Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[OH:22]>[OH-].[Na+]>[OH:14][C:10]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:22])[C:11]1([CH3:13])[CH3:12]
Reactant: CC1(C)C(N)=Nc2ccccc2C1(O)c1ccccc1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)C(=O)Nc2ccccc2C1(O)c1ccccc1

Procedure:
A solution of 2-amino-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (5.32 g., 0.02 mole) in methanol (40 ml.) and 2N aqueous sodium hydroxide (20 ml. ) was heated under reflux for 6 hours. The mixture was poured onto water, extracted with chloroform and the combined extracts washed and dried (MgSO4). After removal of the solvent the residue was crystallised from toluene to give the title compound (4.73g., m.p. 185° - 187° C). [Found: C, 76.25, H, 6.6, N, 5.3% C17H17NO2 requires, 76.4, H, 6.4, N, 5.25%].
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[Cl:18][S:19](O)(=[O:21])=[O:20]>>[F:17][C:2]([F:1])([F:16])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]1[CH:15]=[CH:14][C:13]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:12][CH:11]=1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CCCC1c1ccccc1)C(F)(F)F
Product: O=C(N1CCCC1c1ccc(S(=O)(=O)Cl)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
At 0° C., 2,2,2-trifluoro-1-(2-phenylpyrrolidin-1-yl)ethanone (2.0 g, 8.2 mmol) was added to chlorosulfonic acid (10 mL) and allowed to warm to 25° C. over 30 min. Then the mixture was poured into ice water and extracted with EtOAc. The organic layer was concentrated to obtain 4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzene-1-sulfonyl chloride as a clear oil which was used in the next reaction step without further purification.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])[CH3:26].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[Pd]Br.C(O)C>[CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([C:25](=[O:27])[CH3:26])[CH:33]=3)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: Br[Pd]Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(-c2cccc(-n3cc(C(=O)NC(C)C)c(=O)c4cccnc43)c2)c1

Procedure:
A mixture of N-Isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 4, 3-acetylphenylboronic acid (1.2 eq.), trans-dibromobis(triphenylphosphine)palladium (II) (0.05 eq.), toluene (6 mL/mmol), ethanol (2 mL/mmol) and 2M aqueous sodium carbonate (8 eq.) was refluxed for 1 hour under a nitrogen atmosphere. The mixture was diluted with ethyl acetate and the organic phase was washed with water and brine, dried and evaporated. The crude product was chromatographed on silica gel eluting with a gradient of 20-40% ether in methylene chloride to afford the N-Isopropyl-1-[3-(3-acetylphenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide product as a solid.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH2:27]([N:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[C:17]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]3[CH2:12][N:13]([CH:37]4[CH2:36][CH2:35][N:34]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:39][CH2:38]4)[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CN(C3CCN(Cc4ccccc4)CC3)CCN12
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.4 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.15 g, 0.51 mmol), acetic acid (0.045 mL, 0.79 mmol) and 1-benzyl-4-piperidone (0.12 g, 0.63 mmol) in tetrahydrofuran (5 mL) was added sodium triacetoxyborohydride (0.16 g, 0.75 mmol), and the mixture was stirred at room temperature for 16 hours. 1-Benzyl-4-piperidone (0.060 mL) and sodium triacetoxyborohydride (0.16 g) were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, water and saturated brine, and then dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with amino silica gel column chromatography (hexane:ethyl acetate=98:2 to hexane:ethyl acetate=1:1) and recrystallized from ethyl acetate-hexane to obtain the title compound (70 mg, yield 29%).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1CCCC1=O.O>[CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][CH:25]=3)[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(CCn2c3c(c4cc(C(C)C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.8 %

