Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][CH:5]([CH3:32])[CH:6]([NH:19][C:20]([CH:22]1[CH2:26][CH:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][NH:23]1)=[O:21])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([CH2:16][CH2:17][CH3:18])[O:8]1>CO.CCOCC>[CH3:32][CH:5]([CH3:4])[CH:6]([NH:19][C:20]([CH:22]1[CH2:26][CH:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][N:23]1[CH2:1][CH2:2][OH:3])=[O:21])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([CH2:16][CH2:17][CH3:18])[O:8]1
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(CCC)C(O)C(O)C2O)C1
Reactant: C1CO1
Solvent: CO
Solvent: CCOCC
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(CCC)C(O)C(O)C2O)N(CCO)C1
Reaction time: 48 h
Yield: 34 %

Procedure:
The title compound was prepared according to the process illustrated in Scheme 19. Ethylene oxide was used as the alkylating agent. To a stirred solution of 4-Pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-propyl-tetrahydro-pyran-2-yl)-propyl]-amide (example 103) (12.0 mg 0.029 mmol, 1 equiv) and TEA (100 μL) in MeOH (2 mL) at 0° C. was added condensed ethylene oxide (200 μL) was added and the reaction mixture stirred 48 h. The reaction mixture evaporated to dryness, and the resulting residue was purified by column chromatography on silica 20% 0.25M NH3 in MeOH/DCM to give the crude N alkylated product. The crude product was taken up in Et2O, filtered and the filtrate treated with 2M HCl in Et2O, the precipitated HCl salt was collected washed with Et2O and lyophilized to give the title compound as a colorless powder (4.4 mg 34%).
Reaction SMILES: [Zn](CC)[CH2:2]C.COCCOC.C(I)I.[Si:15]([O:32][CH2:33][CH2:34]/[CH:35]=[CH:36]/[C@@H:37]([NH:42][C:43](=[O:52])[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:38][CH:39]([CH3:41])[CH3:40])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[Si:15]([O:32][CH2:33][CH2:34][CH:35]1[CH2:2][CH:36]1[C@@H:37]([NH:42][C:43](=[O:52])[O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH2:38][CH:39]([CH3:41])[CH3:40])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 513.7 %

Procedure:
To a solution of ZnEt2 (110 mg, 0.844 mmol) in dry DCM (2 mL) was added DME (distilled, 0.088 mL, 844 mmol). The reaction mixture was stirred at rt for 10 min under N2, then cooled to −20° C. and CH2I2 (0.137 mL, 1.687 mmol) was added dropwise over 4 min. After stirring for 10 min, a solution of the alkene 8b (149 mg, 0.281 mmol) in dry DCM (1 mL) was added dropwise over 5 min. The reaction mixture was allowed to warm to rt while stirring. After 10 h, the reaction mixture was quenched with sat. aq. NH4Cl and diluted with DCM and water, the aqueous phase was separated and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 9:1, hexanes/Et2O) afforded 785 mg (68%) of the title compound as a colorless oil. 1H NMR analysis showed only 1 diastereomer (>95:5 dr). [α]D23 −26.8 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3) δ 7.73-7.66 (m, 4 H), 7.48-7.28 (m, 11H), 5.13-4.96 (m, 2 H), 4.62 (appbd, 1 H, J=8.4 Hz), 3.72 (appbt, 2 H, J=6.4 Hz), 3.21 (m, 1 H), 1.80-1.63 (m, 1 H), 1.60-1.25 (m, 4 H), 1.08 (s, 9 H), 0.92 (appd, 6 H, J=6.3 Hz), 0.79 (m, 1 H), 0.51 (m, 1 H), 0.40 (m, 1 H), 0.30 (m, 1 H); HRMS (ESI) m/z calcd for C34H45NO3SiNa 566.3066, found 566.3103.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]([S:27]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])=[O:28])=[CH:25][CH:26]=1.O.[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]([S:27]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: CC(C)(C)CS(=O)(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)CS(=O)(=O)c1ccc(CNc2c(Cl)ccc3c2CCNCC3)cn1
Yield: 79.9 %

