Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16]C(=O)OC)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.CO>O>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][C:7]2[CH:21]=[CH:22][C:4]([Cl:3])=[CH:5][CH:6]=2)=[CH:15][N:14]=1
Reactant: COC(=O)Nc1ccc(OCc2ccc(Cl)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(OCc2ccc(Cl)cc2)cn1
Reaction time: 8 h

Procedure:
10% Sodium hydroxide (8 ml) is added to methyl N-[5-(4-chlorobenzyloxy)-2-pyridyl]carbamate (59 mg, 0.20 mmol), and the mixture is heated rapidly to 85°. About 4 ml of methanol is added to the mixture after it has been heated for 2 hours. Heating is continued, and after another hour about 4 ml more of methanol is added to the mixture. Heating at 85° is continued overnight. The reaction is then cooled, and the methanol is rotoevaporated off. The reaction is poured into water and extracted with chloroform. The organic phase is washed with water and with brine to yield 2-amino-5-(4-chlorobenzyloxy)pyridine.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][NH2:14])=[O:12].C(N(CC)CC)C.C1C=CC(O[C:29](OC2C=CC=CC=2)=[N:30][C:31]#[N:32])=CC=1>C(O)(C)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[O:12][CH:29]([NH:30][C:31]#[N:32])[NH:14][N:13]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: NNC(=O)c1ccc2ccccc2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#CNC1NN=C(c2ccc3ccccc3c2)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
To a stirred solution of naphthalene-2-carboxylic acid hydrazide (0.7 g, 3.76 mmol) in isopropanol (40 ml) was added triethylamine (630 μl, 4.51 mmol) and diphenyl cyanocarbonimidate (0.99 g, 4.14 mmol) and the resulting reaction mixture was stirred at room temperature for 1.5 h. The volatiles were evaporated in vacuo and to the residue was added water (50 ml) and diethyl ether (50 ml). The organic phase was separated and the aqueous phase was acidified to pH=1 with concentrated hydrochloric acid. The precipitate was filtered off and washed with water (3×10 ml) and diethyl ether (2×10 ml) and dried in vacuo at 50° C. which afforded 0.45 g (51%) of the title compound as a solid.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[C:15]([CH3:23])[C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[C:15]([CH3:23])[C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[Cl:20])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Cc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1c(F)c(C)c2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (200 mg) and a 40% aqueous solution (160 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (50 mg), and the mixture was stirred overnight at room temperature. The solvent and the like were distilled off under reduced pressure, and ethanol (0.5 ml) was added to the residue. Solids deposited were collected by filtration and washed with ethanol and diethyl ether to obtain the title compound (8 mg) as a colorless powder.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1.IC>C1COCC1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of LDA (8.66 mL, 2M in heptane/THF/ethylbenzene, 17.3 mmol) in 30 mL THF at −78° C., was added a solution of ethyl 4-bromophenylacetate (4.00 g, 16.5 mmol) in 20 mL THF. The mixture was stirred at −78° C. for 30 min, then a solution of iodomethane (10.7 mL, 2M in methyl tert-butyl ether, 21.5 mmol) was added. The mixture was stirred for 10 min at −78° C., then was removed from the cooling bath and stirred for 30 min. The reaction was quenched with sat. NH4Cl, then diluted with EtOAc. The organic phase washed with water, sat. Na2SO3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 3.07 g of 73A as a colorless oil. MS (ESI) m/z 257.1, 259.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[C:30]([O:34][C:35](=[O:44])[C:36]1[CH:41]=[C:40]([OH:42])[CH:39]=[C:38]([Br:43])[CH:37]=1)([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CC(C)=O.O.Cl>[C:30]([O:34][C:35](=[O:44])[C:36]1[CH:41]=[C:40]([O:42][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:29])[C:10]=2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:39]=[C:38]([Br:43])[CH:37]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CC(C)(C)OC(=O)c1cc(O)cc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)OC(C)(C)C)c2)c1CCC(=O)OCC
Temperature: 70 °C
Yield: 98.8 %

