Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.Br[CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCBr
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-ol (150 mg) and ethyl 4-bromobutyrate (44 μl) are dissolved in N,N-dimethylformamide (3 ml) and thereto is added potassium carbonate (42 mg) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→3:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (117 mg). MS (m/z): 709 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:12]([O:15][CH2:16][CH:17]([CH2:28][O:29][NH2:30])[O:18][CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])(=[O:14])[CH3:13].C(N(CC)CC)C>O1CCOCC1>[C:12]([O:15][CH2:16][CH:17]([O:18][CH2:19][P:20]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:27])[CH2:28][O:29][NH:30][C:6]1[N:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[NH:8][CH:9]=[O:10])(=[O:14])[CH3:13]
Reactant: O=CNc1c(Cl)ncnc1Cl
Reactant: CCOP(=O)(COC(CON)COC(C)=O)OCC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOP(=O)(COC(CONc1ncnc(Cl)c1NC=O)COC(C)=O)OCC
Temperature: 100 °C
Yield: 59.4 %

Procedure:
A mixture of 4,6-dichloro-5-formamidopyrimidine (0.77 g, 4.0 mmol), diethyl [2-acetoxy-1-(aminooxymethyl)ethoxy]methylphosphonate (1.2 g, 4.0 mmol) and triethylamine (0.82 ml, 6 mmol) in dry dioxan (20 ml) was heated at 100° C. for 2 hours. The reaction mixture was cooled, filtered, and the filtrate evaporated to leave an oil which was chromatographed on silica gel (eluant dichloromethane:methanol 97:3) and gave the title compound as a yellow oil (1.08 g, 60%). 1H NMR: δH [(CD3)2SO] 1.23 (6H,t, J=7 Hz, (OCH2CH3)2), 2.03 (3H,s, COCH3), 3.85-4.35 (11H,m, (OCH2CH3)2 +OCH2P+OCH2CHCH2O). m/z: observed 454.1020; C15H24N4O8PCl (M+) requires 454.0996.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10]Cl)[CH:3]=1.[C-:12]#[N:13].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][C:12]#[N:13])[CH:3]=1
Reactant: [C-]#N
Reactant: COc1ccc(Cl)cc1CCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1CC#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
To a solution of (5-chloro-2-methoxy-phenyl)-methanol (17.1 g, 99.1 mmol) in methylene chloride (100 mL) was added thionyl chloride (14.5 mL, 198 mmol). The reaction was stirred at reflux for 3 hours, cooled to room temperature and concentrated in vacuo. The crude product was dissolved in methylene chloride and washed with saturated aqueous sodium hydrogen carbonate then dried over magnesium sulfate. Concentration in vacuo gave 4-chloro-2-chloromethyl-1-methoxy-benzene (18.4 g). To a solution of 4-chloro-2-chloromethyl-1-methoxy-benzene (18.4 g, 96.4 mmol) in acetonitrile (100 mL) was added potassium cyanide (12.5 g, 193 mmol) and 18-crown-6 (2.54 g, 9.64 mmol). The reaction was stirred 12 hours at ambient temperature, diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by passing it through a pad of silica gel, eluting with methylene chloride to give the title compound (17.2 g).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH2:24][C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[C:18]1([CH2:24][C:25]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 98 %

Procedure:
To a suspended CH2Cl2 (2 ml) solution of 2-chloro-1-methylpyridinium iodide (306 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), phenylacetic acid (136 mg, 1.0 mmol) and 2,6-lutidine (257 mg, 2.4 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 98% yield.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[Cu][C:30]#[N:31].CN1CCCC1>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Agent: CN1CCCC1
Product: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Temperature: 130 °C
Yield: 76.5 %

Procedure:
A mixture of 1-bromo-4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (190 mg, 0.43 mmol), copper(I) cyanide (76.3 mg, 0.85 mmol) and N-methyl-pyrrolidine (3 mL) was heated at 130° C. for 1 h. After cooled, reaction mixture was partitioned between ethyl acetate and water. Organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. Crude product was purified by silica gel chromatography (eluting with 2%-25% ethyl acetate in methylene chloride) to give the title compound (129 mg). MS-(+)-ion: M+1=392.80.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH2:23]Br>CN(C)C=O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[O:9][CH2:23][CH2:22][N:11]3[C:10](=[N:14][CH:13]=[CH:12]3)[C:4]=2[CH:3]=1
Reactant: BrCCBr
Reactant: Oc1cc(F)c(Br)cc1-c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cc2c(cc1Br)-c1nccn1CCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 224.7 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 4-bromo-5-fluoro-2-(1H-imidazol-2-yl)phenol (755 g, 2.94 mol, 1.00 equiv) in N,N-dimethylformamide (7.5 L), Cs2CO3 (3350 g, 10.28 mol, 3.50 equiv), followed by the addition of 1,2-dibromoethane (2208 g, 11.75 mol, 4.00 equiv). The resulting solution was stirred overnight at 80° C. To this was added 1,2-dibromoethane (200 g). The resulting solution was stirred at 80° C. for 5.5 h. This reaction was repeated for 2 times. The reaction mixture was cooled to room temperature and diluted with 20 L of ice/water. The solids were collected by filtration, washed with 2×4 L of water and dried to afford 1870 g (crude) of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a gray solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][CH3:10])[N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[S:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[NH2:15]>Cl>[CH2:9]([C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:18]([S:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:12]([F:11])[CH:13]=2)[CH:5]=1)[CH3:10]
Reactant: CCc1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Sc2ccncc2)c(F)c1
Agent: Cl
Product: CCc1cc(Nc2ccc(Sc3ccncc3)c(F)c2)nc(N)n1
Temperature: 25 °C
Yield: 3.4 %