Procedure:
Dissolve 7-chloro-6-{[6-(2,2-dimethylpropane-sulfonyl)-pyridin-3-yl-methyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (142 mg, 0.27 mmol) in methanol (5 mL). Add lithium hydroxide hydrate (23 mg, 0.54 mmol) and stir for 1 h. Mix with silica gel (1 g), concentrate in vacuo, and purify by chromatography on silica gel (12 g) eluting with DCM/(chloroform:methanol:concentrated NH4OH) (1:0 to 9:1 gradient) to give 7-chloro-6-{[6-(2,2-dimethylpropane-sulfonyl)-pyridin-3-yl-methyl]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (91 mg, 78%). MS (APCI) m/z: 422 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:35][C:36](=[O:38])[CH3:37])[CH2:7][NH:8][C:9](=[O:34])[C:10]1[C:15]([I:16])=[C:14]([C:17](=[O:30])[NH:18][CH2:19][CH:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:21][O:22][C:23](=[O:25])[CH3:24])[C:13]([I:31])=[C:12]([NH2:32])[C:11]=1[I:33])(=[O:3])[CH3:2].[C:39](Cl)(Cl)=[O:40].C1(C)C=CC=CC=1>O1CCOCC1>[C:23]([O:22][CH2:21][CH:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][NH:18][C:17](=[O:30])[C:14]1[C:13]([I:31])=[C:12]([N:32]=[C:39]=[O:40])[C:11]([I:33])=[C:10]([C:9](=[O:34])[NH:8][CH2:7][CH:6]([O:35][C:36](=[O:38])[CH3:37])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:15]=1[I:16])(=[O:25])[CH3:24]
Reactant: O=C(Cl)Cl
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(=O)OCC(CNC(=O)c1c(I)c(N=C=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Temperature: 60 °C

Procedure:
To a solution of acetic acid 1-acetoxymethyl-2-[3-amino-5-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-benzoylamino]-ethyl ester (15 g, 17 mmol) in 1,4-dioxane (40 mL) was added a solution of 20% phosgene in toluene (100 mL, 11 eq) at ambient temperature. The mixture was then heated to 60° C. for 15 hours. The reaction mixture was cooled to ambient temperature and then concentrated at reduced pressure to give an off white solid. Dioxane (50 mL×2) was added and removed slowly at reduced pressure to give an off-white solid which was placed on a vacuum line to remove any residual solvent. The material was used without further purification
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9]Br.C(OC)(=O)[CH2:12][C:13]([O:15]C)=[O:14].[H-].[Na+].Cl>>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:12][C:13]([OH:15])=[O:14]
Reactant: Fc1cccc(CBr)c1Br
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: O=C(O)CCc1cccc(F)c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask charged with 2-bromo-1-(bromomethyl)-3-fluorobenzene (2.0 g, 7.5 mmol) and a stir bar was added dimethyl malonate (20.0 mL, 174 mmol). The solution was cooled to 0° C. in an ice bath. To this solution was carefully added sodium hydride (0.597 g, 14.9 mmol) in small portions. When the addition was done, the reaction was kept stirring for another 30 minutes. The reaction was quenched with NH4Cl, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The residue was dissolved in acetic acid (50 mL). To this solution was added HCl (50 ml, 330 mmol), and the reaction was heated to reflux for 16 hours. Analysis by LC showed formation of the desired acid. Most of the solvent was removed on a rotary evaporator. The remaining solution was diluted with 50 mL of water, and extracted with ether (50 mL×3). The extracts were combined, and washed with 1N NaOH (50 mL×2). At that point, all the acid was in the aqueous as the salt. The aqueous washes were combined, acidified, and back extracted with DCM (100 mL×2). The extracts were combined, dried over Na2SO4, and concentrated to afford 3-(2-bromo-3-fluorophenyl)propanoic acid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[NH:5][C:6]([NH:13][CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[C:7]([F:12])[C:8](=[N:10][NH2:11])[N:9]=1.C(NC(C)C)(C)C.[CH:27]1([CH2:32][C@H:33]([CH2:37][N:38]([CH:46]=[O:47])[O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[C:34](O)=[O:35])[CH2:31][CH2:30][CH2:29][CH2:28]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([NH:10][NH:11][C:34](=[O:35])[C@H:33]([CH2:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:37][N:38]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH:46]=[O:47])[C:7]([F:12])=[C:6]([NH:13][CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[N:5]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: NN=c1nc(Cl)[nH]c(NCc2ccsc2)c1F
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2ccsc2)c1F)OC1CCCCO1
Reaction time: 8 h

