Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:5]2[C:6](=O)[O:7]C(=O)[NH:9][C:4]=2[CH:3]=1.C([O-])(=O)C.[NH4+:21]>C(O)(=O)C>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:5]=1[C:6]([NH2:21])=[O:7]
Reactant: [NH4+]
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2c(=O)o1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: NC(=O)c1cc([N+](=O)[O-])c(Cl)cc1N
Temperature: 100 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
7-Chloro-1,4-dihydro-6-nitro-2H-3,1-benzoxazine-2,4-dione (6.5 g, 26.8 mmol) was suspended in glacial acetic acid (70 mL). Ammonium acetate (6.2 g, 80.6 mmol) was added, and the resulting mixture was heated to 100° C. with stirring for 3 hours. After cooling to room temperature, the brown solution was poured into distilled water (200 mL) to precipitate a yellow solid which was collected by filtration and washed well with water and ether. This material was first air dried, then dried overnight under high vacuum to provide 2-amino-4-chloro-5-nitrobenzamide (4.9 g, 23.0 mmol, 86%): 1H NMR (DMSO-d6): δ 6.92 (s, 1H), 7.49 (br s, 1H), 7.89 (br s, 2H), 8.22 (br s, 1H), 8.53 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([S-])(=[S:16])OCC.[K+].O.Cl>N1C=CC=CC=1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:12](=[S:16])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 168.2 %

Procedure:
In accordance with well known procedures, (see Batista-Parra, A. et al. Heterocycles, 2003, 60, 1367), a suspension of 2-amino-4-nitrophenol (1.54 g, 10 mmol) and potassium O-ethyl carbonodithioate (1.68 g, 10.5 mmol) in dry pyridine (10 mL) was stirred at 120° C. for 6 h, and then at room temperature for 16 h. The solution was poured into water and aqueous hydrochloric acid was added. The resulting precipitate was collected by filtration, washed with dilute aqueous hydrochloric acid, followed by water and then dried in the vacuum oven to afford 3.3 g (84%) of the title compound.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:29][CH:30]=4)=[O:3])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1ccc(N2CCCCC2)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(N4CCCCC4)cc3)(CC1)CC2
Yield: 19.6 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and N-(4-aminophenyl)piperidine (61.4 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-piperidinylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (14.6 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([N+:15]([O-])=O)[CH:14]=[C:8]2[CH2:7]1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([NH2:15])[CH:14]=[C:8]2[CH2:7]1
Reactant: [H][H]
Reactant: COCCCN1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: COCCCN1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A solution of 309a (300 mg, 1.25 mmol) in ethanol (20 mL) was added Pd/C (10%, 30 mg). The reaction was charged with hydrogen gas (via balloon) and stirred at room temperature for 1 h. After the reaction was complete, the mixture was filtered through a plug of CELITE®. The filtrate was concentrated under reduced pressure to afford 309b as a yellow solid (250 mg, 92%), which was used without further purification in the next step. MS-ESI: [M+H]+ 211.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]=[C:10]([C:16]([O:18]CC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:16](=[O:18])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=CNc1cccc(Br)c1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(Br)ccc2c1=O
Temperature: 250 °C
Yield: 69.4 %

Procedure:
Dowtherm (50 mL) was taken in double neck round bottom flask (100 mL) and heated to 250° C. in sand bath. At this temperature diethyl {[(3-bromophenyl)amino]methylidene}propanedioate (Intermediate 32, 10.0 g, 29.2 mmol) was added and the reaction temperature was maintained for another 1 h at 250° C. After completion of the reaction, the reaction mixture was cooled to room temperature, a white solid was collected by filtration and dried to yield 6.0 g (69.3%) ethyl 7-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylate.
Reaction SMILES: [N:1]1[NH:2][N:3]=[CH:4][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC.Br[C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25]([OH:27])=[O:26]>CN(C=O)C.[Cu]I>[Cl:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:23]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)[C:24]=1[C:25]([OH:27])=[O:26]
Reactant: O=C(O)c1c(Cl)cccc1Br
Reactant: c1cn[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1c(Cl)cccc1-n1nccn1

