Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH:13]1([CH2:18][CH2:19][C:20](OCC)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C.O1CCCC1.C(OCC)C>[CH:13]1([CH2:18][CH2:19][C:20](=[O:21])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CCC1CCCC1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCC1CCCC1)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
125 g. of dimethyl methylphosphonate were dissolved in 720 ml. of tetrahydrofuran and the solution cooled to -65°C. To this solution a solution of butyllithium [prepared from 150 g. of butyl bromide and 14.5 g. of lithium] in 550 ml. of diethyl ether was added dropwise. To the mixture a solution of 52.5 g. of ethyl 3-cyclopentylpropionate in 280 ml. of tetrahydrofuran was added drop-wise and the reaction mixture was stirred at the same temperature for 2 hours and afterwards at 0°C. overnight. The reaction mixture was then neutralised with acetic acid, concentrated under reduced pressure and the resulting residue after the addition of water was extracted with diethyl ether. The ethereal extract was dried over sodium sulphate, the solvent distilled off and the residue distilled under reduced pressure to obtain 47 g. (yield 61.2%) of the title compound as a colourless oil, b.p. 142°- 144°C./0.4 - 0.5 mm.Hg. NMR spectrum (tetrachloromethane): δ = 3.84 (6H, doublet), 3.19 (2H, doublet), 2.42 (2H, triplet), 2.0 - 1.09 (11H, multiplet).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[NH:28][C:27]5[CH:26]=[CH:25][N:24]=[CH:23][C:22]=5[CH:21]=4)[C:15](=[O:29])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:30]=1.[H-].[Na+].[CH3:33]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[N:28]([CH3:33])[C:27]5[CH:26]=[CH:25][N:24]=[CH:23][C:22]=5[CH:21]=4)[C:15](=[O:29])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:30]=1
Reactant: CI
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2cnccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)cc2cnccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
4-(6-Chlorobenzo[b]thiophene-2-sulfonyl)-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)piperazin-2-one (0.59 g, 1.28 mmol), EXAMPLE 214, is dissolved in anhydrous DMF (30 ml), cooled in an ice bath, treated with 60% sodium hydride (0.061 g, 1.53 mmol) and stirred at room temperature for 30 minutes. The solution is treated with methyl iodide (83 mL, 1.33 mmol) and warmed to room temperature over 4 hours. The reaction is quenched with ammonium chloride solution, diluted with ethyl acetate and separated. The organic layer is washed with brine (3×), dried (Na2SO4) and concentrated. The residue is purified by flash chromatography (5-10% MeOH/CH2Cl2) to provide the title compound (0.31 g, 0.65 mmol). 1H NMR (CD3OD, 300 MHz) δ8.55 (d, 1H), 7.99 (dd, 1H), 7.82 (m, 3H), 7.49 (dd, 1H), 7.43 (d, 1H), 6.55 (s, 1H), 4.75 (s, 2H), 3.96 (s, 2H), 3.52 (m, 4H), 3.86 (s, 3H), 3.49 (s, 3H). Ion Spray MS, [M+H]+=477.
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]\[CH2:4][OH:5].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([O:5][CH2:4]/[CH:3]=[CH:2]\[CH2:1][OH:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC/C=C\CO
Reactant: BrCc1ccccc1
Product: OC/C=C\COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
14.6 g of sodium hydride (60 % in oil) was washed with n-pentane under an argon gas. After drying, 150 ml of dry dimethylformamide (hereinafter referred to simply as DMF) was added thereto to form a suspension. 75 g of (Z)-2-buten-1,4-diol was dropwise added thereto at 0° C. under stirring over a period of 30 minutes. The mixture was stirred at room temperature for 1.5 hours, and 44 g of benzyl bromide was added at 0° C. under stirring. The mixture was stirred at the same temperature for 30 minutes, and then the temperature was returned to room temperature. The mixture was stirred at 50° C. overnight. The reaction solution was poured into ice water and extracted with diethyl ether. The ether solution was washed sequentially with water and with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to distillation under reduced pressure (2.5 mmHg, 134°-138° C.) to obtain 29 g of (Z)-4-benzyloxy-2-buten-1-ol as colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:30])=[C:13]([NH:15][C:16](=[O:29])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:25][CH2:24]4)[C:18]=3[Cl:28])[CH:14]=2)=[N:6][CH:7]=1.[S-:31][C:32]#[N:33].[K+].BrBr>C(O)(=O)C>[NH2:33][C:32]1[S:31][C:7]2[C:2]([N:1]=1)=[CH:3][CH:4]=[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([F:30])=[C:13]([NH:15][C:16](=[O:29])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:24][CH2:25]4)[C:18]=3[Cl:28])[CH:14]=1)[N:6]=2
Reactant: N#C[S-]
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc(N)cn4)ccc3F)c2Cl)CC1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.2 %

