: Cc1c(-c2ccccc2)oc2c(C=O)cccc2c1=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1c(-c2ccccc2)oc2c(/C=C/C(=O)O)cccc2c1=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 7.92 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Uneyama, K. et al., Bull. Chem. Soc. Jap. 58; 2361, (1985)) 3.75 g of malonic acid and 0.46 ml of piperidine in 15 ml of anhydrous pyridine was stirred at 100° C. for 3 hours. After cooling to 20°-25° C. the reaction mixture was poured into a mixture of 90 g of crushed ice and 33 ml of hydrochloric acid (d=1.18). The resultant precipitate was collected by suction filtration, washed with water and crystallized twice from 95% ethanol to give 5.5 g of the title compound, m.p. 226°-2291° C.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][CH:21]=[N:22]4)[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](C1C(N[C@@H](C2C=CC=CC=2)C)=NC(C2C=CC=C3C=2C=CC=N3)=CC=1)([O-])=O.[CH2:55]([OH:57])C>[Pd]>[C:1]1([C@H:7]([N:9]2[C:10]3=[N:11][C:12]([C:17]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:18]=4[CH:19]=[CH:20][CH:21]=[N:22]5)=[CH:13][CH:14]=[C:15]3[NH:16][C:55]2=[O:57])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: C[C@@H](Nc1nc(-c2cccc3ncccc23)ccc1N)c1ccccc1
Agent: [Pd]
Agent: C[C@@H](Nc1nc(-c2cccc3ncccc23)ccc1[N+](=O)[O-])c1ccccc1
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2ccc(-c3cccc4ncccc34)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
(R)—N2-(1-Phenylethyl)-6-(quinolin-5-yl)pyridine-2,3-diamine. A solution of (R)-3-nitro-N-(1-phenylethyl)-6-(quinolin-5-yl)pyridin-2-amine (1.10 g, 2.97 mmol) in ethanol (95 mL) was purged with nitrogen for several minutes. Following addition of palladium on carbon (0.125 g, 1.18 mmol), the flask was evacuated and a hydrogen filled balloon was placed on the reaction. After stirring at room temperature for 18 h, the reaction was filtered and the solvent removed under reduced pressure to afford the title compound (0.77 g, 76% yield). MS (ESI) m/z 341.3 [M+1]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].N[OH:20].C([O-])([O-])=O.[Na+].[Na+].[CH2:27]1[CH2:31]OC[CH2:28]1>O.O>[CH2:31]([CH:5]([CH:6]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:4][C:2]([OH:20])=[O:3])[CH:27]=[CH2:28]
Reactant: C1CCOC1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCC(OC(=O)O)C1c2ccccc2-c2ccccc21
Reaction time: 2 h
Yield: 68 %