Procedure:
2-Chloro-5-fluoro-6-[(3-thienylmethyl)amino]-4(1H)-pyrimidinone hydrazone dihydrochloride (1.0828 g) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid diisopropyl amine salt form (1.63 g, 3.8 mmol) were dissolved in DMF (9 mL). NMM (2.1 mL, 19.1 mmol) was added, followed by HOAt (0.512 g, 3.76 mmol) and EDC (0.722 g, 3.77 mmol). After stirring overnight, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(3-thienylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a reddish brown solid (0.7045 g). LCMS: (M+H−THP)+=471.1.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1OC.[Br:20]C1C=CC(CC(O)=O)=CC=1>>[Br:20][C:8]1[CH:7]=[CH:6][C:5]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(CC(=O)c2ccccc2)cc1OC
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: O=C(Cc1ccc(Br)cc1)c1ccccc1

Procedure:
Prepared by the same two step synthesis described in the synthesis of Intermediate 7, starting from 2-(4-bromophenyl)acetic acid.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[NH:7][C:6](=[O:8])[CH:5]1[CH2:9][CH2:10][O:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:2].C([O:27][CH:28](O)[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30])C.C1C=CC=CC=1>O>[CH2:1]([S:3][CH:4]1[N:7]([CH:28]([OH:27])[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C:6](=[O:8])[CH:5]1[CH2:9][CH2:10][O:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])[CH3:2]
Reactant: CCSC1NC(=O)C1CCOC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Solvent: O
Product: CCSC1C(CCOC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
4-Ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-azetidine (9.0 g), p-nitrobenzyl glyoxylate ethyl hemiacetal (8.15 g) and benzene (350 ml) were heated at reflux for 20 hours under a nitrogen atmosphere using a Dean-Stark water separator. The solution was then concentrated in vacuo and the residue was dissolved in 700 ml of dichloromethane. The dichloromethane solution was washed two times with water, dried over anhydrous sodium sulfate and concentrated in vacuo to a yellowish semi-solid (15.0 g) of the title compound. The NMR spectrum in deuterochloroform showed peaks at 1.02-1.52 (c, 8H); 2.6 (m, 2H); 3.3 (m, 1H); 4.1 (b, 1H); 4.78-5.56 (c, 5H); 7.48 (d, 4H); and 8.18 (d, 4H) ppm. The IR spectrum in dichloromethane showed absorptions at 5.62 and 5.7 microns.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C:12](=[O:29])[NH:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=2)=[O:10])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:36]>C(N(CC)CC)C>[C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C:12](=[O:29])[NH:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:16][CH:15]=2)=[O:10])=[CH:5][CH:4]=1)(=[S:36])[NH2:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)nc2)cc1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)nc2)cc1

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (a) (2.29 g), pyridine (105 ml), triethylamine (15 ml) and H2S gas were reacted to give t-butyl 4-[3-(6-thiocarbamoylpyrid-3-ylcarbonyl)ureido]phenoxyacetate (2.76 g) as a yellow solid: m.p. 248°-249° C. (decomposes); NMR Spectrum (DMSO-d6) 1.44 (9H, s), 4.62 (2H, s), 6.90 (2H, d), 7.49 (2H, d), 8.48 (1H, dd), 8.58 (1H, d), 9.10 (1H, d), 10.02 (1H, bs), 10.30 (1H, br s), 10.49 (1H, s), 11.30 (1H, s); Mass Spectrum m/Z 431 (M+H)+.
Reaction SMILES: CN(C)C([O:5][C@H:6]1[CH2:10][N:9]([C:11](OCCCCCCCC)=O)[C@H:8]([CH2:22][CH2:23][O:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:5][C@H:6]1[CH2:10][N:9]([CH3:11])[C@H:8]([CH2:22][CH2:23][O:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:7]1
Reactant: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCOc1c(CCc2ccccc2)cccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CCc2ccccc2)c1OCC[C@@H]1C[C@@H](O)CN1C
Yield: 58.9 %

