Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:4]=1[O:5][CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:2].[BH4-].[Na+].Cl>O1CCCC1.O.O>[OH:2][CH2:1][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:4]=1[O:5][CH:6]([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C)Oc1c(C=O)cccc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)Oc1c(CO)cccc1OC
Reaction time: 2 h
Yield: 70.6 %

Procedure:
A solution ethyl 2-(2-formyl-6-methoxyphenoxy)propionate (2.60 g) in tetrahydrofuran-water (9:1) was ice-cooled and sodium borohydride (185 mg) was added. The mixture was stirred at the same temperature for two hours. Diluted hydrochloric acid (1N, 5 ml) was added to the solution and the mixture was stirred for an hour. The mixture was diluted with water and was extracted with ethyl acetate. The organic layer was separated and washed with brine and dried over magnesium sulfate. After concentration, the crude product was purified on a column of silica gel (29 g) eluting with a mixed solvent of toluene and ethyl acetate (7:1) to give ethyl 2-(2-hydroxymethyl-6-methoxyphenoxy)propionate (1.85 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([I:15])=[N:6]1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CN(C)C=O>[I:15][C:7]1[C:8]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:14])[N:5]([CH2:4][CH2:3][CH2:2][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:6]=1
Reactant: Nc1ncnc2c1c(I)nn2CCCBr
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2CCCN1CCOCC1
Temperature: 70 °C
Reaction time: 66.25 h
Yield: 48 %

Procedure:
A suspension of 1-(3-bromopropyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 1.31 mmol) in dimethylformamide (10 mL) was treated with morpholine (0.137 g, 1.572 mmol) and triethylamine (0.133 g, 1.31 mmol). The reaction mixture was stirred at 70° C. for 66.25 h. Solvent was removed under reduced pressure. Dichloromethane (15 mL) and 1 N hydrochloric acid (20 mL) were added. The layers were partitioned and the aqueous layer was washed with dichloromethane (100 mL). The aqueous layer was neutralized to pH 14 and then extracted with dichloromethane (250 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient of 10% methanol in dichloromethane to 50% methanol in dichloromethane over 58 minutes on a 35 g ISCO column. The column afforded 0.244 g (48%) of pure 3-iodo-1-(3-morpholinopropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.194 (s, 1H), 4.327-4.293 (t, 2H), 3.485-3.364 (m, 4H), 2.253-2.238 (m, 6H), 1.963-1.895(m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) R, 0.71 min (100%), MH+ 389.0.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][CH2:24][CH2:25][OH:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].Cl>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][CH2:24][CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(COCCO)ccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Chloro-5-[(2-hydroxyethoxy)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.228 g, Example 25a) and triethylamine (0.21 ml) in dichloromethane (10 ml) were cooled to 5° C. under nitrogen and methanesulfonyl chloride (0.1 ml) was added. The mixture was stirred at room temperature for 20 h then poured into 2 N hydrochloric acid, and extracted into ethyl acetate. The combined extracts were washed with 2 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution then brine, and dried over magnesium sulfate. The organics were filtered and concentrated under reduced pressure to afford the subtitled compound as a white solid (0.160 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH:38]([NH2:41])([CH3:40])[CH3:39]>>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][CH:38]([CH3:40])[CH3:39])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: CC(C)N
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Product: CC(C)Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.20 g, 0.35 mmol) and isopropylamine (2 mL) the title compound was obtained as a yellow solid (0.15 g, 0.25 mmol, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 14.28 (br. s., 1H), 8.35 (d, J=7.2 Hz, 1H), 7.84 (s, 1H) 7.67-7.51 (m, 2H), 7.47 (d, J=6.8 Hz, 1H), 7.33-7.07 (m, 3H), 5.90 (d, J=6.6 Hz, 1H), 4.08 (dq, J=13.3, 6.7 Hz, 1H), 3.88-3.73 (m, 4H), 3.71-3.52 (m, 4H), 1.27 (d, J=6.4 Hz, 6H). MS (ESI): 591 [M+H]+.
