Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH3:46])[N:42]=[N:41][CH:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH3:46])[N:42]=[N:41][CH:40]=5)=[O:56])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cnnn4CCC)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cnnn4CCC)cc2)CCN3CCC)cc1
Reaction time: 0.25 h
Yield: 46 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(1-propyl-1,2,3-triazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.53 g) was dissolved in methylene chloride (15.9 ml), and to the solution was added dropwise a solution of m-chloroperbenzoic acid (0.21 g) in methylene chloride (10.6 ml) at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[(1-propyl-1,2,3-triazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 282) (0.25 g).
Reaction SMILES: [P:1]([O-:5])([O-:4])([OH:3])=[O:2].[Na+].[Na+].P([O-])([O-])([O-])=O.O.[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17]>O>[C:14]([O-:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([O-:24])=[O:23])([C:18]([O-:20])=[O:19])[OH:17].[P:1]([O-:5])([O-:4])([O-:3])=[O:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=P([O-])([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Reagent (ii) is a buffer prepared by first dissolving 144.8 grams (1.020 mol) of disodium hydrogen phosphate in 1.00 liter hot deionized water. The phosphate dissolved in the hot deionized water upon stirring. To this solution 102.95 grams (0.4902 mol) of citric acid monohydrate were added. The resulting solution was then diluted to 10.0 liters with additional deionized water, thus forming a citrate-phosphate solution, with a pH of 5.0.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:26][CH2:25][CH2:24][CH:23]([OH:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)([O-:13])=[O:12].CCN(CC)CC>C(Cl)Cl>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(N2CCCC(O)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 84.1 %

Procedure:
To a dry round bottom flask was added 2M oxalyl chloride (1.392 mL, 2.78 mmol) and CH2Cl2 (10 mL). The resulting solution was cooled to −78° C. DMSO (0.395 mL, 5.57 mmol) was then slowly added to the solution over 10 min. The reaction was stirred at −78° C. for 20 mins. Then 1-(4-nitrophenyl)azepan-4-ol (470 mg, 1.989 mmol) dissolved in CH2Cl2 (5 ml) was added to the reaction and the reaction was stirred at −78° C. for 1.5 hr. After this time, Et3N (1.220 mL, 8.75 mmol) was added to the reaction mixture. The reaction mixture was then diluted with CH2Cl2 (30 ml). The reaction mixture was washed with water (20 ml) and saturated aqueous NaCl (20 ml). The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give the product, 1-(4-nitrophenyl)azepan-4-one (392 mg, 1.673 mmol, 84% yield) as a yellow solid. Anal. Calcd. for C12H14N2O3 m/z 234.2, found: 235.1 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.12 (d, J=9.35 Hz, 2H), 6.66 (d, J=9.35 Hz, 2H), 3.95-3.83 (m, 2H), 3.83-3.72 (m, 2H), 2.92-2.66 (m, 4H), 2.02-1.86 (m, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 209.79, 151.25, 137.70, 126.52, 110.45, 51.82, 45.39, 42.64, 41.79, 23.88.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:16]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:16]=1[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6]
Reactant: CON(C)C(=O)c1ccnc(Br)c1
Reactant: COc1ccc(F)c(F)c1B(O)O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(F)c(F)c1-c1cc(C(=O)N(C)OC)ccn1
Temperature: 90 °C
Yield: 22.8 %

Procedure:
A flask containing 2-bromo-N-methoxy-N-methyl-isonicotinamide (Example 25, using method 2) (3.0 g, 12.2 mmol) 2,3-difluoro-6-methoxyphenylboronic acid (4.6 g, 24.4 mmol)) and 2M aqueous K3PO4 (15 mL, 30.6 mmol) in 1,4-dioxane (40 mL) was successively evacuated and flushed with nitrogen. Pd(PtBu3)2 (268 mg, 0.48 mmol) was then added and the mixture heated at 90° C. for 2 hours. The mixture was cooled, concentrated in vacuo and then partitioned between EtOAc and sat. aqueous NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by SiO2 chromatography (eluting with 30-100% EtOAc/hexane) gave the title compound (0.856 g, 23%). MS(ESI) m/z 309 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:22][CH3:23])[N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:16][C:17]2[CH:21]=[CH:20][N:19]([CH2:22][CH3:23])[N:18]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reactant: CCn1ccc(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Reaction time: 16 h
Yield: 75.1 %

