Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](/[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][OH:16])=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH:1](/[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC/C=C/c1ccccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CCCCCCCCCC/C=C/c1ccccc1C=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of lithium aluminum hydride (22.2 mmoles) in tetrahydrofuran (30 ml) under argon, cooled to 0° C., was added 2-(1-dodecyn-1-yl) benzaldehyde (11.1 mmoles, prepared as in Example 4(a) in tetrahydrofuran (10 ml), dropwise with stirring. After coming to room temperature, the reaction mixture was refluxed for 18 hours. The reaction mixture was then cooled to 0° C., ice was added, followed by ether and dilute hydrochloric acid, and the layers were separated. The organic layer was washed with water and brine. The dried solution was concentrated to give 2-(1-trans-dodecenyl)benzyl alcohol, after recrystallization from acetonitrile. The benzyl alcohol (0.080 mmoles) was dissolved in ethyl acetate (10 ml) under argon and manganese dioxide (12.6 mmoles) was added. The reaction mixture was stirred for 18 hours at room temperature, filtered and the filtrate concentrated to leave an oil which is the desired product.
Reaction SMILES: CCCCCC.[F:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[CH:22]=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([S:29]([N:20]2[C:17]3=[N:18][CH:19]=[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([F:7])[CH:9]=4)[CH:15]=[C:16]3[CH:22]=[CH:21]2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Fc1cccc(-c2cnc3[nH]ccc3c2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1ccccc1)n1ccc2cc(-c3cccc(F)c3)cnc21
Yield: 92.4 %

Procedure:
2.5 M solution of n-Bui in hexane (2.47 mL, 6.18 mmol) was added dropwise to a stirred and cooled (−78° C.) solution of azaindole 7 (1.088 g, 5.13 mmol) in THF (5.5 mL). After the mixture was stirred for 20 min at −78° C., neat PhSO2Cl (0.785 mL, 6.2 mmol) was added dropwise. The mixture turned brown. Stirring at −78° C. was continued for 0.5 b. Cooling bath was removed, the mixture was stirred at r.t. overnight, and separated between AcOEt:saturated aqueous NaHCO3 solution. The aqueous layer was extracted with AcOEt (2×5 mL). Combined organic solutions were washed with brine, dried (MgSO4), concentrated, and separated by means of SGC with hexane:AcOEt as eluent in gradient to afford 12 (1.6705 g, 92%) as white solid. 1H NMR (400 MHz, CDCl3) δ 6.66 (d, J=4.0 Hz, 1H), 7.08 (dddd, J=8.4, 8.0, 2.5, 1.1 Hz, 1H), 7.25 (ddd, J=9.9, 2.5, 1.7 Hz, 1H), 7.33 (ddd, J=7.8, 1.7, 1.1 Hz, 1H), 7.43 (ddd, J=8.0, 7.8, 6.0 Hz, 1H), 7.47-7.53 (m, 2H), 7.57-7.62 (m, 1H), 7.78 (d, J=4.0 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H), 8.21-8.26 (m, 2H), 8.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Oc1ccccc1Br
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(Oc2ccccc2Br)cc1
Temperature: 150 °C
Yield: 37.5 %

Procedure:
To a mixture of 4-fluorobenzaldehyde (2.5 g, 20.2 mmol), 2-bromophenol (3.5 g, 20.2 mmol) and potassium carbonate (3.35 g, 24.3 mmol) is added N,N-dimethylacetamide (20 mL) and the resulting reaction mixture is heated to 150° C. for 12 hours. Once complete, the reaction is cooled to room temperature and diluted with water prior to being extracted with ethyl acetate. The combined extracts are washed with brine and dried over sodium sulfate and concentrated. The resulting yellow oil is purified by column chromatography (5% ethyl acetate in hexanes) to afford 2.1 g of 4-(2-bromophenoxy)benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH2:27]([O:29][C:30](=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:9]1[N:13]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[C:12]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=2[N:10]=1)[CH3:28]
