Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][CH:7]=[CH:6]1)(=[O:3])[CH3:2].[OH2:20].[Br-].[Li+].O>C(#N)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][CH:7]([OH:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1OC(O)C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of 3,4,6-tri-O-acetyl-D-glucal (25.0 g) and lithium bromide hydrate (25.0 g) in acetonitrile (750 ml), activated resin prepared as in Example 1 (25.0 g) and water (30 ml) were added and stirred at room temperature for 4 h. The product was isolated as described for Example 1. Crystallization from ethyl acetate-hexane gave the title compound as colorless crystals (17.8 g). [α]D20 =+71.2°±2° (c 1.06, CHCl3). 1H NMR δ: 5.40 (broad s, H-1α), 5.35 (m, H-3α), 4.9-5.05 (H-4α,β, H-3β, H-1β), 4.18-4.28 (H-6a, H-5α), 4.10 (H-6bβ), 4.06 (H-6bα). 3.65 (m, H-5β), 2.38 (m, H-2eqb), 2.25 (H-2eqα), 1 79 (H-2axα), 1.67 (H-2axβ). MS m/e 273.11 (M-H2O), 213.10, 153.07.
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH3:7][S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH:28][OH:29])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].Cl>O1CCCC1>[CH3:7][S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][N:28]3[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:29]3)=[CH:25][CH:26]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(CNO)cc2)cc1
Reactant: O=C=NC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(Cn3oc(=O)[nH]c3=O)cc2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
0.45 g (4 mmole) N-(chlorocarbonyl)isocyanate was added dropwise to a solution of 1.2 g (3.6 ml) 4-(2-{4-[hydroxyaminomethyl]phenoxy}ethyl)phenyl methanesulfonate in 20 ml anhydrous tetrahydrofuran at −5° C. and the mixture was stirred at −5° C. for 30 minutes. The reaction mixture was poured on to 2 M hydrochloric acid and extracted with ethyl acetate, dried (sodium sulfate), filtered and evaporated in vacuo. The residue was redissolved in ethyl acetate, and material that did not go into solution was filtered off. The filtrate was evaporated in vacuo, diethyl ether was added to give a white precipitate which was filtered off and recrystallized in diethyl ether/acetone to give 0.223 g of the desired product. The mother liquid was evaporated in vacuo and purified by chromatography on silica gel using dichloromethane:methanol (95:5) as eluent and crystallized in diethyl ether to give 0.09 g more of the desired product (total yield 0.384 g, 26.2%).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:6]([F:22])[C:5]=1Cl)(=[O:3])[CH3:2].[N-:24]=[N+]=[N-].[Na+]>CC(C)=O.O>[F:22][C:6]1[C:5]2[C:4](=[C:1]([CH3:2])[O:3][N:24]=2)[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]
Reactant: COC(=O)c1nc(C(C)=O)c(Cl)c(F)c1Nc1ccccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1nc2c(C)onc2c(F)c1Nc1ccccc1F
Temperature: 65 °C

