Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:17]([S:19]C)=S)[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:7]=[N:8][CH:9]=1>C(O)C.ClCCl>[CH3:1][NH:2][C:17]([C:10]1([C:6]2[CH:7]=[N:8][CH:9]=[C:4]([Br:3])[CH:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])=[S:19]
Reactant: CSC(=S)C1(c2cncc(Br)c2)CCCCC1=O
Reactant: CN
Solvent: CCO
Solvent: ClCCl
Product: CNC(=S)C1(c2cncc(Br)c2)CCCCC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 33% w/v solution of methylamine in ethanol (5.7 ml) was added dropwise to a stirred solution of 2-(5-bromopyrid-3-yl)-2-methylthiothiocarbonylcyclohexanone (1.33 g, 3.86 mmol) in ethanol (25 ml) and dichloromethane (25 ml) at 0°-5° C. The solution was stirred at room temperature for 5 hours and concentrated in vacuo at 30°-35° C. The residue was purified by flash chromatography over silica gel eluting with ethyl acetate: hexane 4:6 to give (±)-N-methyl-2-oxo-1-(5-bromopyrid-3-yl) -cyclohexanecarbothioamide (0.57 g) m.p. 201°-3° C. NMR(CDCl3) 1.68-2.16(m,4H); 2.46-2.6(m,2H); 2.66-2.8(m,2H); 3.17-3.17-3.19 (d,3H); 7.74-7.78(dd,1H); 8.38-8.39(d,1H), 8.58-8.59(d,1H); 8.8-9.0(broad singlet). Calculated for 47.7%; H,4.6%; N,8.6%. Found C, 48.2%; H,4.7%; N,8.5%.
Reaction SMILES: Br.C(O)(=O)C.[CH:6]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH2:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1)(=[O:10])=[O:9])=[CH2:7].[CH3:28][S:29](C)=O>>[CH3:28][S:29][CH2:7][CH2:6][S:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1)(=[O:9])=[O:10]
Reactant: C=CS(=O)(=O)NCCCc1ccc(C2=NNC(=O)CC2)cc1
Reactant: CS(C)=O
Agent: Br
Solvent: CC(=O)O
Product: CSCCS(=O)(=O)NCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 64.4 %

