Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:12]([OH:14])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:21]([N:23]([CH2:24][CH3:25])[C:12]([CH:4]1[CH2:3][C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5]1)=[O:14])[CH3:22]
Reactant: CCNCC
Reactant: O=C1CC(C(=O)O)Sc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C1CC(=O)c2ccccc2S1
Temperature: 0 °C
Yield: 65.1 %

Procedure:
(+−)-4-Oxo-thiochroman-2-carboxylic acid (10.4 g, 50 mmol), prepared as described in T. Okubo et at (Bioorg. Med. Chem. 2004; 12: 3569-3580), in dry DCM (100 ml) was stirred under an atmosphere of nitrogen at room temperature with oxalyl chloride (12.6 g, 100 mmole) and one drop of DMF for 18 h. The reaction was then evaporated in vacuo to a gum and then redissolved in DCM (100 ml), cooled to 0° C. on an ice bath, stirred and treated dropwise with diethylamine (8.03 g, 110 mmol) in DCM (20 ml) over a period of 1 h. The reaction was allowed to warm to room temperature over 1 h and 10% aqueous potassium carbonate solution (100 ml) was added and the reaction mixture vigorously stirred. The DCM solution was separated. The aqueous solution was extracted with two further batches of DCM (100 ml) and the combined extracts were dried over magnesium sulphate. The DCM solution was concentrated in vacuo to give a dark green oil that crystallized on standing. The crystalline solid was triturated with diethyl ether (50 ml) and filtered to give the title compound (50) (8.57 g, 65%) as a pale green solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δ 1.06 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H), 3.0-3.5 (m, 6H), 4.25 (m, 1H), 7.15-7.21 (m, 2H), 7.32-7.39 (m, 1H), 8.10-8.14 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C>[Si:10]([O:1][CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(CO)C(=O)OCC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=C(CO[Si](C)(C)C(C)(C)C)C(=O)OCC
Reaction time: 2 h
Yield: 72.5 %

Procedure:
10.8 g of ethyl 2-(hydroxymethyl)acrylate (Organic Synthesis, Coll, Vol 8, 265, 1993) was diluted with 80 ml of N,N′-dimethylformamide, and 18.8 g of tert-butyldimethylsilyl chloride and 11.3 g of imidazole were added thereto. The resulting mixture was incubated at room temperature for two hours. After the reaction terminated, water was added, and the resulting solution was extracted with ethyl acetate. The organic layer was washed five times with water and saturated chloride water, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate:n-hexane=1:30) to obtain the title compound (14.7 g, 73%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:10]=O>C(O)C(C)C>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH2:2][CH3:10]
Reactant: C=O
Reactant: CC(=O)c1ccccc1
Solvent: CC(C)CO
Product: CCC(=O)c1ccccc1

Procedure:
0.5 liter per hour of a mixture of acetophenone and a 30% strength solution of formaldehyde in isobutanol (the molar ratio of acetophenone to formaldehyde being 8:1) was reacted at 180° C., under 30 bar H2 pressure, in the apparatus, and over the catalyst, described in Example 1. The yield of propiophenone obtained was 52.8%, based on formaldehyde employed.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=O)[C:15]12[O:26]CCCO1)(=[O:11])=[O:10].Cl[CH2:28][C:29]1([C:35]#[N:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:28][C:29]4([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:35][N:36]=[C:16]3[C:15](=[O:26])[C:14]=2[CH:13]=1)(=[O:11])=[O:10]
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Reactant: N#CC1(CCl)CCCCC1
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C1=NCC3(CCCCC3)CN12

