Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:14]([C:17]([OH:19])=O)=[CH:15][S:16][C@H:11]12)=[O:8].CN1CCOCC1.ClC(OCC)=O.[C:51]1([SH:57])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(OCC)(=O)C.C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[C:14]([C:17]([S:57][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:19])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: Sc1ccccc1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)O)=CS[C@H]12
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)Sc3ccccc3)=CS[C@H]12
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a cooled (-10° C.), stirred solution of benzhydryl 7-(2-thienylacetamido)-3-carboxy-2-cephem-4-carboxylate (.267 g., 0.5 mmol.) in 25 ml. of methylene chloride under an argon atmosphere was added 0.152 g. (1.5 mmol.) of N-methylmorpholine. The reaction mixture was then cooled to -20° C. and 0.135 g. (1.25 mmol.) of ethyl chloroformate was added. The mixture was stirred at 0° for 30 minutes after which time the mixture was cooled to -10° and 0.165 g. of thiophenol was added. After stirring the reaction mixture at 0° for 1 hour, ethyl acetate was added, and the resulting solution was washed successively with aqueous sodium bicarbonate, water, and brine and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave a product which was chromatographed on a silica gel column using a tolueneethyl acetate gradient to provide 0.208 g. (66.5%) of the title product: ir (CHCl3) 1798 cm-1 (β-lactam C = 0); nmr (CDCl3) 3.80 (s, 2, side chain CH2), 5.06 (d, 1, J = 4.0 Hz, C6 --H), 5.42 (q, 1, J = 4.0 and 8.0 Hz, C7 --H), 5.70 (s, 1, C4 --H) and 7.87 ppm (s, 1, C 2 --H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:4]3[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=3)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1cccc(-c2ccc(Cn3ccnc3)cn2)c1

Procedure:
Synthesized using 3-aminophenylboronic acid 230 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Orange solid. Yield: 144 mg, 0.56 mmol, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.11 (s, 2H), 6.72 (ddd, J=7.6, 2.4, 0.9 Hz, 1H), 6.89 (brs, 1H), 7.08 (bs, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.28 (dt, J=7.8, 1.3 Hz, 1H), 7.33 (t, J=2.2 Hz, 1H), 7.41 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (brs, 1H), 7.62 (d, J=8.2 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 113.3, 116.0, 117.0, 119.0, 120.5, 129.6, 129.9, 130.1, 135.6, 137.2, 139.5, 146.9, 148.3, 157.6; MS (ESI): m/z=251.13 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH:11]=O.[F:13][C:14]1[CH:31]=[CH:30][C:17](/[CH:18]=[N:19]/[C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH2:22][O:23][C:24]3=[O:29])=[CH:16][CH:15]=1.[CH2:32]([OH:34])[CH3:33]>C(OCC)(=O)CC>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]2[CH:11]([C:3]3[N:2]([CH3:1])[C:10]4[CH:9]=[CH:8][N:7]=[CH:6][C:5]=4[N:4]=3)[C:32](=[O:34])[C:33]3[C:25]([C:24]([O:23][CH2:22][CH3:21])=[O:29])=[CH:26][CH:27]=[CH:28][C:20]=3[NH:19]2)=[CH:30][CH:31]=1
Reactant: O=C1OCc2c(/N=C/c3ccc(F)cc3)cccc21
Reactant: CCO
Reactant: Cn1c(C=O)nc2cnccc21
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1nc3cnccc3n1C)C(c1ccc(F)cc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
To a solution of 1-methyl-1H-imidazo[4,5-c]pyridine-2-carbaldehyde (400 mg, 2.48 mmol), (E)-4-(4-fluorobenzylideneamino) isobenzofuran-1(3H)-one (634 mg, 2.48 mmol) in ethyl propionate (20 ml) were added a solution of sodium ethanoxide in ethanol [sodium (171 mg, 7.45 mmol) in ethanol (10 mL)] at 0° C. Then the mixture was stirred at room temperature overnight. Then the mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by chromatography (silica gel, petroleum ether/ethyl acetate=25:1 to 5:1) to give the title compound (150 mg, yield 14%). LC-MS (ESI) m/z: 445 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C@@H:9]3[CH2:13][C:14]4[C:19]([C@H:8]3[C:7]=2[CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4.C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C@@H:9]3[CH2:13][C:14]4[C:19]([C@H:8]3[C:7]=2[CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4
Reactant: COc1cc2c(cc1Cl)C=CN[C@@H]1Cc3ccccc3[C@@H]21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc2c(cc1Cl)CCN[C@@H]1Cc3ccccc3[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
The crude Compound N from step D was dissolved in 20 mL absolute ethanol and treated with 0.12 grams (1.91 mmol) sodium cyanoborohydride. To this was added 0.108 mL glacial acetic acid, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with 10 mL 1M HCl and stirred for 30 minutes. The reaction was made basic with 30% NaOH and extracted into 250 mL ethyl actetate. The organic layer was dried (MgSO4) and evaporated to give 350 mg (53%) of trans-5,6,7,7a,8,12b-hexahydro-2-methoxy-3-chlorobenz[d]indeno[2,1-b]azepine (Compound P) as an oil, 200 MHz NMR (CDCl3) d 3.60-3.85(m,3H), 3.10-3.40(m,4H), 3.71(s,3H), 4.54(d,1H,J=8 Hz), 7.07(s,1H), 7.16(s,1H), 7.20-7.40(m,4H).
