Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH2:22])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH:22][C:30](=[O:32])[CH3:31])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
2-{[1-(Phenylsulfonyl)-1H-indol-5-yl]oxy}ethanamine (Intermediate 24, 9.6 g, 30 mmol) in DCM (100 mL) was treated with triethylamine (12.8 mL, 91.0 mmol) and 4-dimethylaminopyridine (1.9 g, 15 mmol). The solution was cooled to 0° C. and acetyl chloride (4.3 mL, 61 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and washed with saturated aqueous NaHCO3 (50 mL) and 1 M HCl (2×50 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (10.3 g). MS m/z 359 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:12][C:11]2[CH:10]=[CH:9][NH:8][C:7](=[O:13])[C:6]=2[CH:5]=1.C[O:15][CH:16]([O:19]C)[CH2:17]Br.O>CN(C=O)C>[OH:15][CH:16]([OH:19])[CH2:17][N:8]1[CH:9]=[CH:10][C:11]2[O:12][C:4]([CH3:3])=[CH:5][C:6]=2[C:7]1=[O:13]
Reactant: Cc1cc2c(=O)[nH]ccc2o1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(=O)n(CC(O)O)ccc2o1
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 0.32 g) was suspended in DMF(10 ml), and was cooled to 0° C. in an ice water bath. 2-Methyl-5H-furo[3,2-c]pyridin-4-one (0.57 g) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. Bromoacetaldehyde dimethylacetal(2.3 ml) was added thereto, and the mixture was stirred at 80° C. for 5 hours. Water was added to the reaction liquid, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. A 3N-hydrochloric acid(2 ml) was added to an acetone solution (10 ml) of the residue, and the liquid was stirred at 70° C. for 10 hours. Water was added to the reaction liquid and stirred at room temperature. The precipitated insoluble matter was separated, washed with water, and dried to give the title compound(0.56 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=O>C1(C)C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(-c3cccs3)oc(=O)c2c1
Temperature: 25 °C

Procedure:
2-Amino-5-methylbenzoic acid (0.5 g) and triethyl amine (10 ml) were mixed in dry toluene (20 ml). 2-Thienylcarbonyl chloride (1.07 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT for 24 h, then heated to 80° C. for 1 h. After cooling on ice the precipitate was filtered off and the filtrate evaporated to dryness. The residue was partitioned between methylene chloride and potassium carbonate (2N), the organic layers separated, dried over magnesium sulfate and evaporated to dryness. The raw product was purified by column chromatography on silicagel using heptane/ethyl acetate as eluent.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CCCCO>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cc(Cl)ncn2)cc1
Yield: 91.5 %

Procedure:
A mixture of 4,6-dichloropyrimidine (Aldrich, 3.6 g, 24.2 mmol), 4-methoxybenzylamine (2.7 g, 19.7 mmol), DIPEA (5 ml, 28.8 mmol), and n-BuOH was heated at reflux for 3 h. The mixture was concentrated and the residue treated with H2O (150 mL) and EtOAc (175 mL). The EtOAc phase was separated, washed with saturated aq. NaHCO3 solution and brine, dried (MgSO4), and concentrated to give the title compound (4.5 g) which was used without further purification. 1H NMR (DMSO-d6) δ 8.29 (s, 1H), 8.13 (br s, 1H), 7.25 (d, 2H, J=8.2 Hz), 6.90 (d, 2H, J=8.2 Hz), 6.56 (s, 1H), 4.48 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:23])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:10]>CS(C)=O.O>[CH2:9]([O:11][C:12]([C@@H:13]1[CH2:2][C@H:14]1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[O:23])[CH3:10]
Reactant: CCOC(=O)C=Cc1ccc(OC)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(OC)cc1
Reaction time: 0.67 h
Yield: 26.8 %