Procedure:
9-Fluorenylmethyl chloroformate (5.65 g, 0.022 mol) was added portionwise to a stirred solution of the amino alcohol 4 (7.5 g, 0.02 mol) and Na2CO3 (5.26 g, 0.05 mol) in a mixture of THF (150 ml) and water H2O (150 ml) at 0° C. The reaction mixture was allowed to return to room temperature, stirred for a further 2 h, and then extracted with EtOAc (3×50 ml). The combined organic phase was washed with H2O (3×50 ml) and brine (3×25 ml), dried over magnesium sulphate and evaporated in vacuo to give a dark red oil. This was purified by flash column chromatography (petroleum ether 40-60/EtOAc, 1:1) to afford 5b as a pale yellow oil (8.11 g, 68%): 1H NMR (270 MHZ, CDCl3): δ 1.72-2.18 (m, 6H); 2.9 (t, J=6.4, 2H); 3.43-3.91 (m, 3H); 3.81 (s, 3H); 4.25-4.54 (m, 5H); 4.61-4.65 (m, 2H); 5.21-5.37 (m, 2H); 5.85-6.0 (m, 1H); 6.85 (s, 1H); 7.31-7.79 (m, 9H); 8.77 (br s, 1H); 13C NMR (67.8 MHZ, CDCl3): δ 25.1, 28.4, 35.3, 47.0, 56.7, 60.9, 64.3, 65.4, 66.3, 67.1, 106.4, 111.7, 118.3, 120.0, 125.2, 127.1, 127.2, 127.8, 131.5, 131.9, 141.3, 143.7, 144.4, 150.2, 153.8, 170.3; MS (FAB): 601 (M+.+1); HRMS: calcd for C34H36N2O8 600.667, found 600.2175. IR (film): ν 3315, 2952, 1727, 1597, 1522, 1452, 1392, 1322, 1174, 1117, 1017.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:31])[N:4]2[CH2:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]3)([OH:15])[C:6]3=[C:7]([F:12])[CH:8]=[N:9][C:10]([CH:11]=1)=[C:5]23.Cl>ClCCl.CO.O1CCOCC1>[NH2:23][CH:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:13]2([OH:15])[C:6]3=[C:7]([F:12])[CH:8]=[N:9][C:10]4[CH:11]=[C:2]([Cl:1])[C:3](=[O:31])[N:4]([C:5]=43)[CH2:14]2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)c(Cl)cc4ncc(F)c2c43)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1CCN(CC2(O)Cn3c(=O)c(Cl)cc4ncc(F)c2c43)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of crude 1,1-dimethylethyl {1-[((4R/S)-8-chloro-3-fluoro-4-hydroxy-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (˜1 g, 2 mmol) in dichloromethane/methanol (20 mL/20 mL) was treated with a 4M solution of HCl in 1,4-dioxane ((20 mL) was stirred at room temperature, under argon, for 30 min. The reaction mixture was evaporated, dissolved in water (˜10 mL), basified by addition of solid sodium carbonate and evaporated. The residue was stirred with a 15% solution of methanol in dichloromethane (3×200 mL). The combined organic layers were dried over magnesium sulphate, evaporated and chromatographed eluting with a gradient of dichloromethane and 2M ammonia/methanol affording the product (215 mg, 27%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][O:11][CH2:10][C:9]=2[S:8][C:7]=1[NH2:15])=O)C.[CH:16]([NH2:18])=O>>[N:15]1[C:7]2[S:8][C:9]3[CH2:10][O:11][CH2:12][CH2:13][C:14]=3[C:6]=2[C:4](=[O:3])[NH:18][CH:16]=1
Reactant: CCOC(=O)c1c(N)sc2c1CCOC2
Reactant: NC=O
Product: O=c1[nH]cnc2sc3c(c12)CCOC3
Temperature: 25 °C
Yield: 42 %

Procedure:
2-Amino-4,5-dihydro-7H-thieno[2,3-c]pyran-3-carboxylic acid ethyl ester (26 g, 0.114 mol) was dissolved in formamide (200 ml) and the resulting mixture was heated at reflux temperature for 1.5 h. After cooling to room temperature the precipitate was filtered off, washed with water (2×80 ml) and dried in vacuo at 50° C. for 18 h which afforded 10.0 g (42%) of 5,6-dihydro-8H-pyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one as a solid.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH2:12]Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C1C=CC=CC=1.O>[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH2:12][C:5]([CH3:12])([CH3:6])[CH:4]=[O:1]
Reactant: [OH-]
Reactant: COc1ccc(CCl)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(CC(C)(C)C=O)c(Br)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 103.7 %

Procedure:
A mixture of NaOH (4.9 g), and (Bu)4NI (1 g) in benzene (14 mL) and water (4.9 mL) was heated at 70° C. under argon to obtain a homogeneous mixture. To this mixture was added dropwise a mixture of isobutylaldehyde (10.1 g, 140 mmoles), and the product of Step 1 (25 g, 106 mmoles) in benzene (38 mL). After the addition, the resulting mixture was stirred at 70° C. for 6 h under argon. It was cooled, diluted with water, and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with water, dried (Na2SO4) and concentrated to dryness. This residue was purified by silica gel flash chromatography using 5% EtOAc in hexane. The appropriate fractions (monitored by TLC) were combined and concentrated to dryness to give the desired product (14.9 g, ˜50%). NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.O>C1COCC1>[N:9]1[N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[N:3][C:2]=3[O:18][C:19]3([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]3)[C:12]2=[CH:11][CH:10]=1
Reactant: Clc1ncccc1-n1cccn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1nccc12
Temperature: 70 °C
Yield: 5.4 %

