Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+].CCCCCC.C(OCC)(=O)C>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCCC
Product: COc1ccc(-c2ccc(OC)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 199.5 %

Procedure:
4-Methoxyphenylboronic acid (3.00 g, 19.7 mmol) and 4-chloro-3-nitroanisole (3.69 g, 11.6 mmol) were dissolved in a mixture of dioxane (40 mL) and water (10 mL). K2CO3 (5.44 g, 23.2 mmol) and Pd(PPh3)4 (1.14 g, 0.6 mmol) were added. The reaction mixture was heated in argon to 80° C., kept at this temperature overnight (TLC monitoring: hexane/ethyl acetate, 4:1), cooled, and filtered through Celite. The latter was washed with CH2Cl2, and the filtrate was evaporated. The residue was dissolved in CH2Cl2, and the solution was evaporated to give 6.0 g of crude biphenyl 10h that was cyclized without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11])[NH2:5].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][C:16]=2[N+:28]([O-:30])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1Cl
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1Nc1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A suspension of 12.7 g (60 mmols) of 3-chloro-4-trifluoromethoxyaniline and 15.15 g (60 mmols) of 1-chloro-2,4-dinitronaphthalene in 150 ml of water was heated to the boil. 5.6 g (67 mmols) of sodium bicarbonate were introduced in the course of 30 minutes and heating was continued for 2 hours under reflux. After the mixture had cooled to 20° C., the product was filtered off. 24 g of 1-(3-chloro-4-trifluoromethoxyphenylamino)-2,4-dinitronaphthalene of melting point 140° C. were obtained; after recrystallization from ethanol, 17.4 g of melting point 159° C. were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[C:4]2[N:3]=1.[C:17]1([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH:14]([NH:13][C:11]([C:10]1[CH:9]=[N:8][N:5]2[CH:6]=[CH:7][C:2]([NH:26][S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])=[N:3][C:4]=12)=[O:12])([CH3:16])[CH3:15]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CC(C)NC(=O)c1cnn2ccc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)NC(=O)c1cnn2ccc(NS(=O)(=O)c3ccccc3)nc12
Temperature: 85 °C
Yield: 39.6 %

