Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH:2]([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[CH3:31][O:32][CH2:33][CH2:34]Cl>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:34][CH2:33][O:32][CH3:31])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COCCCl
Reactant: Cc1ccccc1Nc1c(C(=O)C(C)C)cnc2c(O)cccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCCOc1cccc2c(Nc3ccccc3C)c(C(=O)C(C)C)cnc12
Yield: 11.3 %

Procedure:
A mixture of 3-isobutyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (5.0 g, 15.6 mmol), potassium t-butoxide (2.63 g, 23.4 mmol) and 2-chloroethyl methyl ether (2.85 ml, 31.2 mmol) in tetrahydrofuran (250 ml) was heated at reflux for 3 days, then the solvent evaporated. Water was added, the product extracted into dichloromethane, and the organic extracts dried and evaporated. Chromatography (silica gel, ethyl acetate/2% acetic acid/0-5% methanol) removed unchanged starting material, then further chromatography (silica gel, 1-1.5% methanol in dichloromethane) and crystallisation from petroleum ether (40-60) gave 3-isobutyryl-4-(2-methylphenylamino)-8-(2-methoxyethoxy)quinoline (0.67 g), m.p. 68°-70°.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][CH2:16][C@@H:17]([OH:19])[CH3:18]>>[C@@H:17]([O:19][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH2:16][CH3:15])[CH3:18]
Reactant: CC[C@H](C)O
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Product: CC[C@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to Example B4(c) from 2-Fluoro-5-methanesulfonyl-benzoic acid (example B4(b)) and S-(+)-2-butanol. White solid. MS (m/e): 271.1 ([M−H], 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25]>O1CCCC1>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([O:13][CH3:25])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(F)c2F)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2cccc(F)c2F)CCN(C(=O)OC(C)(C)C)C1
Yield: 55.3 %

Procedure:
Preparation according to Preparation 2. Tert-butyl-3-(2,3-difluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (8.12 g, 27.1 mmol) in dry tetrahydrofuran (50 mL), sodium hydride (60% dispersion in mineral oil, 1.63 g, 40.7 mmol), iodomethane (3.38 mL, 54.3 mmol). Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (4.7 g, 55%). MS m/z (rel. intensity, 70 eV) 240 (bp), 237 (72), 183 (81), 171 (82), 57 (87).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[CH:3]=1.[Li]>N>[O:8]=[C:4]1[CH2:3][CH:2]([C:1]([OH:11])=[O:10])[CH:7]=[CH:6][CH2:5]1
Reactant: COc1cccc(C(=O)O)c1
Agent: N
Agent: [Li]
Product: O=C1CC=CC(C(=O)O)C1

Procedure:
To synthesize methyl cis-3,5-dihydroxy-5-(trimethylsilylethynyl)cyclohex-1-ene-1-carboxylate, m-anisic acid is subject to the Birch reduction with lithium in ammonia to produce 5-oxocyclohex-2-ene-1-carboxylic acid, followed by methylation of thusproduced cyclohex-2-ene-1-carboxylic acid to methyl 5-oxocyclohex-2-ene-1-carboxylate with diazomethane, trimethylsilyl-ethynylation of thus-produced cyclohex-2-ene-1-carboxylate with cerium dichloride trimethylsilylacetylene to produce methyl cis-5-hydroxy-5-(trimethylsilylethynyl)cyclohex-2-ene-1-carboxylate, conversion to an epoxide and opening of the resulting epoxide ring to produce the cis-3,5-dihydroxy compound.