Reaction SMILES: C[O:2][C:3](=[O:32])/[C:4](/[O:30][CH3:31])=[CH:5]/[C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:8][CH:7]=1.[OH-].[K+].Cl>CO.O>[CH3:31][O:30]/[C:4](=[CH:5]\[C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:8][CH:7]=1)/[C:3]([OH:32])=[O:2]
Reactant: COC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
To a suspension of 45.81 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid methyl ester (100.9 mmol) in 920 ml of methanol, a solution of 40.15 g of potassium hydroxide (615.3 mmol) in 92 ml of water was added within 5 minutes. The white suspension was stirred for 90 min at 100° C. The formed yellowish reaction solution was cooled to 60° C., 54 ml of conc. hydrochloric acid were added dropwise within 5 min (pH 3-4) and the resulting thick suspension was cooled to 0° C. The solid was filtered off and washed with 1000 ml water in four portions. The filter cake was suspended in 920 ml of ethanol at 80° C. for 1 h and after at 0° C. for 2 h. The white crystals were filtered off, washed with 300 ml of cold (−15° C.) ethanol in two portions and dried to constant weight (20° C./5 mbar/16 h) to afford 41.66 g (95%) of the title compound with a purity of >99.9% according to HPLC (method described in Example 10). m.p.: 189-190° C. MS: 434.2 (M−H)−. 1H-NMR (CDCl3): 2.41 (s, 3H); 3.11 (t, J=6.6, 2H); 3.79 (s, 3H); 4.47 (t, J=6.8, 2H); 6.88 (d, J=8.8, 1H); 7.30-7.40 (m, 2H); 7.40-7.47 (m, 3H); 7.49 (d, J=5.6, 1H); 8.00-8.10 (m, 2H); 8.12 (d, J=8.4, 1H); COOH very br.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[N+:15]([O-])=O)[CH:2]1[O:4][CH2:3]1.C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Fe].CCO.O>[OH:4][CH2:3][CH:2]1[NH:15][C:7]2[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:6]=2[O:5][CH2:1]1
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc2c(c1)NC(CO)CO2
Temperature: 25 °C

Procedure:
Iron powder (0.670 g, 12 mmol) was added into EtOH/H2O (v/v=6:1, 100 mL) solution of 2,4-dinitrophenyl glycidyl ether (0.480 g, 2 mmol) and acetic acid (1 mL, 17.5 mmol) at reflux temperature. The reaction mixture was refluxed continuously for 120 minutes, and cooled to room temperature, saturated Na2CO3 solution was used for adjusting pH=8, the solution was leached out with C salt for concentrating ethanol and water in the filtrate, and the solid ethanol was obtained (10 mL×4). Ethanol phase was dried with anhydrous MgSO4 and filtered to obtain crude products; the above crude products were separated with silica gel column chromatography (ethanol as developing agent), and 2,3-dihydro-3-hydroxymethyl-6-amino-[1,4]-benzoxazine (0.149 g, 42%) was prepared.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([CH2:7][CH3:8])=[N:4][C:3]=1[C:9]([O:11]CC)=O.ClC(Cl)(O[C:18](=[O:24])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:7]([C:5]1[S:6][C:2]2[NH:1][C:18](=[O:24])[N:41]([CH2:40][CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:9](=[O:11])[C:3]=2[N:4]=1)[CH3:8]
Reactant: CCOC(=O)c1nc(CC)sc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(=O)n(CCc3ccccc3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution (30 mL) of ethyl 5-amino-2-ethyl-1,3-thiazole-4-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.32 g) and triethylamine (0.23 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-phenylethanamine (0.95 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (40 mL), sodium ethoxide (20% ethanol solution, 2.2 g) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.48 g, 64%).