Procedure:
1.7 g of dimethylsulfoxide was added to a 25% hydrogen bromide-acetic acid suspension (50 ml) containing 5.30 g of 6-[4-(3-vinylsulfonylaminopropyl)phenyl]-4,5-dihydropyridazin-3(2H)-one, and the mixture was stirred at room temperature for 4.5 hours. After hydrogen bromide and acetic acid were removed, a 15% aqueous sodium methyl mercaptide solution (100 ml) was added to the residue, and the mixture was stirred at 60° C. for 1.5 hours. After cooling, the mixture was neutralized with hydrochloric acid, and crystal was collected by filtration, washed with water, dried and then recrystallized from acetonitrile to obtain 3.90 g of 6-[4-(3-(2-methylthioethyl)sulfonylaminopropyl)phenyl]pyridazin-3(2H)-one.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:61][CH3:62])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[CH:41]([CH3:40])[CH2:61][CH3:62])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 36E (0.020 g, 0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate, to give the title compound (0.026 g, 68% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.76 (m, 18 H), 1.16 (m, 1 H), 1.29 (m, 1 H), 1.52 (m, 1 H), 1.76 (s, 1 H), 2.39 (s, 3 H), 2.68 (m, 4 H), 3.20 (m, 2 H), 3.50 (s, 3 H), 3.83 (m, 2 H), 4.13 (m, 2 H), 4.67 (m, 2 H), 6.66 (d, J=9.56 Hz, 1 H), 7.07 (m, 7 H), 7.22 (d, J=8.09 Hz, 2 H), 7.31 (m, 1 H), 7.66 (t, J=7.72 Hz, 1 H), 7.86 (m, 6 H), 8.63 (d, J=4.04 Hz, 1 H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:15]#[N:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-:24].[Na+]>OS(O)(=O)=O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]([NH2:16])=[O:24]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)c2ccccc2Cl)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C(c1ccccc1Cl)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
4-[(2-Chloro-phenyl)-cyano-methyl]-piperazine-1-carboxylic acid tert-butyl ester (11) (1.0 g, 2.98 mmol) was dissolved in H2SO4 (5.0 mL) and allowed to stir at room temperature for 18 h. The reaction mixture was cautiously poured over ice (50 mL) and made basic with 5N NaOH (50 mL). The desired product was extracted into EtOAc (100 mL) The organic phase was concentrated to dryness yielding 0.64 g (85%) product.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Br[C:7]1[C:11](OC)([CH3:12])[CH2:10][CH2:9][C:8]=1[CH3:15].O>CCOCC>[CH2:1]([C:7]1[C:11]([CH3:12])=[CH:10][CH2:9][C:8]=1[CH3:15])[C:2]1[C:3]([CH3:4])=[CH:2][CH2:1][C:3]=1[CH3:4]
Reactant: [Li]CCCC
Reactant: COC1(C)CCC(C)=C1Br
Solvent: CCOCC
Solvent: O
Product: CC1=CCC(C)=C1CC1=C(C)CC=C1C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
One equivalent of n-butyl lithium was added to a solution in which 7.038 g (34.3 mmol) of 2-bromo-3-methoxy-1,3-dimethyl-cyclopentene compound prepared in the example 3 was dissolved in 38 ml of ether at −25° C. nitrogen atmosphere. When white solid was precipitated, the temperature was elevated to 10° C. and the reaction was continued for further 10 minutes. The temperature was lowered to −25° C. and the fulvene compound prepared in the example 2 was added. Completion of reaction is determined by the development of yellow color of the reaction mixture. 50 ml of water was added to the reaction mixture and the solvent was removed using the rotatory evaporator. 50 ml of 2N HCl solution was added to the organic layer extracted with 50 ml of ethyl acetate, and the resulting mixture was vigorously shaked for 2 minutes. Water layer was removed by layer separation and the organic layer was neutralized with 50 ml of a saturated sodium bicarbonate solution. Isolated organic layer was dried over magnesium sulfate, and then the vacuum distillation was preformed to give 4.17 g of yellow 2,2′-methylenebis(1,3-dimethyl-1,3-cyclopentadiene) compound. Yield: 61%.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[S:32][C:20]2=[N:21][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][C:24]([CH3:25])=[C:19]2[C:18]=1[NH2:33])=[O:16])[CH3:13]>CC(C)=O>[CH2:12]([O:14][C:15]([C:17]1[S:32][C:20]2=[N:21][C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:23][C:24]([CH3:25])=[C:19]2[C:18]=1[NH:33][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:11])=[O:16])[CH3:13]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)c1sc2nc(-c3ccccc3)cc(C)c2c1N
Solvent: CC(C)=O
Product: CCOC(=O)c1sc2nc(-c3ccccc3)cc(C)c2c1NC(=S)NC(=O)c1ccccc1
Yield: 92.8 %

Procedure:
5 ml (13.3 mmol) acetonic benzoyl-isothiocyanate solution (2 M) is added to 2.78 g (8.9 mmol) 3-amino-4-methyl-6-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid ethyl ester in 10 ml acetone and refluxed for 2 h. The precipitate precipitated after cooling is sucked off, washed with some water and ethanol, suck dried and dried in vacuo at 50° C. 3.93 g (93%) 3-(3-benzoylthioureido)-4-methyl-6-phenyl-thieno[2,3-b]pyridine-2-carboxylic acid ethyl ester is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:10]=[O:11].Cl.[F:13][C:14]1[N:38]=[CH:37][C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[C:25]([CH3:36])[CH:24]=3)[C:16]=2[CH:15]=1.CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([N:33]1[CH2:32][CH2:31][CH:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:21]3[C:16]4[CH:15]=[C:14]([F:13])[N:38]=[CH:37][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:24][C:25]=2[CH3:36])[CH2:35][CH2:34]1)=[O:11]
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCNCC1
Reactant: O=C=Nc1c(F)cccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)Nc2c(F)cccc2F)CC1
Yield: 76.8 %