Procedure:
Trimethylsulfoxonium iodide (14.15 g, 63 mmol) is suspended in dry DMSO (126 mL) and Sodium hydride (60% in mineral oil, 2.52 g, 63 mmol) is added. The mixture is stirred for 40 minutes and then a solution of 4-methoxycinnamic acid ethyl ester (5 g, 24.2 mmol) in dry DMSO (64 mL) is added and the mixture stirred for 3 hours at room temperature. The mixture is diluted with water and extracted with ethyl acetate, the organic phase is dried by passing through a phase seperator and the solvent is removed under vacuum. The residue is purified by flash chromatography (10% ethyl acetate in cyclohexane) to give the title compound (yield 1.43 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C@H:10]2[CH2:18][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29]([CH2:34][C:35](O)=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1)(=[O:22])=[O:21].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17]2)[C:35](=[O:36])[CH2:34][C:29]2[NH:28][C:27]3[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=3[S:31](=[O:32])(=[O:33])[N:30]=2)[C@H:10]2[CH2:18][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirred solution of (1S,2R,3S,4R)-3-(2-cyclopropyl-ethylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (338.2 mg, 1.35 mmol) in anhydrous N,N-dimethylformamide (10 mL) under a nitrogen atmosphere, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1 g, 493 mg, 1.48 mmol), N-methylmorpholine (0.33 mL, 2.96 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (284 mg, 1.48 mmol) were added sequentially. After shaking at 25° C. for 21 h, additional (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 150 mg, 0.45 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (85 mg, 0.44 mmol) were added. After another 26 h, a 1.0 M aqueous hydrochloric acid solution (12 mL) was added and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with saturated aqueous brine solution (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-{(2-cyclopropyl-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a red oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C25H34N4O7S2 566.19, found 567.4 [M+H+].
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[C:6]1([S:12]([O-:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Na+]>CO>[CH3:5][C:3](=[CH2:4])[CH2:2][S:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:14])=[O:13]
Reactant: C=C(C)CCl
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CO
Product: C=C(C)CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 98128.3 %

Procedure:
A solution of 3-chloro-2-methyl-propene (80 ml, 0.81 mmol) in dry methanol (450 ml) was stirred at room temperature during the addition of sodium benzenesulfinate (200 g, 1.22 mmol). The resulting suspension was refluxed for 20 hours, cooled to room temperature and concentrated in vacuo. The residue was poured onto water (600 ml) and the resulting solid filtered, washed three times with water (200 ml) and dried under vacuum for two days to give (2-methyl-prop-2-ene-1-sulfonyl)-benzene (156 g, 99%) which was used in the next step without further purification.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[OH:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1c[nH]cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cnc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
4-Hydroxymethylimidazole hydrochloride (10 g) was suspended in dichloromethane (200 ml). ρ-Toluenesulfonyl chloride (15.58 g) was added and triethylamine (25.8 ml) was added dropwise to the stirred reaction mixture which was allowed to stir at room temperature overnight. The mixture was washed with water (2×100 ml) and brine (1×100 ml) and the organic layer was dried and evaporated to leave a clear oil which was recrystallised from ethyl acetate/hexane to afford the title compound as a white crystalline solid (15 g, 80%). 1H NMR (360 MHz, CDCl3) δ2.44 (3H, s), 4.55 (2H, s), 7.21 (1H, s), 7.35 (2H, d, J=8.0 Hz), 7.62 (2H, d, J=8.0 Hz 7.98 (1H, s). MS (CI+) m/z 253 (M+H, 100%).
Reaction SMILES: [CH2:1]1[N:6]([C:7]2[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][O:3][CH2:2]1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.[H-].[Na+]>CN(C)C=O>[N:6]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[O:13][C:15]2[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:20]=2)[CH2:1][CH2:2][O:3][CH2:4][CH2:5]1
Reactant: Oc1ccccc1N1CCOCC1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCOCC2)ccc1[N+](=O)[O-]
Yield: 83.6 %

Procedure:
By using 0.72 g of 2-(4-morpholino)phenol, 1.15 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.17 g of sodium hydride (55% by weight) and 10 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 1.44 g of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].CC(C)([O-])C.F[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]>C1COCC1.C(OCC)(=O)C>[F:18][C:16]1[CH:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COCCO
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-ethanol in 4 ml dry THF, was added tert-butoxide (378 mg, 3.37 mmol) at 0° C. The resulting mixture was added dropwise to the solution of 2,4-difluoro-1-nitro-benzene (536 mg, 3.37 mmol) in 5 ml dry THF at 0° C. The mixture was stirred at 0° C. for 30 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give 4-Fluoro-2-(2-methoxy-ethoxy)-1-nitro-benzene. 4-Fluoro-2-(2-methoxy-ethoxy)-1-nitro-benzene (1.35 g, 6.3 mmol) was treated with p-methoxybenzylamine (1.64 mL, 12.6 mmol) in dimethyl sulfoxide at 80° C. in a sealed tube for 4 hr. After work up with ethyl acetate and water isolated N-(4-methoxybenzyl)3-(2-methoxyethoxy)-4-nitrobenzenamine intermediate. RP-HPLC: 2.13 min; ES-MS (M+H)+=346; To this intermediate added trifluoroacetic acid and heated the reaction mixture at 80° C. for 1 hr to deprotect the p-methoxybenzyl functionality to give final product 3-(2-methoxyethoxy)-4-nitobenzenamine. RP-HPLC: 1.14 min; ES-MS (M+H)+=213; 1H-NMR (MeOH-d4) δ (ppm): 3.4 (s, 3 H), 3.8 (t, 2 H), 4.10 (t, 2 H), 6.2 (dd, 1 H), 6.26 (d, 1 H), 7.76 (d, 1 H).
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1)([OH:3])=O.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH2:51]>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:7][CH:6]2[O:5][CH2:4][C:1](=[O:3])[NH:51][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH2:44][CH2:43][CH2:42][CH2:41][O:40][CH3:39])=[CH:17][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)O)cc1
Reactant: COCCCCc1ccccc1N
Product: COCCCCc1ccccc1NC(=O)COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Example 3a, 0.537 g of tert-butyl 3-carboxymethoxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 34b) and 0.296 g of 2-(4-methoxybutyl)phenylamine are reacted. The title compound is obtained as a yellow oil. Rf=0.27 (1:1 EtOAc-heptane); Rt=5.98.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[Br:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1Br
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c(F)c(F)c(F)c(F)c1Br