Reaction SMILES: [CH:1](Cl)([OH:5])[CH:2]([Cl:4])[Cl:3].N1C=CC=CC=1.Cl[C:14]([S:16][Cl:17])=[O:15].C(Cl)[Cl:19]>>[Cl:3][C:2]([Cl:19])([Cl:4])[CH2:1][O:5][C:14]([S:16][Cl:17])=[O:15]
Reactant: O=C(Cl)SCl
Reactant: ClCCl
Reactant: OC(Cl)C(Cl)Cl
Solvent: c1ccncc1
Product: O=C(OCC(Cl)(Cl)Cl)SCl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To an ice cold vigorously stirred (mechanical stirrer) solution of trichloroethanol (50.0 ml, 0.52 mol) and pyridine (42.0 ml, 0.52 mol) in 300 ml of methlene chloride, chlorocarbonylsulfenyl chloride (43.5 ml, 0.52 mol) was added dropwise over 30 min. After the addition the solution was stirred at 0° for 1.5 hr. The ice bath was removed and the stirring continued for 1.5 hr. The mixture (solid formed) was washed with ice--H2O and ice cold sat. NaCl. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure. After removal of the solvent an oily solid remained. The solid was removed by triterration with ether and filtration of the solid. The filtrate was condensed under reduced pressure and the process repeated until, after removal of the solvent from the filtrate, the liquid could be filtered without the aid of solvent. The yellow liquid was distilled under reduced pressure: bp 54°-59° (0.25 mm; bath temp. 80°-90°); NMR (CDCl3 ) δ 5.0 (S, 2H).
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2]>C1C=CC=CC=1>[CH2:4]=[CH:3][C:1]1[CH:2]=[CH:4][CH:3]=[CH:1][CH:2]=1.[CH2:2]=[CH:1][CH:3]=[CH2:4]
Reactant: [Li]C(C)CC
Solvent: c1ccccc1
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
A 3-arm star styrene/butadiene block copolymer was synthesized using standard high vacuum techniques, M. Morton et al., J. Rubber Chem. and Technol., 48, 359 (1975). An example of the general polymerization procedure is as follows: A 1000 ml all-glass reactor was attached to the vacuum line and flamed with a hand torch to remove surface moisture. Approximately 500 ml of benzene was distilled into the apparatus and magnetic stirring was commenced. An ampule containing 0.0165 mol of sec-butyl lithium in benzene was released into the vessel through a breakseal. Styryl oligomers of an average length of four (4) units were then formed by opening an ampule containing 0.0655 mol of styrene monomer. The contents of the reactor changed in color from a clear water-white to a deep orange over the course of 24 hours at 25° C. To prepare for the addition of butadiene and to increase the amount of 1,2 enchainment in the polybutadiene segment, 0.717 mol of triethyl amine (TEA) was distilled into the reactor after being stirred over n-butyl lithium; the molar ratio of TEA/ living chain end was 45:1. The reaction mass changed to a dark red color during the step. An ampule containing 1.70 mol of 1,3 butadiene was then slowly released into the vessel, which was held at 10° C. by means of a constant temperature bath, over the course of five (5) hours. The viscosity of the mixture increased markedly during this period, and the color faded to a pale yellow. After warming the viscous solution to room temperature and stirring for an additional 48 hours, 0.0049 mol of methyl trichlorosilane in benzene solution was added from an ampule to couple the polymer chains and form the three-arm star polymer. The linking reaction was allowed to proceed at 40° C. for 72 hours.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:6][C:7](=[O:24])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][CH:20]=[N:19][CH:18]=2)=[C:13]([O:22][CH3:23])[CH:12]=1)=[O:9])([CH3:5])[CH3:4].[C:25]([CH2:29][C:30](O)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.CN(C)CCCN=C=NCC.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O.ClCCl>[CH3:23][O:22][C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]([NH:6][C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][C:30](=[O:31])[CH2:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[CH:16]=[CH:15][C:14]=1[C:17]1[O:21][CH:20]=[N:19][CH:18]=1
Reactant: CC(C)(C)CC(=O)O
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)CN)ccc1-c1cnco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)CNC(=O)CC(C)(C)C)ccc1-c1cnco1
Reaction time: 16 h

Procedure:
30 mg (0.09 mmol) of N-(2-amino-1,1-dimethyl-ethyl)-N′-(3-methoxy-4-oxazol-5-yl-phenyl)-oxalamide, 52 mg (0.45 mmol) of tert-butylacetic acid, 86 mg (0.45 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 69 mg of HOAt were dissolved and stirred in 2 ml of dimethylformamide. After stirring for 16 hours the mixture was diluted with 10 ml of dichloromethane and washed with 10% citric acid solution in water, saturated sodium hydrogen carbonate solution and brine. The organic solution was then dried with solid magnesium sulphate, filtered and evaporated to give N-(3-methoxy-4-(5-oxazolyl)phenyl]-N′-[2-(3,3-dimethylbutyramido)-1,1-dimethylethyl]oxalamide as a pale yellow solid, MS: m/e 431.3 [M+H]+.