Procedure:
2-Amino-4-chloro-6-ethylpyrimidine (Intermediate A8, 55.1 mg, 0.25 mmol) and Intermediate B7(39.4 mg, 0.25 mmol) were suspended in 0.01 M aqueous HCl (500 μL). The mixture was refluxed for 6 h. The reaction was cooled to room temperature and the solvent was evaporated by vacuum. The residue was purified by reversed phase chromatography on a YMC Pack-pro C18 column (trademark) eluting with acetonitrile/H2O (10:90-90:10 gradient). The compound was further purified by preparative TLC eluting with CH2Cl2-MeOH (90:10). Desired compound (2.9 mg, 0.0085 mmol; 34% yield); 1H NMR (Methanol-d4) 8.16 (dd, J=1.7, 4.7, 2H), 8.00-8.04 (m, 1H), 7.37 (m, 2H), 6.93 (dd, J=1.8, 4.9, 2H), 5.91 (s, 1H), 2.39 (q, J=7.7, 2H), 1.13 (t, J=7.5, 3H); ES MS [M+H]+=342; TLC (CH2Cl2-MeOH, 90:10); Rf=0.48.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[N:16]1[C:24]2[C:19](=[CH:20][C:21]([NH2:25])=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[N:16]1[C:24]2[C:19](=[CH:20][C:21]([NH:25][C:26](=[O:28])[CH3:27])=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: COc1cc2ncnc(N3CCc4cc(N)ccc43)c2cc1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc2ncnc(N3CCc4cc(NC(C)=O)ccc43)c2cc1OC
Temperature: 20 °C
Reaction time: 7.5 h
Yield: 46 %

Procedure:
To 1-(6,7-dimethoxy-quinazolin-4-yl)-2,3-dihydro-1H-indol-5-ylamine (102 mg, 0.316 mmol; free-base from Example 83) and 4-(N,N-dimethylamino)pyridine (51.2 mg, 0.42 mmol) in CH2Cl2 (5 mL) was added acetic anhydride (88 μL, 0.93 mmol). The mixture was stirred at 20° C. for 7.5 hours, quenched with H=O (5 mL), stirred 30 min. and diluted with CHCl3 (15 mL). The organic phase was separated and washed with saturated aqueous NaHCO3, dried over Na2SO4(s), filtered and concentrated in vacuo. Flash chromatography on silica (3.5% MeOH/CHCl3) afforded 53 mg of product. (M.P. >250° C. (dec); LC-MS: 365 (MH+); anal. RP18-HPLC RT: 2.79 min.).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([S:11][CH3:12])[CH:5]=[C:4]([CH3:13])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][CH2:22][CH2:23][OH:24]>>[CH3:20][O:21][CH2:22][CH2:23][O:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([S:11][CH3:12])[CH:5]=[C:4]([CH3:13])[N:3]=1
Reactant: COCCO
Reactant: CSc1cc(C)nc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCOc1nc(C)cc(SC)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 5 h

Procedure:
2-Chloro-6-methyl-4-methylthio-3-nitropyridine (2.80 g, 12.81 mmol) was dissolved in 2-methoxyethanol (40 mL). Potassium carbonate (1.90 g, 13.75 mmol) was added to the solution, followed by stirring for 5 hours at 60° C. The mixture was allowed to stand for cooling. Subsequently, the resultant mixture was extracted with ether-water, and the organic layer was washed with saturated brine, followed by drying sodium sulfate anhydrate and concentration under reduced pressure. The obtained residue was purified through silica gel column chromatography [(1) (eluent: n-hexane/ethyl acetate=4/1→n-hexane/ethyl acetate=2/1), (2) (eluent: chloroform)], to thereby yield 2-[(2-methoxyethyl)oxy]-6-methyl-4-methylthio-3-nitropyridine as a pale yellow oil (2.21 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.[BrH:10]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:10])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Br
Product: Clc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
100 ml of HBr (48%) were heated to 90° and treated portionwise with 1.43 g (0.01 mol) of 4-chlorobenzyl alcohol. The mixture was stirred for 1/4 hr. and then cooled to room temperature. The mixture was extracted with ethyl acetate and the organic phase was washed with water and saturated sodium chloride solution and dried over sodium sulfate. 1.82 g (88.6%) of 4-chloro-benzyl bromide were obtained as colorless crystals; m.p. 53°-55°.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1.O.NN>CO.[Ni]>[CH3:1][N:2]([CH3:21])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1
Reactant: CN(C)C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN(C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Yield: 98.6 %