Procedure:
To a solution of 8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.877 mmol) in N-methyl 2-pyrolidone (2 mL) was added powdered potassium hydroxide (0.2 g, 3.5 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyridine (0.104 g, 0.877 mmol) was added and stirred for further at 120 deg C. for 20 h. Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (5% Me OH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) and further purified with preparative TLC to provide the desired compound as brown oil (0.045 g, 15% yield). 8-Isopropyl-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.045 g, 0.129 mmol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.016 g, 0.129 mmol) in THF (2 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.045 g, 80% yield).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.B(F)(F)F.[CH3:16]COCC.[Si](C=[N+]=[N-])(C)(C)C>C(OCC)C.C(=O)(O)[O-].[Na+]>[O:1]1[CH2:2][CH2:3][C:4](=[O:11])[CH2:16][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]1=2
Reactant: O=C1CCOc2ccccc21
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: FB(F)F
Agent: O=C([O-])O
Product: O=C1CCOc2ccccc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chromanone (9.54 g, 64.3 mmol) in diethyl ether at 0° C. was slowly added boron trifluoride diethyl etherate (16.3 ml, 128.6 mmol), followed by the dropwise addition of 2M TMSCHN2 in diethyl ether. The mixture was allowed to stir for 1 hour at 0° C. before diluting with sat. sodium bicarbonate solution and diethyl ether. The organic phase was dried, concentrated, and purified on silica to give 2,3-dihydro-5H-benzo[b]oxepin-4-one.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22](N(OC)C)=[O:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][C:6]([CH3:29])=[N:5]1)([CH3:3])[CH3:2].O1CCC[CH2:31]1.C[Mg]Br>CCOCC>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22](=[O:23])[CH3:31])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][C:6]([CH3:29])=[N:5]1)([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(=O)c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 0 °C

Procedure:
2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-N-methoxy-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide (2.0 g, 0.0050 mol) was dissolved in Tetrahydrofuran (20 mL, 0.3 mol). The reaction was cooled at 0° C. 3.0 M of Methylmagnesium bromide in Ether was added dropwise. The reaction was allowed to warm to room temperature over a 1 hour period. LCMS shows complete conversion to desired product. The reaction was cooled back to 0° C. and quenched with saturated aqueous ammonium chloride. The reaction mixture was diluted with H2O and the crude product was extracted with Ethyl Acetate The organic extracts were combined, dried over Na2SO4, filtered and concentrated to dryness. The crude was purified on silica gel (0→10% MeOH/DCM) to yield 1-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)ethanone as an orange solid.
Reaction SMILES: N1(CC[C:9]2([C:27]([O-:29])=[O:28])[C:14](CCN3CCOCC3)([C:15]([O-:17])=O)[CH:13]3[CH2:26][CH:10]2[CH:11]=[CH:12]3)CCOCC1.C1(=O)OC(=O)C=C1>>[CH:13]12[CH2:26][CH:10]([CH:11]=[CH:12]1)[CH:9]1[C:27]([O:29][C:15](=[O:17])[CH:14]21)=[O:28]
Reactant: O=C([O-])C1(CCN2CCOCC2)C2C=CC(C2)C1(CCN1CCOCC1)C(=O)[O-]
Agent: O=C1C=CC(=O)O1
Product: O=C1OC(=O)C2C3C=CC(C3)C12

Procedure:
reacting a diene compound of formula 2 with maleic anhydride to produce 5-norbornene-2,3-dicarboxylic anhydride;
Reaction SMILES: [Br:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[CH3:20].FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[Br:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][NH2:9])=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc(OCCNC(=O)OC(C)(C)C)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCCN)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 2-(4-bromo-3,5-dimethylphenoxy)ethylcarbamate (310 mg) in dichloromethane (8 mL) is added trifluoroacetic acid (700 μL). The mixture is stirred for 12 hours at room temperature. Then saturated aqueous K2CO3 solution is added, the mixture is stirred for 30 minutes and the phases are separated. The organic phase is washed with saturated aqueous K2CO3 solution and dried (MgSO4). The solvent is evaporated to give the title compound. Yield: 200 mg; LC (method 7): tR=0.83 min; Mass spectrum (ESI+): m/z=244 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].C([N:17](CC)C1C=CC=CC=1)C.C(C1C=CC(C)=C(S([O-])(=O)=O)C=1)(=O)C>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([NH2:17])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCN(CC)c1ccccc1
Reactant: CC(=O)c1ccc(C)c(S(=O)(=O)Cl)c1
Agent: CC(=O)c1ccc(C)c(S(=O)(=O)[O-])c1
Product: CC(=O)c1ccc(C)c(S(N)(=O)=O)c1

Procedure:
Thus obtained 5-acetyl-2-methylbenzenesulfonyl chloride was dissolved in 790 g of tetrahydrofuran, then 81 g of ammonia gas was added at a temperature below 10° C. 800 Grams of water was added to this reaction mixture, and tetrahydrofuran was removed by evaporation to crystallized 5-acetyl-2-methylbenzenesulfonamide. The crystals were collected by filtration, and dried to obtain 176.8 g (0.83M) of 5-acetyl-2-methylmethylbenzenesulfonamide. Melting point: 150.5°-151.5° C. The yield was 95% on the basis of 5-acetyl-2-methylbenzenesulfonyl chloride, and was 83% on the basis of N,N-diethylaniline salt of 5-acetyl-2-methylbenzenesulfonate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1.[F:15][C:16]([F:26])([F:25])[CH:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)CCl.S(=O)(=O)(O)O.O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([F:15])([F:25])[F:26])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCC(O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCCl
Product: CCCCCCC(OC(=O)c1ccc2cc(O)ccc2c1)C(F)(F)F
Reaction time: 48 h
Yield: 31.9 %