Procedure:
A mixture of 5-chloro-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide (95.5 mg, 0.40 mmol, 1.0 equiv), benzenesulfonamide (62.0 mg, 0.40 mmol, 1.0 equiv) and cesium carbonate (312 mg, 0.96 mmol, 2.4 equiv) in 1,2-dimethoxyethane (8 mL) was heated to 85° C. for 72 hours. The solvent was removed in vacuo, and the resultant residue dissolved in water. The pH of the solution was then adjusted to about 5 by the addition of 1M HCl aqueous solution and extracted with dichloromethane (2×30 mL). The organic extracts were concentrated under vacuum and the residue purified by flash column chromatography on silica gel (gradient: 0 to 10% methanol in dichloromethane) to afford 57.0 mg (40%) of 5-benzenesulfonylamino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid isopropylamide as a solid. LCMS (ESI) m+H=360.3; 1H NMR (400 MHz, DMSO-d6) δ: 12.2 (s, 1H), 8.97 (d, 1H), 8.30 (s, 1H), 8.01 (d, 2H), 7.64 (m, 4H), 6.64 (m, 1H), 4.13 (m, 1H), 1.21 (d, 6H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:29][C:30]1[C:31]([Cl:42])=[CH:32][C:33]2[S:34][CH2:35][C:36](=[O:41])[N:37]([CH3:40])[C:38]=2[N:39]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[Cl:42][C:31]1[C:30]([CH2:29][NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]=[CH:18][C:17]3=[O:28])[CH2:10][CH2:9]2)=[N:39][C:38]2[N:37]([CH3:40])[C:36](=[O:41])[CH2:35][S:34][C:33]=2[CH:32]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4nc5c(cc4Cl)SCC(=O)N5C)C(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4nc5c(cc4Cl)SCC(=O)N5C)CC3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To 20 mL of a chloroform solution containing 0.23 g of tert-butyl(7-chloro-4-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethyl)(1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 20 mL of trifluoroacetic acid was added and stirred at room temperature for 12 hours. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.16 g of 1-(2-(4-((7-chloro-4-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a pale brown foam.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2.[OH-].[Na+].CN(C)[CH:27]=[O:28]>>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[C:10]2[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: Fc1ccc(-n2ccc3cc(Cl)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Phosphorus oxychloride (12.5 g, 0.081 mol) was added to N,N-dimethylformamide (29.5 g, 0.19 mol) at 0°-5° C. After stirring for 10 minutes a solution of 5-chloro-1-(4-fluorophenyl)indole (20 g, 0.081 mol) in N,N-dimethylformamide (50 mL) was added at 0°-5° C. The reaction mixture was stirred for 0.5 h and subsequently poured into ice. The resulting mixture was made alkaline with concentrated NaOH and after stirring for 1 h at room temperature the mixture was extracted with diethyl ether (2×250 mL). The combined organic phases were dried (Na2SO4),the solvents evaporated and the remaining oil was purified by column chromatography (eluted with ethyl acetate/heptane 1:1) affording pure title compound 20.1 g (90%) which crystalized from heptane: mp 152°-154° C.; 1H NMR (CDCl3) δ 7.20-7.35 (m, 4 H), 7.50 (dd, 2 H), 7.85 (s, 1 H), 8.35 (s, 1 H), 10.05 (s, 1 H). Anal. (C15H9NO) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:29])=[C:4]([C:8]2[C:20]3[C:19]4[CH:18]=[CH:17][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:15][C:14]=4[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.COC(OC)OC.[NH:37]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[C:40](=O)[O:39][C:38]1=O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O1CCCC1.CS(C)=O.CCOC(C)=O>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:1]5[C:40](=[O:39])[C:41]6[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=6)[N:37]=[CH:38]5)[C:3]=4[CH3:29])=[N:9][N:10]=[C:11]([C:26]([NH2:28])=[O:27])[C:12]=3[NH:13][C:14]=2[CH:15]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)nnc(-c3cccc(N)c3C)c12
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=[N+]([O-])[O-]
Agent: [La+3]
Solvent: O
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)nnc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Temperature: 95 °C
Yield: 4.4 %

Procedure:
A sealed pressure tube containing 1-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxamide (0.2785 g, 0.712 mmol), trimethoxymethane (0.701 mL, 6.40 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (0.232 g, 1.423 mmol), and lanthanum nitrate hexahydrate (0.092 g, 0.213 mmol) in tetrahydrofuran (3.56 mL) was heated at 95° C. for 6 hr and cooled to room temperature. EtOAc (100 mL) was added, and the resulting mixture was washed with water (20 mL), 1N aq. NaOH (20 mL), water (20 mL) and brine (20 mL) successively. It was then dried over MgSO4 and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 24 g column eluting with 1-10% MeOH/CH2Cl2 to give crude product. This crude was dissolved in DMSO (0.2 mL) and MeOH (0.6 mL) and purified by reverse phase HPLC. The appropriate fractions were collected, basified with NaHCO3 (solid), and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combined extract was dried over Na2SO4 and concentrated in vacuo to give (0.0163 g, 0.031 mmol, 4.4% yield) as a light yellow solid. LC/MS (M+H)=521.18; 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropoisomer) δ ppm 12.24 (s, 1H), 8.76 (br. S, 1H), 8.71 (br. S, 1H), 8.53 (s, 1H), 8.48 (s, 1H), 8.26 (t, J=6.9 Hz, 1H), 8.00 (br. S, 1H), 7.89-7.94 (m, 1H), 7.80 (s, 1H), 7.74 (d, J=5.6 Hz, 1H), 7.60-7.70 (m, 2H), 7.41 (d, J=2.2 Hz, 1H), 6.88 (d, J=8.9 Hz, 1H), 4.15-4.21 (m, 2H), 3.72 (t, J=4.3 Hz, 2 H), 3.33 (s, 3H), 1.81 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].CO[C:9](=[O:19])[CH:10]([O:12][C:13]([CH3:18])([CH3:17])[C:14](=[O:16])[CH3:15])[CH3:11]>O1CCCC1>[CH3:18][C:13]1([CH3:17])[C:14](=[O:16])[CH2:15][C:9](=[O:19])[CH:10]([CH3:11])[O:12]1
Reactant: COC(=O)C(C)OC(C)(C)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1OC(C)(C)C(=O)CC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a mixture of potassium tert-butoxide (28.5 g, 0.254 mol) in tetrahydrofuran (200 ml) cooled to 0° C., is added a solution of 2-(1,1-dimethyl-2-oxopropoxy)propionic acid methyl ester (24 g, 0.127 mol) in tetrahydrofuran (50 ml). The reaction mixture is stirred at 0° C. for 3 hours. The reaction mixture is quenched with ice cold water, and the aqueous phase is extracted with diethyl ether (3×200 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 2,2,6-trimethylpyran-3,5-dione (7.5 g) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[S:16])[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH2:23]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]3=[S:16])[CH2:5][CH2:6]2)=[O:32])=[CH:34][CH:35]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: S=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)N2CCC(n3c(=S)[nH]c4ccccc43)CC2)cc1
Reaction time: 18 h
Yield: 85.4 %