Reaction SMILES: [CH2:1]1[O:14][C:4]2([CH2:11][CH2:10][CH:9]3[CH2:12][CH:5]2[CH2:6][CH2:7][CH:8]3[NH2:13])[O:3][CH2:2]1.C(N(CC)CC)C.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.O>[CH2:2]1[O:3][C:4]2([CH2:11][CH2:10][CH:9]3[CH2:12][CH:5]2[CH2:6][CH2:7][CH:8]3[NH:13][C:30]([O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])[O:14][CH2:1]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CCC2CC1CCC21OCCO1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CCC2CC1CCC21OCCO1)OCc1ccccc1
Reaction time: 8 h

Procedure:
1.97 g of 6-Amino-bicyclo[3.3.1]nonan-2-one ethylene ketal (98) were dissolved in 30 mL of dry dichloromethane and 1.52 mL of dry triethylamine and 1.42 mL of benzylchloroformate were added. The mixture was stirred overnight, taken up in water and extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate and evaporated to dryness. The crude product was purified by chromatography to give 0.92 g of the desired product. Rt=3.18 min (Method E). Detected mass: 332.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(OCC)(=O)C.[Pd]>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:2]=1[F:1])[CH3:8]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N)cc1F

Procedure:
To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAc was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 hour to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The pH of the solution was adjusted to 4 with aqueous NaOH. The mixture was extracted with more ethyl acetate. The combined organic layers were washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80° C. for 1 hour. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 hours and concentrated to dryness. Ethyl 2-fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation converted ethyl 2-fluoro-4-nitrobenzoate into the title compound. 1H NMR δ 7.77 (t, J=8.4 Hz, 1H), 6.41 (dd, J1 =8.6, J2 =2.2 Hz, 1H), 6.33 (dd, J1 =13.0, J2 =2.2 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 4.3 (b, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.[CH3:23][Mg]Br.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O.O>[OH:1][C:2]1([CH3:23])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)CC(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(O)CN(C(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
To a cooled solution (ice water bath) of di-tert-butyl 6-oxo-1,4-diazepane-1,4-dicarboxylate (570 mg, 1.82 mmol) in THF (10 mL), was added dropwise a solution of methylmagnesium bromide (3 M in Et2O, 0.79 mL, 2.36 mmol). The mixture was allowed to warm to room temperature and stirred for 16 hr. Aqueous saturated ammonium chloride solution (5 mL) was added and the mixture diluted with EtOAc (30 mL) and water (30 mL). The layers were separated and the organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-70% EtOAc/isohexane) gave di-tert-butyl 6-hydroxy-6-methyl-1,4-diazepane-1,4-dicarboxylate as an oil (0.45 g). To a solution of this oil (0.45 g, 1.36 mmol) in MeOH (2 mL), was added HCl in 1,4-dioxane (4 M, 6.8 mL, 27.3 mmol) and the solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure. The residue was dissolved in MeOH and passed through an SCX column washing with MeOH and eluting with 1 N ammonia in MeOH. The solvent was removed under reduced pressure to afford 6-methyl-1,4-diazepan-6-ol as an oil. To this amine in EtOH (3 mL) was added 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (209 mg, 1.29 mmol) and DIPEA (0.9 mL, 5.44 mmol) and the mixture was heated in the microwave at 130° C. for 3 hr. The solvent was