Procedure:
To a solution of methyl 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)picolinate (WO 2005/051906) (2 g, 5 mmole) in a mixture of acetone (36 ml) and H2O (12 ml) is added NaN3 (487 mg, 7.5 mmol). The reaction is heated at 65° C. for 16 h and cooled to room temperature. Acetone is concentrated and the resulting mixture is extracted with EtOAc (2×50 ml). The combined organic solution is washed with brine (50 ml), dried over MgSO4 and concentrated to give a yellow solid. To the solid is added H2O (24 ml) and the reaction is heated at reflux for 3 h. The reaction is cooled to room temperature, filtered, and washed with H2O. The resulting solid is dried under high vacuum with P2O5 at 65° C. for 24 h to give the title compound.
Reaction SMILES: C(O)C.[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=5)[C:27]([C:36]([O:38]C)=[O:37])=[CH:26][C:25]4=[O:40])[CH2:18][CH2:17]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.[OH-].[Na+]>O>[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][N:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=5)[C:27]([C:36]([OH:38])=[O:37])=[CH:26][C:25]4=[O:40])[CH2:20][CH2:21]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(C(=O)O)cc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To 1 mL of an ethanol solution containing 0.12 g of methyl 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate, 0.5 mL of 5 mol/L aqueous sodium hydroxide solution was added and stirred for 1 hour. 2 mL of water was added, removed ethanol under reduced pressure, adjusted to pH 6.0 with 6 mol/L hydrochloric acid, and the resulting solid was filtered to afford 40 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:6]([OH:7])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].O([CH2:28][C:29]([F:32])([F:31])[F:30])S(C(F)(F)F)(=O)=O>CN(C=O)C.C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:11]=[CH:12][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][C:6]=1[O:7][CH2:28][C:29]([F:32])([F:31])[F:30]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
To a mixture of isovanillic acid methyl ester (3.0 g, 0.18 mol) and potassium carbonate (41.4 g, 0.30 mol) in DMF (100 ml) was added a solution of trifluoroethyl triflate [Burdon et al Tetrahedron 21, 1 (1965)] (65.0 g, 0.28 mol) in CH2Cl2. The mixture was stirred at room temperature for 18 h then evaporated to 50 ml, the mixture partitioned between ether and H2O, the organic layer washed with H2O and saturated brine, then dried over MgSO4 and evaporated. The resulting solid was triturated with hexane to give the subtitle compound as an off-white solid (42.55 g, 90%). Rf 0.47 (CH2Cl2). MS m/z 265 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:29](OS(OCC)(=O)=O)[CH3:30].[NH4+].[OH-]>O.CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)=[N:11][C:10]([C:23]([F:24])([F:25])[F:26])=[N:9]2)=[CH:6][CH:7]=1)[CH3:30]
Reactant: CCOS(=O)(=O)OCC
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A mixture of 1-(4-hydroxy-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole (4 g, 10.4 mmol), KOH (1.5 g, 26.8 mmol) and DMF (40 ml) was stirred at room temperature for 1 h. Then diethylsulfate (1.6 ml, 12.2 mmol) was added, the reaction mixture stirred at room temperature for 13 h, NH4OH (20 ml) added and the mixture poured into water (1 l). The precipitate was filtered, washed several times with water and dried. Recrystallization from ethanol yielded a white solid (3.7 g, 88%).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].Cl[CH2:14][C:15](Cl)=[O:16]>C(Cl)(Cl)Cl>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]2[C:15](=[O:16])[C:14](=[C:14]3[C:15](=[O:16])[C:7]4[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[CH2:11][CH3:12])=[CH:5][C:6]=4[O:10]3)[O:10][C:6]=2[CH:5]=1)[CH3:12]
Reactant: O=C(Cl)CCl
Reactant: CCN(CC)c1cccc(O)c1
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1ccc2c(c1)OC(=C1Oc3cc(N(CC)CC)ccc3C1=O)C2=O
Temperature: 65 °C
Yield: 32.8 %

Procedure:
1 g (6 mmol) of 3-diethylamino-phenol is dissolved is 20 ml of chloroform with exclusion of moisture. 1 g (9 mmol) of chloroacetyl chloride is added dropwise in the course of 30 minutes. Silica gel (about 10 g in total) is then introduced until the entire reaction solution has been absorbed, and the mixture is heated at 60-70° C. for 6 days. Finally, the silica gel is filtered off with suction through a G4 frit and washed with chloroform until the wash solution remains colourless. The dark red organic phases are combined and the solvent is stripped off on a rotary evaporator. 0.4 g of a dark red solid is obtained and is subsequently separated into the isomers by column chromatography over silica gel using chloroform as the solvent. The cis-isomer is obtained in the first runnings as a blue fraction, and the trans-isomer is obtained as a red-violet fraction. After the solvents have been stripped off, the resulting colorant isomers are dried at 95° C. under an oil pump vacuum for 7 hours.
Reaction SMILES: Cl.[CH:2]1([NH:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>>[CH:2]1([N:8]([OH:9])[C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[O:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ONC1CCCCC1
Reactant: CSc1ccc(N=C=O)cc1
Agent: Cl
Product: CSc1ccc(NC(=O)N(O)C2CCCCC2)cc1
Yield: 21.4 %

Procedure:
Using the general method of Compound 1, N-cyclohexylhydroxylamine hydrochloride (1.5 g, 10 mmol) was reacted with 4-(methylthio)phenyl isocyanate (1.6 g, 10 mmol) to provide 0.60 g of the desired product as a white solid m.p. 151°-153° C. Analysis: Calculated for C14H20N2O2S: %C, 59.97; %H, 7.19; %N, 9.99; Found: %C, 60.06; %H, 7.14; %N, 9.95.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Reaction time: 72 h
Yield: 98.3 %

Procedure:
(60 g (0.3 mol) of 4-hydroxybenzophenone, 42 g of benzyl chloride, 45.6 g of potassium carbonate, 0.5 g of potassium iodide and 1 litre of dimethylformamide are introduced into a flask. Stirring is carried out at room temperature for 72 hours. The mixture is filtered and concentrated to dryness without exceeding 30° C. The residue is taken up in methylene chloride and washed with a 10% sodium carbonate solution and then with a saturated lithium chloride solution. The mixture is dried over sodium sulphate and concentrated to dryness. There are obtained 85 g of 4-benzyloxybenzophenone. Yield: 99%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14]O)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:36]>C(Cl)Cl>[Br:36][CH2:14][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CBr)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 236.7 %