Reaction SMILES: [CH3:1][SiH:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:13][CH:14]([CH2:17][CH3:18])[CH2:15][OH:16].Cl>N1C=CC=CC=1>[CH3:1][SiH:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:16][CH2:15][CH:14]([CH3:13])[CH2:17][CH3:18])=[O:8])=[CH:5][CH:4]=1
Reactant: C[SiH](C)c1ccc(C(=O)Cl)cc1
Reactant: CCC(C)CO
Agent: Cl
Solvent: c1ccncc1
Product: CCC(C)COC(=O)c1ccc([SiH](C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20.0 g (0.101 mol) of 4-dimethylsilylbenzoyl chloride were added dropwise at 10° C.-15° C. to a solution of 8.90 g (0.101 mol) of 2-methylbutan-1-ol in 20 ml of dry pyridine. The reaction solution was stirred for one hour at 25° C., poured onto ice and acidified using HCl. The organic phase was separated off, diluted with toluene and washed by shaking three times with 10% HCl. It was washed with water and dried over sodium sulfate. After the toluene had been stripped off in vacuo on a rotary evaporator, distillation gave 2-methylbutyl 4-dimethylsilylbenzoate; boiling point 86° C.-110° C./0.05 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[Cl-].[OH:12][NH3+:13].C(=O)(O)[O-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[N:13][OH:12])[NH2:6])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (7.2 mmol) of 3,4-difluorobenzonitrile was initially charged in 30 ml of ethanol, and a solution of 0.5 g (7.2 mmol) of hydroxylammonium chloride and 0.6 g (7.2 mmol) of sodium bicarbonate in 11 ml of water was added at RT. The reaction mixture was stirred at RT for 16 h, concentrated under reduced pressure and reacted without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([CH:29]1[CH2:34][CH2:33][CH:32](OS(C)(=O)=O)[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26]>CC(O)(C)C.CC(=O)CC>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:32]3[CH2:33][CH2:34][CH:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:30][CH2:31]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCc2cc(OC3CCC(C(C)(C)C)CC3)ccc2C1
Temperature: 100 °C
Yield: 58.6 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.1 g, 4.4 mmol), cesium carbonate (4.3 g, 13 mmol), and methanesulfonic acid 4-tert-butyl-cyclohexyl ester (2.2 g, 8.8 mmol) in t-BuOH (12 mL) and 2-butanone (6.0 mL) was heated in a sealed vial at 100° C. overnight. The mixture was partitioned between water and ether. The organic phase was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified via a silica gel column eluted with EtOAc in hexanes from 0 to 30% to give white precipitate (1.0 g, yield: 58%). 1H NMR (400 MHz, CDCl3) δ 6.99 (d, 1H), 6.74 (dd, 1H), 6.67 (d, 1H), 4.49 (s, 2H), 4.07 (m, 1H), 3.61 (s, 2H), 2.78 (m, 2H), 2.18 (d, 2H), 1.85 (d, 2H), 1.48 (s, 9H), 1.37 (m, 2H), 1.18-1.00 (m, 3H), 0.87 (s, 9H).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH:11][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:7][CH:6]=1)(=[O:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)c1ccc(CCN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(CCNS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension under argon of 4-acetylphenethylamine hydrochloride (1 g) in dichloromethane (20 ml) was added triethylamine (0.94 ml) and stirring continued for 15 minutes. The mixture was cooled to 4° C., then 4-methylphenylsulphonyl chloride (1.29 g) in dichloromethane (5 ml) added dropwise over 30 minutes. The reaction mixture was stirred for 18 hours at ambient temperatuLe, then diluted with further dichloromethanie (50 ml), washed with water, dried (MgSO4) and evaporated. Trituration of the residue gave N-(2-[4-acetylphenyl]ethyl)-4-methylphenylsulphonamide, 1.58 g, as a yellow crystalline solid: m.p. 124°-126° C.; NMR (d6 DMSO) δ 7.84(2H,d), 7.63(3H,m), 7.37(2H,d), 7.29(2H,d), 2.98(2H,q), 2.75(2H,t), 2.55(3H,s), 2.39(3H,s); m/e 318(M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.Cl.[CH3:16][O:17][C:18](=[O:30])[C@@H:19]([NH2:29])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH3:16][O:17][C:18](=[O:30])[C@@H:19]([NH:29][C:12]([C:4]1[CH:3]=[C:2]([OH:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:14])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23]
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5 g 4-Hydroxy-quinoline-2-carboxylic acid and 5 g of (S)-2-Amino-pentanedioic acid 5-tert-butyl ester 1-methyl ester hydrochloride in 50 ml of DMF, 4.0 g of HOBT, 5.1 g of EDC and 6 g of NEM was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by re-crystallisation from ethyl acetate and dried under reduced pressure. Yield: 6.5 g.