Procedure:
To a solution of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (9.48 g, 20.1 mmol), 3-bromo-5-hydroxy-benzoic acid tert-butyl ester (5.0 g, 18.3 mmol) in N,N-dimethylformamide (100 mL) and acetone (200 mL) was added potassium carbonate (25.3 g, 183 mmol) at room temperature. The resulting suspension was heated to 70° C. for 24 h. Then, the reaction mixture was cooled to room temperature and diluted with water and 10% aq. HCl. The organic compound was extracted into ethyl acetate and the combined organic extracts were washed with water and brine solution. The organic layers were dried over anhydrous sodium sulfate and removal of the solvent under reduced pressure gave the crude product which was purified on a silica gel column eluting with 0-20% ethyl acetate in hexanes to afford the title compound (12 g, 99%) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:14][NH:13][C:12](=[O:15])[CH2:11]2)[C:5]2[N:16]([CH:19]3[CH2:21][CH2:20]3)[CH:17]=[N:18][C:4]=2[CH:3]=1.[O:22]1[CH2:25][CH:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[CH:19]1([N:16]2[C:5]3[C:6]([O:8][CH2:9][C@H:10]4[CH2:14][NH:13][C:12](=[O:15])[CH2:11]4)=[N:7][C:2]([C:35]4[CH:36]=[CH:37][C:32]([N:29]5[CH2:30][CH2:31][N:26]([CH:24]6[CH2:25][O:22][CH2:23]6)[CH2:27][CH2:28]5)=[CH:33][CH:34]=4)=[CH:3][C:4]=3[N:18]=[CH:17]2)[CH2:21][CH2:20]1
Reactant: CC1(C)OB(c2ccc(N3CCN(C4COC4)CC3)cc2)OC1(C)C
Reactant: O=C1C[C@@H](COc2nc(Br)cc3ncn(C4CC4)c23)CN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1C[C@@H](COc2nc(-c3ccc(N4CCN(C5COC5)CC4)cc3)cc3ncn(C4CC4)c23)CN1

Procedure:
(R)-4-(((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)methyl)pyrrolidin-2-one (50 mg, 0.14 mmol), 1-(oxetan-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (63.28 mg, 0.18 mmol), Cesium Carbonate (137.18 mg, 0.42 mmol), & PEPPSI″-IPr catalyst (20 mg, 0.03 mmol) were taken up in dioxane (4 ml) and water (1 mL) and heated in a sealed tube at 100° C. for 45 minutes. Reaction was then chromatographed in silica gel 0-30% DCM/MeOH providing 94 mg of (R)-4-(((3-cyclopropyl-6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)methyl)pyrrolidin-2-one. (68 mg, 84%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.01-7.91 (m, 2H), 7.71-7.57 (m, 2H), 7.05-6.95 (m, 2H), 5.82-5.64 (m, 2H), 4.63-4.34 (m, 6H), 3.69 (td, J=7.0, 3.5 Hz, 1H), 3.55-3.34 (m, 2H), 3.37-3.12 (m, 9H), 2.98 (p, J=7.9 Hz, 1H), 2.50-2.32 (m, 6H), 2.20 (dd, J=16.7, 7.0 Hz, 1H), 1.27-0.97 (m, 6H). ESI MS m/z 489 [M+H]+; HPLC, 1.24 min, 97.5% (AUC).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC[C:28]1[N:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:28]3[N:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Clc1ccc(CBr)nn1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)nn3)c2CC1

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 3-bromomethyl-6-chloropyridazine to give 3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. Use a method similar to the General Procedure 1-4 to give the title compound as an off-white powder. MS (APCI+) m/z: 340 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[NH:15][C:14]2([CH3:22])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+].N[C@H]1CCCC[C@@H]1N>O1CCOCC1.[Cu]I.O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][OH:9])[CH:3]=1)[C:14]2([CH3:22])[CH3:21]
Reactant: OCc1cncc(Br)c1
Reactant: CC1(C)NC(=O)c2ccc(Cl)cc21
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(CO)c1
Temperature: 150 °C
Yield: 90.1 %

Procedure:
In a 25-mL sealed tube, (5-bromo-pyridin-3-yl)-methanol (900 mg, 4.8 mmol), 5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediate A-12 [C], 858 mg, 4.4 mmol), CuI (200 mg, 1.1 mmol), Cs2CO3 (3.0 g, 9.2 mmol) and (+)-(S,S)-1,2-diaminocyclohexane (0.4 mL, 3.2 mmol) were dissolved in dioxane (8.0 mL). The resulting reaction mixture was heated at 150° C. for 3 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×125 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to yield the title compound (1.2 g, 90%) as a light yellow solid. MS: 303.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:32]1([C:35]2[CH:39]=[CH:38][N:37]([CH2:40][C:41](O)=[O:42])[N:36]=2)[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][N:37]3[CH:38]=[CH:39][C:35]([CH:32]4[CH2:33][CH2:34]4)=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)Cn1ccc(C2CC2)n1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cn3ccc(C4CC4)n3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79 μmol), (3-cyclopropyl-pyrazol-1-yl)-acetic acid (17.74 mg, 106 μmol) and DIPEA (48.97 μL, 277 μmol) in THF (3 mL), T3P (166 μL, 277 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (91%, 42 mg) that was taken directly on to the next step.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][OH:9])[N:6]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][CH2:8][CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[S:3][CH:4]=1
Reactant: BrCCCCCCBr
Reactant: Cc1nc(CCO)cs1
Solvent: O
Product: Cc1nc(CCOCCCCCCBr)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-methyl-4-thiazoleethanol (2.22 g), 1,6-dibromohexane (7.1 ml) 12.5M aqueous sodium hydroxide (4 ml) and TAB (0.1 g) was stirred rapidly at room temperature for 16 h. The reaction mixture was diluted with water (30 ml), extracted with ether (3×30 ml) and the combined organic extracts were washed with water (30 ml) and brine (30 ml), dried and concentrated. The residual oil was purified by FCC eluting with diethyl eter-hexane (1:3) to give the title compound as an orange oil (2.21 g), t.l.c. (ether-hexane 1:3) Rf 0.17
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=[O:8])=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(O)c(C(=O)CBr)c1
Temperature: 80 °C

