Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:29][CH2:28][C:23]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2/[C:19](/[C:48]2[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=2)=[CH:20]\[CH:21]2[CH2:29][CH2:28][C:23]3([O:24][CH2:25][CH2:26][O:27]3)[CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCC3(C2)OCCO3)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(/C(=C/C2CCC3(C2)OCCO3)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 82.4 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(1,4-dioxa-spiro[4.4]non-7-yl)-vinyl ester (1 g, 1.72 mmol), 4-(methanesulfonyl)phenylboronic acid (862 mg, 4.31 mmol) and dichlorobis(triphenylphosphine)palladium (II) (121 mg, 0.17 mmol) in dioxane (10 mL) was added an aqueous sodium carbonate solution (2 M, 2.15 mL). The resulting mixture was subjected to microwave irradiation for 4 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded (Z)-1-benzenesulfonyl-2-[2-(1,4-dioxa-spiro[4.4]non-7-yl)-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (800 mg, 82%) as a white solid: LC/MS m/e calcd for C29H28N2O6S2 [M+H]+ 565.68, observed 565.5.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.BrC1C=CC(N[CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=C(C=1)C#N.[C:41](=[O:44])([O-])[O-].[Na+].[Na+]>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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:2]=[CH:3][C:41]([O:44][CH2:33][CH2:34][N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[C:17]([C:18]#[N:19])[CH:16]=2)=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: N#Cc1cc(Br)ccc1NCCN1CCOCC1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2ccc(OCCN3CCOCC3)c(C#N)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.190 g, Example 33), 5-bromo-2-(2-morpholin-4-yl-ethylamino)benzonitrile (0.31 g, Example 47a)), 2M aqueous sodium carbonate (0.75 ml) and tetrakis(triphenylphosphine)palladium (0) (0.025 g) in ethanol (2 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil which crystallised under high vacuum over 24 hours. Trituration with diethyl ether resulted in isolation of the title compound as a foam (0.19 g).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[C:4]([OH:5])[CH:3]=1.O.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:5][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:6]=1[O:7][CH3:8])[C:1]([O:12][CH3:14])=[O:11]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(OC)c(O)c1

Procedure:
A 25 g quantity of isovanillic acid was suspended in 250 ml of methanol, and 1.5 g of p-toluenesulfonic acid monohydrate was added. The mixture was heated and refluxed overnight. After completion of the reaction, methanol was distilled off under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. After washing with saturated brine twice, the organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 24.5 g of white crystalline methyl 3-hydroxy-4-methoxybenzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:35]([O:39][C:40](=[O:53])[CH2:41][CH2:42][C:43]1[CH:48]=[C:47]([Cl:49])[C:46]([CH:50]=O)=[C:45]([Cl:52])[CH:44]=1)([CH3:38])([CH3:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:50]/[C:46]2[C:45]([Cl:52])=[CH:44][C:43]([CH2:42][CH2:41][C:40]([O:39][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:53])=[CH:48][C:47]=2[Cl:49])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(C=O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/c2c(Cl)cc(CCC(=O)OC(C)(C)C)cc2Cl)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
To a solution of 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.64 g, 6.0 mmol) in DMF (15 mL) was added triphenylphosphine (1.57 g, 6.0 mmol) and the mixture was heated at 100° C. for 30 min. To this solution was added a solution of 3-(3,5-dichloro-4-formylphenyl)-propionic acid tert-butyl ester (1.50 g, 4.95 mmol) (from Example 6-25) in DMF (5 mL) in one portion, followed by pulverized potassium carbonate (1.37 g, 9.9 mmol) and the mixture was heated at 100° C. for 18 h. The reaction mixture was partitioned between ethyl acetate and water, washed with brine, dried with MgSO4, filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate/heptane to obtain 4-{(E)-2-[4-(2-tert-butoxycarbonylethyl)-2,6-dichlorophenyl]-vinyl}-3-nitrobenzoic acid methyl ester as a yellow solid. MS (m/z) 497.1 (M+18); 1H NMR (DMSO-d6, 400 MHz) δ 8.49 (d, J=1.64 Hz, 1H), 8.28 (dd. J=8.15, 1.58 Hz, 1H), 8.14 (d, J=8.21 Hz, 1H), 7.47 (s, 2H), 7.47 (d, J=16.7 Hz, 1H), 7.33 (d, J=16.4 Hz, 1H), 3.93 (s, 3H), 2.83 (t, J=7.33 Hz, 2H), 2.58 (t, J=7.33 Hz, 2H), 1.37 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])C1C=CC=CC=1C(O[Si](C)(C)C)C#N.Cl.[OH:20][CH:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1C(F)(F)F)[C:22](=[NH:26])[O:23][CH2:24][CH3:25]>>[OH:20][CH:21]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([C:2]([F:18])([F:17])[F:1])[CH:32]=1)[C:22](=[NH:26])[O:23][CH2:24][CH3:25]
Reactant: CCOC(=N)C(O)c1ccccc1C(F)(F)F
Reactant: C[Si](C)(C)OC(C#N)c1ccccc1C(F)(F)F
Agent: Cl
Product: CCOC(=N)C(O)c1cccc(C(F)(F)F)c1