Procedure:
1500 mg of (2R,4R)-4-dimethylcarbamoyloxy-2-{2-[6-methoxy-2-(2-phenylethyl)phenoxy]ethyl}-1-octyloxycarbonylpyrrolidine [prepared as described in step (a) above], 25 ml of tetrahydrofuran and 300 mg of lithium aluminum hydride were allowed to react together and subsequently treated in the same manner as described in step (b) of Example 1. The concentrated substance thus obtained was purified by silica gel column chromatography, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 552 mg (yield 59%) of the title compound as a colorless solid substance.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH:30][CH3:31]>O1CCOCC1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][N:30]([CH3:31])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4]
Reactant: CNCc1ccc(Cl)cc1Cl
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(CC(=O)c1cccc([N+](=O)[O-])c1)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-(3-nitrophenyl)ethanone (2 g, 8.23 mmol, 1.00 equiv), triethylamine (3.4 g, 4.00 equiv), (2,4-dichlorophenyl)-N-methylmethanamine (1.9 g, 10.05 mmol, 1.20 equiv), 1,4-dioxane (50 mL). The resulting solution was stirred for 2 h at room temperature at which time it was judged to be complete by LCMS. The mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100˜1:50). This resulted in 1.5 g (50%) of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(3-nitrophenyl)ethanone as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])=O>>[CH2:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH2:46][O:39][C:38]1[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[CH:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=3[CH2:17]2)=[CH:3][C:2]=1[F:1])[CH3:41]
Reactant: CCN(CC)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: CCN(CC)CCOc1ccc(CN(c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 31.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N,N-diethylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.9 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[CH:8][C:7]=1[CH2:13][CH3:14]
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CCO[C@@H](Cc1ccc(O)cc1CC)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1CC)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], (2S)-2-ethoxy-3-(2-ethyl-4-hydroxy-phenyl)-propionic acid methyl ester was reacted with 4-chloromethyl-2-(4-chloro-phenyl)-thiazole (example 14 a]) in the presence of cesium carbonate and potassium iodide to yield (2S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-ethyl-phenyl}-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]([CH3:31])([CH3:30])[CH2:7][N:8]1[C:27](=[S:28])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:29])C.O>FC(F)(F)C(O)=O>[CH3:30][C:6]([CH3:31])([CH2:7][N:8]1[C:27](=[S:28])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:29])[CH2:5][C:4]([OH:32])=[O:3]
Reactant: CCOC(=O)CC(C)(C)CN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC(=O)O)CN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Temperature: 90 °C
Yield: 82.9 %

Procedure:
Compound 7 (300 mg, 0.66 mmol) was dissolved in trifluoroacetic acid (TFA, 9 ml). Water (3 ml) was added and the resulting mixture was heated at 90° C. for 16 hours. The reaction mixture was then filtered, washed with ethanol and the solvents were evaporated under reduced pressure to give Compound 8 (234 mg, 83% yield) as an orange solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].Br[C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([Cl:19])[CH:18]=1)[C:15](=[O:20])[N:14]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:23]=1)[CH2:13]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:19][C:17]1[CH:18]=[C:10]([C:3]#[C:2][CH2:1][N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:11]=[C:12]2[C:16]=1[C:15](=[O:20])[N:14]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:23]=1)[CH2:13]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Reactant: C#CCN1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CO
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Product: O=C1c2c(Cl)cc(C#CCN3CCCC3)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A mixture of 1-prop-2-ynyl-pyrrolidine (0.024 mL, 0.22 mmol), 5-bromo-7-chloro-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.086 g, 0.20 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-chloro-2-(4-phenoxy-benzyl)-5-(3-pyrolidin-1-yl-prop-1-ynyl)-2,3-dihydro-isoindol-1-one (0.061 g, 66%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.83 (m, 4H), 2.65 (m, 4H), 3.64 (s, 2H), 4.23 (s, 2H), 4.76 (s, 2H), 6.93-7.38 (m, 10H), 7.43 (s, 1H).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)(=[S:3])[NH2:2].Cl[CH2:17][C:18](=O)[CH3:19].C(N(CC)CC)C.CCOC(C)=O>O1CCOCC1>[CH3:19][C:18]1[N:2]=[C:1]([CH:4]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]2)[S:3][CH:17]=1
Reactant: CC(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)C1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1csc(C2CCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a stirred solution of tert-butyl 3-carbamothioylpyrrolidine-1-carboxylate (100 mg, 0.44 mmol) in dry dioxane (1 mL) was added 1-chloropropan-2-one (80 mg, 0.87 mmol) and triethylamine (132 mg, 1.31 mmol). The mixture was stirred at room temperature for over night and refluxed for overnight. The reaction mixture was added EtOAc (10 mL), washed with water (5 mL×3) and brine (5 mL), dried over Na2SO4, filtered, concentrated and purified by preparative TLC (PE:EA=1:1) to give tert-butyl 3-(4-methylthiazol-2-yl)pyrrolidine-1-carboxylate (90 mg, 75%) as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][CH:9]=[C:8]([C:11](=O)[CH2:12]Br)[CH:7]=1)=[O:5])C.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:8]3[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[O:10][CH:9]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1cc(C(=O)CBr)co1
Product: CCOc1ccc(-c2nc(-c3coc(C(=O)O)c3)cs2)cc1OCC

Procedure:
5-Ethoxycarbonyl-3-(α-bromoacetyl)furan and 3,4-diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(5-carboxy-3-furyl)thiazole.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1C
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccccc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.