Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc2C1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc2c(c1)CCC(N1CCCC1)=C2

Procedure:
1155 g (6.4 mol) of 6-chloro-3,4-dihydro-2(1H)-naphthalenone are dissolved in 5 l of toluene, 500 g (7.0 mol) of pyrrolidine and subsequently a solution of 26 g (0.14 mol) of p-toluenesulfonic acid monohydrate in toluene are added dropwise thereto and the mixture is boiled under reflux on a water separator. When about 120 ml of water have separated, 4 l of toluene are distilled and the mixture is left to cool slowly. A solid thereby crystallizes out. Filtration and washing with acetone gives 1-(6-chloro-3,4-dihydro-2-naphthyl)-pyrrolidine with melting point 117°-118°. Concentration of the mother liquor, suspension of the residue in ether, filtration and washing with acetone gives an additional portion of the above product with melting point 117°-118°.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9]([C:11]1[C:16](O)=[C:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=1[CH3:21])=[O:10])[CH3:7]>>[CH2:6]([O:8][C:9]([C:11]1[C:16]([Cl:3])=[C:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=1[CH3:21])=[O:10])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)c(C)c(=O)n(C)c1C
Product: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Phosphorous oxychloride (20.0 mL, 216 mmol) was added to 4-hydroxy-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester and heated to 80° C. After two hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was poured onto ice and carefully neutralized with saturated NaHCO3, and diluted with EtOAc. After stirring for 16 hours, the organic layer was separated and the aqueous layer was reextracted with EtOAc repeatedly. The pH of the aqueous layer was adjusted to pH 11 with saturated K2CO3 and extracted with EtOAc (2×). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give 3.42 g (89%) clean desired product.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([CH2:11][CH:12](O)[CH:13]=[CH2:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O>CCOCC>[Cl:3][CH2:14]/[CH:13]=[CH:12]/[CH2:11][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: C=CC(O)CC1CCCCC1
Solvent: CCOCC
Solvent: O
Product: ClC/C=C/CC1CCCCC1
Reaction time: 8 h

Procedure:
Thionyl chloride (50.5 ml) was added dropwise over 1 hour to a stirred solution of 1-cyclohexyl-3-buten-2-ol (50 g) (obtained as described in European Patent Application, Publication No. 258183) in dry ether (1 litre). The solution was allowed to stand overnight and then water (750 ml) was added, and the mixture was stirred for 1 hour. The organic phase was separated, washed with water (500 ml) and saturated sodium chloride solution (2×250 ml) and dried (MgSO4). The solvent was removed by evaporation and the residual liquid distilled under high vacuum to give (2E)-1-chloro-4-cyclohexylbut-2 -ene (B), as a clear liquid (42.2 g), b.p. 64-68° C. at 0.5 mm Hg; NMR: 0.8-1.8(complex m, 11H), 2.0(t, 2H), 4.0(d, 2H), 5.5-5.9(complex m, 2H); microanalysis, found: C, 69.5; H, 10.0; Cl, 20.3%; C10H17Cl requires: C, 69.5; H, 9.9; Cl, 20.5%.
Reaction SMILES: [CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][CH:12]([N:17]1[C:30]3[CH:29]=[CH:28][C:27]([C:31]#[N:32])=[CH:26][C:25]=3[S:24][C:23]3[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si]([N:37]=[N+:38]=[N-:39])(C)C.C([Sn](=O)CCCC)CCC>C(COC)OC>[CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][CH:12]([N:17]1[C:30]3[CH:29]=[CH:28][C:27]([C:31]4[NH:39][N:38]=[N:37][N:32]=4)=[CH:26][C:25]=3[S:24][C:23]3[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1N2C1CC2CCC(C1)N2CCc1ccccc1
Agent: CCCC[Sn](=O)CCCC
Solvent: COCCOC
Product: c1ccc(CCN2C3CCC2CC(N2c4ccccc4Sc4cc(-c5nnn[nH]5)ccc42)C3)cc1
Temperature: 150 °C

Procedure:
To a solution of 10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonitrile, 2aa (10 mg, 29 μmol) in dimethoxyethane was added trimethylsilyl azide (15 μL, 115 μmol) and dibutyltin oxide (1.5 mg), and the mixture was heated in a microwave for 15 min at 150° C. The mixture was allowed to cool to rt, and purified via reverse phase HPLC (eluent: CH3CN in water containing 0.1% TFA) to yield title compound 10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenothiazine, 3aa as a TFA salt and as a mixture of endo and exo isomers. MS m/z (MH+) 481.2.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.C(O[C:25](=O)[N:26](C)[C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[CH3:12][C:9]1([CH3:13])[O:8][C:6]2[N:7]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH:26][CH3:25])=[N:28][CH:29]=3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[O:11][CH2:10]1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNc1ccc(-c2nc3c(c(N4CCOCC4)n2)OCC(C)(C)O3)cn1
Temperature: 120 °C
Yield: 31.1 %

