Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:44][CH:45]1[O:49][CH2:48][CH2:47][O:46]1.CS(C)=O>C1COCC1.O>[O:46]1[CH2:47][CH2:48][O:49][CH:45]1[CH2:44][N:18]1[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:30])[F:31])[CH:23]=2)[N:21]=[C:17]1[CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: BrCC1OCCO1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CC2OCCO2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
The solution of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (1100.00 mg; 2.46 mmol; 1.00 eq.) in 2.0 ml of THF was cooled to −20° C., NaHMDS (541.00 mg; 2.95 mmol; 1.20 eq.) was added dropwise and the resulting mixture was stirred at RT for 30 mins. 2-Bromomethyl-[1,3]dioxolane (0.76 ml; 7.38 mmol; 3.00 eq.) was added and stirred at RT for 5 min. DMSO (10 ml) was added and the mixture was placed in microwave at 100° C. for 2 hr. The reaction mixture was cooled and diluted with water and extracted with EA. The organic layer was washed with brine, separated, dried and concentrated. The residue was subjected to snap column (100 g), eluted with 20%-80% EA in hexane to give the title compound (1000 mg, yield 76.2%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:11]([Cl:13])=O.C(Cl)[Cl:17]>CN(C=O)C>[Cl:13][CH2:11][C:5]1[CH:4]=[CH:3][C:2]([C:1]([Cl:17])=[O:9])=[CH:7][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: ClCCl
Reactant: O=C(O)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(CCl)cc1
Yield: 94 %

Procedure:
Benzoic acid (20.0 g, 117 mmol) was suspended in 100 mL of freshly distilled methylene chloride with stirring under a nitrogen atmosphere. Approximately 2 drops of DMF was added to the suspension, followed by the dropwise addition of oxalyl chloride (29.7 g, 234 mmol) over a 0.5 h period. The reaction mixture was stirred at ambient temperature for 17 h. The reaction mixture was then concentrated in vacuo @45°-50° C. Toluene (30 mL) was three times added to the residual oil and removed by azeotropic distillation. The oil was then distilled under reduced pressure to give 20.8 g (94% yield) of the title compound; b.p. 139°-149° C. (12 mm Hg); 1H NMR (CDCl3) d 4.63 (s, 2H), 7.54 (d, 2H), 8.12 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CCCC)CCCC)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([CH:19]=[CH:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: C=CC(=O)OCC
Reactant: Brc1ccc(C=Cc2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=Cc1ccc(C=Cc2ccc(Br)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 5.6 %

Procedure:
25.8 g (0.1 mol) of 4,4'-dibromostilbene, 10 g (0.1 mol) of ethyl acrylate, 18.5 g (0.1 mol) of tri-n-butylamine, 0.224 g (0.001 mol) of palladium acetate and 0.6 g (0.002 mol) of tri-o-tolylphosphine are added under argon to 50 ml of p-xylene. The reaction mixture is stirred at 90° C. for 4 hours. Working up gives 2 g (6% of theory) of ethyl 4-bromostilbene-4'-acrylate. Melting point 166.9° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:41])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27](=[O:29])[CH3:28])[CH:24]=[CH:23][C:22]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]OS(C)(=O)=O>CCCCCC.C(OCC)(=O)C>[C:27]([C:25]1[CH:24]=[CH:23][C:22]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])=[C:21]([CH2:20][CH2:19][C:18]([OH:41])=[O:17])[CH:26]=1)(=[O:29])[CH3:28]
Reactant: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCOS(C)(=O)=O
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCCOc2ccc(C(C)=O)cc2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 11 and starting with 0.2 g (1 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.39 g (1 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]-5-acetylbenzenepropanoic acid methyl ester (from example 32), 5-acetyl-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid was obtained in 64.3% overall yield, as a colorless solid, mp 115°-118° C. (recrystallized from hexane-ethyl acetate).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:23]([O:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][N:43]([CH2:46][C:47](O)=[O:48])[C:42](=[O:50])[N:41]=1)=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:47](=[O:48])[CH2:46][N:43]1[CH:44]=[CH:45][C:40]([NH:39][C:37]([O:36][CH:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])=[N:41][C:42]1=[O:50])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Yield: 84.9 %