Reactant: CCOC(=O)CCCCCBr
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: CCOC(=O)CCCCCOc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and (6-bromo-hexanoic acid ethyl ester CAS Reg. No. 25542-62-5). Brown sticky solid (70%). MS (Turbo Spray): m/z=519.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][N:14](C)C=O>C(OCC)C.[C-]#N.[Zn+2].[C-]#N.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>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][O:9][CH3:10])=[CH:7][C:2]=1[C:13]#[N:14]
Reactant: CN(C)C=O
Reactant: COCc1ccc(OC)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: COCc1ccc(OC)c(C#N)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
To a solution of 2-bromo-1-methoxy-4-methoxymethyl-benzene (460 mg, 1.991 mmol) in dimethylformamide (5 mL) at room temperature was added zinc cyanide (140.3 mg, 1.195 mmol). The reaction mixture was degassed by passing argon through for 30 min before tetrakis(triphenylphosphine)palladium (138 mg, 0.119 mmol) was added. The reaction mixture was heated at 80° C. for 12 h and stirred at room temperature for 2 d. It was diluted with diethyl ether (50 mL) and washed with sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 30% ethyl acetate in hexanes yielded 2-methoxy-5-methoxymethyl-benzonitrile (268 mg, 76%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C(#N)C>[CH2:16]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]2[C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[NH:1][C:23]2=[O:24])[CH2:15][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Cl)cc1NC1CCN(Cc2ccccc2)CC1
Solvent: CC#N
Product: O=c1[nH]c2ccc(Cl)cc2n1C1CCN(Cc2ccccc2)CC1
Yield: 64.7 %

Procedure:
A mixture of 12.71 g of the compound obtained in step B) and 8.9 g of 1,1'-carbonyldiimidazole in 130 ml of acetonitrile is refluxed for 3 hours. The solvent is evaporated off under vacuum, the residue is taken up with water, extracted with DCM, washed with a saturated solution of NaHCO3 and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/MeOH mixture (92/8; v/v) as the eluent. 8.9 g of the expected product are obtained after recrystallization from absolute ethanol. M.p.=204°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:12][C:9]2[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)(=[O:21])=[O:22])=[C:16]([F:24])[CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: Nc1ccc(Cl)c2cccnc12
Product: O=S(=O)(Nc1ccc(Cl)c2cccnc12)c1ccc(Cl)cc1F
Yield: 33.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-chloroquinolin-8-amine (Intermediate 27) (50 mg, 0.28 mmol), 4-chloro-2-fluorobenzenesulfonyl chloride (96 mg, 0.42 mmol) gave the title compound (35 mg, 35%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:40][C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[C:20]([C:28]5[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:30][CH:29]=5)=[N:21][N:22]([CH2:24][CH2:25][NH:26][CH3:27])[CH:23]=4)=[C:13]3[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].[OH-].[Na+].[CH2:43]=O.O>CO.[OH-].[OH-].[Pd+2]>[CH3:27][N:26]([CH3:43])[CH2:25][CH2:24][N:22]1[CH:23]=[C:19]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:40][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:6]=4)=[CH:12][C:13]=23)[C:20]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:32][CH:33]=2)=[N:21]1
Reactant: CNCCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: C=O
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
