Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][C:10]2[N:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:28]([O:31][CH2:32]C)(=[O:30])C>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:32][O:31][C:28]([C:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][C:2]([CH3:20])([CH3:1])[CH2:11][C:10]=2[N:9]=1)=[O:30]
Reactant: CCOC(C)=O
Reactant: CC1(C)CCc2ccc(OS(=O)(=O)C(F)(F)F)nc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(n1)CC(C)(C)CC2
Yield: 86 %

Procedure:
Trifluoro-methanesulfonic acid 7,7-dimethyl-5,6,7,8-tetrahydro-quinolin-2-yl ester (3.1 g, 10.0 mmol) was dissolved in methanol (45 mL) and ethyl acetate (45 mL). PdCl2(dppf)-CH2Cl2 adduct (311 mg, 381 μmol) and triethylamine (1.52 g, 2.1 mL, 15.0 mmol) were added and the mixture was stirred in an autoclave at 110° C. with a CO pressure of 70 bar for 24 h. The solvents were evaporated to give a red-brown oily residue that was purified by gradient chromatography on silica with ethyl acetate in heptane. The chromatography yielded 1.9 g (86%) of the title compound as white solid; LC-MS (UV peak area/EIC) 100%, 220.1335 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15](=O)[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15](=[S:29])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])[CH3:2]
Reactant: CCOC(=O)COc1cc(F)c(C)cc1C(=O)NCc1ccc(Br)cc1F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)COc1cc(F)c(C)cc1C(=S)NCc1ccc(Br)cc1F
Temperature: 115 °C
Yield: 177.9 %

Procedure:
A stirring solution of [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (0.816 g, 1.83 mmol) in pyridine (3.7 mL, 0.5 M) was treated with phosphorus pentasulfide (0.41 g, 0.92 mmol) and heated to 115° C. for 3 h. The reaction was allowed to cool to room temperature, diluted with ethyl acetate and successively washed with 1 M HCl and saturated aq NaCl. The organic layer was dried over Na2SO41 filtered, and concentrated under reduced pressure. The resulting brown oil was dissolved in a minimal amount of methylene chloride and flushed through a plug of silica using 40% ethyl acetate in heptane as the eluant. The filtrate was concentrated to afford [2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (0.75 g, 89%) as a yellow solid: mp 98-100° C.; Rf 0.45 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 mHz) δ 10.15 (bs, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.38 (t, J=8.4 Hz, 1H), 7.26-7.23 (m, 2H), 6.53 (d, J=10.8 Hz, 1H), 5.08 (d, J=5.4 Hz, 2H), 4.67 (s, 3H), 4.20 (q, J=7.2 Hz, 2H), 2.23 (s, 2H), 1.27 (dt, J1=6.8 Hz, J2=0.6 Hz, 3H).
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOC(C)=O>[O:59]1[CH2:60][CH2:61][N:56]([C:11](=[O:12])[CH2:10][C@@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:22])(=[O:24])=[O:23])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:29])[F:30])(=[O:27])=[O:26])[CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:57][CH2:58]1
Reactant: C1COCCN1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)N2CCOCC2)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino) butanoic acid (INTERMEDIATE 8, 1.99 g, 4.01 mmol) and HATU (1.83 g, 4.82 mmol) in DMA (18.0 ml) was treated with morpholine (0.35 ml, 4.02 mmol) and DIPEA (1.40 ml, 8.02 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour and then diluted with EtOAc (250 ml). The organic layer was washed with water (3×250 ml), 1M aq. NaHSO4 (200 ml), and saturated aq. NaHCO3 (200 ml). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to provide a sticky foam. The foam was dissolved in EtOAc (40 ml) and washed with water (2×250 ml). During the second wash material precipitated. EtOAc (80 ml) was added and the resulting mixture was shaken, resulting in redissolution of the precipitate. The mixture was further dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was dissolved in a few ml of DCM resulting in the formation of a precipitate. Finally, evaporation of the volatiles under reduced pressure afforded the title product (2.02 g, yield: 89%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CO.C(Cl)Cl>[CH3:25][N:10]([CH2:9][CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Oc1ccc(C2CCC(NCCOc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CN(CCOc1ccccc1)C1CCC(c2ccc(O)cc2)CC1
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a stirred solution of 4-[4-(2-phenoxyethylamino)cyclohexyl]phenol (0.35 g, 1.13 mmol) in a mixture of MeOH (10 mL), water (1 mL) and CH2Cl2 (5 mL) was added p-formaldehyde (0.17 g, 5.62 mmol). The reaction mixture was stirred for 2 hours, sodium triacetoxyborohydride (0.33 g, 1.58 mmol) was added and stirring was continued overnight. Solid NaOH was added, until the solution turned clear. Silica gel was added, and the solvents were removed under reduced pressure. Purification by flash chromatography (10:1 CH3Cl:MeOH) gave 4-{4-[methyl(2-phenoxyethyl)amino]cyclohexyl}-phenol (264 mg, 72%) as a white solid: mp 216-220° C.; IR (KBr): 3149, 2936, 1599 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.14 (br s, 1H), 7.34 (dd, J=9, 9 Hz, 2H), 7.00 (d, J=9 Hz, 5H), 6.68 (d, J=9 Hz, 2H), 4.42 (br s, 2H), 3.61-3.33 (m, 3H), 2.82 (s, 3H), 2.92 (t, J=5 Hz, 2H), 2.49 (tt, J10, 2 Hz, 1H), 2.19 (dd, J=10, 2 Hz), 1.88 (br d, J=10 Hz, 2H), 1.74 (dddd, J=10, 10, 10, 2 Hz, 2H), 1.47 (dddd, J=10, 10, 10, 2 Hz, 2H); CI-MS (methane) (m/z): 326 [M+H]+; HPLC: method A, 5.64 min (95.3%); method B, 9.63 min (99.2%); Anal. Calcd for C24H33NO.HCl: C, 69.69; H, 7.80; N, 3.87. Found: C, 69.44; H, 7.81; N, 3.80.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]([C:25]([CH3:27])=[O:26])=[CH2:24]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH2:24][CH2:23][C:25](=[O:26])[CH3:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(CNCc2ccc(Cl)cc2Cl)C1
Reactant: C=CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)CCN(Cc1ccc(Cl)cc1Cl)CC1CN(C(=O)OC(C)(C)C)C1
Yield: 81.4 %