Procedure:
By the procedures of Examples 2 and 11 (Method A) 2-(2-trifluoromethylphenyl)-2-trimethylsiloxyethanenitrile (15.5 g.) in 500 ml. of saturated ethanolic hydrogen chloride was converted to ethyl 1-hydroxy-1-(3-trifluoromethylphenyl)methanecarboximidate [9.6 g., 70%; m/e 247; ir (KBr) 1661, 1389, 1333, 1305, 1163, 1117 cm-1 ].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Br[C:11]1[CH:20]=[N:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:17]2[CH:18]=[N:19][CH:20]=[CH:11][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccncc1Br
Reactant: NCc1ccc(Cl)cc1
Product: COC(=O)c1ccncc1NCc1ccc(Cl)cc1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield from 4-chlorobenzylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.94 (d, 1H, J=5.0 Hz), 7.82 (br s, 1H), 7.62 (d, 1H, J=5.0 Hz), 7.24-7.32 (m, 4H), 4.47 (d, 2H, J=5.7 Hz), 3.89 (s, 3H). [M+H] calc'd for C14H13ClN2O2, 277, 279. found 277, 279.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:7][CH:8]=2)C=[CH:2]1.P(Cl)(Cl)(Cl)=O.[OH-:24].[K+].Cl.Cl[CH2:28][CH2:29]Cl>CN(C)C=O>[O:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:10][C:6]2[CH:7]=[C:8]3[C:9](=[CH:4][CH:5]=2)[NH:1][CH:2]=[C:28]3[CH:29]=[O:24])[CH2:14][CH2:15]1
Reactant: [OH-]
Reactant: ClCCCl
Reactant: c1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(OCCN3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Under an argon atmosphere, a solution of 4-[2-(1H-indol-5-yloxy)ethyl]morpholine (0.12 g, 0.5 mmol) in 1,2-dichloroethane (2.0 mL) was added dropwise with a solution of phosphorus oxychloride (0.1 mL) and N,N-dimethylformamide (0.1 mL) in 1,2-dichloroethane (1.0 mL). The mixture was stirred at room temperature for 1 hour, and then added with 3 N aqueous potassium hydroxide, and the mixture was stirred at 60° C. for 2 hours. The aqueous layer was adjusted to pH 7 with 3 N hydrochloric acid, and then extracted with ethyl acetate. The resulting organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was suspended in a mixed solvent of ethyl acetate and hexane and thereby washed to obtain 5-(2-morpholinoethoxy)-1H-indole-3-carboxaldehyde (0.068 g, 50%).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[C:19]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([CH2:30][S:31]([CH3:33])=[O:32])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])(O)=O.[Na+]>ClCCl>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:42])([CH3:43])[C:14]([N:16]([C:18]2[C:19]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][CH:27]([CH2:30][S:31]([CH3:33])(=[O:54])=[O:32])[CH2:28][CH2:29]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(CS(C)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCC(CS(C)(=O)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
To a solution of 0.22 g (0.33 mmol) (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfinylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide in 5 ml dichloromethane were added 142 mg (70%, 0.58 mmol) 3-chloroperbenzoic acid at 0° C. After completed addition, the reaction mixture was allowed to warm to room temperature and stirred over night. An aqueous solution of sodium hydrogensulfite was added and the mixture was stirred for 10 min. Basification with 1 N aqueous sodium hydroxide solution was followed by extraction with three portions of dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.13 g (55%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=O)[N:5]([CH3:13])[C:4]=2[N:3]=1.[CH3:14]I.[C:16](=[O:19])([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[N:10]([CH3:14])[C:9]2[C:8](=[O:11])[N:7]([CH3:6])[C:16](=[O:19])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: CI
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(nc(Br)n2C)n(C)c1=O
Temperature: 60 °C

