Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:20](=[O:21])[N:19]([CH3:22])[C:10]3[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:38][CH3:39])[CH2:28][CH2:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:26].CO>CN1CCCC1=O>[CH2:38]([N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35][C:12]2[N:13]=[CH:14][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=4)[C:20](=[O:21])[N:19]([CH3:22])[C:10]=3[N:11]=2)=[CH:36][CH:37]=1)[CH3:39]
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(S(C)(=O)=O)nc21
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: CCN(CC)CCOc1ccc(Nc2ncc3cc(Oc4ccc(F)cc4)c(=O)n(C)c3n2)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(4-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 8-Step A-B, 0.35 g, 1 mmol) and 4-(2-diethylaminoethoxy)aniline (0.625 g, 3 mmol) in 0.5 mL 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the free amine. This was suspended in ethyl acetate (1-2 mL), hydrochloric acid in ether (1M, 1.2 eq) was added and the reaction was stirred for 30 minutes. Isolation of the solid via filtration and drying provided 0.085 g of the hydrochloride salt (Mass spec. M+1=478, MP=245.2-246.1° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.O1CCCC1.[F:16][C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>C(N(CC)CC)C>[F:16][C:17]1[CH:18]=[C:19]([S:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccc2[nH]ncc2c1)c1cccc(F)c1
Yield: 36.6 %

Procedure:
3-Fluoro-N-(1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 1 from 0.4 g of 5-amino-1H-indazole, 20 ml of tetrahydrofuran, 0.83 ml of triethylamine and 0.88 g of 3-fluorobenzenesulfonyl chloride. 0.32 g of 3-fluoro-N-(1H-indazol-5-yl)-benzenesulfonamide is thus obtained in the form of a cream solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[C:22]1([C:28]([CH2:35][CH2:36][CH3:37])([CH2:32][CH2:33][CH3:34])[C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[C:22]1([C:28]([CH2:35][CH2:36][CH3:37])([CH2:32][CH2:33][CH3:34])[C:29]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCC(CCC)(C(=O)Cl)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of diethyl malonate (3.03 g, 18.77 mmol) and anhydrous magnesium chloride in acetonitrile (36 mL) at 0° C. was treated with triethylamine (5.2 mL, 37.55 mmol), stirred at 0° C. for 30 min, stirred at 25° C. for 3 hours, cooled to 0° C. and treated dropwise with a solution of the product of Example 1D (18.77 mmol) in acetonitrile (15 mL) over 10 min and stirred at 50° C. for 18 hours. The solution was cooled to 25° C. and concentrated in vacuo. The solids were suspended in ethyl acetate and cooled to 0° C., treated with 4N HCl solution until all solids had dissolved. The organic layer was extracted with water (2×) and with saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (4.51 g, 66%). 1H NMR (300 MHz, CDCl3): δ 7.32 (m, 5 H), 4.50 (s, 1 H), 4.04 (q, J=7.35 Hz, 4 H), 1.97 (m, 4 H), 1.28 (m, 3 H), 0.98 (m, 10 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22]([NH2:24])=[O:23].C(N(CC)CC)C>C(=O)([O-])[O-].[Ag+2].CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:21][C:22](=[O:23])[NH2:24])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Reactant: NC(=O)CBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCc1ccc(NCC(N)=O)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 20.5 %