Procedure:
To a solution of 3-[(2,4-dichlorobenzylamino)-methyl]-azetidine-1-carboxylic acid tert-butyl ester (200 mg, 0.58 mmol) in CHCl3 (3 mL) is added methyl vinyl ketone (0.12 mL, 1.45 mmol). The reaction is refluxed under N2 overnight and concentrated. The crude product is purified by flash chromatography on silica gel eluting with 5% EtOH (10% NH4OH)/chloroform to yield 196 mg (81%) of 3-{[(2,4-dichlorobenzyl)-(3-oxo-butyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CD3OD) δH: 7.46-7.44 (2H, m), 7.35-7.32 (1H, m), 3.95-3.91 (2H, m), 3.7 (2H, s) 3.5-3.45 (2H, m), 2.9-2.75 (3H, m), 2.74-2.65 (4H, m), 2.1 (3H, s), 1.46 (9H, s). Mass spectrum (ion spray): m/z=415.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[CH:3]=1.CC(O)=[O:27]>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[C:3]2[C:12]3[C:11](=[CH:16][CH:15]=[C:14]([C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[O:18])[CH:13]=3)[NH:10][C:4]=2[C:5]([C:6]([NH2:7])=[O:27])=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(F)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: NC(=O)c1ccc(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Temperature: 160 °C