Procedure:
The title compound (2.99 g, 85%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid (1.90 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 11.00 (s, 1H), 8.86 (brs, 1H), 8.27 (d, 1H), 8.18 (d, 1H), 7.89 (d, 0.6H), 7.83 (d, 0.4H), 7.68˜7.61 (m, 2H), 7.45˜7.26 (m, 10H), 6.94 (t, 1H), 6.79 (s, 1H), 4.81 (s, 1.2H), 4.62 (s, 0.8H), 4.35 (s, 0.8H), 4.13 (q, 0.8H), 4.06 (s, 1.2H), 4.03 (q, 1.2H), 3.59 (t, 1.2H), 3.44˜3.39 (m, 2H), 3.21 (t, 0.8H), 1.19 (t, 1.2H), 1.13 (t, 1.18H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[CH2:11][C:12]([CH3:25])([C:14]2[C:19](=[O:20])[C:18]([CH3:21])=[C:17]([CH3:22])[C:16](=[O:23])[C:15]=2[CH3:24])[CH3:13])=[CH:5][CH:4]=1.[OH:27][C:28]1[CH:38]=[CH:37][C:31]2[N:32]=[C:33]([C:35]#[N:36])[S:34][C:30]=2[CH:29]=1.N1C(C)=CC(C)=CC=1C>C1COCC1>[C:35]([C:33]1[S:34][C:30]2[CH:29]=[C:28]([O:27][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[CH2:11][C:12]([CH3:25])([C:14]4[C:19](=[O:20])[C:18]([CH3:21])=[C:17]([CH3:22])[C:16](=[O:23])[C:15]=4[CH3:24])[CH3:13])=[CH:5][CH:4]=3)[CH:38]=[CH:37][C:31]=2[N:32]=1)#[N:36]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc(CBr)cc2)=C(C)C1=O
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Product: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc(COc3ccc4nc(C#N)sc4c3)cc2)=C(C)C1=O
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of N-(4-(bromomethyl)phenyl)-3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanamide (0.23 g, 0.57 mmol), 6-hydroxy-2-cyanobenzothiazole (0.15 g, 0.86 mmol), 2,4,6-collidine (0.125 ml) and Ag2CO3 (0.24 g, 0.86 mmol) in 15 ml of dry THF was stirred at room temperature over night. After removal of solid by filtration, the compound was purified by silica chromatography using heptane and ethyl acetate as eluent to give a yield of 40%. The product was further purified by HPLC to remove small contamination of 2-cyano-6-hydroxybenzothiazole. 1H NMR (300 MHz, CD2Cl2) δ 7.4-7.5 (m, 3H), 7.35-7.42 (m, 2H), 7.32 (dd, 1H), 7.25 (s, br, 1H, NH), 7.18 (dd, 1H), 5.15 (s, 2H, CH2O), 2.99 (s, 2H, CH2), 2.14 (s, 3H, CH3), 1.92 (s, 6H, CH3), 1.47 (s, 6H, CH3). MS (m/e): 514.2 (M+).
Reaction SMILES: [C:1](=[C:3]1N=C2C=CC=CC2=N1)=O.[CH:12]([S:15]([N:18]1[C:22]2[CH:23]=[C:24]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH2:35])(=[O:17])=[O:16])([CH3:14])[CH3:13].C([Mg]Br)C.CO>C(OCC)C>[CH:12]([S:15]([N:18]1[C:22]2[CH:23]=[C:24]([C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([OH:34])[CH2:1][CH3:3])[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH2:35])(=[O:16])=[O:17])([CH3:14])[CH3:13]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Reactant: O=C=C1N=c2ccccc2=N1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: CO
Product: CCC(O)(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1