Procedure:
A solution of compound 112 (0.21 g, 0.735 mmol) in dry methanol (5 mL) was treated with Ra—Ni (0.05 g) followed by hydrazine hydrate (0.22 mL, 7.359 mmol) at room temperature. The reaction was placed in a pre-heated oil bath and refluxed for 5 min. The reaction brought to room temperature, filtered through celite bed and washed with methanol (2 10 mL). The solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 113 (0.185 g, quantitative) as a foam. mp 63-65° C.; 1H NMR (DMSO-d6) δ 1.40-1.52 (m, 1H), 1.97-2.02 (m, 1H), 2.08-2.57 (m, 11H), 4.47 (s, 2H), 5.99 (brs, 1H), 6.47 (dd, 1H, J=1.8, 8.4 Hz), 6.99 (d, 1H, J=0.9 Hz), 7.04 (d, 1H, J=8.7 Hz), 7.13 (d, 1H, J=2.4 Hz), 10.55 (s, 1H); ESI-MS m/z (%): 256 (MH+, 100), 211 (41).
Reaction SMILES: [C:1]1([C:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])([CH3:9])C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]1([C@H](N)CC)C=CC=CC=1>>[C:1]1([CH:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[CH2:9][CH3:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(Nc1nc(N)c2ncn([C@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Reactant: CC[C@@H](N)c1ccccc1
Product: CCC(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Yield: 34.6 %

Procedure:
Combine the acetonide (2) (3.4 g, 9.95 mmol) with (R)-1-phenylpropylamine (8.62 g) and heat to reflux for 18 hours. Remove some of the excess amine by distillation. After cooling, purify by flash chromatography (3% methanol in dichloromethane). Triturate the product with diethyl ether to provide the secondary amine (3) (1.38 g); 1H NMR (CDCl3) δ 7.41 (1H, s), 7.21-7.34 (4H, m), 7.14-7.22 (1H, m), 5.69 (1H, d), 5.50 (2H, s), 5.25 (1H, d), 5.10 (1H, t), 5.01 (1H, q), 4.90 (1H, q), 4.41 (1H, s), 3.93 (1H, d), 3.80 (1H, d), 1.82 (2H, pent), 1.60 (3H, s), 1.32 (3H, s), 0.94 (3H, t); IR (KBr) 3450-3100, 1633, 1599 cm-1. Anal. Calcd for C22H28N6O4 : C, 59.99; H, 6.41; N, 19.08. Found: C, 59.99; H, 6.38; N, 18.71.
Reaction SMILES: [S:1]1[CH:9]2[C:4]([CH2:5][NH:6][CH2:7][CH2:8]2)=[CH:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[C:22]([Si:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)Cl)([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[Si:26]([O:10][C:2]1[S:1][C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C1C=C2CNCCC2S1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1cc2c(s1)CCNC2)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A mixture of 2.00 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluenesulfonate, 1.84 g of tert-butyldiphenylchlorosilane, 0.66 g of triethylamine and 7 ml of methylene chloride was stirred at room temperature (20° C.) for 3 hours. The produced 2-(tert-butyldiphenylsilyloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-p-toluenesulfonate was not isolated, and 0.96 g of 2-chlorobenzyl chloride and 1.21 g of triethylamine were added thereto. The mixture was allowed to react at room temperature (20° C.) for 1.5 hours by further stirring and then left to stand overnight to obtain a reaction mixture.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (212 mg, 2.25 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(2-chlorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 28; 350 mg, 1.03 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (236 mg, 1.23 mmol) and 1-Hydroxybenzotriazole (166 mg, 1.23 mmol) in DMF (20 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. Water (50 ml) was added to the mixture and the mixture was filtered to yield the title compound as a white solid. 400 mg.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:9]1([C:15]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CO>[OH:5][C:4]1[CH:3]=[N:2][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=1
Reactant: NCC(N)=O
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a stirred suspension of glycinamide hydrochloride (1.1 gm, 10 mmol) in 20 mL MeOH at 0° C. was added 20% NaOH (10 mL, 50 mmol). A clear solution formed and was treated slowly portionwise with benzil (2.1 gm, 10 mmol) as a solid. The yellow solution was stirred at 0° C. for 2 hours and then neutralized to approximately pH=7 with concentrated HCl. The bright yellow color disappeared and a tan precipitate formed. The material was isolated by filtration with MeOH and triturated with EtOAc to give 2-hydroxy-5,6-diphenylpyrazine (2 gm, 80%). 1H-NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.42-7.31 (m, 4H), 7.39-7.21 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F-:13].[K+]>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([F:13])=[O:5]
Reactant: O=C(Cl)c1cc(F)c(F)cc1Cl
Reactant: [F-]
Agent: [K+]
Product: O=C(F)c1cc(F)c(F)cc1Cl