Procedure:
To a solution of 2-chloro-3-pyrazol-1-yl-pyridine (338 mg, 1.88 mmol) in THF (3.4 mL) at −78° C. was added butyllithium (979 μL of 2.5 M, 2.45 mmol) dropwise over 5 minutes. The reaction mixture was then stirred at the temperature for 15 minutes before the addition of tert-butyl 4-oxopiperidine-1-carboxylate (562.5 mg, 2.82 mmol). The reaction was allowed to come to 25° C., then heated at 70° C. for 4 hours. The reaction mixture was poured into water, and extracted with EtOAc (3×). The organics were combined, washed with brine, dried (Na2SO4) and evaporated to dryness to yield a crude mixture that was purified by column chromatography (5 to 30% EtOAC in hexanes) to give the title product (35 mg, 5%) that was used in the next step without further purification. ESI-MS m/z calc. 342.2, found 343.3 (M+1)+. Retention time: 1.46 minutes (3 min run).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Cl-].Cl[CH2:15][C:16]1[C:17]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][CH:23]=2)=[NH+:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH:27]([N:26]1[C:22]([C:17]2[C:16]([CH2:15][O:1][C:2]3[C:10]([CH:11]=[O:12])=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[CH:4][CH:3]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:23][CH:24]=[N:25]1)([CH3:29])[CH3:28]
Reactant: O=Cc1c(O)ccc2cn[nH]c12
Reactant: CC(C)n1nccc1-c1[nH+]cccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)n1nccc1-c1ncccc1COc1ccc2cn[nH]c2c1C=O
Temperature: 50 °C
Yield: 51.5 %

Procedure:
6-Hydroxy-1H-indazole-7-carbaldehyde (0.14 g, 0.86 mmol, 1 eq.) was dissolved in N,N-dimethylformamide (4 ml). 3-(Chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-1-ium chloride (0.235 g, 0.86 mmol, 1 eq.) and potassium carbonate (0.36 g, 2.6 mmol, 3 eq.) were added and the reaction mixture was stirred in a 50° C. heat block for 16 h. The reaction mixture was then cooled, and ethyl acetate (100 ml) and water (50 ml) were added. The phases were separated and the aqueous phase was extracted with more ethyl acetate (2×50 ml). The combined organic phases were washed with water (50 ml) and aqueous saturated sodium chloride solution (50 ml), and dried over sodium sulfate. After concentration the residue was purified by silica gel chromatography (5-70% ethyl acetate/hexanes). Product fractions were triturated with diethyl ether and lyophilized from acetonitrile/water to give 6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-1H-indazole-7-carbaldehyde (0.16 g, 51%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 11.59 (s, 1H), 10.58 (s, 1H), 8.74 (dd, J=4.4, 1.6 Hz, 1H), 8.02 (d, J=1.6 Hz, 1H), 8.01 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.42 (dd, J=7.9, 4.8 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.36 (d, J=1.8 Hz, 1H), 5.22 (s, 2H), 4.66 (septet, J=6.6 Hz, 1H), 1.46 (d, J=6.6 Hz, 6H). MS (ESI) m/z 362 [M+H]+.
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=O)[CH:11]([C:18]([N:20]([CH3:22])[CH3:21])=O)[CH2:10]2.Cl>O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH2:12][CH:11]([CH2:18][N:20]([CH3:22])[CH3:21])[CH2:10]2
Reactant: CN(C)C(=O)C1Cc2cc(Cl)ccc2NC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC1CNc2ccc(Cl)cc2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.4 %

Procedure:
1M Borane/THF complex (33 ml) was added to a THF (300 ml) suspension of 6-chloro-N,N-dimethyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxamide (2.135 g). The reaction mixture was heated under reflux for 6 hours, and left standing for cooling. The reaction mixture was ice-cooled, to which was added water (5 ml) and 6N hydrochloric acid (30 ml). The mixture was stirred at room temperature for 15 hours, then concentrated. 3N aqueous sodium hydroxide solution was added to the residue to make basic, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/4). The obtained crude crystals were washed with hexane to obtain the entitled compound (1.432 g).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].[H-].[Na+].[H][H].Br[CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1>CN(C)C=O.O>[CH2:1]([N:4]([CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[C:2]#[CH:3]
Reactant: BrCCCOC1CCCCO1
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN(CCCOC1CCCCO1)C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 88.8 %