Procedure:
The 1-hydroxy-1-(C1 -C7 alkyl)benzyl derivatives, the carbinols, can also be prepared by reacting the corresponding carbonyl derivative with the appropriate Grignard reagent followed by hydrolysis. The carbonyl benzimidazole, 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole, is reacted with ethylmagnesium bromide in anhydrous ethyl ether and then hydrolyzed to form the carbinol, 1-isopropylsulfonyl-2-amino-6-(1-phenyl-1-hydroxy-1-propyl)benzimidazole. The Grignard reagent, ethylmagnesium bromide, is made from ethylbromide and metallic magnesium in anhydrous ethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.C(O[Si](C)(C)CO[CH:16]1[CH2:18][CH2:17]1)C.[BH4-].[Na+]>CC(O)=O.CO.C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:16]2[CH2:18][CH2:17]2)=[C:4]([Cl:9])[CH:3]=1
Reactant: CCO[Si](C)(C)COC1CC1
Reactant: Nc1ccc(Br)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Clc1cc(Br)ccc1NC1CC1
Temperature: 68 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-chloroaniline [C.A.S. 38762-41-3], (1 g, 4.843 mmol) in AcOH (19 ml) and MeOH (10 mL) stirred at room temperature and under nitrogen atmosphere was added dropwise (1-ethoxycyclopropyloxy-trimethylsilane [C.A.S. 27374-25-0] (1.199 ml, 5.57 mmol). The reaction mixture was then refluxed at 67-69° C. for 3 h. The mixture was then concentrated in vacuo to yield intermediate D30′. In another flask, NaBH4 (0.366 g, 9.687 mmol) was suspended in THF (10 mL) and cooled to 5° C. Then, BF3.Et2O complex (1.228 ml, 9.687 mmol) was added dropwise. The resulting reaction mixture was stirred under a N2 atmosphere at 5° C. for 1 h. Then, to this mixture was added a solution of D30′ in THF (5 mL) dropwise at 5-10° C. over 20 min. After stirring at r.t. for 5 h., at reflux temperature for 2 h., and then removing THF by distillation, the mixture was cooled to r.t. and poured into water. The resulting mixture was extracted with Et2O. The organic layer was washed with water and dried (Na2SO4) followed by the removal of the volatiles under vacuo. The crude product thus obtained was purified by column chromatography (silica gel; Heptane/EtOAc 99:1 as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D30 (0.390 g, 32.6%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[NH:7][C:6]1=[O:14].[F:16][C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([S:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=2)(=[O:25])=[O:24])[C:6]1=[O:14]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CN(C)CCn1c(=O)[nH]c2cccnc21
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CCn1c(=O)n(S(=O)(=O)c2cccc(F)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(2-dimethylaminoethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (20 mg, 0.10 mmol) in THF at room temperature is treated with 3-fluorophenyl-sulfonyl chloride (26 mg, 0.12 mmol), followed by diisopropylethylamine (25 μL, 0.20 mmol) and DMAP (5 mg), stirred at room temperature for 12 h and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by Gilson preparative HPLC1 to give the title compound, [M+H] 365, retention time (RT) 2.54 minutes. 1HPLC Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm (i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0 mL/min; Solvent A: 0.02% formic acid in water; Solvent B 0.02% formic acid in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1.Cl>CN(C=O)C>[ClH:13].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[C:2]1=[O:10]
Reactant: Clc1ncnc2ccc(N3CCOCC3)cc12
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1c1ncnc2ccc(N3CCOCC3)cc12
Yield: 13.1 %

Procedure:
Using a procedure analogous to that described in Example 26, oxindole (0.32 g, 2.4 mmol) was added to sodium hydride (110 mg, 2.8 mmol) in DMF (15 ml) and the solution was treated with 4-chloro-6-morpholinoquinazoline (200 mg, 8 mmol), (EP 0566226), in DMF (8 ml). The product so obtained was treated with ethereal hydrogen chloride to give 4-(oxindol-3-yl)-6-morpholinoquinazoline hydrochloride (120 mg, 43%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)O1.Br[C:18]1[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([CH:24]=1)[NH2:23].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:18]2[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([NH2:23])[CH:24]=2)=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2ccc(F)cc2)OC1(C)C
Reactant: Cc1ccc(Br)cc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(F)cc2)cc1N
Yield: 43 %