Procedure:
A mixture of [4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (0.8 g, 3.03 mmol), 2-bromoacetamide (0.46 g, 3.33 mmol), triethylamine (0.2 mL, 3.33 mmol), and DMF (30 mL) was stirred at 80° C. for 20 hours. TLC indicated that the reaction was not complete. Silver carbonate (0.92 g, 3.33 mmol) was thus added. The reaction was further stirred at 80° C. for 24 hours. The reaction mixture was passed through a silica plug. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3:1 ethyl acetate/dichloromethane, v/v) to provide 390 (0.20 g, 22%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.55 (m, 4H), 2.50 (t, 2H), 3.03 (t, 2H), 3.70 (s, 2H), 6.52 (d, 211), 7.00 (d, 2H).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:37]1[N:41]=[C:40]([NH2:42])[S:39][N:38]=1)[C:12]([NH:14][CH:15]1[C:35](=[O:36])[N:17]2[C:18]([C:32]([OH:34])=[O:33])=[C:19]([CH2:22][S:23][C:24]3[N:28]([CH2:29][C:30]#[CH:31])[N:27]=[N:26][N:25]=3)[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])(C)(C)C.C(O)=O.Cl>C(=O)(O)[O-].[Na+]>[C:6]([CH2:8][O:9][N:10]=[C:11]([C:37]1[N:41]=[C:40]([NH2:42])[S:39][N:38]=1)[C:12]([NH:14][CH:15]1[C:35](=[O:36])[N:17]2[C:18]([C:32]([OH:34])=[O:33])=[C:19]([CH2:22][S:23][C:24]3[N:28]([CH2:29][C:30]#[CH:31])[N:27]=[N:26][N:25]=3)[CH2:20][S:21][C@H:16]12)=[O:13])([OH:7])=[O:5]
Reactant: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3nsc(N)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
A mixture of 7-[2-tert-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(3.5 g), formic acid (35 ml) and conc. hydrochloric acid (1.0 ml) was stirred for an hour at room temperature. The reaction mixture was evaporated and the residue was pulverized with diethyl ether and dried. Thus obtained product (3.2 g) was dissolved in an aqueous solution of sodium bicarbonate and ethyl acetate was added thereto. The mixture was adjusted to pH 1 with 6 N hydrochloric acid and then filtered. The ethyl acetate layer was separated from the filtrate, washed with a saturated aqueous solution of sodium chloride, treated with activated charcoal, dried over magnesium sulfate and then evaporated. The residue was pulverized with diethyl ether and dried to give a crude product (2.0 g). The product was dissolved in an aqueous solution of sodium bicarbonate and the solution was acidified with 6 N hydrochloric acid. The precipitates were collected by filtration, washed with water and then dried to give 7-[2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.0 g), mp. 160° to 165° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].CC1C=C(C)[N:29]([C:33](N)=[NH:34])N=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:33](=[NH:29])[NH2:34])[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: N#Cc1cccc(N(C(=O)NC2CCNCC2)C2CCCCCC2)c1
Solvent: c1ccncc1
Product: N#Cc1cccc(N(C(=O)NC2CCN(C(=N)N)CC2)C2CCCCCC2)c1
Temperature: 110 °C
Yield: 74.7 %

Procedure:
N-(3-Cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (0.05 g, 0.126 mmol) was dissolved in pyridine (2 ml) and 3,5-dimethylpyrazole-1-carboxamidine (0.037 g, 0.188 mmol) was added under a nitrogen atmosphere. The reaction was heated to 110° C. for 6 h, then was allowed to cool and was concentrated to give a viscous amber oil. The product was purfied by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 15 min. The product eluted at 13.8 minutes was concentrated to give N-(3-cyanophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea as an amorphous solid (0.036 g); LRMS (M+H)+ m/z 341.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>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.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:21]=1
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: Cc1ccc(B(O)O)c(C)c1
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(-c2ccc(C)cc2C)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 104.6 %

Procedure:
(2,4-Dimethylphenyl)boronic acid (3.0 g, 20.0 mmol), ethyl 3-bromobenzoate (4.3 g, 18.8 mmol) and cesium carbonate (9.8 g, 30.0 mmol) were added to a mixture of ethanol (20 mL) and toluene (80 mL), and after argon substitution, tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 70° C. for 18 hrs. The reaction mixture was cooled and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to give the title compound (5.0 g, yield 100%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:14][O:13][CH2:12]3)[N:7]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:6]=2[CH:22]=1.[I:23]C1C=CC2N=C(C(Cl)(Cl)Cl)N(C3C=CN=C(N)N=3)C=2C=1>COCCO>[I:23][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:7]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:6]=2[CH:22]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(I)cc32)n1
Reactant: Nc1nccc(-n2c(OC3COC3)nc3ccc(Br)cc32)n1
Solvent: COCCO
Product: COCCOc1nc2ccc(I)cc2n1-c1ccnc(N)n1