Procedure:
4-Fluoro-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile (100 mg, 0.246 mmol) was mixed with Pd(OAc)2 (138 mg, 0.615 mmol) in AcOH (7 mL) in a sealed microwave tube. The mixture was heated in microwave at 160° C. for 90 mins. The mixture was filtered and washed with 5 ml AcOH. The filtrate was concentrated and purified using preparative HPLC to give 4-fluoro-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide. MS (ESI) m/z 342.13 (M+H). 1H NMR (DMSO-d6) δ ppm 11.87 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 8.03 (dd, 1H, J=8.3, 5.0), 7.83(d, 1H, J=8.6), 7.53 (m, 2H), 7.08(m, 1H), 3.64-3.57 (bm, 8H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:11])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](=O)[CH:13]([CH3:15])[CH3:14]>>[CH:13]([CH:15]1[NH:10][CH2:9][CH:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:11]1)([CH3:14])[CH3:12]
Reactant: NCC(O)Cc1ccccc1
Reactant: CC(C)C=O
Product: CC(C)C1NCC(Cc2ccccc2)O1

Procedure:
3-Phenyl-2-hydroxypropylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to give 2-isopropyl-5-benzyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give N-isobutyl-3-phenyl-2-hydroxypropylamine. The propanolamine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3-dichlorophenylimino)-3-isobutyl-5-benzyl-1,3-thiazolidine HCl salt.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][C:15]=2[CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.[OH-].[Na+]>O.C(OCC)(=O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:15]([CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[CH:16]=1
Reactant: CC1(C)CC(c2cc(-c3ccccn3)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)CC(c2cc(-c3ccccn3)ccc2N2CCNCC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 90.3 %

Procedure:
A mixture of 4-[4-pyridin-2-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (42 mg, 0.088 mmol) produced in Example (100a), trifluoroacetic acid (0.1 mL, 1.30 mmol) and dichloromethane (1 mL) was stirred for 17 hours and 50 minutes at room temperature. The reaction mixture was cooled in an ice water bath, and then 5N aqueous solution of sodium hydroxide was added to make the mixture basic. Then, ethyl acetate and water were added and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give 30 mg of a crude product of the title compound as a light yellow oil.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O-:13])=O)[C:6]([O:8]CC)=[O:7])C.[CH3:14][S:15]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][NH:24]2)(=[O:17])=[O:16].P(=O)(O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>O.C(O)C>[CH3:14][S:15]([O:18][C:19]1[C:20]2=[C:25]3[N:24]([CH2:23][CH2:22][CH2:21]2)[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11](=[O:13])[C:26]3=[CH:27][CH:28]=1)(=[O:16])=[O:17]
Reactant: CS(=O)(=O)Oc1cccc2c1CCCN2
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Oc1ccc2c(=O)c(C(=O)O)cn3c2c1CCC3
Temperature: 110 °C
Yield: 66.8 %

Procedure:
21.6 g of ethyl ethoxymethylenemalonate was added to 22.4 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline and the mixture was heated at 110° C. on an oil bath for 30 minutes while stirring, during which time distillation of ethanol was observed. After heating, 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide was added to the mixture and the mixture was allowed to react on an oil bath at 140° C. for 45 minutes. After completion of the reaction, the mixture was allowed to cool to room temperature and poured into 400 ml of water, followed by rendering the mixture neutral with a 40% aqueous sodium hydroxide solution to precipitate crystals. The crystals thus-obtained were mixed with 150 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat refluxed for 40 minutes during which time the crystals were dissolved to form a uniform solution. The solution was treated with activated carbon while hot and filtered. The filtrate was allowed to cool and adjusted to a pH of 2 to precipitate crystals which were filtered. Recrystallization of the crude crystals thus-obtained from dimethylformamide gave 21.3 g of 8-methanesulfonyloxy-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 270° to 275° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Br[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)=[O:8]>>[OH:4][CH2:3][CH2:2][S:1][CH2:6][C:7]([C:9]1[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=1)=[O:8]
Reactant: OCCS
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Product: COc1cc(C(=O)CSCCO)cc(OC)c1OC
Yield: 76.9 %

Procedure:
Substantially the same procedure as in Reference Example 13 was repeated using 2-mercaptoethanol (0.82 g) and 2-bromo-3',4',5'-trimethoxyacetophenone (Compound XIa, 2.60 g) obtained in Reference Example 1 to give 2-(2-hydroxyethylthio)-3',4',5'-trimethoxyacetophenone (Compound IX-12, 1.98 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[NH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)Br
Reactant: O=c1[nH]cc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)n1cc(-c2ccc(Cl)cc2)n(C2CC2)c1=O