Procedure:
The compound obtained in Step A (32.2 mmol) is dissolved in glacial acetic acid (40 ml) and then 48.3 mmol of bromine are added. The mixture is heated at 80° C. for 2 hours and is then hydrolysed using ice-cold water. The precipitate obtained is filtered off, washed with water until a pH of 5-6 is obtained, and then dried and recrystallised.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:45]([O:47][C:48](=[O:51])[CH2:49][NH2:50])[CH3:46]>CN(C=O)C.O>[CH2:45]([O:47][C:48](=[O:51])[CH2:49][NH:50][C:19](=[O:21])[CH2:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=1)[CH3:46]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CNC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 130 %

Procedure:
DIPEA (390 mg, 0.52 mL, 3.02 mmol) was added to a stirred solution of 3-[4-hydroxy phenyl]propionic acid (100 mg, 0.60 mmol) in DMF (10 mL). HOBT (90 mg, 0.67 mmol) and EDCI.HCl (290 mg, 1.51 mmol) were added at room temperature. After 2 minutes glycine ethyl ester hydrochloride (100 mg, 0.72 mmol) was added. The resulting mixture was stirred at room temperature for 48 hours. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 196 mg of [3-(4-hydroxy-phenyl) propionylamino]-acetic acid ethyl ester. 1H NMR (CDCL3): δ 7 (d, 2H), 6.65 (d, 2H), 6.0 (bs, 1H), 4.15 (q, 2H), 4.0 (d, 2H), 3.5 (s, 2H), 2.8 (t, 2H), 2.45 (t, 2H), 1.2 (t, 3H), LC-MS purity: 68.23%.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:17]1[CH:22]=[C:21]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:15])=[O:5])[CH:20]=[CH:19][CH:18]=1
Reactant: CON(C)C(=O)c1cc2ccccc2[nH]1
Reactant: OB(O)c1cccc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
Activated molecular sieves (6.0 g) 4 Å were placed in an oven dried flask and cooled to room temperature under nitrogen. To the flask was charged with N-methoxy-N-methyl-1H-indole-2-carboxamide (0.45 g, 2.2 mmol), (3-fluorophenyl)boronic acid (0.94 g, 6.7 mmol), cupric acetate (0.60 g, 3.3 mmol), and methylene chloride (80 mL) and then pyridine (0.72 mL, 8.9 mmol). The reaction mixture was stirred at room temperature over weekend, then filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-25% EtOAc in hexane) to give the title compound (0.30 g, 46%). LCMS calculated for C17H16FN2O2(M+H)+: m/z=299.1. Found: 299.0.
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]([CH:19]=1)[C:9]([O:11]CC1C=CC=CC=1)=[O:10].Cl>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]([CH:19]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Solid LiOH (0.53 g, 12.59 mmol) was added to a stirred solution of phenylmethyl 5-bromo-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 4; 1 g, 2.52 mmol) in tetrahydrofuran (20 ml) and water (4.00 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. After cooling to room temperature, the solvent was removed to obtain a white solid, which was dissolved in water (100 ml) and stirred in ice-water bath. 1N HCl (aq) was added to adjust the pH to 4. The white solid was filtered and dried in vacuum to yield the title compound as a white solid. 0.78 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: COCCN
Product: COCCNS(=O)(=O)c1cccc(Br)c1
Yield: 96.9 %

Procedure:
Prepared by general procedure III from 3-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and 2-methoxyethyl amine (1.62 g, 22 mmol) to give the title compound (5.7 g, 99%) as light-yellow liquid. MS (ISP) 294.0 [(M+H)+].
Reaction SMILES: [C:1]([N:4]([CH2:14]C)[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:16](Cl)(=O)CC>C1C=CC=CC=1>[C:1]([N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH2:2][CH3:16]
Reactant: CCC(=O)Cl
Reactant: CCN(C(C)=O)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: CCC(=O)N(C)c1ccc([N+](=O)[O-])cc1

