Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.CN(C)C1C=CN=CC=1>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1C(CO)CCC1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(CO)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl 2,5-bis(hydroxymethyl)-1-pyrrolidinecarboxylate (commercially available, for example from J&W Pharmlab, 7.57 g, 32.7 mmol) in dichloromethane (200 mL) was added triethylamine (4.79 mL, 34.4 mmol), 4-dimethylaminopyridine (0.20 g, 1.64 mmol) and p-toluenesulfonyl chloride (6.55 g, 34.4 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was diluted with DCM (200 mL) and the solution washed with water (200 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum. The residue was purified by silica chromatography (Biotage SP4, eluting 30% EtOAc in iso-hexane (3 column volumes), a gradient from 30-50% (over 6 column volumes) then 50% EtOAc (3 column volumes)) to yield the title compound as a colourless gum (2.28 g).
Reaction SMILES: CN(C=O)C.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:31][C:32]1[C:37]([CH2:38]Br)=[C:36]([O:40][CH3:41])[C:35]([O:42][CH3:43])=[C:34]([O:44][CH3:45])[C:33]=1[O:46][CH3:47].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH2:38][C:37]2[C:32]([Br:31])=[C:33]([O:46][CH3:47])[C:34]([O:44][CH3:45])=[C:35]([O:42][CH3:43])[C:36]=2[O:40][CH3:41])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1c(Br)c(CBr)c(OC)c(OC)c1OC
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1c(Br)c(OC)c(OC)c(OC)c1OC)(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.6 %

Procedure:
A DMF (120 ml) suspension of ethyl 2-(4-benzyloxyphenyl)-2-ethoxycarbonylacetate (12.0 g, 35.1 mmols), 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (16.9 g, 45.6 mmols) and potassium carbonate (14.5 g, 105 mmols) was stirred at room temperature for 6 hours, and then 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (2.60 g, 7.02 mmols) was added thereto stirring was continued at room temperature for further 6 hours. Water was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (11.0 g) as crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][C:12]([O:15][C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13].CCN(CC)CC>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:22]2[CH2:21][CH2:20][CH:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24][CH2:23]2)[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1nc(Cl)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.3 %