Procedure:
365 g (1.33 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoic acid [Tetrahedron 2.3, 4719 (1967)] are introduced into 2 l of thionyl chloride and the mixture is heated under reflux for 11 hours until the evolution of gas stops. Excess thionyl chloride is stripped off in vacuo and the residue is distilled.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:9]=1[CH3:10])=[N+]=[N-]>C(O)C.[Pd]>[CH3:10][C:9]1[NH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[CH2:4][NH2:1]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)nc1CN
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To solution of 4-azidomethyl-5-methyl-2-phenyl-1H-imidazole (1.22 g) in ethanol (50 ml) was added 10% Pd/C (0.10 g). The reaction mixture was hydrogenated at room temperature and 1.1 bar for 30 minutes, the catalyst was filtered off over a pad of celite. The filtrate was evaporated to dryness under high vacuum to obtain C-(5-methyl-2-phenyl-1H -imidazol-4-yl)-methylamine (1.06 g) as a light yellow foam which was sufficiently pure to be used directly in the next step.
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:29]=[C:30]([F:32])[CH:31]=1)[O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])=[CH:16][CH:15]=1.Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:1]1([S:7][N:21]([CH2:20][CH2:19][O:18][C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:29]=[C:30]([F:32])[CH:31]=[C:10]([F:9])[CH:11]=3)=[CH:28][CH:27]=2)[C:22](=[O:26])[O:23][CH2:24][CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: ClSc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N(CCOc1ccc(Oc2cc(F)cc(F)c2)cc1)Sc1ccccc1

Procedure:
5.7 g of freshly distilled phenylsulfenyl chloride in 10 ml of toluene are added dropwise at 0° to +5° C. in the course of 30 minutes to a solution of 12 g of ethyl 2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate in 40 ml of pyridine, with stirring. After this, the mixture is stirred for 4 more hours at room temperature. The reaction mixture is poured into 300 ml of 2N hydrochloric acid and ice, and the mixture is extracted twice using diethyl ether. The combined organic phases are washed to neutrality with water and sodium chloride solution and dried over sodium sulfate. The solvent is distilled off in vacuo, and the residue is purified by chromatography on silica gel (eluent: hexane/diethyl ether, 20:1), which gives pure ethyl N-phenylthio-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate, nD20 : 1.5700.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12].[CH2:13]([O:15][C:16]([C:18]1[C:19]([O:36][CH3:37])=[C:20]2[N:25]([CH:26]=1)[N:24]=[CH:23][N:22]=[C:21]2NC1C=CC(C)=C(O)C=1)=[O:17])[CH3:14]>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1[C:19]([O:36][CH3:37])=[C:20]2[N:25]([CH:26]=1)[N:24]=[CH:23][N:22]=[C:21]2[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:3][C:4]1=[O:12])=[O:17])[CH3:14]
Reactant: CCOC(=O)c1cn2ncnc(Nc3ccc(C)c(O)c3)c2c1OC
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ncnc(C3C(=O)Nc4ccccc43)c2c1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.6 %

