Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[C:23]([CH:26]=O)[CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[C:23]([CH2:26][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH:22]=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3]
Reactant: COc1cc(-c2cc3c(C=O)cccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3c(CN4CCCC4)cccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 35.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-4-formylindol-2-yl]isoindolinone (0.299 g, 0.597 mmol) was dissolved in acetonitrile (15.0 mL), and the solution was treated with pyrrolidine (0.997 mL, 11.9 mmol), acetic acid (0.684 mL, 11.9 mmol) and sodium triacetoxyborohydride (0.633 g, 2.99 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=3/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-4-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (0.117 g, yield 35%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[N:5]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16].O>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH3:18])[C:15]([NH:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[N:5]=1)=[O:16]
Reactant: Cc1nc(N)nc(C)c1Cl
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(NC(=O)N(C)C)nc(C)c1Cl
Reaction time: 1 h

Procedure:
Sodium hydride (6 g., 55%, 0.137 mole) is added to a mixture of 2-amino-4,6-dimethyl-5-chloropyrimidine (19.5 g., 0.125 mole) in 250 ml of toluene. The mixture, under a nitrogen atmosphere is heated to reflux and stirred for one hour. Another portion of sodium hydride (6 g., 55%, 0.137 mole) is added and after two hours of reflux, dimethyl carbamoyl chloride (13.9 g., 0.125 mole) is added. After one hours of reflux the reaction is cooled, water is added, the toluene is removed by vacuum concentration and the product is extracted into petroleum ether from which it is crystallized by evaporation. N,N-Dimethyl-N'-(4,6-dimethyl-5-chloro-2-pyrimidinyl)urea melting at 127°-129° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[C:15]([NH:23][C:24]([NH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Solvent: CCOCC
Product: COc1cc(NC(=S)NC(=O)c2ccccc2)c(C(N)=O)cc1OC
Reaction time: 24 h
Yield: 96.3 %

Procedure:
To a stirred mixture of 4 g of 2-amino-4,5-dimethoxybenzamide and 200 ml of ether was added dropwise, e solution of 3.3 g of benzoyl isothiocyanate in 100 ml of ether over 15 minutes. After 24 hours, the solid was collected, giving 7 g of the desired product as white crystals, mp 204°-207° C. (dec.).
Reaction SMILES: [F:1][C:2]1([F:52])[C:6]2[N:7]([CH2:14][C:15]([NH:17][C@H:18]([C:28]3[C:33]([C:34]4[CH:35]=[CH:36][CH:37]=[C:38]5[C:42]=4[N:41]([CH3:43])[N:40]=[C:39]5[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:32][N:31]=[C:30](SC)[N:29]=3)[CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)=[O:16])[N:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:5]=2[C@H:4]2[CH2:51][C@@H:3]12.C1C=C(Cl)C=C(C(OO)=O)C=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:74][C:75]1([OH:79])[CH2:78][NH:77][CH2:76]1>C(Cl)Cl>[F:1][C:2]1([F:52])[C:6]2[N:7]([CH2:14][C:15]([NH:17][C@H:18]([C:28]3[C:33]([C:34]4[CH:35]=[CH:36][CH:37]=[C:38]5[C:42]=4[N:41]([CH3:43])[N:40]=[C:39]5[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[CH:32][N:31]=[C:30]([N:77]4[CH2:78][C:75]([OH:79])([CH3:74])[CH2:76]4)[N:29]=3)[CH2:19][C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)=[O:16])[N:8]=[C:9]([C:10]([F:11])([F:13])[F:12])[C:5]=2[C@H:4]2[CH2:51][C@@H:3]12
Reactant: CSc1ncc(-c2cccc3c(NS(C)(=O)=O)nn(C)c23)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)n1
Reactant: CC1(O)CNC1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(NS(C)(=O)=O)c2cccc(-c3cnc(N4CC(C)(O)C4)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 36B (30 mg, 0.039 mmol) was dissolved in 3 mL of CH2Cl2 and to it was added m-CPBA (17.5 mg, 77%, 0.078 mmol). The reaction mixture was allowed to stir at rt for 20 min. To the reaction mixture was added N,N-diisopropylethylamine (0.2 mL, 0.017 mmol) and 3-methylazetidin-3-ol hydrochloride (34 mg, 0.39 mmol). The reaction mixture was allowed to stir at room temperature for 30 min and then partitioned between EtOAc and brine. The organic layer was separated, washed with brine and dried over Na2SO4 and concentrated. The residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title product. 1H NMR (400 MHz, methanol-d4) δ 8.53 (dd, 1H), 8.25 (d, 1H), 7.83 (m, 1H), 7.36-6.52 (m, 3H), 6.47-6.22 (m, 2H), 4.85 (m, 3H), 4.40-3.94 (m, 4H), 3.75-2.67 (m, 8H), 2.51 (m, 2H), 1.60 (s, 3H), 1.51-1.23 (m, 1H), 1.18-0.88 (m, 1H). MS (m/z): 808.01 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH:23][C:24](=[O:27])[CH2:25][NH2:26])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].[CH3:30][C:31]([CH3:33])=O.[BH3-]C#N.[Na+].C(OCC)(=O)C>CO>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH:23][C:24](=[O:27])[CH2:25][NH:26][CH:31]([CH3:33])[CH3:30])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)[CH3:29]
Reactant: CC(C)=O
Reactant: CCN(CC)c1ccc(NC(=O)C2(NC(=O)CN)CCc3ccccc3C2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(CC)c1ccc(NC(=O)C2(NC(=O)CNC(C)C)CCc3ccccc3C2)cc1
Yield: 23 %