Procedure:
To a solution of 2-hydroxy-6-carboxynaphthalene (2 g) and optically active 1,1,1-trifluoro-2-octyl alcohol (2.2 g) in ethylene chloride (50 ml) was added a few drops of conc. sulfuric acid, and the solution was refluxed under stirring for about two days. The solution obtained was poured in water in order to collect the organic layer. The layer was washed with aqueous sodium hydroxide solution and water, in this order, and dried over anhydrous magnesium sulfate. The solution was distilled to remove the solvent. The residue was purified by silica-gel column chromatography (developer : chloroform) to obtain the titled compound (1.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:35]2[CH:34]=[N:33][C:32]([Cl:31])=[CH:37][CH:36]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: OB(O)c1ccc(Cl)nc1
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(Cl)nc2)sc1C(=O)OCC

Procedure:
Prepared from 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester, example 81(b), and 2-chloropyridine-5-boronic acid under conditions analogous to experimental example 81(c). MS: (+) m/z 534.3 (M+1).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(CCCC(=O)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 226.5 %

Procedure:
The crude acid chloride (2.07 g, 9.7 mmol) and anisole (1.26 g, 11.6 mmol) were dissolved in 1,2-dichloroethane (32 mL) and chilled in an ice bath. The mixture was treated with aluminum chloride (3.9 g, 29.1 mmol) in portions, stirred for 5 minutes, then mixed with ice water (50 mL). The mixture was extracted with dichloromethane (3×10 mL), and the extracts were combined, washed with saturated sodium chloride (100 mL), dried (MgSO4), then concentrated under reduced pressure. The residue was flushed through silica gel with 10:1 hexane/ethyl acetate then concentrated to give 1,4-bis-(4-methoxyphenyl)butan-1-one (2.49 g, 82%). 1H NMR (400 MHz, CDCl3): 7.90 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 3.86 (s, 3H), 3.78 (s, 3H), 2.90 (t, J=7.3 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H), 2.02 (m, 2H) ppm. IR (NaCl): 1674, 1602, 1244 cm-1.
Reaction SMILES: C([Mg]Br)C.C1COCC1.I[C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1.C1(C)C=CC(S([C:30]#[N:31])(=O)=O)=CC=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:30]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1)#[N:31]
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CSc1nc(I)n2ccsc12
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1nc(C#N)n2ccsc12
Temperature: -5 °C
Yield: 49.1 %

Procedure:
A 1 M ethylmagnesium bromide/THF solution (2.0 ml) was added in an argon atmosphere at −40° C. to a solution of 405 mg of 5-iodo-7-methylthioimidazo[5,1-b]thiazole in 12 ml of dry THF. The mixture was stirred at the same temperature for 30 min. p-Toluenesulfonyl cyanide (372 mg) was added thereto. The temperature of the system was raised to −5° C. over a period of one hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was added thereto, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate:hexane=3:1:1) to give 131 mg of 5-cyano-7-methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:22]=[CH:23][C:24]([F:25])=[C:19]([Cl:18])[CH:20]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3ccc(F)c(Cl)c3)cc2sc1=O

