Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(Br)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(Br)ccc1OS(=O)(=O)c1ccc(C)cc1
Yield: 99.7 %

Procedure:
Dissolve 4-bromo-2-methoxy-phenol (1.032 g, 5.08 mmol) in CH2Cl2 (10 mL), and treat with TsCl (0.969 g, 5.08 mmol) followed by Et3N (1.06 mL, 7.62 mmol). Stir the reaction at RT for 2 h. Dilute with EtOAc (100 mL) and wash with water (2×30 mL). Dry with Na2SO4, filter, and concentrate to give 1.81 g (100%) of the title compound. MS/ES m/z (81Br) 380.9 [M+Na]+.
Reaction SMILES: [Br-].Br[C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:26][C@@:24]3([CH3:25])[C@@H:20]([CH2:21][C@@H:22]([CH3:32])[C@@H:23]3[C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[C@H:19]3[C:10]2=[C:11]2[C:16]([CH2:17][CH2:18]3)=[CH:15][C:14](=[O:33])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[NH4+:34].[Cl-]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Pd](Cl)Cl.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2]>[CH:29]1([C:27]([C@H:23]2[C@H:22]([CH3:32])[CH2:21][C@H:20]3[C@H:19]4[C:10]([C@@H:9]([C:6]5[CH:5]=[CH:4][C:3]([C:7]6[CH:8]=[CH:3][CH:4]=[CH:5][N:34]=6)=[CH:8][CH:7]=5)[CH2:26][C@:24]23[CH3:25])=[C:11]2[C:16](=[CH:15][C:14](=[O:33])[CH2:13][CH2:12]2)[CH2:17][CH2:18]4)=[O:28])[CH2:30][CH2:31]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Reactant: [NH4+]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4ccccn4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
(PPh3)2PdCl2 (4 mg, 0.006 mmol), ferrocene palladium dichloride (6 mg, 0.009 mmol) and 2-pyridylzine bromide (2 mL, 1.0 mmol) were added to a solution of (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one (200 mg, 0.41 mmol) in THF (4 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 5 hours at 60° C. and then cooled to room temperature. A saturated aqueous NH4Cl solution was added and the mixture was extracted three times with dichloromethane. The combined organic layers were dried through a phase separate filter and evaporated to dryness. Purification by HPLC followed by lyophilisation gave (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(2-pyridinyl)phenyl]estra-4,9-dien-3-one (80 mg, 0.16 mmol, 40% yield). 1H NMR (400 MHz, CDCl3): δ 0.33 (s, 3H), 0.80-2.87 (m, 24H), 4.46 (d, J=7 Hz, 1H), 5.80 (s, 1H), 7.20-7.23 (m, 1H), 7.25-7.29 (m, 2H), 7.68-7.77 (m, 2H), 7.89-7.92 (m, 2H), 8.67 (dt, J=5 and 1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][N:25]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].O.[OH-].[Li+].C1COCC1>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][N:25]=2)=[O:23])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: COC(=O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)-methyl 6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinate (11.5 g, 24.61 mmol) in MeOH (140 mL, Aldrich) was added lithium hydroxide hydrate (2.065 g, 49.2 mmol, Aldrich). The mixture was stirred at room temperature for 5 min followed by the addition of THF (5 mL, Aldrich) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, cooled to 0° C. and was adjusted to pH=6-7 with concentrated HCl. EtOAc (300 mL) was added to the adjusted pH mixture, and the resulting mixture was stirred at room temperature for 15 min. The organic layer was collected and the aqueous phase was extracted with EtOAc (1×200 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was then dissolved in MeOH (400 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The solid mixture was then purified by silica gel flash column chromatography using ISCO instrument (solid loading, 40% EtOAc/hexane, then 10% MeOH in EtOAc) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.75 (br. s., 1H), 9.85 (d, J=7.4 Hz, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.58 (d, J=4.7 Hz, 1H), 8.48 (dd, J=8.1, 2.1 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.83 (t, J=9.3 Hz, 1H), 7.50-7.61 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 6.58 (d, J=7.2 Hz, 1H). MS (ESI, positive ion) m/z: 454.0 (M+H)