Procedure:
5.0 g (22.5 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-fluorobenzene, 1.87 mL (15 mmol) of 5-bromo-2-methylaniline, 1.73 g (1.5 mmol) of tetrakis(triphenyl phosphine)palladium (0), and 7.33 g (15 mmol) of cesium carbonate were heated under reflux for 8 hours in 150 mL of THF. After completion of the reaction, THF was distilled off under reduced pressure, and ethyl acetate was added to separate the solid by filtration. The organic layer was then washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography, thereby giving 4′-fluoro-4-methylbiphenyl-3-amine (yield: 43%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([CH:23]=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].CI.[CH3:29]C(O)=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:29])[CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([CH:23]=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(NC1CCc2cc3ccccc3n2C1)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C1CCc2cc3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Step 8 (3 g) in 100 mL of DMF were added 0.4 g of NaH (60% in mineral oil) and 1.2 mL of MeI. After stirring for 1 h at room temperature, 1 mL of AcOH was added and the mixture was concentrated under vacuum and the residue was dissolved in 200 mL of 1:1 hexane/EtOAc and filtered through a pad of silica gel. The filtrate was concentrated and the residue was swished from 2:1 hexane/EtOAc to give 2.5 g of the title product. 1H NMR (500 MHz, acetone-d6) δ 8.10 (m, 2H), 7.47 (m, 3H), 7.28 (d, 1H), 7.09 (dd, 1H), 7.02 (dd, 1H), 6.15 (s, 1H), 4.55 (m, 1H), 4.20 (m, 1H), 3.88 (t, 1H), 3.05-3.12 (m, 1H), 2.92-3.02 (m, 1H), 2.97 (s, 3H), 1.92-2.02 (m, 1H), 1.66 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:19][N+:16]([O-:18])=[O:17])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: Cc1cc(C=O)ccc1O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1cc(C=C[N+](=O)[O-])ccc1O
Temperature: 45 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
Commercially available 3-methyl-4-hydroxybenzaldehyde (1.00 g, 7.34 mmol), ammonium acetate (850 mg, 11.0 mmol), and nitromethane (7.00 mL) were mixed, and the mixture was stirred at 45° C. for 5 hours. Then, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 2-methyl-4-(2-nitrovinyl)phenol (1.05 g, yield 80%). This compound (1.05 g, 5.86 mmol) was dissolved in THF (30.0 mL), then lithium aluminum hydride (642 mg, 16.9 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Subsequently, sodium sulfate decahydrate (5.45 g, 16.9 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 30 minutes. The resulting precipitate was filtered out, and the filtrate was concentrated under reduced pressure. A hydrogen chloride-ethyl acetate solution (4.00 mol/L, 10.0 mL, 40.0 mmol) was added thereto, and precipitated crystals were collected by filtration to give 2-methyl-4-(2-aminoethyl)phenol hydrochloride (188 mg, yield 17%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:6]1)=[O:4].C(N(CC)CC)C.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>C1COCC1>[CH3:1][O:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:33]([C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=3)(=[O:35])=[O:34])[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)N1CCC(c2cccc(N)c2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N1CCC(c2cccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)c2)C1
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of 3-(3-amino-phenyl)-pyrrolidine-1-carboxylic acid methyl ester (500 mg, 2.27 mmol) and triethylamine (500 mg, 4.94 mmol) in THF (20 ml) at 10° C. 4-trifluoromethoxy-benzenesulfonylchloride (600 mg, 2.3 mop was added. The mixture was allowed to come to room temperature and was stirred for 16 h. The mixture was poured into water and extracted three times with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over MgSO4 and evaporated under reduced pressure to give the product as a brown oil (1 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C(Cl)=O.Cl.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([C@@H:32]2[C@H:37]([NH2:38])[CH2:36][CH2:35][S:34][CH2:33]2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH3:22].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([C@@H:32]2[C@H:37]([NH:38][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)=[O:11])[CH2:36][CH2:35][S:34][CH2:33]2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH3:22]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCOc1cc([C@H]2CSCC[C@H]2N)ccc1OC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc([C@H]2CSCC[C@H]2NC(=O)c2ccc(C(=O)OC)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 4-(methoxycarbonyl)benzoic acid (11.35 g) in DCM (300 ml) are added 5 drops of DMF and the reaction mixture is stirred for 20 min at RT under a nitrogen atmosphere. To this suspension oxalyl chloride (5.67 ml) dissolved in DCM (60 ml) is slowly added at 0° C. (ice bath The ice bath is removed and the mixture is stirred for 4 h at RT. DCM (3×200 ml) is added to the reaction mixture and the volatiles are co-evaporated under reduced pressure (three times). Finally all volatiles are removed under vacuo to obtain an oil, which is dissolved in DCM (200 ml) and added dropwise to a solution of (3R,4R)-3-(3-ethoxy-4-methoxyphenyl)tetrahydro-2H-thiopyran-4-amine hydrochloride (18.23 g; compound C13) and DIPEA (41.1 ml) in DCM (200 ml) at 0° C. under nitrogen atmosphere. After stirring for 12 h at RT the reaction is quenched by addition of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase is separated, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The resulting residue is suspended in DIP (300 ml) and heated under reflux for 3.5 h. The suspension is stirred for 2 d at RT and subsequently cooled to 0° (ice bath). The suspension is filtered and the filter cake is washed with little amounts of DIP and dried in vacuo for 12 h at 60° C. to give the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](Cl)=[N:6][S:5][N:4]=1.[S:9]([NH2:19])(=[O:18])([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>>[CH3:1][O:2][C:3]1[C:7]([NH:19][S:9]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:10])=[O:18])=[N:6][S:5][N:4]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COc1nsnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1nsnc1NS(=O)(=O)c1ccc(N)cc1
Yield: 96 %