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][CH:6]=1.[CH:17]1([Mg]Br)[CH2:19][CH2:18]1>O1CCCC1>[CH:17]1([C:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=2)=[O:15])[CH2:19][CH2:18]1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: O=C(c1ccc(C(F)(F)F)nc1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (1.00 g, 4.27 mmol) in tetrahydrofuran (30 mL) at 0° C. was added 0.5 M of cyclopropylmagnesium bromide in tetrahydrofuran (20 μL, 0.01 mol) dropwise over 15 minutes. The mixture was stirred at 0° C. for 30 minutes then at room temperature overnight. The reaction was quenched with 1N HCl. Solvent was removed and the aqueous layer was extracted with ethyl acetate. Thr organic layers were combined and dried with MgSO4, filtered and concentrated. The crude product was purified by silica gel column (0-60% ethyl acetate/hexane) to obtain a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](I)[C:3]=1[CH3:10].N#N.[CH3:13][CH2:14][OH:15].[Li][CH:17](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[F:1][C:2]1[C:3]([CH3:10])=[C:4]([CH2:13][C@H:14]([OH:15])[CH3:17])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1c(F)cc(F)cc1I
Reactant: CCO
Reactant: [Li]C(C)CC
Agent: FB(F)F
Agent: N#N
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(F)cc(F)cc1C[C@@H](C)O
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
A solution of 1,5-difluoro-3-iodo-2-methylbenzene (5.08 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −100° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −100° C. to −90° C. The mixture was stirred at −100° C. to −90° C. for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silicagel, EtOAc/hexane 1:9, Rf=0.45 in EtOAc/hexane 3:7) to give (2R)-1-(3,5-difluoro-2-methylphenyl)propan-2-ol (1.20 g, 32%) as pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.02 (t, J=8.47 Hz, 1H), 6.75 (t, J=9.6 Hz, 1H), 4.04 (m, 1H), 2.69-2.76 (m, 2H), 2.22 (s, 3H), 1.46 (d, J=4.35 Hz, 1H), 1.24 (d, J=6.21 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH:8]=1)([O-])=O.C(O)CCC.[H][H]>[Pd].C(N(CC)CC)C>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:23]=[CH:24][CH:25]=[CH:26][C:4]=2[NH2:1])[CH:8]=1
Reactant: O=[N+]([O-])c1ccccc1Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Nc1ccccc1Oc1cccc(Oc2ccccc2N)c1
Temperature: 25 °C

Procedure:
A mixture of 145.3 g of 1,3-bis(2-nitrophenoxy)benzene, 340 mL of butanol, 9 mL of triethylamine, and 1.7 g of 5% palladium on carbon was heated to 70° C. in a 1.0 liter stainless steel stirred autoclave and pressurized with hydrogen to 4.1 MPa. This pressure was maintained for 1 hour after the hydrogen uptake had ceased. The autoclave was cooled to room temperature and discharged. The product slurry redissolved on reheating; the solution was filtered through diatomaceous earth to remove the catalyst, cooled to room temperature, and the product precipitated with hexane. The precipitated product was recovered by filtration and vacuum dried at 70° C. The yield of 1,3-bis(2-aminophenoxy)benzene was 95.2 g (79%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH:17]([C:22]([O:24][CH3:25])=[O:23])[O:18][C:19](=[O:21])[CH3:20])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](O)=[O:44])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>ClCCl.C(OCC)(=O)C>[Br:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](=[O:44])[NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:11][C:12]=3[CH:17]([C:22]([O:24][CH3:25])=[O:23])[O:18][C:19](=[O:21])[CH3:20])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23
Reactant: COC(=O)C(OC(C)=O)c1cc(CNC(=O)OC(C)(C)C)ccc1N
Reactant: O=C(O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C(OC(C)=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.5 %

Procedure:
A mixture of 4-tert-butoxycarbonylaminomethyl-2-(1-methoxycarbonyl-1-acetoxymethyl)aniline (500 mg, 1 mmol), (S)-9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (475 mg, 1.4 mmol), triethylamine (0.55 mL), and Bop-Cl (360 mg, 1.4 mmol) in dichloromethane (15 mL) was stirred for 48 h at room temperature and diluted with ethyl acetate (200 mL). The mixture was washed with 5% potassium hydrogen sulfate, water, 1/15 phosphate buffer (pH 7.5), water, and brine, successively, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 0.3% acetic acid/ethyl acetate to give 340 mg of the title compound (50%).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15]Cl.[C:22]([O:31][CH3:32])(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25]>C(OCC)(=O)C>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15][O:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[C:22]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1ccccc1O