Procedure:
7-(3-Chloro-4-fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 3-chloro-4-fluoro-phenylboronic acid under conditions analogous to Example 7(a). MS ESI(+) m/e: 365.10 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]3[N:31]=[C:30](S(C4C=CC(C)=CC=4)(=O)=O)[S:29][N:28]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(#N)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]3[N:31]=[C:30]([O:9][C:7]4[C:6]([CH3:10])=[CH:5][C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=4)[S:29][N:28]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)c2nc(C3(c4ccc(Cl)cc4)CC3)ns2)cc1
Reactant: Cc1cc(O)c(C)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Oc2nc(C3(c4ccc(Cl)cc4)CC3)ns2)c(C)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
0.70 g (5.12 mmol) of 2,5-dimethyl-4-hydroxyaniline is placed in 18 ml of acetonitrile, 0.85 g (6.14 mmol) of potassium carbonate is added at ambient temperature and the mixture is stirred at ambient temperature for 30 min. Subsequently, 2.0 g (5.12 mmol) of 3-[1-(4-chloro-phenyl)cyclopropyl]-5-[(4-methylphenyl)sulphonyl]-1,2,4-thiadiazole are added and the reaction mixture is stirred at 50° C. for 12 h. After cooling, the reaction mixture is concentrated using a rotary evaporator and the residue is taken up in dichloromethane, extracted twice with water, dried over Na2SO4 and freed from the solvent under vacuum. 1.46 g of clean product are obtained (76.9% yield, log P (pH 2.3)=4.44).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[NH:8].[OH:13][CH2:14][C:15]([CH2:17]O)=O.[Cl-].[NH4+].[OH-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:7]2[NH:9][C:15]([CH2:14][OH:13])=[CH:17][N:8]=2)[CH:10]=1
Reactant: O=C(CO)CO
Reactant: COc1ccc(Br)cc1C(=N)N
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1-c1ncc(CO)[nH]1
Temperature: 90 °C

Procedure:
A mixture of 5-Bromo-2-methoxy-benzamidine (1.5 g), 1,3-dihydroxy-acetone dimer (1.0 g), ammonium chloride (1.3 g), tetrahydrofuran (3 mL) and concentrated aqueous ammonium hydroxide (10 mL) was heated at 90° C. for 3 h. The reaction mixture was chilled on ice and the precipitated product was collected and recrystallized from methanol to afford 2-(5-Bromo-2-methoxyphenyl)-5-hydroxymethyl-imidazole as a yellow solid.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]=[CH2:4].P(Br)(Br)[Br:16]>>[Br:16][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: BrP(Br)Br
Reactant: C=CC(C)(O)CCC=C(C)CC(C)C
Product: CC(=CCBr)CCC=C(C)CC(C)C

Procedure:
Following the procedure of Example 9, 3,7,9-trimethyl-1,6-decadien-3-ol and phosphorus tribromide are reacted to form 1-bromo-3,7,9-trimethyl-2,6-decadiene.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[O:12][CH2:13][C:14]#[N:15].O.C(Cl)Cl.CO>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[O:12][CH2:13][CH2:14][NH2:15]
Reactant: COc1ccc(OCC#N)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(OCCN)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.6 %

Procedure:
To a cold (0° C.) suspension of LiAlH4 (1.73 g, 45.6 mmol) in anhydrous THF (72 ml), was added dropwise a solution of (3,4-dimethoxy-phenoxy)-acetonitrile (5.88 g, 30.4 mmol) in anhydrous THF (42 ml). The resulting mixture was allowed to warm-up and stirred at RT for 20 h under nitrogen. The reaction mixture was combined with a mixture of H2O/2N NaOH(aq) (4/1) to destroy the excess of LiAlH4. The white suspension was filtered and the solid was washed with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2Cl2/MeOH: 9/1) gave the title product (4.65 g, 77%).
Reaction SMILES: O.O.P([O-])([O-])(O)=O.[Na+].[Na+].O.O.P([O-])(O)(O)=O.[Na+].[C:18]([NH:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH3:36])=[C:31]([CH2:37][CH3:38])[CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:19].[OH-].[Na+]>O.CC(C)=O>[C:18]([NH:21][C@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH3:36])=[C:31]([CH2:37][CH3:38])[CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:19]
Reactant: CCOC(=O)C(Cc1ccc(CC)c(CC)c1)NC(C)=O
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)[C@@H](Cc1ccc(CC)c(CC)c1)NC(C)=O
Temperature: 37 °C
Reaction time: 4 h

Procedure:
27 mL Alcalase 2.4 L FG (Novozymes A/S; DK 2880 Bagsvaerd) were added to a solution of 38.0 g (213.5 mmol) disodium hydrogen phosphate dihydrate in 500 mL water at a temperature of 37° C. and the pH was adjusted to 7.5 by the addition of sodium dihydrogen phosphate dihydrate. Then at 37° C. with stirring 29.7 g (101.9 mmol) ethyl 2-acetylamino-3-(3,4-diethyl-phenyl)-propionate dissolved in 150 mL acetone was added dropwise. The pH value of the reaction mixture was kept constantly kept in the range from pH 7.4 to pH 7.6 by the addition of 1 M NaOH. After the addition had ended the mixture was stirred for 4 h at 37° C. The reaction mixture was extracted three times with tert-butylmethylether, the combined organic extracts were washed with 15% K2CO3 solution, dried and evaporated down under reduced pressure.