Procedure:
500 mg (2.13 mmol) of 5-(4-chlorophenyl)-1-cyclopropyl-1,3-dihydro-2H-imidazol-2-one from Example 118A are dissolved in 5 ml acetonitrile and treated with 386 mg (2.13 mmol) of ethyl 2-bromopropionate and 1388 mg (4.26 mmol) of caesium carbonate. The mixture is stirred under reflux overnight. It is then concentrated, the residue is partitioned between dichloromethane and water, the organic phase is separated, and this is dried over sodium sulphate and again concentrated. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 200:1→100:1) and thus yields 338 mg (45% of theory) of the target compound.
Reaction SMILES: [C:1]([C:4]1([NH:9]C(=O)OC(C)(C)C)[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].[ClH:17]>O1CCOCC1>[ClH:17].[NH2:9][C:4]1([C:1]([NH2:2])=[O:3])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1(C(N)=O)CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C1(N)CCCC1

Procedure:
A solution of tert-butyl 1-carbamoylcyclopentylcarbamate (305 mg, 1.33 mmol) in 4N HCl in dioxane (5 mL) and aq. 6N HCl (3 mL) was stirred at room temperature for 3 h. It was then concentrated in vacuo to give 1-aminocyclopentanecarboxamide hydrochloride as a solid (214 mg).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[C:5]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[CH3:24]N(C)CCN(C)C.C([Li])CCC.CCCCCC.CI>C1COCC1>[CH3:16][CH:15]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:13][C:5]1[C:6]2[C:7]([CH3:12])([CH3:11])[CH2:8][O:9][C:10]=2[C:2]([CH3:24])=[CH:3][CH:4]=1)[CH3:17]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)[Si](Oc1ccc(Br)c2c1C(C)(C)CO2)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c2c1OCC2(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
[(7-bromo-3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy][tris(1-methylethyl)]silane (Intermediate 25, 7.1 g, 17.72 mmol) was dissolved in anhydrous THF (72 mL) and cooled to 0° C. Tetramethylethylenediamine (8.0 mL, 53.16 mmol) was added and the yellow solution was stirred at 0° C. for 10 min. A solution of 1.6 M butyllithium in hexane (22.5 mL, 35.4 mmol) was added drop wise over 10 minutes and then stirred at 0° C. for 15 min. Methyl iodide (11 mL, 177.2 mmol) was added drop wise over 6 min. The white solid was removed by filtration and the wet cake was washed in with THF. The combined organic layers were evaporated to dryness. The residue was dissolved in ethyl acetate and washed twice with aqueous NaHCO3 and once with water. The organic solution was dried on anhydrous Na2SO4 and evaporated to dryness, to give brown oil. The residue was purified by flash chromatography on silica gel using cyclohexane to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound (3.6 q) as a brown oil.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][NH:7][C:8](=[O:51])[CH2:9][CH2:10][NH:11][C:12](=[O:50])[C@H:13]([OH:49])[C:14]([CH3:48])([CH3:47])[CH2:15][O:16][P:17]([OH:46])(=[O:45])[O:18][P:19]([OH:44])(=[O:43])[O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[C:36]3[N:35]=[CH:34][N:33]=[C:31]([NH2:32])[C:30]=3[N:29]=[CH:28]2)[C@H:24]([OH:37])[C@@H:23]1[O:38][P:39]([OH:42])([OH:41])=[O:40])(=[O:3])[CH3:2].[C:52]([O-])(=O)C>>[C:1]([S:4][CH2:5][CH2:6][NH:7][C:8](=[O:51])[CH2:9][CH2:10][NH:11][C:12](=[O:50])[C@H:13]([OH:49])[C:14]([CH3:47])([CH3:48])[CH2:15][O:16][P:17]([OH:46])(=[O:45])[O:18][P:19]([OH:44])(=[O:43])[O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[C:36]3[N:35]=[CH:34][N:33]=[C:31]([NH2:32])[C:30]=3[N:29]=[CH:28]2)[C@H:24]([OH:37])[C@@H:23]1[O:38][P:39]([OH:42])([OH:41])=[O:40])(=[O:3])[CH:2]=[CH2:52]
Reactant: CC(=O)[O-]
Reactant: CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Product: C=CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Reaction time: 0 h

