Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br-:17]>>[Br:17][CH:10]([C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: [Br-]
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Product: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Yield: 48 %

Procedure:
According to the procedure of Example 7, Part C, ethyl 3-(3-cyanophenyl)-3-oxopropionate (3.2 g, 14.7 mmol) was converted into the crude bromide, which was purified by flash chromatography (elution with 4:1 hexanes/ethyl acetate) to afford 2.1 g (48%) of the title compound. MS(H2O, GC/MS) 296/298 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[CH:20]=[C:19]([CH2:21][C:22]3[CH:23]=[N:24][C:25]([O:28]C)=[CH:26][CH:27]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[O:10])[CH2:6][CH2:5][O:4][CH2:3]1.C[Si](I)(C)C>C(Cl)Cl>[OH:28][C:25]1[N:24]=[CH:23][C:22]([CH2:21][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:9]([NH:8][C@H:7]3[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]3[OH:1])=[O:10])[CH:20]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(Cc2cc(C(=O)N[C@H]3CCOC[C@@H]3O)nc3ccccc23)cn1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Cc2ccc(O)nc2)c2ccccc2n1
Temperature: 50 °C

Procedure:
To a solution of N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-4-[(6-methoxypyridin-3-yl)methyl]quinoline-2-carboxamide (0.15 g, 0.38 mmol) in CH2Cl2 was added trimethylsilyl iodide (0.15 mL, 1.1 mmol). The reaction mixture was heated to 50° C. for 16 h and cooled to room temperature and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 0-15% methanol in methylene chloride to afford 4-[(6-hydroxypyridin-3-yl)methyl]-N-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]quinoline-2-carboxamide (L1) that gave a mass ion (ES+) of 380.4 for M+H+.
Reaction SMILES: ClCCl.C(OC(=O)[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=3)[C:31]([CH3:40])=[CH:30][C:29]2=[O:41])[CH2:22][CH2:21]1)[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>O.C(OCC)(=O)C>[CH3:39][O:38][C:35]1[CH:36]=[C:37]2[C:32]([C:31]([CH3:40])=[CH:30][C:29](=[O:41])[N:28]2[CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][CH:20]([NH:10][CH2:11][CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:25][CH2:24]2)=[CH:33][CH:34]=1
Reactant: COc1ccc2c(C)cc(=O)n(CCN3CCC(N(CCCc4ccccc4)C(=O)OC(C)(C)C)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(NCCCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
To 2 mL of a dichloromethane solution containing 0.16 g of tert-butyl(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(3-phenylpropyl)carbamate, 0.5 mL of trifluoroacetic acid was added under ice-cooling and stirred for 1.5 hours, thereafter the mixture was raised to the room temperature and left to stand for one night. The solvent was removed under reduced pressure, and to the residue thus obtained, ethyl acetate and water were added, and adjusted to pH 12.3 with 20% aqueous sodium hydroxide solution. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.11 g of 7-methoxy-4-methyl-1-(2-(4-((3-phenylpropyl)amino)piperidin-1-yl)ethyl)quinolin-2(1H)-one as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[CH:20]=[CH:19][C:11]([O:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Cl:28][CH2:29]Cl.CCCCCC>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[CH:20]=[CH:19][C:11]([O:12][C:13]([CH3:18])([CH3:17])[C:14]([O:16][CH2:29][Cl:28])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CCCCCC
Product: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)OCCl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101 %