Procedure:
To the solution of 2H-1,2,3-triazole (CAS number 288-36-8; 4.0 g, 57.97 mmol) in DMF (14 ml) was added cesium carbonate (18.84 g, 57.97 mmol), trans-1-N,2-N-dimethylcyclohexane-1,2-diamine (0.510 g, 5.80 mmol), copper(I) iodide (0.276 g, 1.45 mmol) and 2-bromo-6-chlorobenzoic acid (CAS number 93224-85-2; 6.78 g, 28.98 mmol) at 0-10° C. The reaction was subjected to microwave irradiation at 125° C. for 15 minutes and was then partitioned between ethyl acetate (3×100 ml) and water (100 ml). The aqueous layer was acidified with 2M HCl (aq) to give pH 2 and then extracted with ethyl acetate (3×100 ml). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. This was then purified by column chromatography (0-3% methanol/DCM) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][NH:8][CH:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])([O:5][CH3:6])=[O:4].[CH2:31]([O:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]O)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:1][O:2][P:3]([CH2:7][NH:8][CH:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][NH:41][C:39]([O:38][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:40])=[O:16])=[O:11])([O:5][CH3:6])=[O:4]
Reactant: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)O)OC
Reactant: O=C(NCCCCCO)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)OCCCCCNC(=O)OCc1ccccc1)OC
Reaction time: 20 h

Procedure:
The compound of example 12(g) is prepared as follows: N-[2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionic acid (700 mg; 1.61 mmol) in dimethyl formamide (DMF) (10 ml) is treated sequentially with N-benzyloxycarbonyl-5-aminopentanol (400 mg; 1.98 mmol) in DMF (2 ml), 1-hydroxybenzotriazole (HOBT) (265 mg; 1.96 mmol), 4-N,N-dimethylaminopyridine (DMAP) (239 mg; 1.96 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) (553 mg; 3.22 mmol). The mixture is stirred for 20 hours, then partitioned between ethyl acetate (50 ml) and 1N HCl(30 ml). The organic layer is washed with a saturated solution of sodium bicarbonate (30 ml), then with brine (30 ml) before being dried over anhydrous sodium sulfate. After concentration under reduced pressure, the oily residue is purified by column chromatography on silica gel, eluting first with ethyl acetate, then with 5% methanol in methylene chloride to yield N-benzyloxycarbonyl-5-aminopentyl N-[2-(dimethylphosphonomethyl amino)-3-(4-biphenylyl)-propionyl]-3-aminopropionate as an oil; Rf(SiO2 ; MeOH/CH2Cl2):0.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:21][C:22](=O)N(C)C)=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:35]=[CH:34][C:31](CBr)=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:21][CH2:22][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: CN(C)C(=O)Sc1c(C#N)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)(C)OC(=O)N1CCc2ccc(C#N)c(SCc3ccc(F)cc3)c2CC1
Yield: 86.7 %

Procedure:
Use a method similar to the General Procedure 7, using 3-tert-butoxycarbonyl-7-cyano-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (123 mg, 0.33 mmol) and 4-fluorobenzyl bromide (204 mg, 1.64 mmol), to give 3-tert-butoxycarbonyl-7-cyano-6-(4-fluoro-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (118 mg, 87%).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=[C:6]([NH2:17])[C:5]=2[CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C@H:27]2[CH2:32]N[CH2:30][CH2:29][NH:28]2)[CH:22]=[CH:23][CH:24]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C@@H:27]2[NH:28][CH2:29][CH2:30][N:17]([C:6]3[C:5]4[CH:4]=[C:3]([CH3:2])[S:12][C:11]=4[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[N:7]=3)[CH2:32]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccc(CC[C@H]2CNCCN2)c1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc(Cl)c2)C1
Temperature: 105 °C
Reaction time: 48 h
Yield: 49.4 %

Procedure:
Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (829.8 mg, 3.12 mmol), (S)-2-[2-(3-chloro-phenyl)-ethyl]-piperazine (1.40 g, 6.24 mmol), N,N-diisopropylethylamine (403.6 mg, 3.12 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate and water. Remove the organic layer and wash it with 1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 673.9 mg (50%) of the title compound as a brown foam: mp 68–74°, dec; mass spectrum (ES+): m/e=437.31.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].Cl>C(O)C#C>[CH2:28]([O:27][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[C:29]#[CH:30]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1ccccc1
Agent: C#CCO
Agent: Cl
Agent: [Na]
Product: C#CCOc1nc(-c2ncccn2)nc(NS(=O)(=O)C=Cc2ccccc2)c1Oc1ccccc1OC
Temperature: 25 °C
Yield: 168.7 %