Procedure:
The title compound was prepared by the procedure described for the synthesis of 4-[6-bromo-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine by reacting 4-[6-iodo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine with 2-methoxyethanol: LC-MS: m/z=+412 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:23])O[C:14](=[O:22])[C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:3]1.C[N:25](C=O)C.N>O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:23])[NH:25][C:14](=[O:22])[C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3ccncc3)C(=O)OC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Solvent: O
Product: Cn1cc(C2=C(c3ccncc3)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
200 mg of 3-(1-methyl-3-indolyl)-4-(4-pyridyl)furan-2,5-dione were treated with 5 ml of DMF and 5 ml of 33% aqueous ammonia. The resulting solution was heated at 140° C. for 17 hours. After cooling, the suspension was diluted with water. The product was filtered off, washed with water and dried to give 144 mg of 3-(1-methyl-3-indolyl)-4-(4-pyridyl)-1H-pyrrole-2,5-dione, m.p. 332°-334° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[CH3:27]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:25]=[C:26](\[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])/[CH3:27])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)c1ccccc1F
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF (5 mL), Copper (I) iodide (19 mg, 0.1 mmol) L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-1% MeOH-DCM. The product was further purified by HPLC. Yield: 10 mg. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.25 (s, 1H), 7.10 (m, 3H), 6.90 (m, 2H), 6.82 (m, 1H), 6.70 (s, 1H), 4.62 (d, 1H), 4.0 (d, 1H), 3.70 (m, 1H), 3.20 (m, 1H), 2.92 (m, 1H), 2.82 (s, 3H), 2.70 (m, 1H), 2.0 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]4[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH:4]=[N:3]1.[N:29]([CH2:32][CH3:33])=[C:30]=[O:31]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:20]([C:21]4[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:30]([NH:29][CH2:32][CH3:33])=[O:31])=[CH:27][CH:28]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:13][CH2:14]2)[CH:4]=[N:3]1
Reactant: CCN=C=O
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CN)cc3)CC2)cnn1C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCNC(=O)NCc1ccc(-c2nccnc2N2CCN(Cc3cnn(C)c3C)CC2)cc1
Temperature: 50 °C
Yield: 66.9 %

Procedure:
Dissolve 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamine (0.35 g, 0.93 mmol) in tetrahydrofuran (6 mL). Add isocyanato-ethane (1 eq., 0.06 g, 0.84 mmol). Add 4-(dimethylamino)pyridine (0.05 eq., 0.005 g, 0.043 mmol). Heat at 50° C. for 17 hr. Purify by normal phase chromatography with eluent 4% 7N ammonia-methanol/ethyl acetate to give 1-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzyl}-3-ethyl-urea (0.252 g, 62%). MS (ES): m/z=449.3[M+H]. Dissolve (0.252 g, 0.56 mmol) in acetonitrile (1 mL) and water (4 mL). Add aq. 1 N HCl (1 eq., 0.56 mmol, 0.56 mL). Freeze the solution to −78° C. in a dry-ice/acetone bath. Place the solution in the lyophilizer for 48 hr. to give the title compound (0.250 g, 97% yield). MS (ES): m/z=449.3 [M+H].
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[Si:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=1[CH2:32][CH3:33])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[F:34][C:35]([F:44])([F:43])[C:36](N1C=CN=C1)=[O:37]>C1COCC1>[Si:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH2:30][C:36](=[O:37])[C:35]([F:44])([F:43])[F:34])=[CH:25][C:24]=1[CH2:32][CH3:33])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: O=C(n1ccnc1)C(F)(F)F
Reactant: CCc1cc(C(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C(=O)CC(=O)C(F)(F)F)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a stirred solution of 1,1,1,3,3,3-hexamethyldisilazane (1.79 g, 11.1 mmol) in THF (37 ml) was added n-butyl lithium (1.52 M solution in hexane; 7.3 ml, 11.1 mmol) dropwise at 0° C., and the mixture was stirred at 0° C. for 30 minutes, then cooled at −78° C. A solution of 1-(4-[[tert-butyl(dimethyl)silyl]oxy]-3-ethylphenyl)-1-ethanone (2.57 g, 9.23 mmol) in THF (40 ml) was added dropwise, and the mixture was stirred at −78° C. for 1 hour. 1-(Trifluoroacetyl)imidazole (2.0 g, 12.2 mmol) was added, and the mixture was stirred at −78° C. for 3 hours, and quenched with water. The reaction mixture was warmed up to room temperature, and diluted with ethyl acetate. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without further purification. (3.45 g, 99% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][OH:28])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:32].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([C:27]([OH:32])=[O:28])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C1[C@@H](CO)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N1Cc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
In 20 ml of acetone was dissolved 0.5 g of trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-methanol obtained in Example 46. To the solution was added dropwise, while stirring at room temperature, 0.5 ml of a Jones reagent. The reaction mixture was stirred for one hour at room temperature, which was then concentrated under reduced pressure The concentrate was subjected to extraction with ethyl acetate. The organic layer was washed with water and dried, then the solvent was distilled off under reduced pressure. From the residue was obtained 0.23 g of trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-carboxylic acid as white crystals, m.p.177°-178 C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])[CH2:3][CH2:2]1.[CH3:19][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:19])=[O:12])=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Morpholino-3-nitrobenzoic acid prepared in the same manner as in Example 10(1) (3.0 g) is dissolved in methanol (15 ml), and thereto is added dropwise a 10% solution of trimethylsilyldiazomethane in n-hexane in an equimolar amount, and the mixture is stirred at room temperature for one hour. Methanol is distilled off under reduced pressure, and the residue is extracted with ethyl acetate. The extract is washed with 5% aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and ethyl acetate is distilled off under reduced pressure to give methyl 4-morpholino-3-nitrobenzoate (3.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[N+:6]([O-])[C:7]([CH3:13])=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:18]>ClCCl>[CH2:11]([O:10][C:9]1[CH:8]=[C:7]([CH2:13][OH:18])[N:6]=[N:5][C:4]=1[O:3][CH2:1][CH3:2])[CH3:12]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOc1cc(C)[n+]([O-])nc1OCC
Solvent: ClCCl
Product: CCOc1cc(CO)nnc1OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3,4-Diethoxy-6-methylpyridazine 1-oxide (1.44 g) was initially charged in dichloromethane (50 ml) and admixed dropwise at RT with trifluoroacetic anhydride (2.5 ml). After 2.5 h, the mixture was concentrated to dryness and the residue was taken up with ethanol and saturated potassium carbonate solution. After stirring at RT for 4 h, the mixture was concentrated to dryness again and the residue was admixed with water and dichloromethane. Removal of the organic phase was followed by extraction twice more with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified twice using silica gel with dichloromethane/methanol as the eluent. The product-containing fractions were combined and dried. 716 mg of the desired product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:28])([F:27])[C:21]([F:26])([F:25])[CH2:22][CH2:23]I>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[N:7][N:8]2[CH2:23][CH2:22][C:21]([F:26])([F:25])[C:20]([F:28])([F:27])[F:19])=[CH:4][CH:3]=1
Reactant: FC(F)(F)C(F)(F)CCI
Reactant: N#Cc1n[nH]c2cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2cc(Cl)ccc12
Temperature: 25 °C