Procedure:
A solution of 1-piperidin-4-yl-1,3-dihydro-benzoimidazole-2-thione (0.2 g, 0.84 mmol) in methylene chloride (20 mL) was treated with pyridine (0.040 mL, 0.497 mmol) and 4-n-butylbenzoyl chloride (0.093 mL, 0.497 mmol). The reaction mixture was stirred for 18 h then purified directly by column chromatography on silica gel using ethyl acetate as the eluent to give (4-butyl-phenyl)-[4-(2-thioxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (0.167 g; 86%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[CH3:28]>>[CH3:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[C:27]=1[CH3:28]
Reactant: Cc1nc[nH]c1C
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: Cc1ncn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])c1C
Yield: 48 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 4,5-dimethyl-1H-imidazole according to the GPB affording 18 mg (48%) of a white powder. Rt=2.43 min.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[C:4](=[O:18])[N:3]1[CH2:19][C:20]([OH:22])=[O:21].S(=O)(=O)(O)O.[C:28](=O)(O)[O-].[Na+]>CO>[CH3:28][O:21][C:20](=[O:22])[CH2:19][N:3]1[C:4](=[O:18])[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=2)[C:2]1=[O:1]
Reactant: O=C([O-])O
Reactant: O=C(O)CN1C(=O)c2ccc(Sc3ccccc3)cc2C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CN1C(=O)c2ccc(Sc3ccccc3)cc2C1=O
Reaction time: 18 h

Procedure:
A mixture of 20 ml of methanol, 6.27 g of (1,3-dioxo-5-phenylsulfanyl-1,3-dihydro-isoindol-2-yl)-acetic acid (20 mmol) and 0.3 ml of concentrated sulfuric acid was refluxed with stirring for 18 h. Then 100 ml of concentrated aqueous sodium bicarbonate solution were added and the mixture was extracted with 100 ml of ethyl acetate. The organic phase was dried over MgSO4 and evaporated in vacuo. 6.30 g of the title compound were obtained; MS-(+)-ion: M+1=328.0; 1H NMR (CDCl3): δ=7.69 (d, 1H), 7.41 to 7.55 (m, 7H), 4.40 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]2[CH2:10][CH2:9][CH2:8]2)=[CH:5][N:6]=1.C(N(C(C)C)CC)(C)C.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:20]1([O:26][C:27](=[O:28])[NH:1][C:2]2[S:3][C:4]([CH:7]3[CH2:10][CH2:9][CH2:8]3)=[CH:5][N:6]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ncc(C2CCC2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ncc(C2CCC2)s1)Oc1ccccc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 212.6 %