To N′-(4-{4-(2-{3-[(dimethylamino)methyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-[2-(methylamino)ethyl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea.3TFA (300 mg, 0.34 mMol) in MeOH (10 mL) was added with stirring at RT aq. 1 N NaOH (1.1 mL, 1.1 mMol), 37 wt. % CH2O in water (50 uL, 0.67 mMol) and 20% Pd(OH)2/C (Pearlman's catalyst) (˜10 mg). A balloon of H2 was attached and the reaction stirred at RT for 3 days. The reaction was evaporated to dryness under vacuum, taken up in (9:1) CHCl3/iPrOH (15 mL) and treated with excess methyl isatoic anhydride polystyrene resin (˜500 mg, >1.8 mMol/g). After stirring at RT for 4 h the reaction was filtered, rinsed with (9:1) CHCl3/iPrOH, and the filtrate concentrated to dryness under vacuum. Purification by Gilson HPLC provided the title compound (56.6 mg, 30%) as a white solid. ESMS [M+H]+: 551.6
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH:8]([CH2:10][O:11]C(=O)C)[CH2:7][CH:6]1[N:15]1[C:19]2[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:18]=2[N:17]=[C:16]1Br)(=O)C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:16]2[N:15]([CH:6]3[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9][CH:5]3[OH:4])[C:19]3[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:18]=3[N:17]=2)[CH2:29][CH2:28]1
Reactant: CC(=O)OCC1CC(OC(C)=O)C(n2c(Br)nc3cc(Cl)c(Cl)cc32)C1
Reactant: NC1CC1
Product: OCC1CC(O)C(n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)C1

Procedure:
(±)-(1R*, 2R*, 4S*)-4-(Acetoxymethyl)-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-cyclopentyl acetate (500 mg, 1.50 mmol) was reacted with cyclopropylamine (0.73 mL) in the manner of Example 74. Crude product was chromatographed on silica gel and title compound eluted with 5% methanol-ethyl acetate as a colorless glass which solidified from ethyl acetate-hexanes to white powder (180 mg, 48%), m.p. 251°-253° C.; 1H-NMR(DMSO-d6)δ: 7.54 and 7.45 (both s, 2, aromatic CH), 5.04 (d, J=5.1 Hz, 1, OH), 4.97 (t, J=4.7 Hz, 1, OH), 4.60-4.50 and 4.50-4.30 (both m, 1 each, NCH and OCH), 3.50 (m, 2, OCH2), 2.80 (m, 1, CH), 2.35-2.10 (m, 1, CH), 2.05-1.80 (m, 3, CH2 and CH of cyclopentane), 1.80-1.60 (m, 1, CH), 0.80-0.50 (1 m, 4, 2CH2 of cyclopropyl); mass spectrum (CI): 356 (M+1).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>>[N+:1]([CH:4]=[C:5]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])[NH:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: NCCSCc1nccs1
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)-methylthio)ethylamino]ethylene with an excess of 2-[(2-aminoethyl)thiomethyl]thiazole according to the procedure of Example 2(ii) results in the production of 1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-(2-thiazolylmethylthio)-ethylamino]ethylene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([CH2:17][CH2:18][N:13]3[C@@H:12]3[CH2:19][CH2:20][NH:21][CH2:22][C@H:11]23)[CH:16]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[O:34]>CCC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:14]3=[C:15]([CH2:17][CH2:18][N:13]3[C@@H:12]3[CH2:19][CH2:20][N:21]([CH2:30][CH2:31][CH2:32][C:33]([C:35]4[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=4)=[O:34])[CH2:22][C@H:11]23)[CH:16]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: Clc1ccccc1-c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(CCCN1CC[C@@H]2[C@H](C1)c1cc(-c3ccccc3Cl)cc3c1N2CC3)c1ccc(F)cc1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
(±)-Cis-2-(2-chlorophenyl)-4,5,6a,7,8,9,10,10a-octahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole (26.4 mg, 0.085 mmol) 0.7 ml of MEK. KI (14 mg, 0.085 mmol) and K2CO3(22 mg, 0.26 mmol), and 4-chloro-4′-fluorobutyrophenone (22.2 mg, 0.11 mmol) were added. The suspension was refluxed for 48 h and then cooled to rt. The suspension was filtered and the residue was washed with CH2Cl2 (5 ml). The solution was concentrated in vacuo. The residue was purified by column chromatography (10% MeOH—CH2Cl2) to afford the title compound (18.8 mg, 47%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 8.00–8.04 (m, 2H), 7.41 (dd, 1H, J=1.5, 7.3 Hz), 7.30 (dd, 1H, J=1.8, 7.3 Hz), 7.10–7.20 (m, 4H), 7.01 (s, 1H), 6.96 (s, 1H), 3.68 (bt, 1H, J=6.6 Hz), 3.30–3.50 (m, 2H), 3.10–3.30 (m, 2H), 2.92–3.08 (m, 3H), 2.60–2.92 (m, 2H), 2.38–2.58 (m, 3H), 2.27 (t, 1H, J=11.3 Hz), 1.70–2.05 (m, 4H) ppm. MS (CI, NH3): 475 (base, M+H).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([F:16])=[C:10]([O:14]C)[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].Cl.N1C=CC=CC=1>>[CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([F:16])=[C:10]([OH:14])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Cc2cc(OC)c(F)cc2C1=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC1Cc2cc(O)c(F)cc2C1=O