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH2:15]([O:22][C@H:23]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:25][CH:24]1Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[Cl:1][C:2]1[N:3]([C@@H:24]2[O:25][C@H:26]([CH2:36][O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:23]2[O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: ClC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1cc2nc(Cl)n([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Compound 5 (598 mg 2.7 mmole) was dissolved in dry CH3CN(60 ml) and 97% NaH (80 mg, 3 mmole) was added. The mixture was stirred under N2 for 1 hour at room temperature. Then 2,3,5-tri-O-benzyl-D-arabinofuranosyl chloride (prepared from 2,3,5-tri-O-benzyl-1-O-p-nitrobenzoyl-D-arabinofuranose) (1.83 g, 3 mmole)) dissolved in dry CH3CN (20 ml) was added dropwise. The mixture was stirred under N2 for overnight at room temperature. The reaction solution was filtered through Celite. The filtrate was evaporated to give a syrup and this syrup was subjected to flash column chromatography on silica gel (Kieseigel 60, 230-400 mesh) and eluted with CH2Cl2. The fractions containing 133 were combined and evaporated to give 1.6 g (95.0%) of 133. (IR KBr cm-1 : 1140-1060 (C-O-C)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[Mg].[C:16]1([CH3:24])[C:17]([CH:22]=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>O1CCCC1>[CH3:24][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1)[OH:23]
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Reactant: Cc1ccccc1C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)c1ccc(C2=NC(C)(C)CO2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-bromophenyl)-4,4-dimethyl-2-oxazoline (1 g) in dry tetrahydrofuran (10 ml) are added dropwise magnesium (526 mg) and dry tetrahydrofuran (50 ml) under refluxing. The heating of the mixture is stopped, and thereto is added 2-(4-bromphenyl)-4,4-dimethyl-2-oxazoline (4 g) at a slowly refluxing rate, during which the mixture is stirred for 30 minutes, and then thereto is added o-tolualdehyde (2.16 ml) under ice-cooling. The mixture is stirred under ice-cooling for one hour, and stirred at room temperature for two hours, and the reaction is quenched with adding thereto a saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate, and the organic layer is washed successively with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=4˜2:1) to give 2-{4-[1-(2-methylphenyl)-1-hydroxymethyl]phenyl}-4,4-dimethyl-2-oxazoline (3.07 g) as white powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([CH2:21][OH:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.CCN(CC)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O>[C:11]1([CH:21]=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: OCc1cccc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
To a cold (−78° C.) solution of oxalyl chloride (6.9 mL, 0.079 mol) in dry CH2Cl2 (200 mL) was added dropwise dry DMSO (11.2 mL, 0.158 mol). The mixture was stirred for 10 min, and then a solution of 1-naphthalenemethanol (10.0 g, 0.063 mol) in dry CH2Cl2 (40 mL) was added over 15 min. The mixture was stirred for 10 min, and then Et3N (44 mL, 0.316 mol) was added slowly. The reaction mixture was allowed to warm to room temperature. After 3.5 h, to the pale yellow heterogeneous mixture was added 10% aqueous citric acid (30 mL) and water (100 mL). The organic phase was washed with water (100 mL) and saturated aqueous NaCl (100 mL), dried (anhydrous MgSO4), filtered, and concentrated. Ether-hexane (1:1) was added, and the mixture was filtered. Concentration provided a pale orange oil (9.7 g).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1>CS(C)=O.CO>[CH3:35][O:34][C:32]1[CH:33]=[C:28]([CH2:27][CH2:26][C:24]2[CH:25]=[C:21]([NH:20][C:18]([C:15]3[CH:14]=[N:13][C:12]([N:7]4[CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][CH2:6]4)=[CH:17][N:16]=3)=[O:19])[NH:22][N:23]=2)[CH:29]=[C:30]([O:36][CH3:37])[CH:31]=1
Reactant: C=CCN1CCCNCC1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CO
Solvent: CS(C)=O
Product: C=CCN1CCCN(c2cnc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
1-Prop-2-enyl-1,4-diazepane (224 mg, 1.60 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was diluted with MeOH (5 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product as an orange oil. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (271 mg, 69%) as a yellow solid.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]([CH3:37])([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:26]([C:27](=[O:35])[NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24][O:23][C:22]=3[CH:36]=2)=[CH:14][N:13]=1)[C:6]([O:8]C)=[O:7].O1CCCC1.O>CO>[CH3:4][C:5]([CH3:37])([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:26]([C:27](=[O:35])[NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24][O:23][C:22]=3[CH:36]=2)=[CH:14][N:13]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(c2)OCCN3C(=O)Nc2ccccc2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(COc1ccc(-c2ccc3c(c2)OCCN3C(=O)Nc2ccccc2)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