Procedure:
A mixture of 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid (10.0 g, 31.4 mmol), sodium bicarbonate (13.2 g, 47.1 mmol, 1.5 eq) and tetrabutylammonium hydrogensulfate (2.1 g, 6.3 mmol, 0.2 eq) in water (150 mL) was stirred at room temperature for 15 min. Dichloromethane (150 mL) was added and the mixture was cooled in ice. Chloromethyl sulfochloridate (4.2 mL, 47.1 mmol, 1.5 eq) was added and the mixture was stirred overnight at room temperature. The layers were separated, the organic phase was washed with water (50 mL) and brine, then dried over sodium sulfate. The drying agent was filtered off and the solution was concentrated by rotary evaporation to leave a thick oil. Hexane (50 mL) and seeds were added and rotary evaporation was continued at room temperature to leave chloromethyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate 1 as a white solid (11.6 g, 101% yield). 1H-NMR (CDCl3) δ 7.73 (d, 2 H), 7.70 (d, 2 H), 7.44 (d, 2 H), 6.87 (d, 2 H), 5.77, (s, 2 H), 1.70 (s, 6 H) ppm.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:42])[CH2:7][N:8]([CH2:36][C:37]([O:39]CC)=[O:38])[C:9](=[O:35])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=[CH:12][C:11]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C>>[C:37]([CH2:36][N:8]([C:9](=[O:35])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=[CH:12][C:11]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:7][C:6]([OH:42])=[O:5])([OH:39])=[O:38]
Reactant: CCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)N(CC(=O)O)CC(=O)O)c1
Yield: 94 %

Procedure:
Sodium hydroxide hydrolysis of N-(2-ethoxy-2-oxoethyl)-N-[5-(decyloxy)-2-(phenylmethoxy)benzoyl]glycine ethyl ester under conditions described in Example 81 gave N-(carboxymethyl)-N-[5-(decyloxy)-2-(phenylmethoxy)benzoyl]glycine (94% yield, mp 74°-78°).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[N:10]([O-])=O.[Na+]>OS(O)(=O)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][N:10]=[N:9][C:4]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Br)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Brc1ccc2[nH]nnc2c1
Reaction time: 0.5 h

Procedure:
A mixture of Example 248A (262 mg; 1.4 mmol) in 10% H2SO4 (4 mL) was treated with NaNO2 (120 mg; 1.7 mmol) in water (1 mL), stirred for 30 min., diluted with water, and extracted with EtOAc. The extracts were rinsed with brine, dried (Na2SO4), concentrated and purified by flash chromatography (5% MeOH/CH2Cl2) to provide the desired product.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.C(C(C#N)=C(C#N)C#N)#N.ClCCO[CH:21]([O:29][CH2:30][CH2:31][Cl:32])[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[N:26][CH:27]=1>C(#N)C>[Cl:32][CH2:31][CH2:30][O:29][CH:21]([C:22]1[CH:27]=[N:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:5]#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: ClCCOC(OCCCl)c1ccc(Cl)nc1
Agent: N#CC(C#N)=C(C#N)C#N
Solvent: CC#N
Product: N#CC(OCCCl)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
Trimethylsilyl cyanide (1.88 mL) and tetracyanoethylene (240 mg) were added to a solution of 5-[bis-(2-chloroethoxy)methyl]-2-chloropyridine (2.67 g) in acetonitrile (50 mL), and the reaction solution was heated under reflux for five hours. The reaction solution was left to cool to room temperature, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the resulting residue. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=8:1) to obtain 2.04 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:3].[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24](Cl)=[O:25])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>O1CCCC1>[CH3:3][CH:2]([NH:1][C:24](=[O:25])[CH:23]=[CH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCCC(C)N
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)NC(=O)C=Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
To a stirred solution of 31.0 g. of 2-aminoundecane in 100 ml. of tetrahydrofuran, was added a solution of 19.0 g. 3-(3-nitrophenyl)propenoyl chloride in 100 ml. of tetrahydrofuran, dropwise, during 75 minutes, at ca. 5° C. After the addition, the mixture was allowed to warm to room temperature, and stirring was continued for 45 minutes. The solvent was removed by evaporation in vacuo, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was removed, washed successively with 1 N hydrochloric acid and water, and dried. Evaporation of the solvent in vacuo, followed by recrystallization of the residue from hexane, afforded 26 g. (83% yield) of the title product, m.p. 81°-83° C.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:34]=[N:33][CH:32]=1)(=[O:3])[CH3:2].[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:34]=[N:33][CH:32]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCn1nncc1/C=C1\CNCCC1SC(C)=O
Temperature: 25 °C