Procedure:
To a suspension of 3-bromo-4-nitro-1H-indazole (Preparation B; 8.51 g, 35.2 mmol) in DMF (60 mL) was added 3-(chloromethyl)-1-ethyl-1H-pyrazole hydrochloride (6.37 g, 35.2 mmol) and K2CO3 (14.6 g, 106 mmol). The reaction mixture was stirred for 16 hours. Most of DMF was removed under reduced pressure. The remaining residue was diluted with EtOAc (300 mL) and washed with H2O. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/hexanes 1:5) to provide the product (9.26 g).
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH:9]=[C:10]([CH3:20])[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[CH:6]=[CH:5][N:4]=1>CC(O)=O.Br>[CH3:20][C:10]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]2[CH:6]=[CH:5][NH:4][C:3](=[O:2])[C:8]=2[CH:9]=1
Reactant: CCCCCCCCn1c(C)cc2c(OC)nccc21
Agent: Br
Solvent: CC(=O)O
Product: CCCCCCCCn1c(C)cc2c(=O)[nH]ccc21
Temperature: 105 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-methoxy-2-methyl-1-octyl-1H-pyrrolo[3,2-c]pyridine 8 (0.22 g, 0.80 mmol) in AcOH (10 mL), 48% of HBr (5 mL) was added. The reaction mixture was heated to 105° C., and then stirred for 16 h, cooled to room temperature and evaporated. The obtained residue was dissolved in CH2Cl2 (80 mL), washed with saturated NaHCO3 (30 mL), brine (30 mL), dried over Na2SO4 and evaporated to afford crude product 9, which was used without further purification for next step. Yield: 207 mg (100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([CH:32]=[O:33])=[CH:23][C:24]3[N:28]([CH3:29])[CH:27]=[N:26][C:25]=3[C:30]=2[F:31])=[C:16]([Cl:34])[CH:15]=1>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([CH:32]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[OH:33])=[CH:23][C:24]3[N:28]([CH3:29])[CH:27]=[N:26][C:25]=3[C:30]=2[F:31])=[C:16]([Cl:34])[CH:15]=1
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(O)c3ccccn3)cc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
To a solution of 2-bromopyridine (0.10 mL, 1.04 mmol) in THF (3 mL) at −78° C. is added n-BuLi (0.39 mL, 0.98 mmol, 2.5 M solution in hexane). After stirring for 10 minutes at −78° C., a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbaldehyde 10h (25 mg, 0.064 mmol) in THF (1 mL) is added. The resulting reaction mixture is stirred for 1.5 hours at −78° C., quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (2.5% MeOH in CH2Cl2) to afford the desired product (18 mg, 62%): MS APCI (+) m/z 461, 463 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.31 (d, 1H), 8.16 (s, 1H), 7.65 (m, 3H), 7.38 (d, 1H), 7.10 (m, 1H), 7.00 (dd, 1H), 6.11 (dd, 1H), 6.05 (s, 1H), 3.94 (s, 3H); 19F NMR (376 MHz, CD3OD) −135.79 (s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:23]=[C:22]([O:34][CH3:35])[N:21]=3)[CH2:16][CH:15]2[C:36](=[O:45])[N:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH:43]=[CH2:44])[CH3:38])=[O:13])[CH2:8][CH:7]1C=C)=[O:5])[CH3:2]>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl>[CH2:1]([O:3][C:4]([C:6]12[CH2:7][CH:8]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40][CH2:39][N:37]([CH3:38])[C:36](=[O:45])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[N:23]=[C:22]([O:34][CH3:35])[N:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2cc(-c3ccc(OC)cc3)nc(OC)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4ccc(OC)cc4)nc(OC)n3)CC1C(=O)N2
Yield: 61.8 %

Procedure:
The diolefin 16d (0.95 g, 1.53 mmol) was reacted with Hoveyda Grubbs 2nd generation catalyst (140 mg) in DCE (900 ml) according to the procedure described in Example 13 step d which gave the crude title compound, (560 mg, 62%), (M+H)+565.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]([OH:15])=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[C:10]2=[O:16])=[C:5]1[C:26]([O:28][CH3:29])=[O:27])[CH:2]=[CH2:3].[C:30](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]([O:15][CH3:30])=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[C:10]2=[O:16])=[C:5]1[C:26]([O:28][CH3:29])=[O:27])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCn1c(C(=O)OC)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCn1c(C(=O)OC)c2c(c(OC)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 40 °C