Temperature: 200 °C
Yield: 95.1 %

Procedure:
A mixture of 2-butyl-6-fluoro-5-methoxy-1-indanone (2.0 g) and pyridine hydrochloride (15.0 g) was heated in an oil bath at 200° C. for 75 minutes. After cooling to room temperature, the mixture was partitioned between EtOAc (100 mL) and water (75 mL) containing brine (25 mL). The organic phase was washed with brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide 2-butyl-6-fluoro-5-hydroxy-1-indanone (1.79 g) as a solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([NH:43][C:44]([O:46][C@@H:47]3[C@H:54]4[C@H:50]([O:51][CH2:52][CH2:53]4)[O:49][CH2:48]3)=[O:45])[C@H:23]([OH:42])[CH2:24][N:25]([S:30]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)(=[O:32])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:17][CH:16]=2)(=O)=O)=CC=1.[S:55]1[CH2:59][CH2:58][NH:57][CH2:56]1.CS(C)=O>O>[O:37]1[C:36]2[CH:40]=[CH:41][C:33]([S:30]([N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][C@@H:23]([OH:42])[C@@H:22]([NH:43][C:44](=[O:45])[O:46][C@@H:47]3[C@H:54]4[C@H:50]([O:51][CH2:52][CH2:53]4)[O:49][CH2:48]3)[CH2:21][C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][N:57]4[CH2:58][CH2:59][S:55][CH2:56]4)=[CH:20][CH:19]=3)(=[O:32])=[O:31])=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@H](NC(=O)O[C@H]3CO[C@H]4OCC[C@H]43)[C@H](O)CN(CC(C)C)S(=O)(=O)c3ccc4c(c3)OCO4)cc2)cc1
Reactant: C1CSCN1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCN2CCSC2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 70 °C
Yield: 58.9 %

Procedure:
A mixture of 2-(4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)ethyl 4-methylbenzenesulfonate (50 mg, 0.06 mmol), thiazolidine (0.02 mL, 0.02 g, 0.25 mmol) and dimethylsulfoxide (1 mL) was heated to 70° C. under nitrogen atmosphere for 2 h. The mixture was diluted with water and extracted with ethyl ether (2×). The organic phase was dried (sodium sulfate), evaporated, and the residue was purified by chromatography (silica gel, dichloromethane/methanol, 98:2) to provide the title compound (25 mg) as a solid foam. 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.9-2.0 (1H, m), 2.3 (1H, dd), 2.6-2.8 (7H, m), 2.8-3.0 (5H, m), 3.4-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.0 (2H, br s), 4.05 (2H, br s), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.8 (2H, d), 7.0-7.1 (3H, d), 7.18 (1H, d), 7.2 (1H, s), 7.3 (1H, d); MS: 708 (MH+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([CH2:23][CH2:24][CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:26][CH2:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(OCCCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 3-phenyl-1-propanol and DBU in dioxane. ES-MS m/e (%): 332 (M{37Cl}+H+, 50), 330 (M{35C,}+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[O:4][CH2:3]1.[CH:6]1([N:9]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:8][CH2:7]1>CO.O>[CH:6]1([N:9]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:3][C:2]([OH:4])([CH3:5])[CH3:1])[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:8][CH2:7]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: CC1(C)CO1
Solvent: CO
Solvent: O
Product: CC(C)(O)CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