Reaction SMILES: O.C(O)(C(F)(F)F)=O.[Cl:9][C:10]1[CH:11]=[C:12]([NH:25][C:26](=[O:40])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=2[Cl:39])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18](OCC)[O:19]CC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]([NH:25][C:26](=[O:40])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][C:30]=2[Cl:39])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]=[O:19]
Reactant: CCOC(COc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 0 °C
Reaction time: 48 h

Procedure:
40 mL water and 130 mL TFA was added to a solution of 11.40 g (0.023 mol) of N-[3-chloro-4-(2,2-diethoxy-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide in 130 mL chloroform at 0° C. and the mixture was stirred for 3.5 hours at 0° C. and for 48 hours at RT. The reaction mixture was neutralised with sat. aqueous sodium carbonate solution and exhaustively extracted with dichloromethane. The combined org. extracts were washed with water, dried over magnesium sulphate and evaporated down i. vac.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[N:25]1([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Fc1ccc2nnc(N3CCCC3)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC4)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
Intermediate A (222 mg, 1.36 mmol) was added to a mixture of NaH (60% in mineral oil, 163 mg, 4.08 mmol) in DMF (15 mL) at RT and stirred for 30 min. Intermediate 75a (280 mg, 1.36 mmol) was then added and the resulting mixture heated to 60° C. for 1 h. After cooling, the reaction was quenched with sat. aq. NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 solution and brine, and concentrated in vacuo. The resulting residue was purified by FCC, using 0 to 15% [2M NH3 in MeOH] in DCM, to afford the title compound as a brown solid (65.0 mg, 14%). LCMS (Method 3): Rt 1.89 min, m/z 350 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[Sn](Cl)Cl.O>C(O)C>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:19]([F:21])([F:20])[F:22])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1ccc(N)c(C(F)(F)F)c1
Yield: 89.2 %

Procedure:
A suspension of 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl ester (38.3 g, 115 mmol), tin (II) chloride (87.2 g, 460 mmol) and water (16.6 g, 920 mmol) in ethanol (500 mL) was heated at reflux for four hours. The reaction mixture was concentrated under reduced pressure; the residue was treated with ethyl acetate (300 mL) and aqueous NaOH solution (1 N, 2.5 L). The aqueous layer was extracted with ethyl acetate (3×600 mL). The combined organic layers were washed with brine (1 L), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (10:1) to give 2-(4-amino-3-trifluoromethyl-phenyl)-4-methyl-pentanoic acid ethyl ester (31.1 g, 89%) as a yellow oil: 1H NMR (300 MHz, CDCl3): δ 7.35 (d, 1H, J=2.1 Hz), 7.27 (dd, 1H, J=8.4, 2.1 Hz), 6.69 (d, 1H, J=8.4 Hz), 4.10 (m, 4H), 3.54 (t, 1H, J=7.8 Hz), 1.91 (m, 1H), 1.58 (m, 1H), 1.44 (m, 1H), 1.21 (t, 3H, J=6.9 Hz), 0.90 (d, 3H, J=6.6 Hz), 0.89 (d, 3H, J=6.6 Hz); 13C NMR (75 MHz, CDCl3): δ 174.14, 143.45, 132.22, 128.58, 125.91 (q, J=4 Hz), 124.80 (q, J=271 Hz), 117.35, 113.60 (q, J=29 Hz), 60.60, 48.54, 42.35, 25.77, 22.46, 22.18, 14.04.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=O)[C:8](=[CH:12][CH:13]=1)[C:9]([OH:11])=O.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[CH3:27]O>>[CH3:27][O:25][C:24](=[O:26])[CH2:23][N:22]1[C:14](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[C:5]([O:4][C:3]3[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:2]=3[CH3:1])[CH:6]=2)[C:9]1=[O:11]
Reactant: Cc1cccc(C)c1Oc1ccc(C(=O)O)c(C(=O)O)c1
Reactant: CO
Reactant: NCC(=O)O
Product: COC(=O)CN1C(=O)c2ccc(Oc3c(C)cccc3C)cc2C1=O

Procedure:
4-(2,6-dimethyl-phenoxy)-phthalic acid was reacted with glycine in analogy to Example D-1 b). The crude product was then reacted with methanol in analogy to Example D-1 c); 1H NMR (CDCl3): δ=7.80 (d, 1H), 7.09 to 7.17 (m, 5H), 4.40 (s, 2H), 3.76 (s, 3H), 2.11 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23](O)=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OC(=O)[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](=[O:43])(=[O:42])[NH2:41])=[CH:36][CH:35]=1)(C)(C)C.C(=O)(OC(C)(C)C)N.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].ClCCl>>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[NH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([NH:41][C:23]([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:10][CH:11]=3)[CH:18]=2)=[O:24])(=[O:42])=[O:43])=[CH:38][CH:39]=1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(S(N)(=O)=O)cc1
Agent: CC(C)(C)OC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)c4ccc(CN)cc4)oc3C)cc2)cc1

Procedure:
4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (50 mg) was reacted with (4-sulphamoyl-benzyl)-carbamic acid tert-butyl ester (85 mg) in an analogous manner to that described in Example 2A. The intermediate tert-butyl carbamate was hydrolysed with 1% trifluoroacetic acid/dichloromethane over 24 hours, then concentrated in vacuo to give compound 12 as a white solid (10 mg). LC/MS System C: Rt=4.67 mins, m/z (ES−)=493 (M− 1 for C27H26N2O6S).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][S:7]([C:10]1[S:14][C:13]([NH2:15])=[N:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].[CH:17]1([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1C[O:33][CH2:32]C1>CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][S:7]([C:10]1[S:14][C:13]([NH:15][C:32]([N:23]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:33])=[N:12][CH:11]=1)(=[O:8])=[O:9])[CH3:2]
Reactant: C1CCOC1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CCOC(=O)CNS(=O)(=O)c1cnc(N)s1
Agent: CN(C)c1ccncc1
Product: CCOC(=O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
An equimolar mixture of 1,1-carbonyldiimidazole, (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester and DMAP (5 mol %) in THF was heated for 2 h at 50-60° C. and then cooled to room temperature. Then dicyclohexylamine (1 equivalent) was added and the reaction is stirred overnight at room temperature. The reaction mixture was quenched with water. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude product was dissolved in MeCN and purified (HPLC method 1) to give [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid ethyl ester. This material was dissolved in MeOH and treated with 20 equivalents of 1N NaOH over night at room temperature. MeOH was removed by evaporation. Addition of 1N HCl to pH<1 caused precipitation. The precipitate was isolated by filtration, washed with water and dried to give title compound.
Reaction SMILES: [CH2:1]([S:7][C:8]1[S:22][C:11]2=[N:12][C:13]([O:20][CH3:21])=[C:14]([N+:17]([O-:19])=[O:18])[C:15](=[O:16])[N:10]2[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].OO.[OH2:25].C(O)(=[O:28])C>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH2:1]([S:7]([C:8]1[S:22][C:11]2=[N:12][C:13]([O:20][CH3:21])=[C:14]([N+:17]([O-:19])=[O:18])[C:15](=[O:16])[N:10]2[N:9]=1)(=[O:28])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O
Reactant: CCCCCCSc1nn2c(=O)c([N+](=O)[O-])c(OC)nc2s1
Reactant: CC(=O)O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CCCCCCS(=O)(=O)c1nn2c(=O)c([N+](=O)[O-])c(OC)nc2s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
In 50 ml of acetic acid, 1.9 g of 2-hexylthio-7-methoxy-6-nitro-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one and 0.1 g of sodium tungstate dihydrate were dissolved. The solution was warmed to 50° C., and 3.1 g of a 30% hydrogen peroxide solution was added dropwise, and thereafter the solution was stirred at 52° C. for 1 hour. The reaction mixture was poured into 500 ml of water, and the formed precipitate was collected by filtration. The precipitate was washed with a sodium hydrogen sulfite aqueous solution and water, and recrystallized from ethanol. Thus 1.5 g of 2-hexanesulfonyl-7-methoxy-6-nitro-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one as colorless prismatic crystals was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C@H:5]([C:9](=[O:28])[N:10]1[C@@H:14](C2C=CC=CC=2)[C@@H:13]([C:21]2C=C[CH:24]=[CH:23][CH:22]=2)O[C:11]1=O)[CH2:6]C=O.C1(N)CCCCC1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C@H:5]1[CH2:6][CH2:11][N:10]([CH:14]2[CH2:13][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:9]1=[O:28]
Reactant: O=CC[C@H](Cc1c(F)cccc1Cl)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: NC1CCCCC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1[C@@H](Cc2c(F)cccc2Cl)CCN1C1CCCCC1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
Dissolve (S)-3-(2-Chloro-6-fluoro-benzyl)-4-oxo-4-((4S,5R)-2-oxo-4,5-diphenyl-oxazolidin-3-yl)-butyraldehyde (Preparation 85) (0.384 g, 0.825 mmol) in THF (20 mL). Add cyclohexanamine (0.098 g, 0.99 mmol) and AcOH (0.049 g, 0.82 mmol). Stir the mixture for one hour and then add NaBH(OAc)3 (0.262 g, 1.24 mmol). Stir the reaction mixture for 24 hours until LC-MS shows the starting material has been gone. Add water (20 mL) and extract the aqueous with CH2Cl2 (3×50 mL). Combine the organic layers and dry over Na2SO4. Concentrate and purify by chromatography (Silica gel) to afford (S)-3-(2-Chloro-6-fluorobenzyl)-1-cyclohexylpyrrolidin-2-one (0.172 g, 67%). MS (APCI-pos mode) m,/z (rel intensity) 310 (100), 312 (35).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][CH2:10][NH:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[O:21]1[CH2:26][CH2:25][N:24]([C:27](Cl)=[O:28])[CH2:23][CH2:22]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][CH2:10][N:11]([C:27]([N:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)=[O:28])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN(C)C(=O)N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of N-t-butoxycarbonyl-N,N'-dimethylethylenediamine (1.0 g) and triethylamine (537 mg) in methylene chloride (20 ml) which was cooled to 0° C., was added morpholinocarbonyl chloride (794 mg). The mixture was stirred at 0° C. for 1 hour. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with 5% hydrochloric acid, 1M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. Evaporation of the solvent gave N-t-butoxycarbonyl-N'-(morpholinocarbonyl)-N,N'-dimethylethylenediamine (1.11 g) as an oil.