Procedure:
The title compound was prepared as a yellow foam from 5′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cyclohexanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 430 [M−H].
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@@H:21]([CH2:23][N:24]([CH:34]([CH3:36])[CH3:35])[C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[O:26])[C@H:20]([CH2:37][NH:38][CH:39]2[CH2:41][CH2:40]2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@@H:21]([CH2:23][N:24]([CH:34]([CH3:35])[CH3:36])[C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])=[O:26])[C@H:20]([CH2:37][N:38]([CH:39]2[CH2:40][CH2:41]2)[C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:19]1)=[O:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: O=C(O)Cc1ccccc1
Reactant: CC(C)N(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC1CC1)C(=O)OCC[Si](C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)N(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)Cc1ccccc1)C1CC1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of phenylacetic acid (1.45 g, 10.53 mmol) and (3R,4S)-3-cyclopropylaminomethyl-4-{[isopropyl-(2-trimethylsilanyl-ethoxycarbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (3.2 g, 7.022 mmol) in CH2Cl2 (10 mL), are added triethylamine (1.47 mL, 10.53 mmol) and 1-hydroxy-7-azabenzotriazol hydrate (1.46 g, 10.53 mmol) followed 15 min later by N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (3.06 g, 15.78 mmol). The resulting mixture is stirred for 2 days at RT, then diluted with CH2Cl2 and poured into an aqueous 2M HCl solution. The layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are neutralized with an aqueous saturated solution of NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: hexane/AcOEt 2:1). TLC, Rf (hexane/AcOEt 1:1)=0.42. MS (LC-MS): 574.2 [M+H]+; tR (HPLC, C18 column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/1.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 6.49 min.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6](O)=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:2]1([CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][CH2:6][OH:7]
Reactant: Cc1ccccc1CCC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1CCCO
Temperature: 0 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
Add 2-methylhydrocinnamic acid (18.4 mmol) to anhydrous tetrahydrofuran (100 mL) and cool to 0° C. Slowly add lithium aluminum hydride (2.20 g, 58.0 mmol) and remove the ice bath after 20 minutes. Stir at room temperature under nitrogen for 18 h. Cool the reaction to 0° C. and quench the reaction by slowly adding water (2.2 mL), 15% sodium hydroxide (2.2 mL), and water (6.6 mL). Filter off the aluminum salts. Add brine (100 mL) and 5 N sodium hydroxide (30 mL) to the filtrate and extract with ethyl acetate (3×100 mL). Dry the ethyl acetate extracts with magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 2.65 g (96%) of 3-o-tolyl-propan-1-ol: 1H NMR (CDCl3): 7.18-7.10 (m, 4H), 3.72 (t, 2H), 2.72-2.69 (m, 2H), 2.33 (s, 3H), 1.90-1.83 (m, 2H), 1.60 (br s, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:36]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(=O)[C@H](C)O)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A164) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCC(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(CCCO)cc1

Procedure:
To an oven-dried 150 mL round-bottomed flask charged with 3-(4-aminophenyl)propionic acid (Aldrich, 3.0 g, 18.16 mmol) was added THF (50 mL) and lithium aluminum hydride (Aldrich, 1.0M THF solution, 37 mL, 36.32 mmol) at 0° C. The reaction mixture was added Na2SO4.10H2O after 3 h until there was no visible bubbles. The liquid was filtered. The solid was washed with THF and CH2Cl2. The filtrate was dried over Na2SO4. After filtration and concentration in vacuo, the crude was purified by flash chomatography (7% MeOH—CH2Cl2) to provide the title product. MS (ESI): 152 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([OH:32])[CH2:16][N:17]2[C:25]3[CH:24]=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[C:19]3[CH2:27][N:28]([CH3:31])[CH2:29][CH2:30][C:18]2=3)[CH:8]=[CH:9][C:10]=1[O:11]CC=C)C=C.CN1C(=O)CC(=O)N(C)C1=O>CO.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>[CH3:31][N:28]1[CH2:29][CH2:30][C:18]2[N:17]([CH2:16][CH:15]([C:7]3[CH:6]=[C:5]([OH:4])[C:10]([OH:11])=[CH:9][CH:8]=3)[OH:32])[C:25]3[CH:24]=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[C:19]=2[CH2:27]1
Reactant: C=CCOc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1OCC=C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(O)c(O)c2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
To a solution of 1-(3,4-Bis-allyloxy-phenyl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanol (500 mg, 1.15 mmol) in 10 mL MeOH was purged with nitrogen for 10 min. 1,3-Dimethylbarbituric acid (903 mg, 5.79 mmol) and Pd(PPh3)4 (80 mg, 0.069 mmol) were added under nitrogen and the mixture stirred for 30 min at RT. After the complete conversion of starting material (TLC and LCMS), the MeOH was removed under reduced pressure. 100 mL of saturated sodium bicarbonate was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resultant crude product was purified by HPLC to obtain 160 mg of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzene-1,2-diol. 1H NMR (CD3OD, Free base) δ (ppm): 7.3 (d, 1H), 7.2 (s, 1H), 7.05 (dd, 1H), 6.7 (d, 1H), 6.6 (s, 1H), 6.53 (d, 1H), 4.8 (t, 1H), 4.21 (m, 3H), 4.05 (dd, 1H), 3.34 (m, 1H), 3.3 (m, 1H), 2.88 (dt, 1H), 2.81 (s, 3H), 2.5 (dt, 1H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers II-88a-b.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(Cl)Cl>[CH2:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:19](=[O:22])[CH:20]=[CH2:21])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: C=CCNc1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCN(C(=O)C=C)c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of N-allyl-4-methoxyaniline (1.00 g, 6.13 mmol) in methylene chloride (20 mL) was added K2CO3 (2.12 mg, 15.3 mmol) and acryloyl chloride (548 μL, 6.74 mmol) at 0° C. After 15 min., the reaction was quenched with NaHCO3 (5 mL, sat. aq.) and the organic layer was isolated, concentrated and subjected to flash chromatography (Hexanes:EtOAc 4:1) to yield N-allyl-N-(4-methoxyphenyl)acrylamide (1.29 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1(F)[C:5]([F:7])([F:6])[C:4]([F:9])([F:8])[C:3]1(F)Cl.FC1(F)C(F)=C(F)C1(F)F>>[F:6][C:5]1([F:7])[C:2]([Cl:1])=[CH:3][C:4]1([F:9])[F:8]
Reactant: FC1(F)C(F)(F)C(F)(Cl)C1(F)Cl
Agent: FC1=C(F)C(F)(F)C1(F)F
Product: FC1(F)C=C(Cl)C1(F)F

Procedure:
The converion for 1,2-dichlorohexafluorocyclobutane was 45%, the selectivity or the targeted hexafluorocyclobutene was 94% and a 5.3% selectivity of tetrafluoro-1-chlorocyclobutene was formed as the by-product.
Reaction SMILES: C(O[C:4]1[CH2:5][C@@H:6]([CH2:11][C@H:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](=[O:24])[CH2:14][CH2:13]2)[CH2:7][C:8](=[O:10])[CH:9]=1)C.[CH3:25]COCC.C[Li]>O1CCCC1>[CH3:25][C:4]1[CH2:5][C@H:6]([CH2:11][C@H:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](=[O:24])[CH2:14][CH2:13]2)[CH2:7][C:8](=[O:10])[CH:9]=1
Reactant: CCOC1=CC(=O)C[C@H](C[C@@H]2CCC(=O)N2Cc2ccccc2)C1
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Product: CC1=CC(=O)C[C@@H](C[C@@H]2CCC(=O)N2Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of (5S,1R)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone (3.94 g, 12.0 mmol) in 150 ml of 1:1 tetrahydrofuran:ether was added a solution of methyllithium (41 mL, 1.4M in ether, 57.4 mmol) at -78° C. over 10 min. The mixture was stirred for 30 min at -78° C. and quenched by the addition of 50 mL of 50% aqueous acetic acid. The mixture was allowed to warm to room temperature and was extracted with methylene chloride. The combined extracts were washed with saturated sodium bicarbonate, dried over Na2SO4 and concentrated on a rotary evaporator to give 4.05 g of a crude oil. Chromatography of the crude product on silica gel (100 g) eluting with 1% methanol in ethyl acetate afforded 1.85 g (52% yield) of (5S,1R)-5-[(3-methyl-5-oxo-3-cyclohexen- 1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone as an oil. A sample was evaporatively distilled at 200°-210° C./0.05 torr for analysis. 1H NMR (CDCl3) δ 1.94 (s, 3 H, CH3), 1.35-2.55 (m, 11 H, CH2 and CH), 3.45 (m, 1 H, NCH), 3.95 and 4.98 (AB,Jgem =15 Hz, 2 H, CH2Ph), 3.87 (s, 1 H, vinyl H), 7.50 (m, 5 H, phenyl). MS (EI) m/e 297 (M+). [α]25D =+59.86°(c 0.2155 in methanol). CD (ethanol) 326 ([ϑ]=-1425, max), 283 ([ϑ]=-42, min), 238 ([ϑ]=+13,620, infl), 218 ([ϑ]=+50,100, max), 212 nm ([ϑ]=+39,820°, min). Anal. Calcd for C19H23NO2 : C, 76.74; H, 7.80; N, 4.71. Found: C, 74.55; H, 7.53, N, 7.41.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)CCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)CCc1ccc(N)cc1
Yield: 95 %

Procedure:
2-(4-Nitro-phenyl)-ethanesulfonic acid tert-butylamide (as prepared in the step above, 633 mg, 2.21 mmol) was hydrogenated under balloon pressure in EtOH (20 mL) using 10% Pd/C (100 mg) for 12 h. The reaction mixture was filtered through Celite and concentrated to obtain 2-(4-amino-phenyl)-ethanesulfonic acid tert-butylamide (536 mg, 95%) which was used directly without further purification.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[OH-].[Na+].[CH2:13](O)[CH2:14][OH:15]>>[CH2:14]1[O:15][C:4]2([CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)[O:10][CH2:13]1
Reactant: O=C1CN2CCC1CC2
Reactant: OCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C1COC2(CN3CCC2CC3)O1
Temperature: 200 °C
Yield: 100 %

Procedure:
A mixture of 3-quinuclidinone hydrochloride (5 g, 31 mmol) and ethylene glycol (20 ml) was heated under nitrogen at 200° C. (bath temperature) for 2 h. After cooling, the reaction mixture was poured in an excess of 1 M aqueous sodium hydroxide. Extraction with three portions of ethyl acetate was followed by drying over magnesium sulfate, and evaporation of the solvent to yield the product (5.2 g, 31 mmol, 100%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:15]=3[N:14]=2)=[N:4][CH:3]=1.C(=O)(O)[O-:25].[K+].C1C=C(C([O-])=O)C(C(O[O-])=O)=CC=1.[Mg+2].S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.CO.C(O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:25])[C:13]2[NH:14][C:15]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:16]=3[N:17]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: O=C([O-])O
Reactant: COc1ccc2nc(SCc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A mixture of pyrmetazole (0.112 mole) and potassium bicarbonate (0.145 mole) in 100 mL of water and approximately 250 mL of a 4:1; toluene: ethanol mixture was cooled to -5° to -9° C. with stirring. A solution of MMPP (0.67 mol) in 170 mL of water was added dropwise over a 2 hour period. After the MMPP solution was completely added a solution of sodium sulfite (2.2g) in 10 mL of water was added and the mixture was stirred for 15 minutes. The reaction mixture temperature was allowed to warm to 0° C. during this period. The slurry was then diluted with 200 mL of water and 50 mL of methanol and the pH of the slurry was adjusted to 9.1 by addition of 50% aqueous sodium hydroxide. The slurry was aged at 0° to 5° C. for 1 hour and then was filtered. The solid was washed with 50 mL of water and 40 mL cold methanol. Drying of the solid provided 31.3 g of crude omeprazole (81% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH3:12])=[CH:5]2.CN(C)[CH:15]=[CH:16][N+:17]([O-:19])=[O:18]>FC(F)(F)C(O)=O.CCOC(C)=O.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH3:12])=[C:5]2/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18]
Reactant: CCc1cc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C=C[N+](=O)[O-]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCc1[nH]c2ccc(Cl)cc2c1/C=C/[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The indole 3 (5 mmol) was added to a stirred ice-cooled solution of 1-(dimethylamino)-2-nitroethylene (0.58 g, 5 mmol) in trifluoroacetic acid (5 mL). The mixture was stirred at room temperature under N2, for 0.5 h and then poured onto ice water. The aqueous solution was extracted with ethyl acetate, the combined organic layers were washed with a saturated NaHCO3 solution and then with water. After drying over Na2SO4, the solvent was evaporated under reduced pressure to give a crude orange solid which was suspended in a mixture of EtOAc-Et2O and filtered, or chromatographed on silica gel (cyclohexane/EtOAc, 1:1, as eluent).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].C(N(CC)C(C)C)(C)C.[NH2:26][C@@H:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:26][C@H:27]([CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1sc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (187 mg, 0.62 mmol), N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol)) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (226 mg, 0.40 mmol, 64% yield) as a white foam: LCMS (ES) m/e 569, 571 (M, M+2)+.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13].[Cl-:19].[Li+].C(O)(=O)C>O1CCCC1>[Cl:19][CH2:18][CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: [Cl-]
Reactant: COC(=O)C(C)(C)OCCCCCCCC1CO1
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)OCCCCCCCC(O)CCl
Temperature: 25 °C
Reaction time: 22 h
Yield: 106.8 %

Procedure:
Methyl 2-(8,9-epoxynonyloxy)-2-methylpropionate (26 g) was dissolved in 260 ml of dry tetrahydrofuran, and 6.8 g of lithium chloride and 7 g of acetic acid were added and the mixture was stirred for 22 hours at room temperature. The reaction solution was poured into ice-cold water, extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated to give 31.7 g of the objective compound as oil.
Reaction SMILES: [S:1](=[O:3])=[O:2].[S:4]([O-:7])([O-:6])=[O:5].[Na+:8].[Na+]>O>[S:4]([S:1]([O-:3])=[O:2])([O-:7])(=[O:6])=[O:5].[Na+:8].[Na+:8]
Reactant: O=S=O
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S([O-])S(=O)(=O)[O-]

Procedure:
In another embodiment, the invention relates to a method for producing sodium metabisulfite. In particular, the method comprises introducing a gas stream, having sulfur dioxide, and a liquid stream, having sodium sulfite and water, into a column. The method also comprises absorbing at least a portion of the sulfur dioxide into the liquid stream and reacting at least a portion of the absorbed sulfur dioxide with sodium sulfite to produce a sodium metabisulfite stream. The method further involves evaporating at least a portion of the water from the liquid stream into the gas stream. The method also comprises precipitating sodium metabisulfite from the sodium metabisulfite stream in a crystallizer and withdrawing a slurry of sodium metabisulfite from the bottom of the crystallizer.