Procedure:
To a solution (50 mL) of N-{5-[(5-aminopyridin-2-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (4.23 g, 10 mmol) and potassium thiocyanate (3.89 g, 40 mmol) in acetic acid was added dropwise bromine (2.40 g, 15 mmol) at 15° C., and the mixture was stirred at room temperature for 6 hr. The yellow suspension was filtered through celite, and the yellow insoluble material was thoroughly washed with acetic acid (50 mL). The filtrate and washing solution were combined, and the mixture was concentrated under reduced pressure. The residue was suspended in 0.1N aqueous sodium hydroxide solution (100 mL), and the suspension was extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=100/0→0/100). The obtained residue was crystallized from diethyl ether to give the title compound (3.32 g, 69%) as a pale-yellow powder.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[N:4][CH:3]=1.[CH:20]([Mg]Br)([CH3:22])[CH3:21]>C1COCC1>[Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)([OH:8])[CH:20]([CH3:22])[CH3:21])=[N:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(c2ncc(Br)s2)C(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)carbonyl]cyclohexanecarboxylate (800 mg, 2.31 mmol) in anhydrous THF (16 ml) was treated dropwise over 1 h with isopropylmagnesium bromide (2.31 mmol, 2 M, 1.15 mL) at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for 15 min, the reaction was allowed to reach room temperature. After 1 h, the reaction mixture was quenched with saturated ammonium chloride and taken up in ethyl acetate, washed with brine and dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (0% to 20% EtOAc in hexanes) and then by preparative HPLC reverse phase (C-18) eluting with 55% to 100% water in acetonitrile (0.1% trifluoroacetic acid). The collected fractions were diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford racemic ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxy-2-methylpropyl]cyclohexanecarboxylate as a white solid. MS ESI calc'd. for C16H24BrNO3S [M+H]+ 390, 392. found 390, 392. 1H NMR (500 MHz, CDCl3) δ 7.60 (s, 1H), 4.10 (q, J=7.1, 2H), 2.30-2.20 (m, 1H), 2.17-2.06 (m, 1H), 2.05-1.79 (m, 2H), 1.93-1.81 (m, 1H), 1.62-1.50 (m, 1H), 1.48-1.20 (m, 5H), 1.22 (t, J=7.1, 3H), 0.88 (d, J=9.8, 3H), 0.87 (d, J=9.8, 3H).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH3:13])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+:17]>CO>[NH2:17][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(=O)c1ccccc1
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: CO
Product: COC(=O)C=C(N)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 40.00 g (0.2245 mol) of methyl benzoylacetate in 400 ml of methanol, 70.30 g (1.115 mol) of ammonium formate was added and the mixture was refluxed for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was distilled away under reduced pressure. To the residue, 200 ml of ethyl acetate and 150 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. Then, the organic layer was separated, and the aqueous layer was extracted with 100 ml of ethyl acetate. The organic layer and the extract were combined, washed with water and a brine successively and dried with sodium sulfate. The solvent was removed under reduced pressure, and the residue was then distilled to give the objective methyl 3-amino-3-phenylacrylate (32.44 g, a colorless oil). The yield was 81.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[O:30])=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccncc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccncc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 62 h
Yield: 30.6 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) and commercially available isonicotinic acid (45 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (98 mg) was added, and the admixture was stirred at room temperature for 62 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 22 mg of the title compound (yield: 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18][NH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([NH:19][CH3:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Product: CNC(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 35 %

Procedure:
The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (218 mg, 0.80 mmol) and methyl amine using General Procedure G and was isolated in 35% yield as a white solid. HPLC Rt=10.3 min; 1H NMR (400 mHz, CDCl3) 7.47 (d, J=2.20 Hz, 1H), 7.41 (d, J=8.55 Hz, 1H), 7.24 (dd, J=2.44, 8.55 Hz, 1H), 2.71 (d, J=4.88 Hz, 3H), 2.29-2.21 (m, 2H), 1.93-1.85 (m, 2H), 1.61-1.38 (m, 6H); GC-MS (SCOUT) 12.87 min, M+ 285.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14](=O)[NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[NH2:23])[CH:12]2[CH2:25][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:23][C:17]3[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:16]=3[N:15]=2)[CH:12]2[CH2:25][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)Nc1ccc(Br)cc1N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(Br)cc2[nH]1
Temperature: 130 °C