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-({1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-5-yl}methylidene)-1-(triphenylmethyl)piperidine (7.45 g) in dichloromethane (80 ml) was added trifluoroacetic acid (2.86 ml) with stirring at room temperature. After the resulting mixture was stirred at room temperature for one hour, solvents were removed under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane and methanol (10:1) as the eluent to afford the title compound (5.39 g, including impurities) as an orange-coloured oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][Br:1])=[CH:30][CH:29]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
N-Bromosuccinimide (19 g, 0.107 mole) and benzoyl peroxide (2.5 g, 0.01 mole) were added to p-chlorotoluene (13 g, 0.103 mole) in carbon tetrachloride (100 mL). The reaction mixture was stirred and refluxed gently for 2 hours. When the succinimide rose to the surface, the reaction was finished. The solution was cooled to room temperature and the succinimide was filtered off. The filtrate was evaporated on a rotary evaporator. Then distillation gave p-chlorobenzyl bromide as colorless crystal (80° C.-85° C./1 mm Hg).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=1)[CH2:12][O:13][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: COCOc1cc(Br)c(OCOC)c(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(Br)c(OCOC)c(CO[Si](C)(C)C(C)(C)C)c1
Yield: 97.2 %

Procedure:
Prepare a solution of (3-bromo-2,5-bis-methoxymethoxy-phenyl)-methanol (1.46 g, 4.76 mmol) and imidazole (0.357 g, 5.24 mmol) in DMF (50 mL). Add tertbutyldimethylsilyl chloride (TBSCl) (0.790 g, 5.24 mmol). Stir the reaction for 3 hours and pour into cold H2O (150 mL). Extract the H2O with EtOAc (3×50 mL), combine the extracts, and wash with H2O (2×50 mL) and brine (20 mL). Dry (MgSO4), filter and concentrate to afford the subtitled product (1.95 g, >95%) as an oil that may be used without purification. 1NMR (CDCl3) δ 0.11 (s, 6H), 0.95 (s, 9H),3.47 (s, 3H), 3.51 (s, 3H), 4.84 (s, 2H), 5.02 (s, 2H), 5.12 (s, 2H), 7.15 (d, J=2.9 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H).
Reaction SMILES: C(C1CC2C(=CC=C(OC)C=2Cl)C1=O)CCC.C(C(C)=O)=C.C[O-].[Na+].CO.[CH2:28]([C:32]1([CH2:45][CH2:46][C:47](=[O:49])[CH3:48])[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:42][CH3:43])[C:38]=2[Cl:41])[C:33]1=O)[CH2:29][CH2:30][CH3:31].N1CCCC1.C(O)(=O)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:28]([C:32]12[CH2:45][CH2:46][C:47](=[O:49])[CH:48]=[C:33]1[C:34]1[C:39](=[C:38]([Cl:41])[C:37]([O:42][CH3:43])=[CH:36][CH:35]=1)[CH2:40]2)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCC1(CCC(C)=O)Cc2c(ccc(OC)c2Cl)C1=O
Agent: C=CC(C)=O
Agent: CCCCC1Cc2c(ccc(OC)c2Cl)C1=O
Agent: C[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCC12CCC(=O)C=C1c1ccc(OC)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution 2-butyl-4-chloro-5-methoxy-1-indanone (550 mg, 2.03 mmol) in tetrahydrofuran (4.06 mL) was treated with methyl vinyl ketone (0.203 mL, 2.44 mmol) and 0.5N sodium methoxide in methanol (0.812 mL, 0.406 mmol). The mixture was stirred at room temperature for 90 minutes to effect conversion to 2-butyl-4-chloro-5-methoxy-2-(3-oxobutyl)-1-indanone. The reaction mixture was evaporated under vacuum. The residue in toluene (10 mL) was treated with pyrrolidine (0.170 mL, 2.03 mmol) and acetic acid (0.140 mmol, 2.44 mmol). The resulting mixture was stirred and heated in an oil bath at 80° C. for 2.5 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic phase was washed with 0.1N HCl, saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by preparative layer chromatography on silica gel GF plates to afford 9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=[O:9])[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].[I:14](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.O>CO.C(Cl)Cl>[C:1]([C:5]1[CH:12]=[C:11]([I:14])[CH:10]=[C:7]([CH:8]=[O:9])[C:6]=1[OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=I(=O)Cl
Reactant: CC(C)(C)c1cccc(C=O)c1O
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(I)cc(C=O)c1O
Reaction time: 2 h