removed under reduced pressure. To the crude tert-butyl 6-hydroxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate in DCM (10 mL) was added di-tert-butyl dicarbonate (1.18 g, 5.44 mmol) and DIPEA (0.9 mL, 5.44 mmol). The mixture was stirred at room temperature for 16 hr, the solvent was removed under reduced pressure and the residue dissolved in DCM (30 mL). Water (20 mL) was added and the organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl 6-hydroxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (235 mg, 22% over four steps) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 4.16-3.79 (m, 7H), 3.52-2.81 (m, 4H), 1.70-1.80 (br s, 1H), 1.51 (s, 9H), 1.16 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:14][NH:15][CH3:16].C(N(CC)CC)C.O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([S:9]([N:15]([CH3:16])[CH3:14])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
Commercially available 3,4-difluorophenylsulfonylchloride (117 μL, 0.87 mmol) was dissolved in dichloromethane (5 mL), and dimethylamine hydrochloride (59 mg, 0.73 mmol) and triethylamine (203 μL, 1.45 mmol) were added, followed by stirring at room temperature for 2 hours. To the reaction solution, water (15 mL) was added, followed by extraction twice with dichloromethane (15 mL), and washing was carried out with saturated brine (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, followed by vacuum drying, to afford the desired compound (41.0 mg, yield 26%) as a colorless oil.
Reaction SMILES: [NH:1]([C:13]([O:15]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([CH:38]=O)=[CH:36][CH:37]=1.[NH:40](C(OC(C)(C)C)=O)[C@H:41](C(O)=O)[CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C1C=NC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>>[CH2:3]([C@@H:2]1[NH:1][C:13](=[O:15])[C@H:41]([CH2:42][O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:40]([CH2:38][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[C:10]1=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2cccnc21
Product: COc1ccc(CN2C(=O)[C@H](Cc3ccccc3)NC(=O)[C@@H]2COCc2ccccc2)cc1

Procedure:
TentaGel resin was coupled with FmocPhe (Mitsunobu conditions) and reductively alkylated with anisaldehyde. BocSer(OBzl) was coupled with HOAt/DIC and after Boc-deprotection the DKP formed in 4% TEA/toluene (12 h). Yield: 7.1 mg (8.3%). 1H-NMR (400 MHz, CDCl3): δ=1.60 (dd, J=6.4, 6.4 Hz, 1 H), 3.22 (dd, J=3.4, 10.0 Hz, 1 H), 3.28 (dd, J=2.8, 10.0 Hz, 1 H), 3.44 (dd, J=2.2, 6.4 Hz, 1 H), 3.81 (s, 3 H), 3.85 (d, J=14.6 Hz, 1 H), 4.07 (dd, J=2.2, 6.4 Hz, 1 H), 4.18 (dd, J=2.8 3.4 Hz, 1 H), 4.21 (d, J=8.0 Hz, 1 H), 4.25 (d, J=8.0 Hz, 1 H), 5.54 (d, J=14.6 Hz, 1 H), 6.42 (broad s, 1 H), 6.87-6.89 (m, 2 H), 7.19-7.40 (m, 12 H). 13C-NMR (101 MHz, CDCl3): δ=36.6, 46.5, 55.8, 59.0, 72.1, 73.5, 114.6, 126.9, 127.8, 128.0, 128.2, 128.7, 129.1, 130.2, 130.5, 135.2, 137.4, 159.8, 163.5, 166.7. Anal. Calcd. for C27H28 N2O4.2H2O: C, 67.48; H, 6.71; N, 5.83, found: C, 68.00; H, 6.18; N, 5.65.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[O:39]1[C:38]2[CH:43]=[CH:44][C:35]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]5[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)=[CH:19][CH:18]=5)=[O:15])=[CH:7][C:6]=4[CH:32]=3)=[CH:36][C:37]=2[O:42][CH2:41][CH2:40]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCCO2
