Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:17]([N:21]([CH2:24][CH2:25][CH2:26][CH3:27])[S:22]Cl)[CH2:18][CH2:19][CH3:20].N1C=CC=CC=1.O>CCCCCC>[CH2:17]([N:21]([CH2:24][CH2:25][CH2:26][CH3:27])[S:22][CH2:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN(CCCC)SCl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCCCN(CCCC)SCNC(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 35 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A flask was charged with 15.8 g of 98% 2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate (0.07 mole) and 30.2 g of a 50% solution of dibutylaminosulfenyl chloride (0.077 mole) in hexane under nitrogen atmosphere. To this was added with stirring 7.5 g (0.0455 mole) of triethylamine/sulfur dioxide complex prepared as described in Example 3. Pyridine (6.1 g, 0.077 mole) was then added dropwise with stirring over a period of 16 minutes. The temperature increased from 20.5° C. to 23.5° C. Stirring was continued for three hours after the beginning of pyridine addition during which external heating was supplied to maintain a temperature of 35° C. The mixture was cooled to 10.5° C. and 31 ml of water was added. The mixture was filtered, separated, and the organic layer was concentrated to yield 18.99 g of 75% (by hplc) 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (dibutylaminothio)methylcarbamate (53% chemical yield based on the starting carbamate).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])[CH:16]=[N:17][C:9]1=2)=O)(C)(C)C.[Li+].[OH-]>Cl.O1CCOCC1>[O:11]1[CH2:12][CH2:13][NH:8][C:9]2[N:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:14][C:10]1=2
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(/C=C/C(=O)O)cnc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1cnc2c(c1)OCCN2
Temperature: 25 °C
Yield: 51.8 %

Procedure:
(E)-3-[4-(tert-Butoxycarbonyl)-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-7-yl]acrylic acid (1.17 g, 2.95 mmole) was dissolved in 4 N HCl in dioxane (15 mL). After 72 hr the mixture was concentrated. The residue was taken up in 1:1 MeOH/H2O (20 mL). 1.0 N LiOH (15 mL, 15 mmole) was added and the mixture was heated to reflux. After 18 hr the mixture was cooled to RT and concentrated to approximately ⅓ volume. The mixture was adjusted to pH 6 using 10% HCl. The solid was collected by filtration, washed with H2O and dried in vacuo to give the title compound (315 mg, 52% over 2 steps): MS (ES) m/e 207 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:26])C(=O)C1>CC#N.O>[CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([I:26])=[C:13]([C:15]([F:17])([F:18])[F:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1c[nH]c(COCc2ccccc2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O
Product: FC(F)(F)c1nc(COCc2ccccc2)[nH]c1I
Reaction time: 15 h
Yield: 31.3 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazole (compound 219.1, 1.5 g, 5.85 mmol) in CH3CN (18 mL). NIS (1.6 g, 7.02 mmol) was added to the reaction. The reaction mixture was stirred for 15 h at 85. The reaction mixture was diluted with 30 mL of H2O. The aqueous phase was extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 2×20 mL of Na2S2O3(sat.) and 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:100-1:2) as eluent to furnish 0.7 g (31%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O1CCCC1.Cl[CH2:35][C:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:37]>CN(C)C=O>[CH2:14]([O:13][C:11]([C:7]1[N:8]([CH2:35][C:36](=[O:37])[N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:9]2[C:5]([C:6]=1[NH:16][C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)=[O:12])[CH3:15]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1Nc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Nc2ccncc2)c2ccc(Cl)cc2n1CC(=O)N(CC)CC
Temperature: 0 °C
Yield: 14.8 %