Procedure:
2,6-difluorophenyl Isocyanate (0.199 g, 1.28 mmol) was added to a solution of (6-Fluoro-pyrido[3,4-d]pyrimidin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride (T) (500 mg, 1.28 mmol) and NEt3 (0.388 g, 3.84 mmol) in CH2Cl2 (20 mL). After 1 h the reaction was quenched with water, the layers were separated and the organic layer was washed with 1N NaOH and water, dried over Na2SO4, and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH 97:3) afforded the title compound as a yellow solid (0.50 g, 77%). LRMS: 509.2 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.90 (s, 1H), δ 8.86 (s, 1H), δ 8.58 (s, 1H), δ 8.28 (s, 1H), δ 8.19 (s, 1H), δ 7.55-7.58 (m, 2H), δ 7.20-7.27 (m, 1H), δ 7.04-7.10 (m, 3H), δ 4.58-4.61 (m, 1H), δ 3.69-3.73 (m, 2H), δ 3.33-3.98 (m, 2H), δ 2.19 (s, 3H), δ 1.91-1.96 (m, 2H), δ 1.60-1.66 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C(OCC)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([Cl:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(Cl)CNC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
A stirred mixture of N-benzyloxycarbonylglycine [30 g.; prepared as described in Ber., 65, 1192, (1932)] and dry diethyl ether (190 ml.) was treated at 0° C. with phosphorus pentachloride (32 g.) during 5 minutes. The mixture was stirred at between 0° and 5° C. for a further 20 minutes and the solution was then filtered and the filtrate was evaporated. The residue was triturated with petrol (b.p. 40°-60° C.) and the petrol layer was decanted off, and this procedure was repeated several times, keeping the temperature below 20° C. throughout. A solid formed, which was filtered off to give N-benzyloxycarbonylglycyl chloride (25 g.), which was used immediately in the next stage. N-Benzyloxycarbonylglycyl chloride (13.0 g.) was added in one portion to a stirred solution of 4-amino-3-(3-methoxycarbonyl-2-thioureido)diphenyl thioether (10.0 g.; prepared as hereinbefore described in Example 2) in dry dimethylformamide. The temperature of the mixture rose to 35° C., and the stirring was continued for 20 minutes. The solution was then poured into water. The resulting oil solidified on scratching. The solid was filtered off and recrystallised from a mixture of dimethylformamide and methanol to give 4-(2-benzyloxycarbonylaminoacetamido)-3-(3-methoxycarbonyl-2-thioureido)diphenyl thioether (13.0 g.), m.p. 184°-186° C.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@:24]([CH2:27][OH:28])([CH3:26])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Si:42](Cl)([CH3:45])([CH3:44])[CH3:43].O>ClCCl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@@:24]([CH3:26])([CH2:27][O:28][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@](C)(CO)N2
Solvent: ClCCl
Solvent: O
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@](C)(CO[Si](C)(C)C)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
To a solution of (2R,5S,7R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-7-(4-fluoro-2-methylphenyl)-2-(hydroxymethyl)-N,2-dimethyl-1,8-diazaspiro[4.5]decane-8-carboxamide (Example 18, 80 mg, 0.136 mmol) in Dichloromethane (DCM) (2 ml), TEA (0.021 ml, 0.149 mmol) was added and the reaction mixture was stirred at 0° C. for 5 min. TMS-Cl (0.026 ml, 0.204 mmol) was added dropwise and mixture was stirred at the same temperature overnight. Water (2 ml) was added and two phases were separated. The organic layer was dried and evaporated in vacuo affording the title compound (84 mg) that was used in the next step without further purifications. LC/MS (Basic gradient conditions): Rt=4.205 min, m/z 662 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[CH:13]=[C:12]([C:23]#N)[CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=[O:26]>[Ni]>[CH2:1]([N:8]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[CH:13]=[C:12]([CH:23]=[O:26])[CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2c(c1)c1ccccc1c(=O)n2Cc1ccccc1
Reactant: O=CO
Agent: [Ni]
Product: O=Cc1ccc2c(c1)c1ccccc1c(=O)n2Cc1ccccc1
Yield: 80 %