Procedure:
A solution of 8-bromo-3-methyl xanthine (300 mg; 1.2 mmol) and methyl iodide (1.42 g; 10.0 mmol) in N,N-dimethylformamide (5 ml) was added to potassium carbonate (662 mg; 4.8 mmol) and was heated to 60° C. for 6 hrs. The reaction mixture was poured in water (25 ml) and extracted with ethyl acetate (3×25 ml). The combined extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product was purified by flash chromatography over silica gel eluting with ethyl acetate to yield the desired product. 315 mg; 92% PRO-04-45
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1.C(N(CC)CC)C.[CH3:15][C:16]1([CH3:23])[C:20]([CH3:22])([CH3:21])[O:19][BH:18][O:17]1>C1COCC1.CC(P[Pd]PC(C)(C)C)(C)C>[CH3:15][C:16]1([CH3:23])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:2]2[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=2)[O:17]1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1cc(Br)cs1
Agent: CC(C)(C)P[Pd]PC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)cs1

Procedure:
To 4-bromo-2-methylthiophene (1.5 g, 8.5 mmol) in THF (17 ml) was added bis[(1,1-dimethylethyl)phosphanyl]palladium (218 mg, 0.43 mmol), then N,N-diethylethanamine (2.5 g, 25.4 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.63 g, 12.7 mmol) and the resulting mixture heated at 40° C. under argon for 2 hours. The reaction was cooled and then filtered, washing with tert-butyl methyl ether. The washings were reduced in vacuo and the residue purified by chromatography on silica gel (gradient of hexane to 3% ethyl acetate:hexane) to afford the title compound (D38). MS (ES+) m/e 225 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]2[S:23][CH2:22][C:21](=[O:24])[NH:20][C:19]=2[CH:25]=1>CCO.O>[C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH:9]([OH:10])[CH2:11][NH:14][C:15]1[CH:16]=[CH:17][C:18]2[S:23][CH2:22][C:21](=[O:24])[NH:20][C:19]=2[CH:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)[Si](C)(C)OCCC1CO1
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCC(O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 28.8 %

Procedure:
A solution of (RS)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (4 g, 20 mmol; prepared according to Heterocycles (1987), 25(1), 329-32) and 6-amino-4H-benzo[1,4]thiazin-3-one (4 g, 20 mmol) in EtOH/water 9:1 (140 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a brown oil (2.2 g, 29% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[CH2:36][C:37](Cl)=[O:38]>N1C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[CH2:36][C:37]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1)=[O:38]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Cl
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: c1ccncc1
Product: O=C(c1ccc(-c2ccn(C(=O)Cc3ccc(Cl)cc3Cl)n2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 18.4 %

Procedure:
In the manner of Example 32, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.71 g) in dry pyridine (25 ml) and 2,4-dichlorophenylacetyl chloride (0.56 g), the title compound (0.20 g) was obtained as a crystalline solid, m.p. 130-140° C., resolidifies, m.p. 180-182° C.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.Br[CH2:27][CH2:28][C:29]([N:31]1[CH:36]=[CH:35][C:34](=[O:37])[CH2:33][CH:32]1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=1)=[O:30].O>C1C=CC=CC=1>[F:45][C:40]1[CH:39]=[C:38]([CH:32]2[CH2:33][C:34](=[O:37])[CH2:35][CH:36]3[N:31]2[C:29](=[O:30])[CH2:28][CH2:27]3)[CH:43]=[CH:42][C:41]=1[F:44]
Reactant: O=C1C=CN(C(=O)CCBr)C(c2ccc(F)c(F)c2)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Solvent: O
Product: O=C1CC2CCC(=O)N2C(c2ccc(F)c(F)c2)C1
Reaction time: 3 h