Procedure:
3-tert-butyl salicylaldehyde (1) (8.4 mmol) was dissolved in 100 ml of a mixture of methanol and methylene chloride (3:7). Benzyltrimethylammonium dichloroiodate (3.23 g; 9.2 mmol) and water free calcium carbonate (1.1 g; 11 mmol) were added. After two hours, the excess of calcium carbonate was filtered off. After removal of about 80% of the solvent, 20 ml of a sodium hydrogensulfite solution (5%) was added decolourizing the mixture. Extraction with diethyl ether, drying over sodium sulphate and removal of the solvent yielded the aldehyde as raw product. Purification by recrystallization from n-pentane produced 3-tert-butyl-5-iodosalicylaldehyde in a 48% yield as yellow crystals which are slightly light sensitive and should be stored in the dark.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][N:8]=[C:9]([NH2:13])[CH:10]([OH:12])[CH3:11])=O.C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:8]=[C:9]([CH:10]([OH:12])[CH3:11])[N:13]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CC(O)C(N)=NOC(=O)c1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)c1noc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
27.2 g crude N′-[(3-chlorobenzoyl)oxy]-2-hydroxypropanimidamide was dissolved in ethanol (250 mL) and refluxed for 1 h, followed by addition of 14.0 g (170 mmol) sodium acetate in water (40 mL). After refluxing o.n., cooling to r.t. and addition of water (250 mL) the mixture was concentrated in vacuo to about ½ of its volume, resulting in a precipitate which was filtered off and recrystallized from EA/Hep to yield 6.45 g (25%) of the title compound. 1H NMR: 8.14 (s, 1H), 8.02 (d, 1H), 7.57 (d, 1H), 7.47 (t, 1H), 5.04 -5.14 (m, 1H), 2.51 (d, 1H), 1.67 (d, 3H)
Reaction SMILES: CO[C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[O:4].CC(C)([O-])C.[K+].[F:19][C:20]([F:24])([F:23])[C:21]#[N:22]>C1COCC1>[CH3:12][O:11][C:9]([C:8]1[C:6]([OH:7])=[CH:5][C:3](=[O:4])[NH:22][C:21]=1[C:20]([F:24])([F:23])[F:19])=[O:10]
Reactant: N#CC(F)(F)F
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c(O)cc(=O)[nH]c1C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Dimethyl 1,3-acetonedicarboxylate (34.8 g, 0.2 mol) is slowly added to a solution of potassium t-butoxide (22.4 g, 0.2 mol) in THF (300 mL) at 60° C. After addition, the reaction mixture is stirred at 60° C. for 2 hours. The reaction is allowed to cool to 40° C. and trifluoroacetonitrile gas (100 g, 1.05 mol) is slowly bubbled slowly into the above mixture. The reaction temperature is maintained at 50° C. overnight. The volatile material is removed in vacuo. The residue is dissolved in water (200 mL) and the solution is poured into hydrogen chloride solution (conc. HCl/water 80 mL: 200 mL). The white solid is collected by filtration and dried. After being triturated with chloroform (200 mL), the title product is obtained as a white solid. 1H NMR: (CDCl3) 6.29 (s, 1H), 3.76 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][C:16]([OH:18])=O)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33]>O1CCCC1>[CH3:31][S:32]([NH:35][C:16](=[O:18])[CH2:15][C:12]1[CH:13]=[CH:14][C:7]2[S:6][C:5]3[N:4]=[CH:3][CH:2]=[N:1][C:10]=3[NH:9][C:8]=2[CH:11]=1)(=[O:34])=[O:33]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)Cc1ccc2c(c1)Nc1nccnc1S2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)Cc1ccc2c(c1)Nc1nccnc1S2
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution of 0.259 g of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetic acid in tetrahydrofuran (10 ml) was added in a nitrogen atmosphere 0.18 g of carbonyldiimidazole and the resulting mixture was heated under reflux for 30 minutes. Then the reaction mixture was brought back to room temperature and 0.285 g of methanesulfonamide was added thereto. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.163 g of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@@H:17]([OH:19])[CH3:18])[CH2:8]1)[CH3:5])[CH3:2].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O>[C:35]([O:19][C@H:17]([C@@H:16]1[C@:20]2([CH3:28])[C@H:13]([C@H:12]3[C@H:23]([CH2:22][CH2:21]2)[C@:24]2([CH3:27])[C:9]([CH2:8][C@@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[CH2:26][CH2:25]2)=[CH:10][CH2:11]3)[CH2:14][CH2:15]1)[CH3:18])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)O)[C@@]4(C)CC[C@@H]32)C1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
iii)—A solution of (3β,20S)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-ol (56.9 g) in a mixture of dry pyridine (144 ml) and acetic anhydride (72.4 ml) was stirred at room temperature for 18 h. Water (482 ml) was added and stirring was continued for another 1 h. The product was extracted into ethyl acetate; the combined organic phases were washed with a saturated aqueous solution of sodium hydrogen carbonate and with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,20S)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-ol acetate (compound 4; 66.1 g) which was used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][Cl:37])=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(CO)C(=O)COc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(CCl)C(=O)COc1ccc(Cl)cc1