Procedure:
A solution of 2-amino-5-cyclobutyl thiazole (Preparation 2; 2.5 g, 1 6 mmol) and diisopropylethylamine (2.82 mL, 16 mmol) in methylene chloride (200 mL) was cooled to −78° C. and phenylchloroformate (2 mL, 16 mmol) was added dropwise. The reaction mixture was slowly warmed to 23° C., was stirred for 1 hour at this temperature, than was washed with aqueous saturated sodium bicarbonate (2 times) and brine (1 time), was dried (MgSO4), was filtered, and was concentrated in vacuo. The resulting white solid was purified by silica gel chromatography (5:1 CHCl3-hexanes) to afford 3.5 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N-]CC)C.[Li+].[C:7]([O:11][C:12]1[CH:17]=[C:16]([F:18])[N:15]=[C:14]([F:19])[C:13]=1[F:20])([CH3:10])([CH3:9])[CH3:8].CI>C1COCC1>[C:7]([O:11][C:12]1[C:17]([CH3:1])=[C:16]([F:18])[N:15]=[C:14]([F:19])[C:13]=1[F:20])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC[N-]CC
Reactant: CC(C)(C)Oc1cc(F)nc(F)c1F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)nc(F)c(F)c1OC(C)(C)C
Reaction time: 0.83 h

Procedure:
A freshly prepared solution of lithium diethylamide (LDA) (58.21 mmol) in 30 mL of THF at -78° C. was added to 10.0 g (48.74 mmol) of 4-t-butoxy-2,3,6-trifluoropyridine in 50 mL of THF at -78° C, and the reaction was stirred for 50 min. To the reaction mixture was added 4.3 mL (69.07 mmol) of methyl iodide, and the mixture was stirred at -78° C. for 1 hour and stirred at ambient temperature for 16 hours. The reaction was quenched with saturated NH4Cl solution, extracted with hexane, and the extracts washed with water, dried over MgSO4 and concentrated to give 4-t-butoxy-2,3,6-trifluoro-5-methylpyridine as a pale yellow oil, which was taken directly to the next step. MS (220) (M+H)+ ; 1H NMR (CDCl3)∂: 1.47 (m, 9H), 2.12 (m, 3H). 19F NMR (CDCl3, CFCl3 as reference)∂: 75.91 (dd apparent, J1 =15.0, J2 =22.1 Hz), 93.17 (dd apparent, J1 =15.0, J2 =22.1 Hz), 156.54 (m).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]2[CH2:3]1.N.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([N+:23]([O-:25])=[O:24])[CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc([N+](=O)[O-])ccc1-2
Temperature: 25 °C

Procedure:
2.85 g of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate are dissolved in a mixture of 10 ml of 98 percent nitric acid and 15 ml of 98 percent sulphuric acid and heated to 120° for 2 hours. Subsequently, the mixture obtained is cooled to room temperature, poured onto ice, neutralized with about 25 percent ammonia and extracted with chloroform. The chloroform extracts are dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate, there is obtained ethyl 5,6-dihydro-5-methyl-8-nitro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 197°-198°.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[N:4]([CH3:17])[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:20]1[CH:34]=[C:33]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH:32]=[CH:31][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]>O1CCOCC1.C(=O)(O)[O-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[O:22][C:21]1[CH:31]=[CH:32][C:33]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])=[CH:34][C:20]=1[C:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:18])[N:4]([CH3:17])[CH:5]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(F)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(-c2cc(F)c(=O)n(C)c2)c1
Yield: 26.6 %

Procedure:
The title compound of Example 119, step 2 (40 mg, 0.16 mmol), 1-(2-bromo-4-ethylsulfonylphenoxy)-2,4-difluorobenzene (60 mg, 0.16 mmol), and Pd(dppf)Cl2 (12 mg, 10%) in 1,4-dioxane (880 μL) and saturated bicarbonate solution (aq) (220 μL) were reacted, worked up and purified in a manner similar to Example 117. The title compound (18 mg, 27%) was obtained as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.13 (t, J=7.33 Hz, 3H) 3.34 (q, J=7.33 Hz, 2H) 3.59 (s, 3H) 6.92-6.98 (m, 1H) 7.19-7.27 (m, 1H) 7.50-7.61 (m, 2H) 7.76-7.84 (m, 2H) 7.92-7.96 (m, 1H) 7.97-8.01 (m, 1H) LCMS (M+H)+=424.
Reaction SMILES: Br.Br[C:3]1[N:9]=[C:8](N)[CH2:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[CH:4]=1.[OH2:15].[OH2:16].O.C([O-])(=O)C.[Na+]>O>[CH2:4]1[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[CH2:7][C:8](=[O:15])[NH:9][C:3]1=[O:16]
Reactant: O
Reactant: NC1=NC(Br)=Cc2ccccc2C1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C1Cc2ccccc2CC(=O)N1
Temperature: 85 °C
Yield: 89.9 %