Procedure:
An acetonitrile solution (450 mL) containing the intermediate from Step C (30 g, 169 mmol), potassium carbonate (116.6 g, 844 mmol) and 1,1,1,2,2-pentafluoro-4-iodobutane (97.2 g, 354.7 mmol) was refluxed for 36 hours. The solution was cooled to room temperature and partitioned between EtOAc and water. The organic phase was concentrated and the crude material was filtered through a plug of silica gel using 10% EtOAc/heptanes as the eluent. The isolated material was subsequently recrystallized from heptanes to give the indicated product. 1H NMR (400 MHz, CH3 CN-d3): δ 7.87-7.80 (m, 2H); 7.40 (dd, J=8.7, 1.7 Hz, 1H); 4.77 (t, J=7.0 Hz, 2H); 2.95-2.78 (m, 2H). m/z=324.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:24]([O:26][CH3:27])=[O:25])[C:15](OS(C(F)(F)F)(=O)=O)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH2:30]([O:32]/[CH:33]=[CH:34]/[Sn](CCCC)(CCCC)CCCC)[CH3:31].C(N(CC)CC)C>CN(C=O)C.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>[CH2:33]([O:32]/[CH:30]=[CH:31]/[C:15]1[C:14]([C:24]([O:26][CH3:27])=[O:25])=[N:13][CH:12]=[C:11]2[N:7]([CH2:6][C:5]3[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]=12)[CH3:34]
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](/C=C/OCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO/C=C/c1c(C(=O)OC)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 140 °C
Yield: 35 %

Procedure:
To a stirred solution of methyl 1-(4-fluorobenzyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (1.4 g, 3.24 mmol) and (E)-2-ethoxyvinyl tributyltin [prepared according to A. Leusik, H. A. Budding, J. W. Marsman, J. Organomet. Chem., 1967, 9, 285-294] (2.2 g, 6.48 mmol) in DMF (10 mL) under a nitrogen atmosphere were added triethylamine (0.48 mL, 3.24 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.24 g, 0.32 mmol). The resulting mixture was heated to 140° C. for 2 hours. It was quenched with water, and extracted with ethyl acetate three times. The combined organic extracts were washed with water (2×30 mL), dried over sodium sulfate, concentrated in vacuo and purified by Biotage flash chromatography. Elution with hexane:ethyl acetate (1:1) provided the title compound as brown glue (0.40 g, 35% yield). 1H NMR (MeOD) δ; 8.50 (s, 1H), 7.64 (d, 1H, J=3.3 Hz), 7.22 (t, 2H, J=6.8 Hz), 7.05 (t, 2H, J=6.8 Hz), 6.89 (d, 1H, J=3.3 Hz), 5.53 (s, 2H), 4.02 (q, 2H, J=7.1 Hz), 1.37 (t, 3H, J=7.1 Hz). LCMS (APCI, M+H+): 355.2.