Procedure:
5-Benzyl-6-oxo-5,6-dihydrophenanthridine-2-carbonitrile (1.24 g) and Raney nickel (0.8 g) were suspended in 75% formic acid (25 ml). The suspension was heated under reflux for 1 hour and 40 minutes, and filtered while hot. The filtrate was concentrated and purified by silica gel chromatography (methylene chloride:methanol=50:1) to thereby obtain 1.08 g (yield: 80%) of the title compound as a colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17](=O)[C:16]2[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=2)[O:10][C:9]=1[CH3:21].O.[NH2:23][NH2:24]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([C:16]2[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=2[OH:10])=[N:23][NH:24][C:9]=1[CH3:21]
Reactant: NN
Reactant: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccccc1Br
Solvent: O
Product: Cc1[nH]nc(-c2cc(Cl)c(O)cc2O)c1-c1ccccc1Br

Procedure:
This compounds was synthesised in the same manner as described above. 3-(2-Bromo-phenyl)-6-chloro-7-hydroxy-2-methyl-chromen-4-one (2.5 g, 6.9 mmol), Hydrazine hydrate (10 ml). 4-[4-(2-Bromo-phenyl)-5-methyl-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol precipitated out as an off white solid (0.53 g, 20.2%); Rf 0.5 cf SM 0.85 [ethyl acetate/petroleum ether 40–60° C. (80/20)].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([NH:21][S:22]([CH2:25][CH2:26][NH2:27])(=[O:24])=[O:23])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([NH:21][S:22]([CH2:25][CH2:26][NH:27][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])(=[O:24])=[O:23])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(NS(=O)(=O)CCN)C1
Reactant: O=C(O)c1ccc(Cl)s1
Product: CC(C)(C)OC(=O)N1CC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)C1

Procedure:
3-{2-[(5-Chloro-thiophene-2-carbonyl)-amino]-ethanesulfonylamino}-azetidine-1-carboxylic acid tert-butyl ester was prepared by an analogous procedure as described in example 5 iii) starting from 240 mg (1.3 equiv.) 5-chloro-thiophene-2-carboxylic acid and 308 mg (1.1 mmol) 3-(2-amino-ethanesulfonylamino)-azetidine-1-carboxylic acid tert-butyl ester. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 3-{2-[(5-chloro-thiophene-2-carbonyl)-amino]-ethanesulfonylamino}-azetidine-1-carboxylic acid tert-butyl ester. The title compound was obtained in form of a colorless amorphous material.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)C([Cl:24])=O>CCCCCC>[C:1]([Cl:24])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Yield: 100.6 %

Procedure:
Linoleic acid (100 g; purity 95%, 356 mmoles) was added dropwise over a period of 0.5 hours to a stirred mixture of oxalyl chloride (42 ml; 481 mmoles) and of hexane (120 ml) under nitrogen. After the addition the mixture was refluxed for 1.5 hours and then evaporated under reduced pressure (60° C.; 0.5 mm Hg) to give 107 grams of linoleoyl chloride as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([O:25][C:24]([F:23])([F:34])[F:35])[CH:27]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (495 mg) in DMF (5 mL) was added potassium carbonate powder (763 mg) and 3-(trifluoromethoxy) benzyl bromide (1.41 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a brown solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][NH:8]1)=[O:6])[CH3:3].[CH2:13](N(CC)CC)[CH3:14].C(I)C>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][N:8]1[CH2:13][CH3:14])=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@@H]1C[C@H](O)CN1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCI
Product: CCOC(=O)[C@@H]1C[C@H](O)CN1CC