1,1-Dimethyloxirane (88 μL) is added to N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide (100 mg) in methanol (5 mL). The mixture is stirred for 4 h at room temperature and at 50° C. over night. Since the conversion is still incomplete, another portion of 1,1-dimethyloxirane (88 μL) is added and the mixture is stirred for 8 h at 50° C. The reaction mixture is diluted with water (10 mL) and stirred for 1 h at room temperature. The precipitate is filtered off and washed with water and t-butyl methylether to give the title compound. LC (method 2): tR=1.00 min; Mass spectrum (ESI+): m/z=384 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[S:14][CH:15]=[C:16]([CH3:17])[C:10]=2[CH2:9]1)=O)(C)(C)C.CO.Cl.Cl>C(Cl)(Cl)Cl>[CH3:17][C:16]1[C:10]2[CH2:9][NH:8][CH2:13][CH2:12][C:11]=2[S:14][CH:15]=1
Reactant: Cc1csc2c1CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1csc2c1CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-t-Butoxycarbonyl-3-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (150 mg, 0.49 mmol) was dissolved in chloroform (1 ml), and the solution was mixed with hydrochloric acid methanol solution (2 ml), stirred at room temperature for 8 hours, further mixed with concentrated hydrochloric acid (1 ml) and stirred for 16 hours. The solvent was removed by evaporation from the reaction solution under a reduced pressure, and the thus obtained residue was mixed with 47% hydrobromic acid (6 ml) and stirred at 140° C. for 4 hours. The reaction solution was returned to room temperature and alkalified by adding sodium hydroxide aqueous solution and then the reaction product was extracted there from with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried with anhydrous magnesium sulfate, and then the solvent was removed by evaporation under a reduced pressure to obtain 68 mg (0. 44 mmol, 90% in yield) of the title compound. MW 153.24 (C8H11NS); Mass spectrum EI-MS m/z 153 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16].O.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH:5]2[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C1C(=O)N(C(N)=O)c2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
A stirred slurry of 842 mg (4.0 mmole) of 5-chloro-2-oxindole-1-carboxamide and 1.08 g (8.8 mmole) of 4-(N,N-dimethylamino)pyridine in 15 ml of N,N-dimethylformamide was cooled to ice-bath temperature, and then a solution of 449 mg (4.4 mmole) of acetic anhydride in 5 ml of N,N-dimethylformamide was added dropwise. Stirring was continued for ca. 30 minutes, and then the reaction mixture was poured into a mixture of 75 ml of water and 3 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath and the solid was recovered by filtration. The solid was recrystallized from acetic acid to give 600 mg of fluffy, pale pink crystals, m.p. 237.5° C. (dec.).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].O.[NH:14]1[CH2:17][CH2:16][CH:15]1C(O)=O>C1(C)C=CC=CC=1>[N:14]12[CH2:17][CH2:16][CH:15]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: O=C(O)C1CCN1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC2CC3CCN3C2C1

Procedure:
17.1 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate are heated under reflux overnight in a water separator with 10 g (0.1 mol) of azetidine-2-carboxylic acid in 200 ml of toluene. Unreacted amino acid is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](CCN)=[CH:22][CH:21]=1>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])=[CH:22][CH:21]=1
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Reactant: COc1ccc(CCN)cc1
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=S)Nc2nc3ccccc3s2)cc1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl]imidazole (1.04 g, 4 mmol) and 2-(4-methoxyphenyl)ethylamine (0.62 g, 4 mmol) in N,N-dimethylformamide (15 mL) was stirred at 100° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.85 g (62%) of the title product: