Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[NH2:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([Cl:17])[CH:3]=2)=[CH:21][N:20]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: Nc1ncc(B(O)O)cn1
Product: Cc1c2n(c3c(-c4cnc(N)nc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (59 mg, 72%), MS (ISP) m/z=328.5 [(M+H)+], mp 316° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 2-aminopyrimidin-5-ylboronic acid (45.1 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10].N1C=CC=CC=1.[CH3:17][C:18](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](Cl)=[O:20]>CC(C)=O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:10])=[C:2]([NH:1][C:19](=[O:20])[C:18]([CH3:17])=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=1
Reactant: CC(=Cc1ccccc1)C(=O)Cl
Reactant: COc1ccc(C)c(N)c1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COc1ccc(C)c(NC(=O)C(C)=Cc2ccccc2)c1
Yield: 84.3 %

Procedure:
2-Amino-4-methoxytoluene (13.2 g, 89.7 mmol) and pyridine (10 ml) were dissolved in acetone (112 ml), to which α-methylcinnamoylchloride (19.4 g, 107.6 mmol) was added while cooling and stirring. The mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was dissolved in chloroform, washed with water, dried, and condensed. The residue was purified by alumina chromatography (chloroform), and subjected to recrystallization with chloroform--n-hexane to obtain 21.27 g of the title compound as colorless crystals (84.4%).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[N:6][NH:5][C:4](=[O:15])[CH2:3]1.[CH3:16][N:17]=[C:18]=[O:19]>CS(C)=O>[CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:18]([NH:17][CH3:16])=[O:19])=[N:12][CH:13]=2)=[N:6][NH:5][C:4](=[O:15])[CH2:3]1
Reactant: CN=C=O
Reactant: CC1CC(=O)NN=C1c1ccc(N)nc1
Solvent: CS(C)=O
Product: CNC(=O)Nc1ccc(C2=NNC(=O)CC2C)cn1
Yield: 48 %

Procedure:
A mixture of 0.4 g. (2 mmole) 4,5-dihydro-5-methyl-6-(2-amino-5-pyridyl)-3(2H)-pyridazinone, 10 ml. dimethyl sulphoxide and 0.24 ml. (4 mmole) methyl isocyanate was stirred for 16 hours at ambient temperature, evaporated in a vacuum and the residue triturated with water. There were obtained 0.25 g. of the title compound (48% of theory); m.p. 257°-259° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[CH:18]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[C:24]([NH:23][C:19]1[CH:18]=[C:17]([O:16][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:30][CH:29]=2)[CH:22]=[CH:21][N:20]=1)(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(=O)Nc1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cc(Oc2ccc(NC(=O)Oc3ccccc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenyl chloroformate (0.14 ml) was added dropwise to an ice-cooled stirred solution of 4-(4-aminophenoxy)-2-(butyrylamino)pyridine (0.3 g), triethylamine (0.14 ml) and tetrahydrofuran (10 ml). The cooling bath was removed and the mixture was stirred at room temperature overnight. Silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with silica gel, and column purification was performed (hexane:ethyl acetate=2:1, followed by 1:1). The solvent was distilled off under reduced pressure to obtain the target substance as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[H-].[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2[C:29]([CH2:34]Cl)=[C:30]([Cl:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[I-].[Na+]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2[C:29]([CH2:34][S:12][C:9]3[CH:8]=[CH:7][C:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])=[CH:11][CH:10]=3)=[C:30]([Cl:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: CCC(C)(C)c1ccc(S)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)(C)c1ccc(SCc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
Dissolve 4-(1,1-dimethyl-propyl)-benzenethiol (100 mg, 0.55 mmol) in anhydrous DMF (2 mL). Add sodium hydride (32 mg, 0.78 mmol, 60% dispersion in mineral oil) at room temperature under a nitrogen atmosphere. Stir the mixture for 5 min, then add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (214 mg, 0.55 mmol) in anhydrous DMF (2 mL). Heat the mixture to 45° C., add catalytic sodium iodide and stir the mixture at 45° C. for 6 h. Cool the reaction mixture to room temperature and quench with water. Extract the mixture with EtOAc (4×25 mL). Wash the combined organic extracts with brine. Dry the organic layer over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (20:1 to 17:3 gradient) to obtain 3-tert-butoxycarbonyl-7-chloro-6-[4-(1,1-dimethyl-propyl)-phenylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (105 mg, 40%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[C:6]([O:4][CH2:3][CH2:2][CH2:1][OH:5])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCO
Solvent: c1ccncc1
Product: OCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
To a solution of 76 g of 1,3-propanediol in 0.5 1 of pyridine, cooled to 0° C., were added 278 g of trityl chloride. The mixture was stirred at room temperature for 18 hours, and then the solvent was evaporated in vacuo. The residue was taken up in 600 ml of ethyl acetate. Unsoluble material was filtered off, and the filtrate was washed with 100 ml portions of 3N hydrochloric acid, water, 5% sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. Crystallization of the residual material from 0.5 1 of ethyl acetate afforded 167.3 g of 3-trityloxy-1-propanol as white crystals of m.p. 117°-118° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:13]CC2C=CC=CC=2)=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]=2[CH:12]=1.[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH:21]1([O:1][C:2]2[C:3]([OH:13])=[CH:4][C:5]3[O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]=3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=c1ccc2cc(O)c(OCc3ccccc3)cc2o1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OC3CCCC3)c(O)cc2o1
Reaction time: 3 h

Procedure:
50.0 g (186 mmol) of 6-hydroxy-7-phenylmethoxy-2H-1-benzopyran-2-one, 41.7 g (280 mmol) of cyclopentylbromide, 51.4 g (372 mmol) of potassium carbonate and 5.0 g of potassium iodide are agitated in 500 ml DMF for 18 h at 80° C. This is followed by filtration, evaporation, dissolution in chloroform, washing with water, drying over sodium sulfate and renewed evaporation: yield: 60.0 g (96%) of 6-(cyclopentyloxy)-7-(phenylmethoxy)-2H-1-benzopyran-2-one, fusion point 140°-141° C. (from isopropanol). Of this 15.0 g (45 mmol) in 200 ml ethanol are hydrogenated in the presence of 2.0 g Pd on active carbon (5%) for 3 h at 25° C. and 7 bar hydrogen pressure. After filtration the solvent is removed: yield 9.0 g (82%), fusion point 154°-155° C. (from isopropanol and TBME).
Reaction SMILES: C(O)(=O)C.[BH4-].[Na+].[C:7]1([C@@H:13]([NH:15][C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C>[C:7]1([C@@H:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1N[C@@H](C)c1ccccc1
Temperature: 23 °C
Yield: 90 %

Procedure:
Acetic acid (1.0 L) was added to a reactor followed by sodium borohydride (100 g) with cooling between 16-30° C. under nitrogen in NLT 1 hour and mixed for NLT 30 minutes. Acetonitrile (500 mL) was added and mixed for NLT 30 minutes, and the cooled to below 5° C. A solution of (S)-ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8, 269 g) dissolved in acetonitrile (250 mL) was added in NLT 30 minutes, while maintaining the temperature between 2-8° C. and then the reaction mixture was warmed to 22° C., and mixed for NLT 4 hours. The mixture was cooled below 5° C. and quenched with 1.77 L of 25% aqueous sodium hydroxide solution, water (1.3 L) and heptanes (0.75 L) and the pH was adjusted pH to ˜8.0. The organic layer was separated and the aqueous layer was extracted with heptanes (2×0.75 L), and then the combined heptane layers were washed with water (2×0.75 L) and 3.5 M aqueous sodium chloride solution (0.75 L). The heptane solution was then dried using anhydrous magnesium sulfate and concentrated under vacuum to afford 243.9 g of (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9) as the major isomer.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[C:27]([Cl:38])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[Cl:38][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([F:31])[C:28]=1[O:32][CH2:33][C:34]([F:35])([F:36])[F:37]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCC(F)(F)F)c(Cl)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCC(F)(F)F)c(Cl)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (33 mg, 0.184 mmol) with 2-bromo-N-{4-[3-chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}acetamide (70 mg, 0.156 mmol) in the presence of NaH (11 mg, 0.458 mmol) in dry DMF (5.0 mL) to give 11 mg of the product as an off-white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 3.17 (s, 3H), 3.39 (s, 3H), 4.84 (q, J=8.7 Hz, 2H), 5.32 (s, 2H), 6.23 (s, 1H), 7.35 (s, 1H), 7.82-7.91 (m, 3H), 12.71 (br s, 1H); APCI-MS (m/z) 546.03 (M+H)+.
Reaction SMILES: P(Cl)(Cl)[Cl:2].[C:5]1([O:11][P:12](OC2C=CC=CC=2)[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C)P(=O)(N(C)C)N(C)C>[C:5]1([O:11][P:12]([Cl:2])[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: ClP(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: ClP(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Yield: 181.4 %

Procedure:
32.5 g (0.24 mole) of phosphorus trichloride is added dropwise, with stirring, to a mixture, cooled to 0° to 5° C, of 155.2 g (0.5 mole) of triphenylphosphite and 10.0 g of hexamethylphosphoric acid triamide. The reaction mixture is subsequently heated to room temperature and stirred at this temperature for a further 4 hours. On vacuum distillation of the reaction mixture there is obtained 110 g (61.1% of theory relative to phosphorus trichloride) of diphenylchlorophosphite, b.p. 170°-172° C/11 Torr.
Reaction SMILES: Cl[C:2]1[N:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=1)[N:7]=3.Cl.[F:27][C:28]1([F:32])[CH2:31][NH:30][CH2:29]1>>[F:27][C:28]1([F:32])[CH2:31][N:30]([C:2]2[N:25]=[CH:24][C:5]3[C:6]4[N:10]([CH:9]=[C:8]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=5)[N:7]=4)[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH2:29]1
Reactant: FC1(F)CNC1
Reactant: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Agent: Cl
Product: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1cnc(N3CC(F)(F)C3)cc1OCC2

Procedure:
[5-(8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanol was reacted with 3,3-difluoroazetidine-HCl to give 417 (23 mg) as a colorless solid. LCMS: 418.1. 1H NMR (400 MHz, DMSO) δ 9.14 (s, 1H), 7.85 (s, 1H), 6.16 (s, 1H), 5.87 (dt, J=13.2, 6.6 Hz, 1H), 5.18 (t, J=6.0 Hz, 1H), 4.60-4.47 (m, 4H), 4.41 (overlapping m, 6H), 1.47 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH:23][OH:24])[CH2:20][CH2:21][CH3:22]>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:23]([CH2:19][CH2:20][CH2:21][CH3:22])[O-:24])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCNO
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Product: CCCC[N+]([O-])=Cc1ccc(OCc2ccccc2)c(OC)c1

Procedure:
The title compound was prepared according to the procedures described in Examples 11 using 4-benzyloxy-3-methoxybenzaldehyde and N-n-butylhydroxylamine. The title compound was isolated in 41.7% yield as a solid, m.p. 81.2° C.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4][C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)[CH:9]=1.O1CCCC1>[Fe].C(O)(=O)C>[CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4][C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])[CH:9]=1
Reactant: CC(C)(C)C#Cc1cnn(-c2ccccc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)C#Cc1cnn(-c2ccccc2N)c1
Temperature: 80 °C

Procedure:
A mixture of 4-(3,3-dimethyl-but-1-ynyl)-1-(2-nitro-phenyl)-1H-pyrazole (20 g, 74 mmol), tetrahydrofurane (100 ml) and acetic acid (425 ml of a 5% aqueous solution) was heated to 80° C. Iron powder (66 g, 1.2 mol) was added in small portions at this temperature. The reaction mixture was heated for 5 hours to reflux. After cooling, it was poured onto ice and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated, delivering Compound No. 5.030.r (20 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[S:15][C:14]([S:16]([NH:9][C:3]2[C:2]([Br:1])=[N:7][CH:6]=[C:5]([Cl:8])[N:4]=2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: Nc1nc(Cl)cnc1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Product: O=S(=O)(Nc1nc(Cl)cnc1Br)c1ccc(Cl)s1

Procedure:
Prepared by the method of Example 1 using 3-bromo-6-chloro-2-pyrazinamine and 5-chloro-2-thienylsulphonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(CC(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
750 mg of ethyl 2-[4-[(3S)-1-(t-butoxycarbonyl)-3-pyrrolidyloxy]phenyl]acetate was dissolved in 10 ml of ethanol. 4 ml of 1 N aqueous sodium hydroxide solution was added to the obtained solution. After stirring at room temperature overnight, the solvent was evaporated. 1 N hydrochloric acid was added to the residue. After the same isolation process as that of step 1 in Example 1 with ethyl acetate as the extractant, the title compound was obtained.
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)[CH:3]([NH:6][C:7]([O:9]CC)=[O:8])CO.[K].C([O-])(=[O:25])CCC>C1(C)C=CC=CC=1>[CH3:19][S:18][C:15]1[CH:14]=[CH:13][C:12]([CH:2]2[O:9][C:7](=[O:8])[NH:6][CH:3]2[OH:25])=[CH:17][CH:16]=1
Reactant: CCCC(=O)[O-]
Reactant: CCOC(=O)NC(CO)C(O)c1ccc(SC)cc1
Agent: [K]
Solvent: Cc1ccccc1
Product: CSc1ccc(C2OC(=O)NC2O)cc1

Procedure:
Compound (F) (5 g; 17.5 mmols) has been dissolved in warm toluene (25 ml). To this solution, an equimolar amount of potassium ter.butyrate has been added and the reaction mixture has been refluxed for 3 hours. Afterwards, almost all the solvent has been evaporated; water and ice have been added to the residue and the precipitate has been collected by filtration. The thus obtained crude (G) has been recrystallized from ethanol (3.7 g; yield, 88%); m.p. 130°-131° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])cc1
Yield: 57 %

Procedure:
A mixture of 4-nitrophenol (3.5 g, 25 mmol), 2-(dimethylamino)ethyl chloride hydrochloride (3.6 g, 25 mmol), and potassium carbonate (13.2 g, 125 mmol) in acetone (100 mL) was heated to reflux for 30 hours. The solvent was removed under vacuum. The residue was partitioned between water (150 mL) and ethyl acetate (150 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (3×150 mL) and extracted with dilute aqueous HCl (2×125 mL). These extracts were washed with CH2Cl2 (2×150 mL), made basic (NaOH) and extracted into ethyl acetate (3×75 mL). These organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 3.0 g as a pale yellow solid, in 57% yield; 1H NMR (CDCl3) δ 2.35 (s, 6H), 2.76 (t, J=5.6 Hz, 2H), 4.15 (t, J=5.6 Hz, 2H), 6.96-7.00 (m, 2H), 8.17-8.22 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][NH:10][S:9]2(=[O:15])=[O:14])=[CH:5][CH:4]=1.[I:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[I:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:10]1[S:9](=[O:15])(=[O:14])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=2)[C:12](=[O:13])[CH2:11]1
Reactant: OCc1cccc(I)c1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3cccc(I)c3)S2(=O)=O)cc1
Temperature: 25 °C

Procedure:
A solution of the title B compound, 2-(4-methoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (1.02 g, 3.98 mmol), 3-iodo-benzyl alcohol (1.01 mL, 7.95 mmol) and triphenylphosphine (2.10 g, 8.0 mmol) in THF (50 mL) is cooled to 5° C. and treated with a solution of diethyl azodicarboxylate (1.26 mL, 8.0 mmol) in THF (10 mL). The reaction is allowed to warm to RT over 16 h. The reaction mixture is concentrated to yield a yellow oil. This is chromatographed on a 110 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH2Cl2) to 5:95 over 25 min. Fractions containing product are combined and concentrated to yield an oil, which spontaneously crystalizes. Trituration with Et2O yields 5-(3-iodo-benzyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid: mp=98-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.BrCCCN1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2C1=O>>[CH2:31]([O:32][C:16]([NH:15][CH2:14][CH2:10][CH2:9][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:17])[C:30]1[CH:29]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2cccc(O)c2)c1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2cccc(OCCCNC(=O)OCc3ccccc3)c2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 31 using tert-butyl N-(3′-hydroxybiphenyl-3-ylmethyl)carbamate instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate and N-(3-bromopropyl)phthalimide instead of N-(4-bromobutyl)phthalimide.
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]([CH3:25])=[CH:9][C:10]([NH:16][C:17](=[O:24])[CH2:18][C:19]([O:21]CC)=[O:20])=[C:11]3[C:15]=2[CH2:14][CH2:13][CH2:12]3)=[CH:4][C:3]=1[CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[OH-].[Na+]>CO>[OH:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]([CH3:25])=[CH:9][C:10]([NH:16][C:17](=[O:24])[CH2:18][C:19]([OH:21])=[O:20])=[C:11]3[C:15]=2[CH2:14][CH2:13][CH2:12]3)=[CH:4][C:3]=1[CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(CC3CCOCC3)c2)c2c1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(NC(=O)CC(=O)O)c2c(c1Oc1ccc(O)c(CC3CCOCC3)c1)CCC2
Yield: 95.7 %

Procedure:
To ethyl N-{7-[4-hydroxy-3-(tetrahydropyran-4-ylmethyl)phenoxy]-6-methylindan-4-yl}malonamate (50 mg) were added methanol (10 mL) and a 1 mol/L aqueous solution of sodium hydroxide (8 mL), and the mixture was stirred under an argon atmosphere at 50° C. for 30 min. Adding water (20 mL), the reaction mixture was washed with diethyl ether (10 mL) twice. Adding 1 mol/L hydrochloric acid (20 mL) and brine (10 mL), the aqueous layer was extracted with ethyl acetate (10 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to dryness to give the title compound (45 mg).
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[NH:8][Si](C)(C)C.[C:15]([C:17]1[CH:37]=[CH:36][C:20]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1)#[N:16].Cl>C1COCC1>[C:15]([C:17]1[CH:37]=[CH:36][C:20]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:28]2)=[O:22])=[CH:19][CH:18]=1)(=[NH:8])[NH2:16]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC(=O)CCN1CCN(C(=O)c2ccc(C#N)cc2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CCN1CCN(C(=O)c2ccc(C(=N)N)cc2)CC1

Procedure:
A solution of Li--N(Si(CH3)3)2 in 20 ml of THF, freshly prepared from C4H9Li and 1.13 g of hexamethyldisilazane, is added dropwise at -78°, with stirring, to a solution of 3.15 g of ethyl 3-(4-(4-cyanobenzoyl)piperazin-1-yl)propionate (FAB 316; obtainable by reacting 4-cyanobenzoyl chloride with ethyl piperazin-1-ylpropionate) in 50 ml of THF. The mixture is left to warm up to 20°, with stirring, aqueous hydrochloric acid is added, the mixture is washed with ethyl acetate, sodium hydroxide solution is added to pH 7.5 and the mixture is worked up in conventional manner and evaporated to give ethyl 3-(4-(4-amidinobenzoyl)piperazin-1-yl)propionate, FAB 333.