Lithium hydroxide monohydrate (14.3 mg, 0.342 mmol) was added to a solution of methyl 2,2-dimethyl-3-(5-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)propanoate B-3 (ca. 62.0 mg, 0.114 mmol) in 1:1:1 tetrahydrofuran:water:methanol (1.14 mL) at room temperature. After 12 h of vigorous stirring at room temperature, lithium hydroxide monohydrate (14.3 mg, 0.342 mmol) was added, and the reaction mixture was heated at 65° C. under microwave irradiation for 30 mins. The clear solution was then quenched with a 1 N aqueous solution of hydrogen chloride (1.0 mL) and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give white crystalline 2,2-dimethyl-3-(5-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)propanoic acid B-4 (36.6 mg, Yield=72% over 2 steps). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.23 (s, 6H), 3.88 (t, J=4.10 Hz, 2H), 4.28 (s, 2H), 4.30 (t, J=4.10 Hz, 2H), 6.86 (d, J=8.51 Hz, 1H), 7.01 (dt, J=1.10, 7.41 Hz, 1H), 7.16-7.21 (m, 2H), 7.29 (t, J=7.72 Hz, 2H), 7.50 (d, J=8.20 Hz, 2H), 7.60 (d, J=8.51 Hz, 1H), 7.98 (br d, J=8.51 Hz, 1H), 8.44 (s, 1H), 9.16 (s, 1H), 12.37 (br s, 1H); MS (ESI) [M+1]+ 448.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C([Li])CCC.CN(C)CCN(C)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([CH2:33]Br)[CH:26]=1>C1COCC1>[Br:24][C:25]1[CH:26]=[C:27]2[C:28](=[CH:29][CH:30]=1)[CH2:31][C:3]1([C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[CH2:33]2
Reactant: BrCc1ccc(Br)cc1CBr
Reactant: O=C1Cc2ccccc2N1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12Cc1ccc(Br)cc1C2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of oxindole (363 mg, 2.73 mmol) at −78° C. in THF (15 mL) was added butyllithium (2.5 M in hexanes, 2.29 mL, 5.73 mmol) dropwise, followed by the dropwise addition of tetramethylethylenediamine (0.905 mL, 6.00 mmol). The solution was stirred for 1 h at −78° C., then a solution of 4-bromo-1,2-bis(bromomethyl)benzene [Anderson et al., J. Org. Chem. 1979, 44(9), 1519-1533] (1.87 g, 5.45 mmol) in THF (5 mL) was added dropwise. The reaction solution was stirred at −10 to −20° C. for 2 h and at ambient temperature for 16 h. The reaction mixture was partitioned between saturated NH4CI (50 mL) and EtOAc (50 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=315 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)(=[O:47])[O:9][C@@:10]([CH3:46])([C:13](=[O:45])[C@@H:14]([NH:22][C:23](=[O:44])[C@@H:24]([NH:28][C:29](=[O:43])[C@@H:30]([NH:34][C:35]([C:37]1[S:41][C:40]([CH3:42])=[N:39][CH:38]=1)=[O:36])[CH2:31][O:32][CH3:33])[CH2:25][O:26][CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:11][I:12]>>[C:8](=[O:47])([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:9][C@@:10]([CH3:46])([C:13](=[O:45])[C@@H:14]([NH:22][C:23](=[O:44])[C@@H:24]([NH:28][C:29](=[O:43])[C@@H:30]([NH:34][C:35]([C:37]1[S:41][C:40]([CH3:42])=[N:39][CH:38]=1)=[O:36])[CH2:31][O:32][CH3:33])[CH2:25][O:26][CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:11][I:12]
Reactant: Oc1ccccc1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@](C)(CI)OC(=O)Cl
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@](C)(CI)OC(=O)Oc1ccccc1

Procedure:
Prepared according to procedures described above, using phenol with the intermediate (2S,4S)-1-iodo-4-((S)-3-methoxy-2-((S)-3-methoxy-2-(2-methylthiazole-5-carboxamido)propanamido)propanamido)-2-methyl-3-oxo-5-phenylpentan-2-yl carbonochloridate. 1H NMR (CDCl3): δ 8.02 (s, 1H), 7.40 (t, J=8 Hz, 2H), 7.29-7.10 (m, 10H), 6.98 (d, J=7.2 Hz, 1H), 6.82 (d, J=6 Hz, 1H), 5.51-5.45 (m, 1H), 4.67-4.62 (m, 1H), 4.45-4.41 (m, 1H), 3.83-3.78 (m, 2H), 3.70-3.64 (m, 2H), 3.50 (t, J=4.8 Hz, 1H), 3.45 (s, 3H), 3.32-3.28 (m, 1H), 3.27 (s, 3H), 3.19-3.14 (m, 1H), 2.91-2.86 (m, 1H), 2.74 (s, 3H), 1.55 (s, 3H); MS for C32H37IN4O9S m/z: 782 (M+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[C:19]=1[CH:28]=O.O>O1CCCC1>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[C:19]=1/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cn1cc2c(C=O)c(Cl)ccc2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(Cl)ccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