Procedure:
To a suspension of NaH (60%, 44 mg, 1.1 mmol) in THF (1 mL) was added oxindole (133 mg, 1 mmol). The reaction mixture was stirred for 20 min. at rt. Compound G of example 96 (0.1 mmol) was added. The reaction was stirred for 2 hrs at 25° C. The crude material was purified by preparative HPLC followed by chromatography on silica gel eluting with ethyl acetate to provide 5.5 mg (16%) of a yellow solid. MS: [M+H]+=353; 1H NMR (CDCl3): δ 8.42 (s, 0.4H), 8.10 (s, 0.6H), 7.79 (s, 1H), 7.75-6.88 (m, 4H), 4.33 (m, 2H), 3.57 (s, 3H), 1.37 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH:15][CH2:16][C:17]([NH2:26])([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH3:18])[CH2:6]1)[CH2:12]2)=[O:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[N:15]3[CH2:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)([CH3:18])[NH:26][C:28]3=[O:30])[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: COC(=O)C12CC3CC(C1)C(NCC(C)(N)c1cccc(Cl)c1)C(C3)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C12CC3CC(C1)C(N1CC(C)(c4cccc(Cl)c4)NC1=O)C(C3)C2
Reaction time: 4 h
Yield: 118.8 %

Procedure:
A solution of 4-[2-amino-2-(3-chloro-phenyl)-propylamino]-adamantane-1-carboxylic acid methyl ester (7.9 g) in 40 mL DCM was cooled to −20° C. and triphosgene (3.1 g) (separately dissolved in 10 mL DCM) was added to it drop wise followed by drop wise addition of triethylamine (6.57 mL). The reaction mixture was slowly brought to RT and left at stirring for 4 h. Reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and the DCM layer was separated. The aqueous layer was again extracted with DCM (2×). The combined DCM layers were dried over Na2SO4 and concentrated to afford the crude product, which was purified by column chromatography to give the desired 4-[4-(3-chloro-phenyl)-4-methyl-2-oxo-imidazolidin-1-yl] adamantane-1-carboxylic acid methyl ester (5.0 g) as a mixture of E/Z isomers as a white solid. MS (ES+): 403.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:35]([CH:32]3[CH2:31][CH2:30][N:29]([C:26](=[O:28])[CH3:27])[CH2:34][CH2:33]3)=[O:36])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Product: CC(=O)N1CCC(C(=O)N2C[C@H](c3ccc(Cl)c(Cl)c3)[C@@H](N(C)C(=O)Oc3ccc(F)cc3)C2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-[(3R,4S)-1-(1-acetyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-acetylpiperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a brown oil. MS m/e: 536.1 [M]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:22][O:23][CH2:24][CH2:25]Br>O1CCCC1>[CH3:22][O:23][CH2:24][CH2:25][C:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C1CCCC1
Reactant: COCCBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCCC1(C(=O)OC)CCCC1
Temperature: -70 °C
Yield: 65 %

Procedure:
To a 3 L 3-necked round-bottomed flask equipped with a thermometer and dropping funnel were added diisopropylamine (136 mL, 0.98 mol) and tetrahydrofuran (750 mL). The solution was stirred under nitrogen and cooled in an ice-bath. Through the dropping funnel was added n-butyllithium (2.5 M in hexanes; 376 mL, 0.94 mol), and the solution was allowed to stir at 0° C. for 30 min and then cooled to −70° C. Through the dropping funnel was added a solution of cyclopentanecarboxylic acid, methyl ester (83.04 g, 0.65 mol) in tetrahydrofuran (135 mL). The solution was stirred at −70° C. for 1 h and then a solution of 2-bromoethyl methyl ether (55.5 mL, 0.59 mol) in tetrahydrofuran (135 mL) was added. The solution was stirred at −70° C. for 1 h and then the cooling bath was removed. The solution was stirred at room temperature overnight, then poured into saturated ammonium chloride solution (2 L) and extracted with ether (3×500 mL). The combined ether layers were washed with saturated brine (6×400 mL), dried (Na2SO4), filtered, evaporated, and distilled under vacuum to give 1-(2-methoxyethyl) cyclopentanecarboxylic acid, methyl ester (71.39 g, 59%) as a pale yellow liquid (bp 94-102° C. at 8 mm). This was dissolved in a mixture of tetrahydrofuran (340 mL), methanol (340 mL) and 1 M sodium hydroxide solution (425 mL). The mixture was stirred and heated at 55-60° C. for 24 h and then concentrated under reduced pressure to remove tetrahydrofuran and methanol. Water (400 mL) was added and the solution was extracted with ether (2×200 mL). The aqueous layer was acidified to pH 1 with 1 N HCl (500 mL), and extracted with ether (300 mL, then 2×200 mL). The combined ether layers were washed with saturated brine (2×200 mL), dried (Na2SO4), filtered, and evaporated to give 1-(2-methoxyethyl)cyclopentanecarboxylic acid (63.68 g, 97%) as a yellow liquid.