Procedure:
75.3 g of 3-methoxy-4-chloro-1,2,5-thiadiazole (0.5 mole), 103.32 g of sulfanilamide (0.6 mole) and 207.31 g of potassium carbonate (1.5 mole) were reacted in 195.33 g of dimethysulfoxide (2.5 mole) and worked up as described in Example 2. 137.5 g of crude 3-methoxy-4-(4'-aminobenzene-sulfonamido)-1,2,5-thiadiazole (96.05% of theory) were obtained. The mixture was recrystallized from methanol/water 1:1 with charcoal added, as described in Example 2. 126.87 g of pure product (88.63% of theory) having a melting point of 149°-150° C. were obtained; the product showed no additional spots in TLC and met the colour standard.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:8][NH:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[F:15][C:16]1[CH:17]=[C:18]([C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[C:28](O)=[O:29])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[C:28]([N:7]2[CH2:8][C:3]([O:13][CH3:14])([O:2][CH3:1])[CH2:4][CH2:5][CH:6]2[C:9]([O:11][CH3:12])=[O:10])=[O:29])[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C1CCC(OC)(OC)CN1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: COC(=O)C1CCC(OC)(OC)CN1C(=O)c1nc(C)sc1-c1cccc(F)c1

Procedure:
Methyl 1-(5-(3-fluorophenyl)-2-methylthiazole-4-carbonyl)-5,5-dimethoxypiperidine-2-carboxylate was prepared according to general procedure A using product methyl 5,5-dimethoxypiperidine-2-carboxylate and 5-(3-fluorophenyl)-2-methylthiazole-4-carboxylic acid.
Reaction SMILES: [O:1]1[C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C@H:2]1[CH2:3][OH:4].C(Cl)Cl>CCCCCC.C(OCC)(=O)C>[O:1]1[C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C@H:2]1[CH:3]=[O:4]
Reactant: COC(=O)c1cccc([C@H]2O[C@@H]2CO)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)c1cccc([C@H]2O[C@@H]2C=O)c1

Procedure:
The title compound is prepared analogously to Example 5a) from (2R,3R)-2,3-epoxy-3-(3-methoxycarbonylphenyl)-propanol; light-yellow oil; IR (methylene chloride): 2950, 2820, 1725, 1610, 1590, 1430, 1290, 1255 cm-1 ; Rf =0.33 (hexane/ethyl acetate 3:2).