Procedure:
The reaction is carried out using an analogous method to (9a), using N-methyl-4 nitroanilinc (5 g, 32.86 mmol) in benzene (30 ml), treated with propionyl chloride (15 ml). ES+ (M+1) 208.88.
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:46]=[C:45]([OH:47])[C:38]3[CH2:39][CH:40]([CH2:42][O:43][CH3:44])[O:41][C:37]=3[CH:36]=2)=[O:34])=[N:28]1.[F:48][C:49]1[CH:59]=[C:58](F)[CH:57]=[CH:56][C:50]=1[C:51]([N:53]([CH3:55])[CH3:54])=[O:52]>O>[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:46]=[C:45]([O:47][C:58]3[CH:57]=[CH:56][C:50]([C:51](=[O:52])[N:53]([CH3:55])[CH3:54])=[C:49]([F:48])[CH:59]=3)[C:38]3[CH2:39][CH:40]([CH2:42][O:43][CH3:44])[O:41][C:37]=3[CH:36]=2)=[O:34])=[N:28]1
Reactant: CN(C)C(=O)c1ccc(F)cc1F
Reactant: COCC1Cc2c(O)cc(C(=O)Nc3ccn(C)n3)cc2O1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Solvent: O
Product: COCC1Cc2c(Oc3ccc(C(=O)N(C)C)c(F)c3)cc(C(=O)Nc3ccn(C)n3)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-methoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (204d) and 2,4-difluoro-N,N-dimethyl-benzamide. 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.40 (t, J=8.21 Hz, 1 H) 7.26 (s, 1 H) 7.21 (s, 1 H) 7.00 (dd, J=11.12, 1.52 Hz, 1 H) 6.91 (dd, J=8.46, 1.89 Hz, 1 H) 6.54 (d, J=1.52 Hz, 1 H) 5.01-5.09 (m, 1 H) 3.76 (s, 3 H) 3.50-3.59 (m, 2 H) 3.29 (s, 3 H) 3.10-3.21 (m, 1 H) 2.99 (s, 3 H) 2.85-2.89 (m, 4 H); LCMS for C24H25FN4O5 m/z 469.20 (M+H)+; Anal. Calcd. for C24H25FN4O5.0.63 H2O: C, 60.08; H, 5.52; N, 11.68. Found: C, 60.08; H, 5.19; N, 11.53.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:5]([CH3:7])[CH3:6].[OH-].[Na+].CO>O>[C:8]1([CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:14])=[O:2])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(c1ccccc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C(C(=O)O)c1ccccc1
Yield: 94.4 %

Procedure:
A solution of 165.8 g (0.87 mol) of 2-phenyl-3-methylbutyric acid methyl ester, 52.0 q (1.30 mol) of sodium hydroxide, 1200 ml of methanol and 600 ml of water was heated to reflux for one hour. After evaporation of the methanol under reduced pressure, dilution with water and acidification with conc. hydrochloric acid, the aqueous solution was extracted with ether. The ethereal extracts were washed with water, dried over sodium sulfate and evaporated under reduced pressure, to obtain 146.3 g (95%) of 2-phenyl-3-methylbutyric acid in the form of a yellow oil which was used directly in the next step.
Reaction SMILES: [C:1]1(=O)O[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.ClC(C)CCC(Cl)=O.[Cl:20][C:21]1[CH:30]=[C:25]([C:26]([NH:28][OH:29])=[O:27])[C:24]([OH:31])=[CH:23][CH:22]=1>[Cl-].[Zn+2].[Cl-]>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:31][CH:1]3[CH2:2][CH2:3][CH:4]([CH3:5])[O:29][N:28]3[C:26](=[O:27])[C:25]=2[CH:30]=1
Reactant: O=C(NO)c1cc(Cl)ccc1O
Reactant: O=C1CCCCO1
Agent: CC(Cl)CCC(=O)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=S(Cl)Cl
Product: CC1CCC2Oc3ccc(Cl)cc3C(=O)N2O1

Procedure:
A mixture of 30 g. of γ -valerolactone, 30 ml. of distilled thionyl chloride and 0.5 g. of zinc chloride was heated on a steam bath overnight and then distilled at 15 mm. The distillate was redistilled at 69- 70° and 15 mm. giving 34 g. of 4-chlorovaleryl chloride. The acid chloride was reduced catalytically, reacted with 5-chlorosalicylhydroxamic acid and the resulting intermediate was ring-closed according to the method described in Example 3. The product after recrystallization from trichloroethylene weighed 8.5 g. and melted at 210- 213° C.