Procedure:
To a solution of 4-methoxypyridine (2.7 g) in tetrahydrofuran (50 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 50 mL) was added dropwise at −40° C. to −20° C. over 10 minutes. To this solution, 3-bromopropionyl chloride (2.49 mL) was added dropwise at −40° C. to −20° C., and the reaction solution was stirred at −20° C. for 30 minutes. The reaction solution was poured into a 10% hydrochloric acid solution, and the mixture was stirred for 20 minutes, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 3.4 g of 1-(3-bromopropionyl)-2-(3,4-difluorophenyl)-2,3-dihydro-1H-pyridin-4-one. A solution of tributyltin hydride (5.75 mL) and 2,2′-azobis(isobutyronitrile) (0.657 g) in benzene (50 mL) was added dropwise to a solution of 1-(3-bromopropionyl)-2-(3,4-difluorophenyl)-2,3-dihydro-1H-pyridin-4-one obtained above (3.4 g) in benzene (50 mL) at 90° C. over four hours. The reaction solution was stirred at the same temperature for three hours. The reaction solution was returned to room temperature and poured into water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 1.4 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:8][CH:9]=1
Reactant: O=C1COC(c2ccc([N+](=O)[O-])cc2)=NN1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C2=NNC(=O)CO2)cc1

Procedure:
A solution of 2-p-nitrophenyl-4H,6H-1,3,4-oxadiazin-5-one (Example 17; 2.2 g.) in ethyl acetate (250 ml.) was hydrogenated in the presence of a 5% palladium-on-charcoal catalyst at laboratory temperature and atmospheric pressure until 670 ml. of hydrogen had been absorbed. The mixture was filtered and the filtrate was evaporated to dryness. There was thus obtained as solid residue 2-p-aminophenyl-4H,6H-1,3,4-oxadiazin-5-one, m.p. 253°-255° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].C=O.[C:16]([O-])(O)=[O:17].[Na+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[CH2:16][OH:17]
Reactant: O=C([O-])O
Reactant: COC(=O)Cc1ccc(Cl)cc1Cl
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2,4-dichlorophenylacetic acid methyl ester (1.38 mmol) and paraformaldehyde (1.45 mmol) in 2.7 mL DMSO was added NaHCO3 (0.07 mmol). The reaction mixture was stirred at RT for 2 h and then quenched with water. The mixture was neutralized with 1M HCl solution and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (1/1) gives the desired compound as colorless oil;
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=2)=[C:4]([F:19])[CH:3]=1.[N:20]#[C:21][NH2:22].OS(C(F)(F)F)(=O)=O>C1COCC1>[C:21](=[NH:20])([O:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[C:16]([F:18])=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=2[F:19])=[CH:8][CH:9]=1)[NH2:22]
Reactant: OCCc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Reactant: N#CN
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a solution of 2-(4-(4-chloro-2,6-difluorophenoxy)phenyl)ethanol (1.6 g, 5.62 mmol) and cyanamide (0.600 g, 14.27 mmol) in dry THF (10 mL) under nitrogen was added triflic acid (1.3 mL, 14.64 mmol) at 0° C. The mixture was stirred at room temperature for 2 h. Purification via reverse phase flash chromatography afforded the title compound (1.74 g, 3.65 mmol, 64.9% yield). LCMS: rt=2.66 min, [M+H+]=327
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][C:25]1[C:29](B2OC(C)(C)C(C)(C)O2)=[C:28]([CH3:39])[NH:27][N:26]=1>>[CH3:24][C:25]1[C:29]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=4)=[N:10][C:5]3=[CH:4][CH:3]=2)=[C:28]([CH3:39])[NH:27][N:26]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: Cc1n[nH]c(C)c1-c1ccc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)sc2n1
Yield: 25 %

Procedure:
The titled compound (yield=25%, white solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1D (Example 1) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 2.40 (s, 6H) 7.54 (d, J=8.34 Hz, 1H) 7.66 (d, J=8.34 Hz, 2H) 8.04-8.19 (m, 3H) 12.89 (br. s., 1H); ESI-MS: m/z 408.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@@H:43]1[CH2:48][OH:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:31])([F:32])[F:30])=[CH:28][C:3]=3[C:2]([F:1])([F:34])[F:33])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH2:44][C@@H:43]1[CH2:48][OH:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.