Procedure:
The above mixture of regioisomer 3-(2-Amino-4-bromo-phenylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was dissolved in ethanol and heated to 130° C. in sealed tube overnight and continue heating at 170° C. for 3 days. LC-MS showed desired product and Boc cleaved product (about 1:1 ratio). The mixture was concentrated down and dissolved DCM. Di-tert-butyl dicarbonate (0.6 eq.) was added and reaction was stirred overnight at room temperature. The reaction mixture was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 3-(6-Bromo-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.383 g, 72%) as an orange foam.
Reaction SMILES: [S:1]1[C@H:12]2[CH2:13][C@@H:14]([O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[C@H:15](/[CH:16]=[CH:17]/[C@@H:18]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]2[CH2:10][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S1[C@H]2C[C@@H](O)[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2CC1CCCCC(O)=O.[C:63]([O:82][CH2:83][CH:84](O)[CH2:85][O:86][C:87](=[O:105])[CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])(=[O:81])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80].N1C=CC=CC=1SSC1C=CC=CN=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C1(C)C(C)=CC=CC=1>[C:63]([O:82][CH2:83][CH:84]([O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[S:1][C@H:12]2[CH2:13][C@@H:14]([O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[C@H:15](/[CH:16]=[CH:17]/[C@@H:18]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]2[CH2:10]1)[CH2:85][O:86][C:87](=[O:105])[CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])(=[O:81])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)O)S[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC
Agent: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)O)S[C@H]2C[C@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCC)OC(=O)CCCCC1C[C@@H]2[C@@H](/C=C/[C@H](CCCCC)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
Under an atmosphere of nitrogen, a mixture of 122 mg of (13E)-(6RS,9α,11α,15S)-6,9-epithio-11,15-bis(tetrahydropyran-2-yloxy)prost-13-enoic acid [prepared from (13E)-(6RS,9α,11α,15S)-6,9-epithio-11,15-dihydroxyprost-13-enoic acid (prepared as described in Example 2) by the tetrahydropyran-2-ylation procedure described in Reference Example 1], 143 mg of 1,3-bisstearoyloxy-2-propanol, prepared as described above, 75 mg of dipyridyl disulphide, 90 mg of triphenylphosphine and 3 ml of xylene was stirred at room temperature for 2 hours, then at 40° C. for 2 hours, and at 80° C. overnight. The reaction mixture was poured into water, extracted with ethyl acetate, the extract was washed with water, and a threaded aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (8:1) as eluent to give 51 mg of (13E)-(6RS,9α,11α,15S)-6,9-epithio-11,15-bis(tetrahydropyran-2-yloxy)prost-13-enoic acid 1,3-bisstearoyloxy-2-propyl ester having the following physical characteristic:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+].[Cl-].[NH4+].Cl>O.CN(C=O)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]2[NH:13][N:12]=[N:11][N:8]=2)=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CSc1ccc(C#N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(-c2nnn[nH]2)cc1
Reaction time: 10 h
Yield: 39 %

Procedure:
3.0 g (0.02 mol) of 4-(methylthio)benzonitrile, 1.44 g (0.022 mol) of sodium azide and 0.12 g (0.0022 mol) of ammonium chloride were added to 20 ml of DMF. The reaction system was then stirred at a reaction temperature kept at 100° C. for 10 hours. After the completion of the reaction, water and concentrated hydrochloric acid were added to the reaction system so that it was acidified. The resulting crystal was filtered off, and then recrystallized from isopropyl alcohol to obtain 1.5 g (7.8 mml) of 5-(4-methylthiophenyl)-tetrazole (Compound (III)) (m.p. 222° C.).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:21]([C@@:3]1([OH:4])[C@@H:5]([CH2:6][O:7][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22])[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@]1(O)[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, a mixture of 2′-deoxyuridine dU (2.5 g, 10.95 mmol), TBSCl (7.26 g, 48.2 mmol) and imidiazole (6.56 g, 96.4 mmol) in anhydrous DMF (25 mL) was stirred at 0° C. for two hours and then warmed to room temperature over one hour. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to yield 3′,5′-O-bis-tert-butyldimethylsilyl-2′-deoxyuridine dC.11 (4.62 g, 92%) as a white foam.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[O:18]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20][CH2:19]1>>[CH2:24]1[C:23]2([O:18][CH2:19][CH2:20][CH2:21][O:22]2)[CH2:28][CH2:27][N:26]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:25]1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: C1COC2(CCNCC2)OC1
Product: N#Cc1c(N2CCC3(CC2)OCCCO3)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 597 mg (3.80 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane to give 86 mg (61% of theory) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][SH:6].[OH-].[Na+].Cl[C:10](Cl)=[CH:11][N+:12]([O-:14])=[O:13].Cl>CO.C(Cl)Cl.O>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][S:6][C:10]1=[CH:11][N+:12]([O-:14])=[O:13]
Reactant: CNCCCS
Reactant: O=[N+]([O-])C=C(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CN1CCCSC1=C[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Into 40 ml of methanol were added 5.0 g of 1-methylamino-3-propanethiol and 0.8 g of caustic soda, followed by stirring, to be completely dissolved therein. Then, the mixture was cooled to 0° C. While stirring the solution, a solution of 1.6 g of caustic soda dissolved in 25 ml of methanol and a solution of 2.8 g of 2,2-dichloronitroethylene diluted in 20 ml of methanol were added at the same time dropwise slowly over 50 minutes, and the reaction was carried out for one hour at about 8° C. After the reaction, the reaction mixture was neutralized to pH 7 with 3 N aqueous hydrochloric acid, and then with addition of 60 ml of water, extraction with 50 ml of methylene chloride was repeated four times. The extracts were concentrated to give 3.38 g of tetrahydro-3-methyl-2-(nitromethylene)-1,3-thiazine (yield: 97%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.[CH2:15](I)[CH2:16][CH3:17]>C1COCC1>[CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][C:8]([CH2:15][CH2:16][CH3:17])=[C:4]2[CH2:3]1
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Reactant: CCCI
Solvent: C1CCOC1
Product: CCCc1sc(C(=O)O)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 8.3 %