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc5c(c4)OCCO5)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]pheny]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 2,3-dihydro-1,4-benzodioxin-6-yl borate (114 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:2) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 55) (257 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][O:5][CH2:6][CH2:7][OH:8].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[C:13]([Cl:19])[CH:12]=1.[Cl-:20].[NH4+]>CN(C)C=O>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:9][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Br:10])=[CH:12][C:13]=2[Cl:20])=[C:13]([Cl:19])[CH:12]=1
Reactant: [Cl-]
Reactant: OCCOCCO
Reactant: Clc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(Br)ccc1COCCOCCOCc1ccc(Br)cc1Cl

Procedure:
To a solution of 472 mg (11.8 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (50 ml) was added 500 mg (4.71 mmol) of diethylene glycol in an atmosphere of argon, and the mixture was allowed to react at 40°-50° C. for 30 min. Then, 2.96 g (10.4 mmol) of 4-bromo-2-chlorobenzyl bromide was added, and the mixture was reacted at room temperature for 16 hours. To the reaction solution at 0° C. was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with ethyl acetatehexane (1:3) yielded 2.10 g (4.09 mmol) of 1,9-bis(4-bromo-2-chlorophenyl)-2,5,8-trioxanonane.
Reaction SMILES: C(Br)(Br)(Br)Br.[CH2:6]([NH:13][CH2:14][C:15]1([CH2:27]O)[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])(C)C)=[O:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:29]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:30]=1.C(N(CC)CC)C>C(Cl)Cl.CC#N>[CH2:6]([N:13]1[CH2:14][C:15]2([CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][CH2:23][CH2:26][CH2:29][CH3:30])=[O:21])[CH2:27]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1(CO)CNCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: BrC(Br)(Br)Br
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)N1CCCC12CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
A solution of CBr4 (369.5 g, 1.115 mol) in 1 L of CH2Cl2 was added dropwise to a solution of tert-butyl 2-[(benzylamino)methyl]-2-(hydroxymethyl)pyrrolidine-1-carboxylate (Intermediate 51, 178.5 g, 555 mmol) and triphenylphosphine (292 g, 1.115 mol) in CH2Cl2 (1.8 L) at 0° C. The resulting mixture was stirred at r.t. for 2 h then concentrated in vacuo. The residue was suspended in a mixture of CH3CN (2 L) and triethylamine (563.5 g, 5.57 mol) and refluxed at 80° C. for 24 h. The mixture was then concentrated in vacuo. Purification by FCC, eluting with 1:1 petrol-EtOAc gave the title compound (97.5 g, 58%) as yellow oil; 1H NMR: (300 MHz, CDCl3) 1.47-1.72 (11H, m), 2.30 (2H, m), 3.19 (2H, d), 3.31-3.47 (2H, m), 3.82-4.12 (4H, m), 7.22-7.28 (5H, m).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([CH3:16])=[N:10]2.CO.O.[OH-].[Li+]>C(O)(=O)C>[Cl:15][C:13]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:25])=[C:8]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[C:9]([CH3:16])=[N:10]2)=[C:5]([CH2:4][C:3]([OH:26])=[O:2])[CH:14]=1
Reactant: COC(=O)Cc1cc(Cl)cc2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1nc2cc(Cl)cc(CC(=O)O)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of [7-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yl]acetic acid methyl ester (0.24 g), methanol (10 mL), water (2.0 mL) and saturated aqueous lithium hydroxide solution (1.0 mL) was stirred at room temperature for 17 hours. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the methanol removed under reduced pressure. The resulting precipitate was collected by filtration and washed with water. Crystallisation of the solid from ethyl, acetate gave title compound as a fluffy white solid, 0.16 g