Procedure:
Sodium (185 mg) was dissolved in 5 ml of 2-propyn-1-ol and 390 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide was added thereto with stirring at room temperature. The reaction mixture was stirred at 60° C. for one hour and poured into a mixture of 1N hydrochloric acid and ice. This was extracted with ethyl acetate and the ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by a silica gel column chromatography (chloroform-methanol=100:1 to 30:1). The resulting syrup was crystallized in ether and collected filtration to give 342 mg of N-[6-(2-propynyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[Br:18][C:19]1[CH:20]=[C:21]([SH:28])[C:22](=[CH:26][CH:27]=1)[C:23](O)=[O:24]>N1C=CC=CC=1>[Br:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[N:2]=[C:1]([C:3]3[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=3)[S:28][C:21]=2[CH:20]=1
Reactant: O=C(O)c1ccc(Br)cc1S
Reactant: CC(C)(C)OC(=O)CCc1ccnc(C#N)c1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccc(Br)cc3s2)c1
Yield: 25.1 %

Procedure:
tert-Butyl 3-(2-cyano-4-pyridyl)propanoate (1.3 g, 5.6 mmol) and 4-bromothiosalicylic acid (1.8 g, 8.0 mmol) were dissolved in pyridine (20 ml), and the mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (3:2, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.63 g, 25%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1.[NH4+].[OH-]>C(Cl)Cl.CO>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: CCN1CC(=O)Nc2cc(N)c(OC)cc2C1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCN1CC(=O)Nc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2C1
Yield: 24.8 %

Procedure:
In an analogous manner to procedure 1656g, 8-amino-4-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (70 mg, 0.30 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (101 mg, 0.30 mmol) were coupled to provide N-{(1R,2R)-2-[5-chloro-2-(4-ethyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methane-sulfonamide (40 mg, 20%) as a mustard yellow solid following preparative tlc (DCM/MeOH/c.NH4OH=90/9/1); 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.00 (s, 1H), 7.49 (s, 1H), 7.46 (s, 1H), 6.82 (s, 1H), 5.53 (d, J=7 Hz, 1H), 5.31 (d, J=7 Hz, 1H), 3.94 (s, 3H), 3.74 (s, 2H), 3.40 (s, 2H), 3.29 (m, 1H), 2.87 (s, 3H), 2.77 (q, J=7 Hz, 2H), 2.23 (m, 2H), 1.84 (m, 2H), 1.38 (m, 2H), 1.27 (m, 2H), 1.20 (t, J=7 Hz, 3H); MS (m/e) 538 (M+1); mp 216° C. (dec.).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[Br:9][C:10]1[CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][C:15]=1[F:16]>O1CCCC1.C(OCC)(=O)C>[Br:9][C:10]1[CH:11]=[C:12]([C:17](=[O:19])[CH2:18][C:3]([O:6][CH3:7])=[O:8])[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)c1ccc(F)c(Br)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a suspension of sodium hydride (1.1 g of 60% suspension in mineral oil, hexane-washed, 27.6 mmol) in 50 mL of tetrahydrofuran was added dimethyl carbonate (2.3 mL, 27.6 inmol) and 3'-bromo-4'-fluoroacetophenone (3.0 g, 13.8 mmol). The resulting suspension was stirred at 65° C. for 1 h and then was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:1 hexane/ethyl acetate) to afford 1.0 g (26%) of the title compound. 1H NMR (CDCl3) (data for keto tautomer) δ8.15 (dd, 1H), 7.87 (m, 1H), 7.2 (m, 1H), 3.95 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([OH:22])=[O:21])=[C:11]([CH3:19])[C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:24]>C(Cl)Cl.CO>[CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH3:24])=[O:21])=[C:11]([CH3:19])[C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OC(C)C)ncc(OCc2ccccc2)c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(OCc2ccccc2)cnc(OC(C)C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of 5-(benzyloxy)-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylic acid (131a, 1.4 g, 4.7 mmol) in dry CH2Cl2 (50 mL) and dry MeOH (5 mL) was added dropwise TMSCHN2 (2.6 mL, 5.1 mmol, 2M in hexane) at 0° C. under N2. The reaction mixture was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 10/1) to give methyl 5-(benzyloxy)-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylate (131b, 1.1 g, 75%) as a colorless oil.
Reaction SMILES: [N:1]1[NH:2][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]3[CH2:13][CH2:12][C:11]4=[C:14]([CH:18]=[O:19])[CH:15]=[CH:16][CH:17]=[C:10]4[C:9]=1[C:8]=23.P([O-])(O)(O)=[O:21].[Na+].Cl[O-].[Na+].Cl>CS(C)=O.O>[N:1]1[NH:2][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]3[CH2:13][CH2:12][C:11]4=[C:14]([C:18]([OH:21])=[O:19])[CH:15]=[CH:16][CH:17]=[C:10]4[C:9]=1[C:8]=23
Reactant: O=Cc1cccc2c1CCc1cccc3[nH]nc-2c13
Reactant: O=P([O-])(O)O
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cccc2c1CCc1cccc3[nH]nc-2c13
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
85 mg of 6,7-dihydro-2H-benzo[6,7]cyclohepta[cd]indazole-8-carboxaldehyde prepared in Example 2 was dissolved in 8 ml of dimethyl sulfoxide. To the reaction mixture was added a solution of 0.75 g of sodium dihydrogenphosphate in 4 ml water. Further, a solution of 0.25 g of sodium hypochlorite in 1 ml water was added dropwise at room temperature, followed by stirring for 0.5 hour. To the reaction mixture was added 0.01 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:1), to give 85 mg of the title compound as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[C:10]([C:24]([F:27])([F:26])[F:25])[CH:9]=2)=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.C([O-])(O)=O.[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:23][C:15]1[CH:14]=[C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[CH:32][O:28][CH:29]=4)=[CH:3][CH:4]=3)=[CH:9][C:10]([C:24]([F:27])([F:26])[F:25])=[N:11]2)[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: OB(O)c1ccoc1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1F
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccoc3)cc2)cc1F
Temperature: 25 °C
Yield: 45.2 %