Procedure:
4-Bromo-1H-benzo[d]azepin-2-ylamine hydrobromide (41.2 g) was dissolved in 600 ml of H2O that was previously heated to 85° C. Sodium acetate trihydrate (18.5 g) was added portion wise and the solution was heated to 90° C. for 3 h. Cooling to room temperature caused the precipitation of a white solid that was filtered-off, washed with water and desiccated under reduced pressure to afford the title compound (20.4 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:13](=[O:15])[CH3:14])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2,6-Dichloro-3-nitropyridin-4-amine (208 mg, 1 mmol) was added to acetic anhydride (2 mL), and the reaction mixture was refluxed overnight. After cooled to room temperature, the reaction mixture was basified with aqueous Na2CO3 until the pH was 8. The resulting mixture was then extracted with CH2Cl2. The organic layer was separated, dried over Na2SO4, and concentrated to afford the title compound (240 mg), which was used for the next step without further purification. MS (m/z): 250 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(N)cc1
Yield: 92.5 %

Procedure:
48.3 g (0.216 mole) of ethyl 2-(4-nitrophenyl)propionate was dissolved in 400 ml of ethanol and the solution was hydrogenated with 1 g of palladium black catalyst for 6 hours. Palladium black catalyst was filtered out and ethanol was distilled off to give 48.3 g of the remained oily substance. The oily substance was distilled under reduced pressure to give 38.6 g of ethyl 2-(4-aminophenyl)propionate as distillation fraction at 124°-126° C./1-2 mm Hg.
Reaction SMILES: C[O:2][C:3]1[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:6]2[CH2:7][CH2:8][O:9][C:5]=2[C:4]=1[C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.B(Cl)(Cl)Cl.O>ClCCl>[OH:2][C:3]1[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:6]2[CH2:7][CH2:8][O:9][C:5]=2[C:4]=1[C:18](=[O:27])[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cc1cc2c(c(C(=O)c3ccc(OC)cc3)c1OC)OCC2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1cc2c(c(C(=O)c3ccc(OC)cc3)c1O)OCC2
Temperature: 0 °C

Procedure:
Ethyl 6-methoxy-7-(4-methoxybenzoyl)-2,3-dihydrobenzofuran-5-ylacetate (3.6 g) was dissolved in dichloromethane (40 ml) and cooled to 0° C. To this was added boron trichloride (30 ml 1M). The reaction was allowed to warm to room temperature and, after 2 hours, added to water. The dichloromethane solution was washed 2 times with water, dried, and evaporated. The residue was run on a silica gel column, being eluted with ethyl acetate/hexane to give ethyl 6-hydroxy-7-(4-methoxybenzoyl)-2,3-dihydrobenzofuran-5-ylacetate. Saponification as per Example 3 gave 6-hydroxy-7-(4-methoxybenzoyl)-2,3-dihydrobenzofuran-5-ylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[S:15])[N:6]([CH2:9][C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:7]=1[NH2:8].[C:17](O)(=O)C.C(N)=N>O>[NH:12]1[CH:13]=[CH:14][C:10]([CH2:9][N:6]2[C:7]3[N:8]=[CH:17][NH:1][C:2]=3[C:3](=[O:16])[NH:4][C:5]2=[S:15])=[N:11]1
Reactant: CC(=O)O
Reactant: Nc1c(N)n(Cc2cc[nH]n2)c(=S)[nH]c1=O
Agent: N=CN
Solvent: O
Product: O=c1[nH]c(=S)n(Cc2cc[nH]n2)c2nc[nH]c12
Temperature: 25 °C
Yield: 30.5 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(d) by using 5,6-diamino-1-(1H-pyrazol-3-ylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.63 g, 2.64 mmol, obtained from Example 13(c)) and formamidine acetate (0.41 g, 3.95 mmol) with the exception that after the reaction mixture had cooled to r.t., water (10 mL) was added. The cloudy solution was maintained at 0° C. for 3 h and the precipitate that formed was collected by filtration, washed with water and methanol and dried in vacuo. The material was further purified by recrystallization from DMSO/water to give the title compound (0.20 g, 31% yield).