Procedure:
Under nitrogen, stir and cool to 0° C. a mixture of ethyl 6-chloro-3-(4-pyridinylamino)indole-2-carboxylate (0.50 g, 1.58 mmol) in dimethylformamide (5 mL). Add a 1M solution of potassium tert-butoxide in tetrahydrofuran (1.7 mL, 1.7 mmol) over a 2 min period, and stir for 10 min. Add 2-chlor-N,N-diethylacetamide (0.22 mL, 1.6 mmol) in one portion and stir at ambient temperature overnight. Quench the reaction into water (35 mL), and extract the aqueous mixture with ethyl acetate (2×20 mL). Combine the extracts, wash with water (25 mL), brine (25 mL) and dry over MgSO4. Concentrate under vacuum, and chromatograph the residue on a Redisep silica gel cartridge (10 g) eluting with 5% methanol/dichloromethane to 20% methanol/dichloromethane. Combine all homogenous fractions and concentrate to obtain a solid. Recrystallize the solid from ethyl acetate and obtain 0.1 g of the title compound as a white solid: MS 429(M+H), m.p. 212–214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Ni].CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Agent: [Ni]
Solvent: CO
Product: CCN1CCN(c2ccc(N)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1-(3-chloro-4-nitro-phenyl)-4-ethyl-piperazine (1 g, 3.7 mmol) and Raney Nickel (0.1 g) in MeOH (20 mL) is stirred for 8 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) to afford the title compound as an off-white solid: ESI-MS: 240.1/242.1 [MH]+; tR=0.90 min (system 1); TLC: Rf=0.46 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)[C:11]=3[C:10](=[O:28])[N:9]2[C:29]2[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:19]1[CH2:18][CH:17]([N:12]2[C:11]3[C:10](=[O:28])[N:9]([C:29]4[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=4)[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:15]=3[C:14]([CH3:16])=[N:13]2)[CH2:20]1
Reactant: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(C2CNC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a stirred solution of tert-butyl 3-(4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-6-oxo-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)azetidine-1-carboxylate (Step 138.1a) (280 mg, 0.534 mmol) in CH2Cl2 (4 mL) was added TFA (0.412 mL, 5.34 mmol). The reaction mixture was stirred for 1 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3, and extracted with CH2Cl2. The combined organic layers were dried on Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (NH3 1%/CH2Cl2/MeOH 1-4%) to afford 200 mg of the title compound as a colorless solid. tR: 0.66 min (LC-MS 2); ESI-MS: 424.1 [M+H]+ (LC-MS 2); Rf=0.09 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s, 3H) 1.94 (s, 3H) 3.35 (s, 3H) 3.70-3.78 (m, 2H) 4.06-4.14 (m, 2H) 5.26-5.37 (m, 1H) 6.07 (br. s, 1H) 7.23-7.29 (m, 2H) 7.34-7.40 (m, 3H) 7.71 (d, J=2.74 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:6]2[CH:5]=[C:4]([CH3:14])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[C@H:47]12[CH2:53][C@H:50]([NH:51][CH2:52]1)[CH2:49][O:48]2>CN(C=O)C.O>[C@H:47]12[CH2:53][C@H:50]([N:51]([C:11]([C:10]3[CH:9]=[N:8][N:7]4[C:2]([I:1])=[CH:3][C:4]([CH3:14])=[CH:5][C:6]=34)=[O:13])[CH2:52]1)[CH2:49][O:48]2
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Cc1cc(I)n2ncc(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(I)n2ncc(C(=O)N3C[C@@H]4C[C@H]3CO4)c2c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 47.3 %

Procedure:
To a solution of 7-iodo-5-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (500 mg) in DMF (10 mL) were added HATU (755 mg) and triethylamine (0.531 mL), and the mixture was stirred at room temperature for 3 min. To the reaction mixture was added (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (247 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (300 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]([S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12])=[CH2:10]>C(O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH2:15][CH2:14][S:11](=[O:13])(=[O:12])[CH2:9][CH2:10]2)=[CH:3][CH:4]=1
Reactant: C=CS(=O)(=O)C=C
Reactant: Nc1ccc(O)cc1
Solvent: CCO
Product: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Reaction time: 1 h

Procedure:
A suspension of 8.74 g of 4-aminophenol in 190 ml of ethanol is added dropwise at 50° to 11.34 g of divinyl sulfone, whereupon rinsing is carried out with 50 ml of ethanol and then the mixture is heated to boiling under reflux under argon for 3 hours. After cooling, the mixture is treated with 480 ml of water and stirred for 1 hour at 0°. The precipitated crystals are removed by filtration under suction, washed with 20 percent ethanol and water and dried. By recrystallization from dichloromethane/methanol/ether there is obtained 4-(p-hydroxyphenyl)-tetrahydro-4H-1,4-thiazine 1,1-dioxide of melting point 153°-155°.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:30]=[CH:29][C:11]2[C:12]([CH2:15][O:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[C:20]([C:26](O)=[O:27])[NH:21]4)=[CH:13][O:14][C:10]=2[CH:9]=1)[CH3:2].[NH2:31][CH:32]1[CH2:37][CH2:36][C:35]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][C@H:44]([OH:47])[C@@H:43]([CH3:48])[CH2:42]2)([OH:38])[CH2:34][CH2:33]1>>[OH:38][C:35]1([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][C@H:44]([OH:47])[C@@H:43]([CH3:48])[CH2:42]2)[CH2:34][CH2:33][CH:32]([NH:31][C:26]([C:20]2[NH:21][C:22]3[C:18]([CH:19]=2)=[C:17]([O:16][CH2:15][C:12]2[C:11]4[CH:29]=[CH:30][C:8]([O:7][CH2:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:9][C:10]=4[O:14][CH:13]=2)[CH:25]=[CH:24][CH:23]=3)=[O:27])[CH2:37][CH2:36]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: CCOCCCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Product: CCOCCCOc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-[6-(3-ethoxy-propoxy)-benzofuran-3-ylmethoxy]-1H-indole-2-carboxylic acid 30g and amine 14.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[N:3]=1.FC(F)(F)C(O)=O.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[O:38])=[N:28]1.C(N(CC)CC)C.O>CN(C)C=O>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][N:42]([C:2]3[S:6][N:5]=[C:4]([N:7]4[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]4)[N:3]=3)[CH2:41][CH2:40]2)=[O:38])=[N:28]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsc(Cl)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.1 %