Procedure:
Into a 100-ml egg plant type flask were placed 2.4 g of 1-(p-chlorophenoxy)-3,3-dimethyl-4-hydroxy-2-butanone, 2.6 g of triphenylphosphine and 50 ml of carbon tetrachloride, which were then refluxed for 18 hours. The reaction mixture was cooled, the crystals separating out were filtered off, and the filtrate was concentrated in a vacuum. The residue obtained was purified by silica gel column chromatography, giving 1.8 g of the above-identified desired compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][C:27]([NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Solvent: Cc1ccccc1
Product: CCCCNC(=O)NCCOc1cccc2c1CC(N(CCC)CCC)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.45 g (5 mmol) of 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene were initially introduced into 25 ml of toluene. The reaction was catalyzed using 3 drops of thiethylamine, and 0.63 ml (5.5 mmol) of butyl isocyanate was then added dropwise. The mixture was stirred for 2 h at room temperature. The mixture was evaporated to dryness, and the residue was crystallized from petroleum ether/diisopropyl ether.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@:7]([CH2:9][CH3:10])([OH:8])[CH2:6][CH2:5][N:4]1C(OCC1C=CC=CC=1)=O)[CH3:2]>[Pd].O>[CH2:1]([C@H:3]1[C@@:7]([CH2:9][CH3:10])([OH:8])[CH2:6][CH2:5][NH:4]1)[CH3:2]
Reactant: CC[C@@H]1N(C(=O)OCc2ccccc2)CC[C@@]1(O)CC
Agent: [Pd]
Solvent: O
Product: CC[C@@H]1NCC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Reference Example 4 and using benzyl (2S,3S)-2,3-diethyl-3-hydroxypyrrolidine-1-carboxylate (2.19 g) and 50% water containing-10% Pd/C (0.22 g), the title compound was obtained as a colorless solid (yield: 1.40 g, yield: 94%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([O:11][C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=2[F:19])[CH:3]=1>C(O)C.[Pd]>[F:19][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:12]=1[O:11][C:4]1[CH:3]=[CH:2][N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]=12)[NH2:16]
Reactant: Nc1ccc(Oc2cc(Cl)nc3[nH]ccc23)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 25 °C

Procedure:
3.2 g (11.5 mmol) of 4-[(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3-fluoroaniline are dissolved in ethanol at 50° C. The solution is then allowed to cool to RT, and 2.45 g (2.30 mmol) of 10% palladium-on-carbon are added. The mixture is hydrogenated under a hydrogen pressure of 2 bar overnight. The mixture is, then filtered off with suction through kieselguhr, the kieselguhr is washed with ethanol and the filtrate is concentrated.