Procedure:
S-acetyl CoA synthetase (acetate thiokinase from bakers yeast, Sigma, Saint Louis, Mo., USA; catalogue No. 1765) (1.9 mg/ml) is added. Using the fed-batch approach meaning step-wise addition (feeding) of H-CoA, 15 μl aliquots of H-CoA are added after 5, 10, 15 and 20 minutes, raising the H-CoA concentration by 1 mM each time, and a further 5 mM ATP is added after 25 minutes. Samples are analysed for H-CoA by HPLC (Instrumentation: Agilent Technologies HP1090L with HP1100 Variable Wavelength UV Detector and Chemstation (rev. A.06.01) Data System; column: Luna C18 from Phenomenex, 25 cm×4.6 mm inner diameter, bead diameter 5 μm (No. 92); mobile phase: A: 25 mM ammonium formate (pH 7.0), B: methanol; gradient 5% B for 0 min, then to 30% B in 20 min; flow 1 ml/min (approximately 130 bar), oven temperature 40° C., Detector: UV at 210 nm; injection volume 5 μl, Run time 28 min; peaks are found at the following retention times: ATP approximately 3.710 min, Coenzyme A at approximately 10.554 min, acetyl CoA at approximately 14.457 min, acrylyl CoA at approximately 17.500 min, bisadduct at approximately 15.993 min). When no H-CoA is detected, further 15 μl aliquots of H-CoA are added after 80, 95, 110 and 120 minutes, again raising the H-CoA concentration by 1 mM each time. Further 15 μl aliquots of H-CoA are added after 145 and 155 minutes and sufficient ATP to raise the concentration by 5 mM is added after 150 minutes.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[O:6]=[C:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1>C1COCC1>[OH:6][C:7]1([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:8][CH2:9][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: c1cscn1
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(O)(c2nccs2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 62.6 %

Procedure:
Isopropylmagnesium chloride/lithium chloride complex (1.3 M, 119 mL, 154 mmol) was added to a flask and cooled to 0° C. and then diluted with 50 mL THF. Thiazole (13.0 g, 154 mmol) was added over 30 minutes making sure the temperature did not exceed 5° C. The orange slurry was stirred for 45 minutes and then cooled to −20° C. and ethyl 4-oxocyclohexane-carboxylate (25.0 g, 147 mmol) in THF (25 mL) was added and then stirred for 50 minutes. The solution was cooled to 5° C. and then quenched with HCl (2 M, 100 mL) and extracted with EtOAc (250 mL). The organic layer was washed with aqueous saturated NaHCO3 solution (100 mL), brine (100 mL), evaporated and purified by flash chromatography on silica gel to afford ethyl 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanecarboylate as an oil (23.6 g, 92 mmol).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][N:7]=1)=[O:2].[CH2:8](O)[CH2:9][CH2:10][OH:11].CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:2]1[CH2:8][CH2:9][CH2:10][O:11][CH:1]1[C:3]1[S:4][CH:5]=[CH:6][N:7]=1
Reactant: O=Cc1nccs1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: c1csc(C2OCCCO2)n1
Temperature: 25 °C

Procedure:
A solution of 2-formylthiazole (10 g, 88 mmol), 1,3-propanediol (8 mL) and p-TsOH (100 mg) in benzene (110 mL) was heated at reflux temperature for 15 h with removal of water using a Dean-Stark apparatus. The mixture was cooled to room temperature and washed twice with sat. aq. NaHCO3, twice with water and concentrated. The resulting solid was crystallized from hexane to provide 2-(1,3-Dioxan-2-yl)thiazole as a tan solid (10.4 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:53]3[CH2:54][CH2:55][CH:50]([CH3:49])[CH2:51][CH2:52]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1CCNCC1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-methyl piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethyl-formamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.