Procedure:
To a solution of tert-butyl 4-(5-chloro-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate (169 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was poured to water and the desired product as a solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 126 mg (44.1%) of the desired product.
Reaction SMILES: [BH4-].[Na+].[Li+].[Br-].C([O:7][C:8](=O)[CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1)C>C1COCC1>[CH2:19]([O:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][CH2:9][CH2:8][OH:7])[CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)CNCc1cccc(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCNCc1cccc(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 110.9 %

Procedure:
Next, NaBH4 (3.8 g, 100 mmol) and LiBr (8.7 g, 100 mmol) were added to THF (100 ml), and the mixture was stirred at 80° C. for 1 hour. To this mixture, [(3-benzyloxyphenyl)methylamino]acetic acid ethyl ester (10.8 g) dissolved in THF (20 ml) was added dropwise at room temperature. The mixture was stirred at 80° C. for 5 hours and further at room temperature for 16 hours. After the reaction solvent was evaporated to about half, KH2PO4 (1 M, 200 ml) was slowly added dropwise. The organic layer was extracted with dichloromethane (50 ml) 3 times, dried over Na2SO4 and concentrated to give crude 2-[(3-benzyloxyphenyl)methylamino]ethanol (yield: 10.3 g (90.4%)).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:20])[CH3:19].F[C:24]1[C:29]([F:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:30][C:29]1[C:24]([NH:2][C:3]2([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]2[NH:8][C:9](=[O:21])[O:10][C@@H:11]2[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]2[CH:18]([CH3:19])[CH3:20])=[N:25][CH:26]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:28]=1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)Nc1ncc(C(F)(F)F)cc1F

Procedure:
A solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-amino-2-methylcyclopentyl)carbamate hydrochloride (Intermediate 27; 1.00 g, 3.00 mmol), 2,3-difluoro-5-(trifluoromethyl)pyridine (CAS number 89402-42-6; 0.412 ml, 3.30 mmol) and DIPEA (1.57 ml, 9.01 mmol) in DMSO (10 ml) was subjected to microwave irradiation at 140° C. for 3 hours. The reaction was then partitioned between ethyl acetate (10 ml) and water (10 ml), filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-12% diethyl ether/petrol) to afford the title compound as a single trans-enantiomer.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: O=C(O)C=Cc1ccc(F)cc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
To a mixture of 2-chloro-4-fluorobenzaldehyde (20.0 g, 0.13 mol, Aldrich) and malonic acid (26.2 g, 0.25 mol, Aldrich) in pyridine (100 ml) at 50° C. was added dropwise piperidine (10 ml). After 18 h at 70° C., the mixture was poured into an ice cold solution of concentrated HCl (120 ml) and water (1.5 L). The resulting solid was filtered and washed repeatedly with water to give 24.4 g (96%) of 2-chloro-4-fluoro-cinnamic acid as a white solid: Recrystallization of 1.5 g from acetone:water mixtures gave 1.1 g of 2-chloro-4-fluorocinnamic acid as a white solid: mp 243°-245° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:19])=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)([O-:3])=[O:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[N:28]=[CH:27][CH:26]=[C:25]2[N:34]1[CH2:40][C:39]2[CH:41]=[C:42](Br)[CH:43]=[CH:44][C:38]=2[O:37][CH2:36][CH2:35]1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[N:28]=[CH:27][CH:26]=[C:25]2[N:34]1[CH2:40][C:39]2[CH:41]=[C:42]([C:8]3[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:19])=[N:6][CH:7]=3)[CH:43]=[CH:44][C:38]=2[O:37][CH2:36][CH2:35]1
Reactant: CC1(C)OB(c2cnc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: COc1cc2nccc(N3CCOc4ccc(Br)cc4C3)c2cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1cc2nccc(N3CCOc4ccc(-c5cnc(N)c([N+](=O)[O-])c5)cc4C3)c2cc1OC
Temperature: 93 °C
Reaction time: 18 h
Yield: 60.7 %