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylformamide (DMF)(100 ml), potassium carbonate (17.97 g) and 2,4-dichlorobenzyl chloride (21.50 g) were added to methyl salicylate (15.22 g), and the mixture was stirred at room temperature overnight. Ethyl acetate (1000 ml) was added to the reaction mixture, and the resulting mixture was washed with brine (700 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude methyl 2-(2,4-dichlorobenzyloxy)benzoate. Methanol (100 ml), THF (100 ml), water (20 ml) and 85% potassium hydroxide (7.92 g) were added to the crude product thus obtained, and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. Water (300 ml) was added to the residue, and the pH of the mixture was adjusted to not more than 2, and the resulting crystals were separated by filtration, dried to give 2-(2,4-dichlorobenzyloxy)benzoic acid (29.30 g) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[CH:16]=[C:17]3[O:25][CH2:24][O:23][C:18]3=[CH:19][C:20]=2[C:21]=1Cl)=[O:11].[SH2:26].[Na]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[CH:16]=[C:17]3[O:25][CH2:24][O:23][C:18]3=[CH:19][C:20]=2[C:21]=1[SH:26])=[O:11]
Reactant: O=C(NCCc1ccccn1)c1cnc2cc3c(cc2c1Cl)OCO3
Reactant: S
Agent: [Na]
Solvent: CCO
Product: O=C(NCCc1ccccn1)c1cnc2cc3c(cc2c1S)OCO3
Yield: 77 %

Procedure:
To 10.4 g (0.025 mol) of 8-chloro-[1,3]dioxolo [4,5-g]quinoline-7-carboxylic acid (2-pyridin-2yl-ethyl)-amide in 100 mL of ethanol was added 7.2 g (0.1 mol) of sodium hydrogensulfide and the mixture was heated at reflux for 3 hours. The mixture was cooled and the solids filtered, washed with ethanol, and then with water. The filtrate was concentrated and the solids were suspended in water, collected by filtration, and recrystallized from ethanol to give 6.8 g of the title compound, mp 258-260° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[O:5][C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)=[O:9])[CH3:2].[CH3:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][Mg]Cl>C1COCC1>[CH2:1]([C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[O:5][C:6]1[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=1[C@:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:11]1)([OH:9])[CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH3:31])[CH3:2]
Reactant: CCc1ccccc1Oc1ccccc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: COCCCC[Mg]Cl
Solvent: C1CCOC1
Product: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of (R)-tert-butyl 3-(2-(2-ethylphenoxy)benzoyl)piperidine-1-carboxylate (2.25 g, 4.09 mmol) in THF (7 mL) at −20° C., 4-methoxybutylmagnesium chloride in THF (1.63 M, 5.0 mL, 8.15 mmol) was added dropwise. The resulting solution was warmed to rt slowly, and the completion of reaction was confirmed by LC-MS (˜20 min). The reaction was quenched with satd aq NH4Cl (8 mL) and extracted with ether (4×10 mL). The combined organic layers were washed with water and brine, and solvent was removed under vacuum to give a crude product, which was purified by flash column chromatography to give (R)-tert-butyl 3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (1.52 g, 75%). 1H NMR (CDCl3, 400 MHz) δ: 7.52 (d, 1H), 7.26 (dd, 1H), 7.20-7.00 (m, 4H), 6.78 (d, 1H), 6.60 (d, 1H), 4.34 (d, 1H), 4.00 (d, 1H), 3.30 (t, 2H), 3.24 (s, 3H), 2.78 (dd, 1H), 2.64 (q, 2H), 2.62 (m, 1H), 2.40 (m, 1H), 2.26 (m, 1H), 1.92 (m, 1H), 1.56 (m, 4H), 1.40 (s, 9H), 1.30 (m, 3H), 1.22 (t, 3H); MS m/z 520 (M+Na+).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34]
Reactant: Nc1cccc(S(=O)(=O)NCCO)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCCO)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2-hydroxy-ethyl)-benzenesulfonamide [CAS 436095-41-9] according to general procedure II. Light yellow solid. MS (ISP) 554.0 [(M−H)−]; mp 231° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.Cl>O.[Fe].C(O)C>[I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(I)cnc1Cl
Yield: 92.3 %

Procedure:
5-iodo-3-nitro-2-chloropyridine (230 mg, 0.809 mmol), ethanol (1 mL), water (6 drops), and concentrated HCl (0.020 mL) were stirred at room temperature for 10 min. Iron (500 mg, 8.95 mmol) was then added in small portions and the reaction round bottom flask was placed into a 100° C. oil bath for 20 min. The iron was removed by filtration, washed with ethanol, then the combined ethanol layers were concentrated under reduced pressure. The crude residue was purified by flash chromatography using 9:1 hexane: ethyl acetate to give 5-iodo-3-amino-2-chloropyridine (190 mg, 92%) as a colorless solid.