Procedure:
To a 100-mL round-bottomed flask was added 4,6-dichloro-2-(methylthio)pyrimidine (2.0 g, 10.25 mmol, Sigma-Aldrich) and 4-(n-boc-amino)-piperidine (2.053 g, 10.25 mmol, Sigma-Aldrich) in DCM (25 mL) followed by Et3N (2.139 mL, 15.38 mmol). The reaction was stirred at RT for 5 h, then diluted with DCM (100 mL). The mixture was washed with water, brine, dried MgSO4, filtered and concentrated to give crude tert-butyl 1-(6-chloro-2-(methylthio)pyrimidin-4-yl)piperidin-4-ylcarbamate (3.80 g, 100%) as a white solid. MS (ESI, pos. ion) m/z: 359.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(OO)(=[O:11])C.OO.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[N+:6]([O-:11])[C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: CC(=O)OO
Reactant: Cc1ccc(F)cn1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(F)c[n+]1[O-]
Temperature: 50 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
To the solution of 5-fluoro-2-picoline obtained in Step 4, at 0° C., was added, with vigorous stirring, a cold solution of 40% peracetic acid (prepared by carefully adding 50 mL of 30% hydrogen peroxide solution to 150 mL of glacial acetic acid). The reaction mixture was heated at reflux temperature (50° C.) for 4 days and then poured into 600mL of ice water. The aqueous mixture was adjusted to pH 9 by the addition of potassium carbonate and then was stirred at ambient temperature for 4 hours. The aqueous solution was continuously extracted with methylene chloride for 24 hours and the methylene chloride extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 30.8 g (22% yield) of the title compound; MS DCI-NH3M/Z: 128 (M+H)+ base; 1H NMR (CDCl3) d 2.48 (s, 3H), 7.00 (ddd, 1H), 7.22 (dd, 1H), 8.22 (dd, 1H).
Reaction SMILES: [OH:1][CH:2]1[C:18]([CH3:20])([CH3:19])[C:17](=[O:21])[CH:16]([CH3:22])[CH:15]([OH:23])[CH:14]([CH3:24])[CH2:13][CH2:12][CH2:11][CH:10]2[CH:8]([N:9]2[CH2:25][CH2:26][OH:27])[CH2:7][CH:6]([C:28]([CH3:36])=[CH:29][C:30]2[N:31]=[C:32]([CH3:35])[S:33][CH:34]=2)[O:5][C:4](=[O:37])[CH2:3]1.[C:38](=O)([O:49][CH2:50][CH2:51][S:52][S:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)[O:39]N1C2C=CC=CC=2N=N1>ClCCl.CN(C1C=CN=CC=1)C>[C:38](=[O:39])([O:49][CH2:50][CH2:51][S:52][S:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)[O:27][CH2:26][CH2:25][N:9]1[C@@H:8]2[C@H:10]1[CH2:11][CH2:12][CH2:13][C@H:14]([CH3:24])[C@H:15]([OH:23])[C@@H:16]([CH3:22])[C:17](=[O:21])[C:18]([CH3:19])([CH3:20])[C@@H:2]([OH:1])[CH2:3][C:4](=[O:37])[O:5][C@H:6](/[C:28](/[CH3:36])=[CH:29]/[C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1)[CH2:7]2
Reactant: CC(=Cc1csc(C)n1)C1CC2C(CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1)N2CCO
Reactant: O=C(OCCSSc1ccccn1)On1nnc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@H]2[C@@H](CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)N2CCOC(=O)OCCSSc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-17-[2-hydroxyethyl]-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione in anhydrous dichloromethane at 0° C. was added DMAP (1.2 eq.) and benzo[d][1,2,3]triazol-1-yl 2-(2-(pyridin-2-yl)disulfanyl)ethyl carbonate (1.0 eq.) in tandem. The reaction mixture was stirred at 0° C. under argon and monitored by TLC every 10 min. Additional DMAP (1.2 eq.) and Compound I (2)(1.0 eq.) were added as necessary until all of Compound G was consumed. The reaction was quenched with MeOH (1 mL) at 0° C., the solvent was removed under vacuum, and the residue was purified by chromatography (silica gel, 2.5-5% MeOH in DCM) to afford the title compound as a beige solid. Compound amounts and recoveries are listed below in Table 2. Total yield from 2.95 g of Compound G was 2.80 g (67.9%) of Compound I.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>O.CO>[OH:1][CH:2]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([OH:5])=[O:4]
Reactant: CCCCCCCCCCCCCC=CCC(O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCC=CCC(O)C(=O)O
Temperature: 25 °C

Procedure:
Methyl 2-hydroxy-4-octadecenoate (8.21 g, 0.026 mol, 1.0 eq) is heated under reflux with a large excess of sodium hydroxide (8.4 g, 0.21 mol, 8.1 eq) in water (20 ml) and methanol (20 ml) for 1 hour. After cooling down to room temperature, the mixture is washed with hexane (50 ml) and the organic phase separated. The clear aqueous layer is acidified to pH 1 with concentrated hydrochloric acid and the resultant mixture is extracted with diethylether (3×50 ml), the combined organic layers being washed with brine (50 ml) dried over anhydrous magnesium sulphate and evaporated to give a white solid. This is recrystallised from ethyl acetate/hexane to give the product acid (5) as white needles, 6.35 g (81%), mp 78-79.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:16]=1.[CH3:17]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:17])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]([CH3:14])[CH3:15])[C:6]=2[N:16]=1
Reactant: CC(C)N1CCC(=O)Nc2cnc(Cl)nc21
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.096 g (0.0004 mole) of 2-chloro-9-isopropyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-43), 1 mL of N,N-dimethylacetamide and 0.037 mL (0.0006 mole) of iodomethane at 0 degrees was added 0.024 g (0.0006 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.088 g of 2-chloro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-43) as an yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Na+].[Cl-]>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:11][C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cnc3ccccc3c2)CC1
Reaction time: 16 h
Yield: 56 %