Procedure:
A mixture of methyl 2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (6.08 g, 14.92 mmol), cesium carbonate (6.08 g, 18.65 mmol), and iodomethane (2.79 mL, 44.77 mmol) in DMF (20 mL) was heated at 40° C. overnight. The reaction mixture was filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the title compound. (ES MS M+1=435.2)
Reaction SMILES: ClC(OC(Cl)C)=[O:3].COC1C=CC(CN2CCN(CC3C=CC(N[C:29]([C:31]4[C:32]5[N:33]=[CH:34][CH:35]=[N:36][C:37]=5[C:38]([C:41]5[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[C:43]([O:49][CH3:50])[CH:42]=5)=[CH:39][CH:40]=4)=[O:30])=NC=3)CC2)=CC=1>C1COCC1>[CH3:48][O:47][C:45]1[CH:46]=[C:41]([C:38]2[C:37]3[N:36]=[CH:35][CH:34]=[N:33][C:32]=3[C:31]([C:29]([OH:30])=[O:3])=[CH:40][CH:39]=2)[CH:42]=[C:43]([O:49][CH3:50])[CH:44]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5cc(OC)cc(OC)c5)c5nccnc45)nc3)CC2)cc1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2ccc(C(=O)O)c3nccnc23)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
α-Chloroethyl chloroformate (19 μL, 0.17 mmol) was added to a cold (−78° C.) solution of 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid {5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]pyridin-2-yl}-amide (Example 116) (103 mg, 0.17 mmol) in THF (2 mL). The reaction mixture was stirred for 1 h at −78° C., quenched by addition of MeOH and concentrated. The residue was dissolved in MeOH (5 mL), heated to reflux for 3 h, allowed to cool. The resulting solid was collected by filtration, diluted in in DCM and a saturated aqueous solution of NaHCO3, and extracted with DCM. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 91.5:7.5:1) followed by trituration in Et2O to afford 28 mg of the title compound as a white solid. Title compound: ESI-MS: 485.2 [M+H]+; tR=3.80 min (System 1); TLC: Rf=0.10 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: Br[C:2]1[C:3]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:5]1[CH:4]=[C:3]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:2]([C:38]2[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=2)=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: O=C(Nc1cccnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2cc(C(=O)Nc3cccnc3)c(OCc3ccc(F)cc3F)cc2CN2CCOCC2)cn1
Temperature: 120 °C

Procedure:
To a solution of 5-bromo-2-{[(2,4-difluorophenyl)methyl]oxy}-4-(4-morpholinylmethyl)-N-3-pyridinylbenzamide (may be prepared as described in Example 9; 162 mg, 0.31 mmol) in 1,2-dimethoxyethane (5 ml) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.38 mmol), Pd(Ph3P)4 (21.67 mg, 0.02 mmol) and sodium carbonate (0.63 ml, 0.63 mmol). The mixture was heated at 120° C. in the microwave for 35 minutes, cooled and the solvent removed in vacuo. Purification by MDAP yielded the title compound as a brown solid. 75 mg.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:32])=[C:4]([N:8]2[C:13](=[O:14])[CH:12]([Se]C3C=CC=CC=3)[CH2:11][N:10]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:9]2=[O:31])[CH:5]=[CH:6][CH:7]=1.OO.O>C1COCC1>[Br:1][C:2]1[C:3]([CH3:32])=[C:4]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][N:10]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:9]2=[O:31])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CC([Se]c3ccccc3)C(=O)N(c3cccc(Br)c3C)C2=O)cc1
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2ccc(=O)n(-c3cccc(Br)c3C)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A solution of 3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)-5-(phenylselanyl)dihydropyrimidine-2,4(1H,3H)-dione (5.43 g, 9.73 mmol) in THF (97 mL) was treated with 30% aqueous hydrogen peroxide (5.0 mL, 48.6 mmol) and the mixture was stirred at room temperature for 30 min. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel (220 g), eluting with EtOAc-hexanes (gradient from 25-70%), to provide 3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione as a white solid (2.10 g, 54% yield). Mass spectrum m/z 401, 403 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J=7.9 Hz, 1H), 7.70-7.65 (m, 1H), 7.32-7.28 (m, 2H), 7.25-7.22 (m, 2H), 6.96-6.91 (m, 2H), 5.86 (d, J=7.9 Hz, 1H), 4.89 (d, J=2.4 Hz, 2H), 3.74 (s, 3H), 2.02 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:18]1[CH:23]=[C:22]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:21]([NH2:30])=[C:20]([N+:31]([O-:33])=[O:32])[CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCO>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([C:18]2[CH:23]=[C:22]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:21]([NH2:30])=[C:20]([N+:31]([O-:33])=[O:32])[CH:19]=2)[CH:5]=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: Nc1c(-c2ncccn2)cc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Solvent: CCO
Solvent: O
Product: Nc1c(-c2ncccn2)cc(-c2cncc(F)c2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 95.2 %