Procedure:
To a cooled (−75° C.) solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.0 g, 9.51 mmol) in THF (40 mL) tert.-butyllithium (15 mL, 1.5 N in pentane) is slowly added. The mixture is stirred at −78° C. for 15 min before n-propyliodide (5.22 g, 30.7 mmol) is added. Stirring is continued at −78° C. for 45 min before the reaction is quenched by adding water/methanol 1:1 (10 mL). The mixture is allowed to warm to rt, diluted with tert.-butyl methylether and 10% aq. citric acid solution. The mixture is extracted twice with EA, the combined organic extracts are washed with brine, dried over Na2SO4 and concentrated. The crude product is purified by prep. HPLC to give 5,5-dimethyl-3-propyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (200 mg) as a colourless resin; LC-MS: tR=1.04 min, [M+1]=253.31; 1H NMR (CDCl3): δ 2.98 (t, J=7.0 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.36 (s br, 1H), 2.26 (s, 2H), 1.63 (hex, J=7.6 Hz, 2H), 1.51 (t, J=7.0 Hz, 2H), 0.95 (t, J=7.6 Hz, 3H), 0.94 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[C:1]([C:5]1[O:6][C:7]2[C:13]([S:14]([N:26]3[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH2:24][CH2:25]3)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN1CCNCC1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Product: COCCN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1

Procedure:
Followed the general procedure described in Example 1c, 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride coupled with 2-methoxy-ethyl-piperazine to give the desired product 2a, 1.11 g (82%). LC-MS (m/z) 416.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].COC1C=CC(S)=CC=1.C(OC(=O)C(SC1C=CC(OC)=CC=1)CCCCCC)C>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCCCCCC(Br)C(=O)OCC
Agent: CCCCCCC(Sc1ccc(OC)cc1)C(=O)OCC
Agent: COc1ccc(S)cc1
Product: CCCCCCCC(=O)OCC

Procedure:
2-4-Methoxy-phenylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl-2-bromooctanoate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g, 43 mmol). Yield: 7.24 g (57%); clear oil; MS: 311.2 (M+H)+, 2-4-Methoxy-benzenesulfonyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(4-methoxy-phenylsulfanyl)-octanoic acid ethyl ester (4.0 g, 13.6 mmol). Yield 3.7 g (83%); clear oil; MS: 343.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7]O)=[C:5]([CH3:9])[O:4][N:3]=1.P(Br)(Br)[Br:11]>ClCCl>[Br:11][CH2:7][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[CH3:9]
Reactant: Cc1noc(C)c1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Cc1noc(C)c1CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3,5-dimethyl-1,2-oxazol-4-yl)methanol (805 mg, 6.3 mmol) in anhydrous dichloromethane (60 mL) was added dropwise phosphorus tribromide (1.2 mL, 12.6 mmol). The mixture was stirred at room temperature for 3 hours. Dichloromethane was evaporated, and the residue was dried in vacuo, affording 4-(bromomethyl)-3,5-dimethyl-1,2-oxazole. The product was used without further purification.