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester (88 mg, 0.26 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then evacuated and back filled with nitrogen before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 113 as a white solid (20 mg, 32%). LCMS: RT=2.79 min, [M+H]+=358. 1H NMR (400 MHz, CDCl3): δ 9.04 (1H, d, J=2.4 Hz), 8.35 (1H, dd, J=2.4, 8.6 Hz), 6.39 (1H, d, J=8.6 Hz), 4.84 (1H, broad s), 3.89 (2H, s), 3.85-3.76 (8H, m), 2.97 (3H, d, J=5.2 Hz), 1.45 (6H, s)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1.ClCl>CN(C=O)C.ClCCl>[C:15]1(=[O:20])[N:14]([O:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=2)=[O:3])[C:18](=[O:19])[CH2:17][CH2:16]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: ClCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(B(O)O)cc1
Reaction time: 0.17 h

Procedure:
4-Carboxyphenyl-boronic acid (CPBA, Example 1, 0.25 g, 1.51 mmol) and N-hydroxysuccinimide (0.26 g, 2.26 mmol) were dissolved in 8.5 ml DMF using a magnetic stirrer. 20 ml of dichloromethane (CH2Cl2) was then added, and the solution was stirred for 10 minutes. N,N'-dicyclohexyl-carbodiimide (DCC, 0.93 g, 4.52 mmol) in 3 ml CH2 Cl2 was then added. The solution was left to react under a nitrogen atmosphere overnight (approx. 12 hours) at ambient temperature, and then filtered to remove the insoluble urea byproduct (DCU). The title compound was used in subsequent reactions without further purification.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7]([NH:17][C@H:18]([C:22](O)=[O:23])[CH:19]([CH3:21])[CH3:20])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[Br:1][CH2:2][CH:3]([OH:6])[CH2:4][O:5][C:22](=[O:23])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OCC(O)CBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(O)CBr
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 3-bromo-1,2-propanediol (10.85 g, 70mmole), N-CBz-L-valine (10.05 g, 40 mmole) and DMAP (0.49 g, 4 mmol) in 250 ml dichloromethane was added dropwise a solution of DCC (9.1 g, 44 mmol) in 50 ml dichloromethane at about 10° C. The mixture was stirred for two days at room temperature and then cooled to 5° C. The urethane was filtered and the solution was evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 8 g
Reaction SMILES: [CH3:1][C:2]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[CH:5].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:28]([SnH:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>>[CH3:1][C:2]([O:11][Si:12]([CH3:13])([CH3:14])[CH3:15])([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3]/[CH:4]=[CH:5]/[Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: C#CCC(C)(CCCCC)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCCC(C)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 33.96 g of 4-methyl-4-trimethylsilyloxy nonyne and 150 mg of azobisisobutyronitrile at ambient temperature under argon was added 41 ml of tri-n-butyltin hydride via syringe. The mixture was slowly heated in an oil bath, with a rapid exothermic reaction to 120° C. taking place as the temperature reached 60° C. Heating to 130°-135° C. continued for one hour. The product was then allowed to cool and was then distilled to provide 74.5 g of (E)-4-methyl-4-trimethylsilyloxy-1-tri-n-butylstannyl-1-nonene (b.p. 162°-164° C. at 0.15-0.30 mm).
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (332 mg, 1.31 mmol) and 1-bromotridecane (863 mg, 3.28 mmol), alcohol 33 was obtained as a colorless oil (172 mg, 30% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:19](=[O:20])[O:21][CH2:22][CH3:23])=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(CN)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NCc1ccc(OC)cc1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
A stirred solution of 6.0 mL (0.046 mole) of 4-methoxyphenylmethyl-amine and 6.5 mL (0.047 mole) of triethylamine in 200 mL of tetrahydrofuran was cooled to about 5° C., and a solution of 4.4 mL (0.046 mole) of ethyl chloroformate in 10 mL of tetrahydrofuran was added. Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature, then was poured into a mixture of 200 mL of ice and 200 mL of an aqueous solution saturated with ammonium chloride. This mixture was extracted with 300 mL of diethyl ether, and the extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 4.2 grams (43.8% yield) of ethyl (4-methoxyphenylmethyl)-carbamate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[C:9](/[F:22])=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[S:15][C:14]=1[CH3:20])=[CH:3]\[C:4](O)=[O:5].C[N:24](C)C=O.C(Cl)(=O)C(Cl)=O>C1C=CC=CC=1>[CH3:1]/[C:2](/[CH:7]=[CH:8]/[C:9](/[F:22])=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[S:15][C:14]=1[CH3:20])=[CH:3]\[C:4]([NH2:24])=[O:5]
Reactant: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\C(N)=O
Reaction time: 1 h

Procedure:
A suspension of 0.40 g. (0.12 mmol) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoic acid in 12 ml. of dry benzene was stirred at 23° C. under argon while about 5 mg. of dimethylformamide were added thereto followed by 0.24 g. (0.19 mmole) of oxalyl chloride in 3 ml. of dry benzene. After 1 hour of stirring, dry ammonia was bubbled into the resulting orange solution until a bright yellow color persisted. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried with magnesium sulfate, filtered, and evaporated to give a crude orange solid. This material was purified by chromatography on silica gel using ethyl acetate-hexane (2:3 parts by volume) as the elutant. One crystallization from ethyl acetate gave 70 mg. (18% yield) of pure 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenamide, m.p. 212°-215° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17]=[C:18]([CH3:20])[CH3:19]>C(Cl)Cl.O1CCOCC1>[C:18]([O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C(C)C
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(F)cc(F)c1
Reaction time: 120 h
Yield: 81 %

Procedure:
3,5-Difluorobenzoic acid (25 g, 0.158 mol) was dissolved in DCM (150 mL) and dioxane (50 mL). The mixture was transferred into a stainless steel autoclave. Concentrated sulfuric acid (3.6 mL) was added, followed by isobutene (100 mL). The mixture was kept in the autoclave for 5 days. Excess isobutene and the solvents were removed under reduced pressure, the mixture diluted with EtOAc and washed with water, saturated aqueous sodium hydrogen carbonate and brine. Drying and evaporation gave a dark-yellow oil, which was purified by kugelrohr distillation (80–100° C., 1.0 mbar) to give tert-butyl-3,5-difluorobenzoate (27.51, g, 81% ) as a colorless solid.
Reaction SMILES: [P:1]([O:9]CC)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[S:2].[OH-].[K+:13]>C(O)C>[K+:13].[P:1]([O-:9])([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[S:2]
Reactant: CCOP(=S)(OCC)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOP([O-])(=S)OCC
Yield: 74.1 %

Procedure:
To 86 g (434 mmole) of O,O,O-triethyl thiophosphate in 300 ml of absolute ethanol was added 28 g (440 mmole) of 88% KOH. The resulting mixture was refluxed for 20 hours, filtered while warm, concentrated in vacuo, and triturated with 20% diethyl ether/80%hexanes to yield 67 g of the title compound, a white solid mp 192°-197° C.
Reaction SMILES: NC(N)=O.[CH:5]1([NH:8][S:9]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=2[OH:20])(=[O:11])=[O:10])[CH2:7][CH2:6]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Cl:21])=[O:30])=[C:13]([OH:20])[C:12]=1[S:9]([NH:8][CH:5]1[CH2:7][CH2:6]1)(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O
Reactant: O=C=Nc1ccccc1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O
Yield: 42.9 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-cyclopropyl -3-amino-6-chloro-2-hydroxybenzenesulfonamide (220 mg, 0.84 mmol) and 2-chlorophenylisocyanate (155 mg, 1.01 mmol) were coupled to form the desired urea (150 mg, 43%). LC-MS (m/z) 416.2 (M+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([NH:33][C:34](=[O:36])[CH3:35])[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([NH:33][C:34](=[O:36])[CH3:35])[N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(=O)Nc1nc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cn2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 6-3 (50 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 6-4.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[NH:23][C:22](=O)[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:25])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)([Br:28])=O>O>[Br:28][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:25])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:9][CH:10]=2)[N:23]=1
Reactant: O=c1[nH]n(-c2ccc(Sc3ccccc3)cc2)c(=O)c2ccccc12
Reactant: O=P(Br)(Br)Br
Solvent: O
Product: O=c1c2ccccc2c(Br)nn1-c1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
2-(4-Phenylsulfanyl-phenyl)-2,3-dihydro-phthalazine-1,4-dione (0.10 g, 0.29 mmol) and phosphorus oxybromide (0.33 g, 12 mmol) were stirred at 150° C. for 40 min. H2O (50 ml) was added after cooling to RT. Extraction with DCM, drying of the combined organic phases over Na2SO4, evaporation of the solvent and purification of the raw product by chromatography over silica gel with heptane:DCM (2:1 to 0:1) gave the desired compound (0.10 g, 86%). 1H-NMR: (400 MHz, D6-DMSO) 8.36 (1H, d), 8.11 (1H, d), 8.00 (2H, m), 7.65 (2H, d), 7.44 (7H, m); MS (ESI+)=411.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][N:7]=1.[H][H]>C(O)C.C(N(CC)CC)C.[Pd]>[C:21]1([CH2:20][CH2:19][S:16]([N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:3]3[CH:2]=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:15][CH2:14]2)(=[O:18])=[O:17])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(CCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S(=O)(CCc1ccccc1)N1CCC(CNc2cnccn2)CC1