Procedure:
A mixture of quinolin-3-ylamine (3.62 g, 25.09 mmol, 1.0 equiv, commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.00 g, 25.09 mmol, 1.0 equiv; commercially available) in conc. acetic acid (1.44 mL, 1.51 g, 25.09 mmol, 1.0 equiv) and dichloroethane (50 mL) was stirred at rt for 4 h. Sodium triacetoxyborohydride (6.38 g, 30.11 mmol, 1.2 equiv) was added in one portion and the reaction mixture stirred for an additional time period of 16 h. To the reaction mixture was added a sat. solution of NaCl (2×50 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were washed over a sat. solution of Na2CO3 (50 mL), dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (10:1→9:1). Trituration from heptane/ethyl acetate provided 4.60 g (56%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.36-1.46 (m, 2H), 1.49 (s, 9H), 2.12 (d, J=10.5 Hz, 2H), 3.00 (t, J=11.9 Hz, 2H), 3.47-3.64 (m, 1H), 3.89 (d, J=7.7 Hz, 1H), 4.10 (br s, 2H), 7.03 (d, J=2.7 Hz, 1H), 7.37-7.47 (m, 2H), 7.59-7.64 (m, 1H), 7.89-7.98 (m, 1H), 8.42 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH3:1][Si:2]([C:5]1[CH:6]([Si](C)(C)C)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].C(=O)=O.[B:21](Cl)([Cl:23])[Cl:22]>>[CH3:1][Si:2]([C:5]1[CH:6]([B:21]([Cl:23])[Cl:22])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C1=Cc2ccccc2C1[Si](C)(C)C
Reactant: ClB(Cl)Cl
Agent: O=C=O
Product: C[Si](C)(C)C1=Cc2ccccc2C1B(Cl)Cl
Temperature: -30 °C
Reaction time: 3 h

Procedure:
In a manner similar to the preparation of compound 2, 12.3 g (0.047 mol) of compound 13 were introduced into a round-bottomed flask which was cooled to −30° C. and had a reflux condenser cooled with dry ice. 5.6 g (0.046 mol) of BCl3 were added to this. When the addition was complete, the cooling bath was removed and the reaction mixture warmed to room temperature and was stirred for 3 hours. The temperature was then raised to 55° C. for 6 hours. After cooling and removal of the volatile contents in vacuo, the crude product was obtained. Distillation under a high vacuum gave the purified product, the main isomer of which was identified as follows:
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([CH:20]=[O:21])[C:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.[CH3:22][S-:23].[Na+]>O1CCOCC1.O>[CH3:19][C@H:14]1[O:15][C@@H:16]([CH3:18])[CH2:17][N:12]([C:9]2[C:8]([CH:20]=[O:21])=[CH:7][C:6]3[C:2]([S:23][CH3:22])=[N:3][O:4][C:5]=3[C:10]=2[F:11])[CH2:13]1
Reactant: C[S-]
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@H](C)O1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To an ice cold solution of 3-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde (Intermediate 534, 0.3 g, 0.916 mmol) in dioxane was added sodium thiomethoxide (21% aq solution, 0.134 mL, 1.923 mmol) and stirred at room temperature for 12 hours. Reaction mixture was diluted with water and extracted with EtOAc (50 mL). Organic phase washed with brine (2×10 mL), dried over anhydrous sodium sulfate and, filtered, concentrated to give tilt product as white solid. Yield: 280 mg (90%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1ccc(Br)cn1
Temperature: 0 °C
Yield: 37 %