Procedure:
To a suspension of 12 g of (2S,4S)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochloride obtained in the preceeding para. (1) in 60 ml of chloroform, were added 12.42 g of triethylamine and the combined was added with 17.22 g of ethyl iodide and heat-refluxed for 4 hours. The reaction mixture was after-treated to obtain (2S,4S)2-ethoxycarbonyl-N-ethyl-4-hydroxy pyrrolidine as an oily (product Yield 9.55 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:15][CH2:16][CH3:17])=O.C>N1C=CC=CC=1.CCOCC>[CH2:16]([O:15][C:13]1[O:5][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1)[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOc1nc2cccc(C)c2c(=O)o1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 2-amino-6-methyl benzoic acid (25g., 0.165 mol) in dry pyridine (125 ml) at room temperature under anhydrous conditions was added ethyl chloroformate (47.33 ml, 3 equiv.) in a dropwise manner over 15 minutes. After stirring for 2 hours, the excess pyridine was removed under reduced pressure at a bath temperature of 40° C., and the residue was stirred vigorously in ice-cold water (250 ml) for 15 minutes. The pale yellow powder was collected by filtration, washed with water (100 ml) and air-dried to give the crude product (30.4g). The crude product was treated with active charcoal (2g) in ether (200ml) to afford a white solid after removal of solvent. Recrystallization from EtOAc/pet. ether gave 2-ethoxy-5-methyl-4H-3,1-benzoxazin-4-one (28.1g, 83%) as colorless crystals; m.p. 104°-105° C.; analysis for C11H11NO3 : C, 64.38; H, 5.40; N, 6.83. Found: C, 64.21; H, 5.43; N, 6.80.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:5]=[C:4]([OH:12])[N:3]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[C:21](=[O:22])([O:23][CH2:24][CH3:25])[O:12][C:4]1[CH:5]=[C:6]([C:8]([Cl:10])([Cl:11])[Cl:9])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Oc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)Oc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution was prepared by dissolving 6.17 grams (g) (0.025 mole (m)) of 2-chloro-6-hydroxy-4-(trichloromethyl)pyridine in 100 milliliters of toluene. To this solution was added 2.53 g (0.025 m) of triethylamine. To this mixture was then added 2.71 g (0.025 m) of ethyl chloroformate dissolved in 20 ml of toluene. The mixture was stirred at 50° C. for 4 hours. The salt which formed was removed by filtration and the toluene was removed by evaporation under reduced pressure. Using a short path distillation (Kugelrohr) at 130° C. and 80 millimeters of mercury, 6-chloro-4-(trichloromethyl)-2-pyridinyl ethyl carbonate was obtained in a yield of 6.65 g (83 percent of theory). The product had a refractive index of n(25/d)=1.5354. The structure of the product was confirmed by its NMR spectrum (Compound No. 1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].[I-].[K+].Cl[CH2:11][CH:12]([OH:15])[CH2:13][OH:14]>CC#N>[OH:15][CH:12]([CH2:13][OH:14])[CH2:11][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: OCC(O)CCl
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: OCC(O)Cn1ccnc1
Temperature: 25 °C
Yield: 96 %

Procedure:
Imidazole (3.40 g, 50.0 mmol), pulverized potassium hydroxide (5.61 g, 100 mmol), and potassium iodide (8.30 g, 50.0 mmol) were suspended in CH3CN (100 mL). 3-Chloro-1,2-propanediol (8.29 g, 75.0 mmol) was added, and the mixture was stirred at reflux for 24 h. After cooling to room temperature, additional CH3CN (150 mL) was added to the reaction, which was then filtered through Celite and concentrated. The crude product was then suspended in CH2Cl2 (250 mL), heated to reflux and stirred overnight, and then decanted. The product was still slightly impure by 1H NMR, so the CH2Cl2 wash process was repeated once, to afford a white solid (6.82 g, 96%) after drying in vacuo. 1H NMR (400 MHz, DMSO) δ 7.54 (t, J=1.0 Hz, 1H), 7.11 (t, J=1.2 Hz, 1H), 6.84 (t, J=1.0 Hz, 1H), 5.08 (s, 1H), 4.83 (s, 1H), 4.05 (dd, J=13.9, 3.6 Hz, 1H), 3.84 (dd, J=14.0, 7.2 Hz, 1H), 3.70-3.58 (m, 1H), 3.31 (dt, J=13.8, 9.0 Hz, 3H), 3.19 (dd, J=11.0, 6.5 Hz, 1H).