Procedure:
A mixture of commercially available 3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (125 mg, 0.47 mmol), 4-[6,7-bis(methyloxy)quinolin-4-yl]-7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine (155 mg, 0.47 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (34 mg, 0.05 mmol), cesium carbonate (300 mg, 2.4 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was degassed with nitrogen for 5 minutes and then stirred at 93° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (80 mL) then filtered through a celite bed. The filtrate was washed with brine (2×50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography (0 to 10% methanol-dichloromethane) to give 5-{4-[6,7-bis(methyloxy)quinolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-3-nitropyridin-2-amine (135 mg, 76% yield); MS (EI) for C25H23N5O5: 474 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].CC(N=NC(C#N)(C)C)(C#N)C.C1C=CC=CC=1>>[C:18]1([CH2:17][CH2:16][CH:15]2[C:2]3[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=[CH:11][C:12]=3[O:13][CH2:14]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(OC/C=C/Cc2ccccc2)c(I)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)C(CCc1ccccc1)CO2
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 3-iodo-4-{[(2E)-4-phenyl-but-2-enyl]-oxy}benzoate (13.42 g, 31.73 mmol) and AIBN (0.52 g, 3.17 mmol) in benzene (900 ml) tributyltin hydride (12 ml, 44.43 mol) was added at room temperature and the reaction mixture was warmed to reflux. After 2 h, the solvent was eliminated under vacuum. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate=95/5) affording 9.14 g of the title compound (97% yield).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:26])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].C1CCCCC=1.CO.C(Cl)(Cl)Cl>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([C:5]1[C:6](=[O:26])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(OCc3ccccc3)cc2)CC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1=CCCCC1
Product: CCC(=O)C1=C(O)CC(c2ccc(O)cc2)CC1=O

Procedure:
A solution of 21 g (0.060 mol) of 2-propionyl-3-hydroxy-5-(4-benzyloxyphenyl)cyclohex-2-en-1-one in 250 mL of ethyl acetate and 250 mL of absolute ethanol was treated with 12 mL (0.12 mol) of cyclohexene and 0.7 g of 20 percent palladium hydroxide on carbon (Pearlman's catalyst) and the mixture was heated at reflux for 5 hours. The reaction mixture was cooled slightly and filtered through diatomaceous earth. Evaporation of the filtrate from the mixture gave a crude solid residue. Recrystallization of the residue from a 1:1 ethyl acetate-hexane mixture gave the above named product as a beige crystalline solid in a yield of 13.7 g (88 percent of theoretical). The product melted at 135°-137° C. Rf -0.45 (silica gel, 10:90 MeOH:CHCl3), 1H NMR (CDCl3): δ 1.13 (t, 3H, --CH3), 2.55-3.50 (m, 7H, ring protons and --CH2CH3), 6.60-7.12 (m, 5H, ArH's and ArOH), 18.15 broad s, 1H, enol H).
Reaction SMILES: OO.O[Li].O.C([C@@H]1COC(=O)N1[C:19](=[O:42])[C@H:20]([C@H:28]1[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:31]([CH3:41])([CH3:40])[CH2:30][CH2:29]1)[C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)C1C=CC=CC=1.[O-:43]S([O-])=O.[Na+].[Na+]>C1COCC1.O.C1COCC1>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C@@H:20]([C@@H:28]2[CH2:29][CH2:30][C:31]([CH3:40])([CH3:41])[N:32]2[C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[C:19]([OH:43])=[O:42])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(Br)cc2)CCC1(C)C
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Br)cc2)CCC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
30% H2O2 (0.67 mL, 7.0 mmol) was added to a solution of LiOH—H2O (0.24 g, 5.60 mmol) in THF/water (2:1, 93 mL), and the solution was stirred at room temperature for 10 minutes. The solution was then cooled to 0° C. and treated with a solution of (S)-tert-butyl 5-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-bromophenyl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.60 g, 2.80 mmol) in THF (10 mL). The reaction was stirred at 0° C. for 2 hours and allowed to warm to room temperature and stirred overnight. The reaction was then cooled to 0° C. and treated with 1M Na2SO3 (10 mL) and stirred for 10 minutes. The reaction was then warmed to room temperature and stirred for 10 minutes. The reaction was next concentrated and extracted with EtOAc (2×20 mL). The aqueous layer was then acidified with 1N HCl to a pH of about 1 to about 2 and extracted with DCM (2×20 mL). The combined DCM fractions were dried over sodium sulfate, filtered, and concentrated to give (S)-2-(4-bromophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (1.01 g, 87% yield) as a solid. MS ESI (+) m/z 412 detected.