Procedure:
EXAMPLE 90 was prepared from (3-chloro-pyrazin-2-yl)-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amine by hydrogenation in ethanol-triethylamine over 5% palladium on carbon, 1 atm of hydrogen: MS (m+1)=361.
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:33]>CN(C=O)C.C(Cl)Cl>[CH3:33][N:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:15][CH2:16]2)[C:21]1=[O:29]
Reactant: CI
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C2CCN(C3(c4ccccc4)CCCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a stirred suspension of 1-[1-(1-phenylcycloheptyl)-4-piperidyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one (116 mg, 0.298 mmol) in DMF (1 ml) was added NaH (60% oil suspension, 18 mg, 0.447 mmol) at rt. After 30 min stirring at rt, iodomethane (22.3 μl, 0.358 mmol) was added to the reaction mixture at rt. After 15 min stirring at rt, the reaction mixture was diluted with CH2Cl2, washed with water and brine, dried (Na2SO4), filtered, and concentrated to give pale yellow solid, which was purified by column chromatography (silica gel:5 g, hexane/ethyl acetate:5/1-3/1) to give 83 mg (69%) of white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[S:8])[O:5][C:6]=1[CH3:7].C(N1C(=O)C2=CC=C[CH:21]=[C:14]2[C:13]1=[S:22])CC>>[CH3:1][C:2]1[N:3]=[C:4]([S:8][S:22][CH2:13][CH2:14][CH3:21])[O:5][C:6]=1[CH3:7]
Reactant: CCCN1C(=O)c2ccccc2C1=S
Reactant: Cc1[nH]c(=S)oc1C
Product: CCCSSc1nc(C)c(C)o1

Procedure:
Starting from 4,5-dimethyl-2-thiono-4-oxazoline and N-propylthiophthalimide there is obtained (4,5-dimethyl-2-oxazolyl)propyl-disulphide. nD20 =1.5321. IR (liq.): bands inter alia at 2980, 1635, 1450, 1225, 1173, 1100, 945, 740 cm-1.
Reaction SMILES: [OH-].[Na+:2].CO.[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13]>ClCCl>[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[N-:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13].[Na+:2]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 29 °C

Procedure:
3.47 g of sodium hydroxide and 105 ml of methanol were taken into a round bottom flask and stirred at 29° C. A solution of 30 g of esomeprazole in 150 ml of dichloromethane was added to the above methanolic sodium hydroxide solution and stirred for 1 hour at 26° C. The mass was then distilled under a vacuum of 300 mm Hg at 38° C. The remaining residue was then co-distilled with 450 ml of dichloromethane in three equal lots. To the residue obtained, 60 ml of dichloromethane was added and stirred at 29° C. for 1.5 hours. The separated solid was filtered and washed with 30 ml of dichloromethane to give 32.2 g of Form J of esomeprazole sodium.
Reaction SMILES: [NH2:1][C:2]([CH3:12])=[CH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].O[C:14](=[C:17]1C(=O)OC(C)(C)[O:19][C:18]1=O)[CH2:15][CH3:16]>>[C:4]([C:3]1[C:18](=[O:19])[CH:17]=[C:14]([CH2:15][CH3:16])[NH:1][C:2]=1[CH3:12])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(N)=CC(=O)c1ccccc1
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Product: CCc1cc(=O)c(C(=O)c2ccccc2)c(C)[nH]1
Temperature: 120 °C
Yield: 27.6 %

Procedure:
A mixture of 3-amino-1-phenyl-2-buten-1-one (2.3 g) and 5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (4.0 g) was heated at 120° C. for 1 hour. The mixture was cooled to ambient temperature and the residue was purified by flash chromatography eluting with dichloromethane/methanol (19:1 v/v) to give 3-benzoyl-1,4-dihydro-6-ethyl-2-methyl-4-oxopyridine (0.95 g) as a solid, m.p. 203° C.; NMR (d6 -DMSO): 1.2(t, 3H), 2.07(s, 3H), 2.5(q, 2H), 5.96(s, 1H), 7.44-7.50(m, 2H), 7.57-7.60(m, 1H), 7.72-7.76(m, 2H), 11.3(broad s, 1H); mass spectrum (chemical ionisation, ammonia): 242(M+H)+.