Procedure:
A solution of 2-amino-5-bromopyridine (9.46 g, 20 mmol) and N,N-diisopropylethylamine (3.10 g) in chloroform (20 ml) was added to a solution of methyl chloroformate (2.30 g, 24 mmol) in chloroform (25 ml) dropwise with stirring at 0° C. The reaction mixture was stirred for 20 minutes, filtered and the precipitate was washed with chloroform and dried to afford 1.71 g (37%) of the title product as a white solid. mp 191-192° C. 1H NMR (CDCl3): δ=8.42 (d, 1 H); 8.30 (d, 1 H); 7.91 (d, 1 H); 7.77 (d of d, 1 H); 3.79 (s, 3 H). MS (El): m/z=230, 232 (M+, Br isotopes).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]([O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:6])=[O:4].[CH2:17]([O:29][C:30]1[CH:31]=[N:32][C:33]([C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=2)=[N:34][CH:35]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]([O:7][C:8]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:40](=[O:41])[C:39]2[CH:38]=[CH:37][C:36]([C:33]3[N:34]=[CH:35][C:30]([O:29][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][N:32]=3)=[CH:44][CH:43]=2)=[CH:13][CH:14]=1)=[O:16])[CH3:6])=[O:4]
Reactant: CCCCCCCCCCCCOc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: COC(=O)[C@@H](C)OC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1cnc(-c2ccc(C(=O)Oc3ccc(C(=O)O[C@H](C)C(=O)OC)cc3)cc2)nc1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
In a 50 ml round flask were charged 191 mg (0.85 mmol) of (R)-4-hydroxybenzoic acid 1-(methoxycarbonyl)-ethyl ester as prepared in Example 1-2), 360 mg (0.935 mmol) of 4-(5-dodecyloxypyrimidin-2-yl)benzoic acid, 10.4 mg (0.085 mmol) of N,N-dimethyl-4-aminopyridine, and 20 ml of methylene chloride, followed by stirring at 25 ° C. To the mixture was added 193 mg (0.935 mmol) of DCC to conduct a reaction at 25° C. for 18 hours. After completion of the reaction, the solid was removed by filtration, and the filtrate was washed successively three times with 10 ml portions of water, three times with 10 ml portions of a 5% acetic acid aqueous solution, and three times with 10 ml portions of water. The organic solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using a 20:1 (by volume) mixture of methylene chloride and diethyl ether. Recrystallization from hexane gave 110 mg (0.19 mmol) of Compound (35) in a yield of 22%.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:9]([N:16]([CH2:20][Si](C)(C)C)[CH2:17]OC)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:7]([O:6][C:1]([CH:2]1[CH:3]([CH3:4])[CH2:17][N:16]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:20]1)=[O:5])[CH3:8]
Reactant: C/C=C/C(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1C

Procedure:
102.1 In analogy to example 101.1 ethyl crotonate and N-benzyl-N-(methoxymethyl)tri-methylsilylmethylamine (CAS 93102-05-7) were reacted to give (3RS,4RS)-1-benzyl-4-methyl-pyrrolidine-3-carboxylic acid ethyl ester. Light yellow solid. MS 248.3 ([M+H]+)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:31])=[CH:28][C:27]=1[C:35]([F:36])([F:37])[F:38]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Product: COc1ccc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)cc1C(F)(F)F