Procedure:
To a solution of [3-nitro-5-(trifluoromethyl)phenyl]methanol (13.15 g, 59.5 mmol) in DCM (200 mL) at 0° C. was added PPh3 (18.7 g, 71.4 inmol) and CBr4 (21.7 g, 65.4 mmol). The reaction mixture was allowed to stir and warm to rt overnight. The reaction mixture was poured directly onto a pad of silica and the eluant was concentrated to give 1-(bromomethyl)-3-nitro-5-(trifluoromethyl)benzene as a yellow oil (40 g, 689%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[O:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1nc2ccccc2o1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc2oc(COc3ccc(CCCn4ccnc4)cc3)nc2c1
Yield: 28 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-chloromethylbenzoxazole to give 2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]benzoxazole. The yield was 28%. Recrystallization from ethyl acetate-hexane gave pale brown prisms, mp 81-82° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][NH2:30]>C(Cl)Cl>[NH:29]([C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:16])[NH2:30]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (120 g, 520 mmol) in DCM (250 mL) was added carbonyldiimidazole (96 g, 590 mmol) in portions at room temperature. After 30 minutes, the reaction mixture was added to a freshly prepared solution of hydrazine (27 g, 840 mmol) in DCM (100 mL). After 30 minutes, the reaction was washed with a saturated solution of sodium carbonate, brine, dried over sodium sulfate, filtered and concentrated. The resulting solid was suspended in ether and filtered to give tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 4.15-4.10 (s, 2H), 3.95-3.90 (m, 2H), 2.80-2.60 (m, 2H), 2.25-2.20 (m, 1H), 1.62-1.55 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.OS(O)(=O)=O.[CH3:21][CH2:22]O>>[CH2:21]([O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:12]([F:13])([F:14])[F:15])[CH3:22]
Reactant: CCO
Reactant: O=C(O)Cc1cc(Cl)ccc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(Cl)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (5-Chloro-2-trifluoromethyl-phenyl)-acetic acid (10.0 g, 47.2 mmol) in absolute EtOH (300 mL) at room temperature was added concentrated H2SO4 (4 mL) and the mixture was warmed to reflux. After 4 hrs, the reaction was cooled to room temperature, evaporated under reduced pressure, diluted with DCM (500 mL) and stirred over solid K2CO3. After 1 hr, the resulting mixture was filtered and concentrated to dryness to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]=1[NH:51][S:52]([CH3:55])(=[O:54])=[O:53].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[CH:41][C:36]([F:35])=[C:37]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:38]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2ccc(F)c(NS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 26.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Step 1 example 71) (172 mg, 0.317 mmol) was coupled with N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methanesulfonamide (Intermediate 65) (100 mg, 0.317 mmol) using sodium carbonate (101 mg, 0.952 mmol) and Pd(PPh3)2Cl2 (12 mg, 0.015 mmol) in DME/water (15/2 ml). This afforded 54 mg (26.2% yield). MS: m/z=652.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9](=[O:11])[NH2:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17]([N:19]=[C:20]=[S:21])=[O:18]>CC(C)=O>[C:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20]([NH:19][C:17]([O:16][CH3:15])=[O:18])=[S:21])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:11])[NH2:10]
Reactant: COC(=O)N=C=S
Reactant: NC(=O)Sc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1[N+](=O)[O-]

Procedure:
1 G. of 1-amino-4-carbamoylthio-2-nitrobenzene in 20 ml. acetone is treated with 3.0 g. methoxy carbonyl isothiocyanate at room temperature for several days. The solution is concentrated and the residue triturated with methanol to afford 4-carbamoylthio-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12]C1C=C2C(C(=O)CCN2)=CC=1>>[Cl:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2ccccc12
Reactant: O=C1CCNc2cc(Cl)ccc21
Product: Clc1ccnc2ccccc12

Procedure:
a yield of 4-hydroxyquinoline of 15% relative to the 7-chloro-1,2,3,4-tetrahydroquinolin-4-one converted.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:24]=4[C:25]([O:27]C)=[O:26])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>CC(O)(C)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:24]=4[C:25]([OH:27])=[O:26])[CH2:16]3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](OCc2coc(-c3ccc(F)cc3)n2)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Cc1cccc(CO[C@H]2CCC[C@@H](OCc3coc(-c4ccc(F)cc4)n3)C2)c1C(=O)O
Reaction time: 24 h