To a suspension of sodium hydride (0.488 g, 12.2 mmol) in tetrahydrofuran (10 mL) was added a solution of ethyl diethylphosphonoacetate (2.44 mL, 12.2 mmol) in tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 5-chloro-2-methyl-2H-indazole-4-carbaldehyde (2.16 g, 11.1 mmol) in tetrahydrofuran (10.0 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (2.54 g, yield 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.O.Cl>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6]1([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:7]2=[O:12]
Reactant: COc1cccc2c1CCC2=O
Reactant: BrCCCCCBr
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: COc1cccc2c1CC1(CCCCC1)C2=O

Procedure:
A solution of 20 g 4-methoxyindan-1-one and 24 g 1,5-dibromopentane in 150 ml benzene is added quickly dropwise to a solution of potassium tert.-butylate (produced from 9.7 g potassium and excess tert.-butanol) in 200 ml benzene at 80°. The mixture is refluxed for 4 hours, treated with 50 ml water and 200 ml 2 N hydrochloric acid, and extracted with benzene. Chromatography on silicagel of the benzene phase gives 4'-methoxy-spiro(cyclohexane-1,2'-indan)-1'-one. M.Pt. 94°-96°.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH:26]=O)[CH:21]=1.O>O1CCCC1>[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22](/[CH:26]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:21]=1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: Cc1ccnc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(/C=C/C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A solution of tert-butyl diethylphosphonoacetate (6.2 g, 24 mmol) in tetrahydrofuran (20 ml) was added dropwise to a mixture of sodium hydride (60% in oil, 1.1 g, 26 mmol) and tetrahydrofuran (120 ml) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Successively, a solution of 4-methyl-2-pyridinecarbaldehyde (1.5 g, 12 mmol) in tetrahydrofuran (30 ml) was added dropwise to the mixture at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:5, v/v) were collected and concentrated to give the titled compound (1.9 g, 70%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:4]=2[O:3]1.CN(C)C=O.C(Cl)(=O)OCC.[NH2:29][CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][N:32]1[CH2:36][CH3:37]>O.C(N(CC)CC)C.CC(C)=O>[CH2:36]([N:32]1[CH2:33][CH2:34][CH2:35][CH:31]1[CH2:30][NH:29][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:9]=1)=[O:13])[CH3:37]
Reactant: CC1Cc2cc(S(N)(=O)=O)cc(C(=O)O)c2O1
Reactant: CCN1CCCC1CN
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Temperature: 15 °C
Reaction time: 8 h

Procedure:
To a solution of 6 g of (-)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid [[α]D =-17.04° (dimethylformamide, c=1)] in a mixed solvent of 55 ml of dimethylformamide and 55 ml of acetone is added 5.9 g of triethylamine and the whole is stirred. The system is cooled to 15° C. and 2.7 g of ethyl chlorocarbonate is added dropwise for 10 minutes. After stirring at room temperature for 40-45 minutes, 7.5 g of (+)-2-aminomethyl-1-ethylpyrrolidine is added. The reactant is stirred at room temperature for 20 minutes and allowed to stand overnight. Excess triethylamine and acetone are distilled off under reduced pressure and the residue obtained is poured into 500-600 ml of water while stirring. Precipitated crystals are collected by suction filtration, washed with water and dried. The crude crystals are recrystallized from ethyl acetate to give crystals of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide which is an optically active compound and has a m.p. 163°-164° C. and [α]D =+50.815° (dimethylformamide, c=1).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].CO>O1CCOCC1.C(Cl)(Cl)Cl>[ClH:24].[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccccc2Br)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(c1ccccc1Br)N1CCCNCC1
Yield: 95.69 %

Procedure:
A solution of 4-(2-bromo-benzoyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (500 mg, 1.3 mmol) in 1,4-dioxane.HCl (3 mL) was stirred at 0° C. for 30 minutes. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated under reduced pressure to get a solid, which was washed with ether and dried to afford 400 mg (95.69% Yield) of (2-bromo-phenyl)-[1,4]diazepan-1-yl-methanone hydrochloride.