Procedure:
A solution of tert-butyl prop-2-ynylcarbamate (1.2 g) in anhydrous N,N-dimethylformamide (5 ml) was treated with 60% sodium hydride (0.245 g) in one portion. After evolution of hydrogen had ceased 2-(3-bromopropoxy)tetrahydro-2H-pyran (1.36 g) was added. The reaction mixture was stirred under nitrogen for 48 hours then diluted with water (50 ml) and extracted into ethyl acetate (3×25 ml). The combined extracts were dried over anhydrous sodium sulphate, filtered and concentrated to afford the sub-titled compound (1.61 g) as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.FC(F)CO[C:15]1[N:23]=[C:22]([NH:24][CH3:25])[C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>O.CC#N>[CH3:25][NH:24][C:22]1[C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([N:6]2[CH2:7][CH2:8][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:4][CH2:5]2)[N:23]=1
Reactant: FC(F)(F)C1CCNCC1
Reactant: CNc1nc(OCC(F)F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CNc1nc(N2CCC(C(F)(F)F)CC2)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-trifluoromethyl-piperidine (330 mg, 2.2 mmol), TEA (1.00 mL, 7.2 mmol), 2-(2,2-difluoro-ethoxy)-6-methylamino-5-nitro-nicotinic acid (500 mg, 1.8 mmol, prepared according to WO2010/34799), DMF (5 mL) and MeCN (5 mL) is stirred for 3 h at rt. Then Cs2CO3 (1.5 g, 4.6 mmol) is added and it is stirred overnight at rt and for 6 h at 70° C. Water is added and the mixture is concentrated i.vac. The residue is diluted with water, HCOOH is added and the resulting precipitate is filtered, washed with water and dried.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[C:11]([C:14]([Cl:16])=[O:15])[CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:17](Cl)=[O:18].[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][OH:26])[CH3:21]>>[ClH:16].[ClH:16].[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][O:26][C:17]([C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[CH:13]=[CH:12][C:11]([C:14]([O:26][CH2:25][CH2:24][CH2:23][N:22]([CH2:27][CH3:28])[CH2:20][CH3:21])=[O:15])=[CH:10][C:8]=3[C:9]=2[CH:1]=1)=[O:18])[CH3:21]
Reactant: CCN(CC)CCCO
Reactant: O=C(Cl)c1ccc2sc3ccc(C(=O)Cl)cc3c2c1
Product: CCN(CC)CCCOC(=O)c1ccc2sc3ccc(C(=O)OCCCN(CC)CC)cc3c2c1
Product: Cl

Procedure:
A solution of 7.6 g (0.025 mole) of dibenzothiophene-2,8 -dicarbonyl chloride and 6.5 g (0.05 mole) of 3-diethylaminopropanol in 1 liter of chlorofrom is heated at reflux for two hours. The solution is concentrated to 500 ml, diluted with petroleum ether (75°-90°) and the precipitated solid is crystallized from methanol-isopropanol and finally from water-acetone to yield bis(3-diethylaminopropyl)dibenzothiophene-2,8-dicarboxylate dihydrochloride, M.P. 243°-245°C.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=O.N[C:14]1[C:18](C)=[CH:17][NH:16][N:15]=1>C(O)(=O)C>[CH3:17][C:18]1[CH:14]=[N:15][N:16]2[C:5]([C:7]3[CH:11]=[CH:10][O:9][CH:8]=3)=[CH:4][CH:3]=[N:2][C:12]=12
Reactant: Cc1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1ccoc1
Solvent: CC(=O)O
Product: Cc1cnn2c(-c3ccoc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-furyl)-2-propen-1-one and 3-amino-4-methylpyrazole in glacial acetic acid is heated at reflux temperature for 6 hours. The solvent is removed to give the product of the example.
Reaction SMILES: O[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:22]>C(Cl)Cl>[Cl:22][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Solvent: ClCCl
Product: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
A stirred solution of 2-Hydroxy-5,6-diphenylpyrazine (430 mg, 1.7 mmol) in 5.2 mL POCl3 in a capped reaction vial was heated to 100° C. for 4 hours. The orange solution was cooled to room temperature and stirred rapidly in a mixture of CH2Cl2 (100 mL) and ice cold 10% Na2CO3 (100 mL) for 15 minutes. The organic layer was isolated and washed 2×100 mL with 10% Na2CO3. The organics were isolated, dried (MgSO4), filtered and concentrated to the chloropyrazine, which existed as white solid (450 mg, quantitative). 1H-NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.45-7.39 (m, 4H), 7.36-7.24 (m, 6H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[O:21])[C:3]1=[O:29].[C:30]([OH:40])(=[O:39])[C@@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:32].ClC1C=C(Cl)C=C(C=O)C=1O>>[NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[O:21])[C:3]1=[O:29].[C:30]([O-:40])(=[O:39])[C@@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:32]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Agent: O=Cc1cc(Cl)cc(Cl)c1O
Product: Cc1ccccc1C(=O)CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Product: O=C([O-])[C@H](O)c1ccccc1