Procedure:
4.2 g (9.2 mmol) of 5b were dissolved in 120 ml of t-BuOH. 50 ml of 50% aq. KOH were added, and the mixture was then boiled at 100° C. for 24 hours. For work-up, the mixture was allowed to cool and then diluted with 100 ml of ethyl acetate. The aqueous phase was made slightly acidic by addition of 2 N aqueous HCl and extracted 2 more times with 100 ml of ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated, and the residue was purified by flash chromatography (methylene chloride/methanol/conc. ammonia, 30/5/1). This gave 6b as a white amorphous solid. TLC (methylene chloride/methanol/conc. ammonia, 30/5/1). Rf=0.3. Recrystallization from toluene. C25H26FNO5 (432.42) MS(ESI): 433 (M+H+).
Reaction SMILES: Cl[C:2]([C:4]1([C:12](Cl)=[O:13])[CH2:6][CH:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:3].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:17]=1>ClCCl.C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:2](=[O:3])[C:4]3([CH2:6][CH:5]3[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12](=[O:13])[NH:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]2=3)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1CC1(C(=O)Cl)C(=O)Cl
Reactant: Nc1ccccc1Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC12C(=O)Nc1ccccc1N(c1ccc(Cl)cc1)C2=O
Temperature: 100 °C
Yield: 15.5 %

Procedure:
Ethyl 2,2-bis(chlorocarbonyl)cyclopropanecarboxylate (2 g, crude product from last step) in dichloromethane (10 mL) was added dropwise to a solution of N1-(4-chlorophenyl)benzene-1,2-diamine (2.2 g, 10 mmol) in toluene (50 mL) and the resulting mixture was heated to 100° C. for 48 h. The solvent was evaporated and the residue was purified by CombiFlash (PE:EA=5:1) to obtained ethyl 1-(4-chlorophenyl)-2,4-dioxo-1,2,4,5-tetrahydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2′-carboxylate (500 mg, 13%). LRMS (M+H)+: 384 m/z. 1H NMR (300 MHz, CDCl3): δ 1.07-1.12 (t, J=7.2 Hz, 3H), 1.72-1.81 (m, 1H), 2.16-2.18 (m, 1H), 2.41-2.43 (br, 1H), 3.92-4.00 (m, 2H), 7.20-7.25 (m, 1H), 7.42-7.49 (m, 4H), 7.52-7.65 (m, 3H), 8.06-8.08 (m, 1H).
Reaction SMILES: [CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][OH:7].[CH2:9]=[C:10]([CH3:12])[CH3:11].S(=O)(=O)(O)O.[OH-].[Na+]>ClCCl>[CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][O:7][C:10]([CH3:12])([CH3:11])[CH3:9]
Reactant: C=C(C)C
Reactant: CSC(=S)NCCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CSC(=S)NCCOC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In a sealed glass tube is placed a solution of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester (4.3 g), isobutene (30 ml) and concentrated sulfuric acid (0.1 ml) in dichloromethane (20 ml) prepared at -50° C. to -60° C. The mixture is warmed slowly to room temperature and then left to stand for 17 hours. The reaction mixture is poured into aqueous 0.5% sodium hydroxide and extracted with dichloromethane. The extract is washed with water, dried and concentrated to give N-(2-t-butoxyethyl)dithiocarbamic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:25]4[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1cc(F)cc(F)c1
Product: COc1ccc(-c2nc3cc(-c4cc(F)cc(F)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3,5-difluorophenylboronic acid (136 mg, 0.86 mmol) the subtitle compound was obtained, (120 mg, 64%). 1H NMR (DMSO) δ 8.70(d, 1H), 8.52(dd, 1H), 8.26(d, 1H), 7.96(d, 1H), 7.88(dd, 1H), 7.69(d, 1H), 7.61(dd, 2H), 7.33(tt, 1H), 4.12(s, 3H). MS 383 m/z (M+H)+.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][CH2:21][CH2:22][OH:23])[CH3:19]>>[CH2:18]([O:20][CH2:21][CH2:22][O:23][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)[CH3:19]
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CCOCCO
Product: CCOCCOC(=O)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
(2-Ethoxyethyl)-p-benzoylbenzoate was prepared from para-benzoyl benzoic acid chloride and 2-ethoxyethanol. The structure of the product was confirmed by the presence of carbonyl bands in the infrared spectrum at 1670 and 1730 cm-1. When added at 4% by weight loading to the solution described in Example 1, a cure rate of 15 ft./min./lamp was obtained. A sample in the same test solution was stable after three months storage following the procedure described in Example 5.