Procedure:
To a stirred solution of 5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole (0.15 g, 0.324 mmol) in DME (3.9 mL) was added furan—3-boronic acid (0.044 g, 0.389 mmol), bis(triphenylphosphine)palladium(II)chloride (0.025 g, 0.04 mmol) and saturated NaHCO3 solution (1.3 mL) at room temperature under nitrogen. The mixture was heated at reflux temperature for 4 hours, and cooled down to room temperature. The reaction mixture was filtered through celite, the filtrate was poured into water and the whole was extracted with ethyl acetate (20 mL×3). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo . The residue was purified by flash chromatography eluting with hexane/ethyl acetate (3/1) to give the title compound (0.066 g, 45.2% yield).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C[O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1
Reactant: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CC1Cc2ccc(O)cc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Anhydrous AlCl3 (1.38 g, 10.35 mmol) was added all at once to a solution of ethyl (±)-10,11-dihydro-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate (643.6 mg, 2.07 mmol) in anhydrous CH2Cl2 (21 mL) at 0° C. under argon. The yellow solution was warmed to RT and stirred for 3 h, then was cooled to 0° C. and quenched with cold 3 N HCl (10 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated. Silica gel chromatography (25% EtOAc/hexanes) gave the title compound as a nearly colorless oil (611.7 mg, 100%): TLC Rf 0.26 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.03-7.22 (m, 4H), 6.93 (d, J=8.1 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 6.58 (dd, J=8.1, 2.6 Hz, 1H), 5.00 (s, 1H), 4.25 (d, J=14.9 Hz, IH), 4.11-4.25 (m, 2H), 3.73-3.88 (m, 1H), 3.79 (d, J=14.9 Hz, 1H), 3.28 (dd, J=15.0, 4.1 Hz, 1H), 2.91 (dd, J=15.0, 9.3 Hz, 1H), 2.65 (dd, J=15.6, 4.9 Hz, 1H), 2.53 (dd, J=15.6, 9.5 Hz, 1H), 1.27 (t, J=7.2 Hz, 3H), FTIR (CCl4) 3611 (sharp), 3447 (broad), 1734, 1504, 1291, 1272, 1176, 1152 cm-1 ; MS (ES) m/e 314.2 (M+NH4)+, 297.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[C:10]([CH3:16])[N:11]=[C:12]([CH:14]3[CH2:15][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=2)[N:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1cc(-n2nc(C)nc2C)nc(C)n1
Reaction time: 2 h

Procedure:
A solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (2-3, 500 mg, 2.323 mmol 1.0 eq.) in toluene (35 mL) was heated under nitrogen to 120° C. To the reaction mixture was added ethyl diazoacetate (0.602 mL, 5.81 mmol, 2.5 eq.) dropwise. Upon complete addition, heating was continued for 2 hours. A mix of trans (major) and cis (minor) products were observed. Toluene was removed by roto-evaporation and the resulting residue purified by silica gel column chromatography (0-100% ethyl acetate in hexanes). The major product peak was collected and concentrated to afford ethyl 2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylate (2-4). 1H NMR (500 MHz, CDCl3) δ 7.59 (s, 1H), 4.18 (m, 2H), 2.89 (s, 3H), 2.62 (s, 3H), 2.60 (m, 1H), 2.41 (s, 3H), 2.36 (m, 1H), 1.71 (m, 1H), 1.66 (m, 1H), 1.28 (t, 3H, J=6.4 Hz). LRMS m/z (M+H) 302.3 found, 302.2 required.