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Methoxy-3-trifluoromethyl-benzoic acid. LC-MS (basic): tR=0.96 min; [M+H]+=530.0.
Reaction SMILES: [Br:1]Br.[CH2:3]([CH2:10][C:11](=[O:13])[CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CO>[Br:1][CH2:12][C:11](=[O:13])[CH2:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: BrBr
Solvent: O
Solvent: CO
Product: O=C(CBr)CCc1ccccc1
Temperature: 8.5 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A freshly prepared solution of bromine (258.9 g) in methanol (600 mL) was added dropwise during 1 h 20 min to a stirred solution of benzylacetone (222.3 g) in methanol (600 mL) at 7-10° C. An exothermic reaction took place, and to maintain the necessary temperature (7-10° C.), the flask should be immersed in a ice-water bath. When orange-red color of bromine disappeared, water (1500 mL) was added to the mixture and the obtained mixture was stirred overnight. The organic layer (on the bottom) was separated, water phase was extracted with dichloromethane (2×600 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue was dissolved in hexane (2500 mL) and the obtained solution was kept overnight at −10° C. Precipitated fine crystals (needles) were filtered off, washed on filter with cold hexane, dried under reduced pressure at room temperature to give 1-bromo-4-phenyl-2-butanone (213.0 g, 63% yield), mp 39-40° C. 1H NMR (CDCl3) δ 2.95-3.00 (m, 4H); 3.83 (s, 2H); 7.16-7.30 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O=[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:22]([O:21][C:19]([C:18]1[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:20])[CH3:23]
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Product: CCOC(=O)Cc1nc2ccccc2c(N)c1C(=O)OCC

Procedure:
Prepared as in Example 2a from 2-aminobenzonitrile and diethyl 3-oxopentanedioate as a pale yellow solid (25%). 1H NMR (400 MHz, DMSO-d6) δ 1.19 (t, J=8.0 Hz, 3H), 1.30 (t, J=8.0 Hz, 3H), 4.08 (m, 4H), 4.28 (q, J=8.0 Hz, 2H), 7.50 (m, 1H), 7.73 (m, 2H), 8.10 (bs, 2H), 8.53 (d, J=8.0 Hz, 1H). MS 303 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[C:18]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Product: O=C(Nc1ccccc1C(=O)NCCc1ncc[nH]1)c1ccc(-c2ccccc2)cc1
Yield: 65.1 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 11 using 1.50 g (0.00651 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)ethyl]benzamide, prepared as in Example 6A, and 3.76 g (0.01738 mol) of p-phenylbenzoyl chloride, with the exception that after removing ethyl acetate the final product was recrystallized from an ethyl acetate/methanol solution to provide 1.74 g of the desired titled compound (m.p. 197°-201° C.).
Reaction SMILES: C[O-].[Na+].CO[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[SH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].Cl>CO>[SH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:7]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S
Temperature: 150 °C
Yield: 79.7 %

Procedure:
To a solution of 4.3 ml of 0.5 M sodium methoxide in methanol was added 75 mg of 4-mercapto-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester and 181 mg of glycine. The mixture was heated to 150° C. for 10 minutes using a CEM Discover microwave reactor (City, State). The resultant solution was cooled, and acidified with 1 N HCl solution to produce a yellow precipitate. The precipitate was collected by filtering the solution through a (medium) porous buchner filter funnel, and triturated with methanol to give 68 mg of product; MS (−): m/z 353.02 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:14][Zn]C.O>O1CCOCC1>[Cl:13][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH3:14])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C[Zn]C
Reactant: CCOC(=O)c1c(Cl)cncc1Br
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)cncc1Cl
Temperature: 60 °C
Yield: 90 %

Procedure:
To the solution of ethyl 3-bromo-5-chloropyridine-4-carboxylate (28 g, 105 mmol) in dioxane (300 mL) in a 1 L round bottom flask was added dimethylzinc (105 mL, 1.0 M in hexane) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) dichloromethane complex (1.3 g, 1.6 mmol). The resulting mixture was heated at 60° C. for 20 hours. After cooling, the reaction mixture was poured into cold water (500 mL) and extracted with dichloromethane (3×200 mL). After evaporation of the solvent, the crude product was filtered through a silica pad (10 cm) with 20% ethyl acetate in hexane (400 mL), and the solvent was evaporated. The oily ethyl 3-chloro-5-methylpyridine-4-carboxylate (20 g, 90% yield) was used in the next step without further purification.