Procedure:
Into a 200 cc glass reactor equipped with a reflux condenser, 50 g of 2-chloro-4,5-difluorobenzoylchloride, 13.7 g of spray dried potassium fluoride and 100 g of sulforane were charged and reacted at 135° C. for 4 hours under stirring. After cooling, the inorganic salts were filtered off, and the residue was subjected to distillation under reduced pressure to obtain 42 g of 2-chloro-4,5-difluorobenzoyl fluoride. The physical properties of the obtained 2-choloro-4,5-difluorobenzoyl fluoride were as follows.
Reaction SMILES: C[O:2][C:3]1[C:18]([O:19]C)=[CH:17][C:6]2[C:7](=[O:16])[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[C:18]([OH:19])=[CH:17][C:6]2[C:7](=[O:16])[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(=O)Cc1ccccc1O2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1Cc2ccccc2Oc2cc(O)c(O)cc21
Temperature: 190 °C
Yield: 66.9 %

Procedure:
A mixture of 7,8-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one (5 mg) and pyridine hydrochloride (20 mg) was heated at 190° C. for two hours. Water was added to the reaction mixture followed by extracting with ethyl acetate. This was washed with water and dried over magnesium sulfate and the solvent was evaporated to give the title compound (Compound 13) (3 mg, 60%) as brown plates.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19]=[C:20]=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[NH2:22][OH:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:21])[NH:22][OH:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: NO
Reactant: O=C=Nc1ccc(Oc2ccc3ccccc3c2)c(Cl)c1
Solvent: ClCCl
Product: O=C(NO)Nc1ccc(Oc2ccc3ccccc3c2)c(Cl)c1
Yield: 86.7 %

Procedure:
Fourteen grams of 3-chloro-4-(2-naphthyloxy)phenyl isocyanate were dissolved in 60 ml of methylene chloride, and the resulting solution was added dropwise to 10 ml of an aqueous solution containing 4 g of hydroxylamine at a temperature below 20° C. Precipitated crystals were collected on a filter, washed with water and dried to obtain 13.5 g of N'-[3-chloro-4-(2-naphthyloxy)phenyl]-N-hydroxyurea. Thereafter, 13.5 g of the product was dissolved in 150 ml of a benzene-methanol (1:1) mixture, and 13 ml of dimethyl sulfate and 30 ml of 10 N sodium hydroxide were alternately added dropwise thereto at a temperature below 30° C. After stirring at room temperature, the reaction mixture was diluted with water, followed by extraction with benzene. The benzene layer was washed with water, and the solvent was removed under reduced pressure. The oily substance obtained was purified by column chromatography (silica gel, 100-120 mesh; eluting solvent, tetrahydrofuran-benzene (1:1) mixture) to obtain 7.3 g of N'-[3-chloro-4-(2-naphthyloxy)phenyl]-N-methoxy-N-methylurea. nD25.0 : 1.5860.
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]2[C:10]=1[C:11](=[O:30])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][N:14]2[CH:22]1[CH2:24][CH2:23]1)C1C=CC=CC=1>CC(O)=O.[Pd]>[NH2:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]2[C:10]=1[C:11](=[O:30])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][N:14]2[CH:22]1[CH2:23][CH2:24]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(N)c2c1=O
Yield: 89.2 %

Procedure:
A solution of 5 (5.12 g, 12.3 mmol) in AcOH (200 mL) was hydrogenated under atmospheric pressure over 10% Pd/C (3.0 g) at 50° C. for 2 h. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo to dryness to yield 6 (3.58 g, 89%) which was used crude in the next step.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=O)[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[S:28])[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2ccc(C(F)(F)F)cc2C2CCCC12
Product: FC(F)(F)c1ccc2c(c1)C1CCCC1C(=S)N2
Yield: 61.4 %

Procedure:
Analogously to Example 4, 8-(trifluoromethyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (0.15 g, 0.6 mmol) is reacted with Lawesson's reagent (0.49 g, 1.2 mmol) to form 0.10 g (61%) of product.