Procedure:
A 3 L round-bottom flask was fitted with a mechanical overhead stirrer, a reflux condenser, and a thermometer and purged with N2. 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2) (95.0 g, 421 mmol, 1.2 equiv), 4-bromo-2-nitro-6-(pyrimidin-2-yl)benzenamine (3) (104.55 g, 354 mmol, 1.0 equiv), K3PO4 (93.1 g, 438 mmol, 1.25 equiv, Riedel-deHaen #S29375-366), Pd(OAc)2 (0.80 g, 3.5 mmol, 1 mol %, Aldrich #06410JE) cetyltrimethylammonium bromide (1.28 g, 3.5 mmol, 1 mol %, Aldrich #0823CE) and PPh3 (3.74 g, 14 mmol, 4 mol %, Fluka #1093859) were added followed by EtOH (10 vols) and water (1.1 vols). The heterogeneous reaction mixture was stirred vigorously (>300 rpm) and heated to reflux (80° C.). After 6 hours a sample was removed for analysis of reaction completion (method C). After the reaction was judged complete, the mixture was cooled to 30° C., then water (10 vol) was added and the reaction stirred for 2 h. The resulting slurry was filtered and the filter cake washed with water (2×5 vol) and acetonitrile (2×5 vol). The filter cake was then charged back to the flask and water added (10 vol). The slurry was stirred for 3 h at 30° C. and filtered again. The filter cake was then transferred to a dish and allowed to dry under vacuum at 60-80° C. for 12 h furnishing compound (4) as an orange powder (104.87 g, 88%, purity: 96.14% AUC determined using method A). Typical reaction times were 7.9 min for SM (2) and 6.9 min for product (4).
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][C@H:10]([O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:24][C:25]2[CH:36]=[CH:35][C:28]3[C:29](=[O:34])[N:30]([CH3:33])[CH2:31][O:32][C:27]=3[CH:26]=2)[CH:23]=1)[C:18]([OH:20])=O)[CH2:11][O:12][CH3:13].[NH2:37][C:38]1[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:9][C@H:10]([O:14][C:15]1[CH:16]=[C:17]([C:18]([NH:37][C:38]2[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=2)=[O:20])[CH:21]=[C:22]([O:24][C:25]2[CH:36]=[CH:35][C:28]3[C:29](=[O:34])[N:30]([CH3:33])[CH2:31][O:32][C:27]=3[CH:26]=2)[CH:23]=1)[CH2:11][O:12][CH3:13]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reaction time: 1 h
Yield: 52.9 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.13 mL, 0.97 mmol) was added to a solution of 3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(3-methyl-4-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl)oxy]benzoic acid (0.25 g, 0.65 mmol) in DCM (10 mL) and stirred for 1 hour. 1,1-Dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (0.18 g, 0.97 mmol) then pyridine (0.11 mL, 1.29 mmol) were added and the reaction stirred for a further 45 mins then reduced in vacuo and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was further extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the desired compound as a golden oil (0.19 g). 1H NMR δ (CDCl3): 1.32 (d, 3H), 1.63 (s, 9H), 3.10 (s, 3H), 3.40 (s, 3H), 3.48-3.60 (m, 2H), 4.56-4.60 (m, 1H), 5.18 (s, 2H), 6.54 (d, 1H), 6.73-6.76 (m, 1H), 6.83 (t, 1H), 7.07-7.08 (m, 2H), 7.25-7.26 (m, 1H), 7.95 (d, 1H), 8.00 (d, 1H), 8.65 (s, 1H); m/z 551 (M−H)−
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCC1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 37.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-piperidin-1-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][O:37][C:36]1=[O:40]>C1C=CC=CC=1.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][N:14]([CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][O:37][C:36]4=[O:40])[CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCCl
Reactant: Fc1ccc2c(c1)C(N1CCNCC1)Cc1cc(Cl)ccc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Cl)ccc3Sc3ccc(F)cc32)CC1

Procedure:
19 G. of 1-(2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)piperazine are together with 15 g. of pulverized potassium carbonate, 0.3 g of potassium iodide and 150 ml. of toluene reacted with 20.4 g of N-(beta-chloroethyl)-oxazolidinone and heated under reflux conditions for 20 hours. The reaction mixture is poured over water and diluted with benzene. The organic phase is thereafter washed with saturated, aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained 3-{2-[4-(2-chloro-8-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone which is treated with maleic acid to form the corresponding maleate which has a melting point of 164°-166°.