Procedure:
3-Amino-1,3-dihydro-1-(2'-methylphenacyl)-5-phenyl-2H-1,4-benzodiazepin-2-one, (R)(-)-mandelic acid, and 3,5-dichlorosalicylaldehyde
Reaction SMILES: [NH:1]([C:3]1[S:7][N:6]=[C:5]([CH3:8])[CH:4]=1)[NH2:2].S(=O)(=O)(O)O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH:23]([C:29](=O)[CH3:30])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=O)=[CH:17][CH:16]=1.O>CO>[CH3:28][O:27][C:25](=[O:26])[CH2:24][C:23]1[C:29]([CH3:30])=[N:2][N:1]([C:3]2[S:7][N:6]=[C:5]([CH3:8])[CH:4]=2)[C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(NN)sn1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)Cc1c(C)nn(-c2cc(C)ns2)c1-c1ccc(Cl)cc1

Procedure:
0.301 g (2.0 mmol) of 5-hydrazinyl-3-methylisothiazole and 0.099 ml (2.0 mmol) of concentrated sulfuric acid were added to 0.500 g (2.0 mmol) of methyl 3-[(4-chlorophenyl)carbonyl]-4-oxopentanoate in 10.00 ml of methanol, and the mixture was stirred under reflux for 6 hours. The mixture was poured into water and extracted with ethyl acetate.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:16][NH2:17].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:16][NH:17][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1
Yield: 46 %

Procedure:
A mixture of 2,4-difluoronitrobenzene (5.0 mmol), 3,5-dichlorobenzylamine (5.0 mmol), N,N-diisopropylethylamine (10.0 mmol) and acetonitrile (25 mL) was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5% ethyl acetate in hexanes as eluent to yield the title compound as a yellowish solid (46%). 1H NMR (400 MHz, CDCl3): δ 9.28 (br s, 1 H), 7.88 (m, 1 H), 7.34 (s, 1 H), 7.22 (s, 2 H), 6.44 (m, 1 H), 6.30 (dd, 1 H), 4.43 (d, 2 H).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1.Cl.N1C=CC=CC=1.O>CCOC(C)=O>[OH:19][C:16]1[CH:17]=[CH:18][C:12]2[O:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=3)=[CH:14][C:13]=2[CH:15]=1
Reactant: COC(=O)c1ccc(-c2cc3cc(OC)ccc3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2cc3cc(O)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A mixture of 4-(5-Methoxy-benzofuran-2-yl)-benzoic acid methyl ester (0.5 g, 1.8 mmol) and Pyridine HCl (5 g) was heated to 200° C. After 2 hr, the reaction was cooled and poured into water and exracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated and the product was purified by column chrmatography on silica gel (75% EtOAc/hex) to give a solid (0.21 g, 47%): 1H NMR (DMSO-d6) δ 13.07 (br s, 1 H), 9.29 (br s, 1 H), 8.02 (d, 2 H, J=8.1 Hz), 7.97 (d, 2 H, J=8.7 Hz), 7.46 (m, 2 H), 6.97 (d, 1H, J=2.9 Hz), 6.79 (dd, 1 H, J=9.3 Hz, 2.9 Hz); MS 253 (M−H)−