Procedure:
The amine from Example 13A was dissolved in 1 M pH4 MeOH buffer (82 g NaOAc/L MeOH, add HOAc to pH 4.5) and acetone (12 mg, 0.2 mmol) and NaBH3CN (13 mg, 0.2 mmol) were added. Following stirring for 2 hours ethyl acetate (30 mL) was added and the resulting solution was washed with aqueous NaOH (1N, 2×10 mL). The organic phase was dried over MgSO4, concentrated, and purified by HPLC to provide the titled compound (30 mg, 23% over 3 steps). 1H NMR (300 MHz, DMSO-D6) δ 9.21 (s, 1H), 7.83 (s, 1H), 7.32 (d, J=9.3 Hz, 2H), 7.10 (m, 4H), 6.61 (d, J=9.0 Hz, 2H), 3.28 (q, J=6.9 Hz, 4H), 3.22 (d, J=18.9 Hz, 1H), 3.11 (d, J=18.9 Hz, 1H), 3.07 (s, 2H), 2.77 (m, 2H), 2.45 (m, 2H), 2.09 (m, 1H), 1.05 (t, J=7.2 Hz, 6H), 0.81 (d, J=6.3 Hz, 3H), 0.73 (d, J=6.3 Hz, 6H). MS (ESI) positive ion 437 (M+H)+; negative ion 435 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:23])[CH:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33](O)=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:23])[CH:17]([NH:22][C:33](=[O:34])[CH2:32][C:27]2[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=2)[CH2:18][CH:19]([CH3:20])[CH3:21])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(C)CC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CC(C)CC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-4-methyl-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 22.5, 22.9, 24.2, 25.0, 26.6, 26.7, 42.9, 43.1, 51.9, 56.0, 59.3, 67.3, 102.9, 105.5, 112.3, 112.6, 131.9, 137.4, 169.1, 169.4; MS m/z 476.3 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([C:17](O)=[O:18])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([C:17]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyrrolidine (271 μL, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(pyrrolidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (550 mg, 72%). 1H NMR (CD3OD, 400 MHz) δ 3.93-3.65 (m, 5 H); 3.43-3.28 (m, 4 H) and 2.00-1.81 (m, 4 H).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH:48]1[CH2:53][CH2:52][S:51](=[O:55])(=[O:54])[CH2:50][CH2:49]1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:48]4[CH2:53][CH2:52][S:51](=[O:55])(=[O:54])[CH2:50][CH2:49]4)=[O:43])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: O=S1(=O)CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with thiomorpholine 1,1-dioxide (Syntech Development) to give the title compound. HR-MS (ES, m/z) calculated for C39H49Cl2N6O5S [(M+H)+] 783.2857, observed 783.2856.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:30](=O)[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH2:10][CH2:9]1.Cl.[CH3:34][O:35][NH2:36].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:34][O:35][N:36]=[C:30]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:29])[C:15]3[CH:20]=[C:19]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=3[O:25][CH:26]([CH3:28])[CH3:27])[CH2:12][CH2:13]2)=[C:2]([F:1])[CH:3]=1)[CH3:31]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C(C)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.12 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone was dissolved in 1 ml of a 1:1 mixture of ethanol and water. 0.8 mmol of O-methyl-hydroxylamine hydrochloride was added, followed by 8.4 mmol of sodium acetate. The slurry was stirred overnight at room temperature, diluted with water, extracted with ethyl acetate, dried and concentrated. The resulting gum was triturated with diethyl ether/heptane to yield the title compound as a colorless solid. MS (m/e): 492.3 (MH+, 100%)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[CH3:7].[C:21]([O-])(=[O:23])C.[Na+]>CN(C)C=O>[C:6]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH3:20])[C:13]1[CH:18]=[CH:17][C:16]([CH:21]=[O:23])=[CH:15][CH:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CCN(CCOC(C)=O)c1ccccc1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(CCOC(C)=O)c1ccc(C=O)cc1
Temperature: 0 °C
Yield: 84.2 %

Procedure:
After adding 55.8 g of ice-cooled phosphoryl chloride to 26.6 g of dimethylformamide, a solution of 63.0 g of the 2-(N-ethylanilino)ethyl acetate in 40 ml of dimethylformamide was slowly added at room temperature, this was caused to react for 6 hours at room temperature while stirring, and then poured into an aqueous solution of 150 g of sodium acetate under ice cooling. An organic layer was extracted with ethyl acetate and the solvent was boiled off under reduced pressure. This was refined by silica gel column chromatography to yield 60.2 g of 2-(ethyl(4-formylphenyl)amino)ethyl acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH:11]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[C:32]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9](=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:15]=1)(=[O:34])[CH3:33]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2ccccn2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1

Procedure:
A mixture of 2.0 g of product from Example 4, 8.9 ml acetic anhydride, 0.0863 g 4-dimethylaminopyridine and 30 ml pyridine is heated at reflux temperature for 23 hours, cooled, poured into 150 ml of water and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatogaphy (silica ge1:15-20% ethyl acetate/hexane) to give 1.4 g of the desired product as light yellow crystals.
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[O:23]=[C:24]1[C:29]2=[CH:30][NH:31][C:32]([CH:33]=O)=[C:28]2[CH2:27][CH2:26][O:25]1>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[C:16]3=[CH:33][C:32]2[NH:31][CH:30]=[C:29]3[C:24](=[O:23])[O:25][CH2:26][CH2:27][C:28]=23)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCc4ccccc43)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCc4ccccc43)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-(2,3-Dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:19])([CH3:18])[C:15]([Cl:24])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(Sc2ccc(Cl)cc2)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(Oc1ccc(Sc2ccc(Cl)cc2)cc1)C(=O)Cl

Procedure:
A mixture of 15 g (0.0465 mol) of p-(p-chlorophenylthio)-phenoxy-isobutyric acid (CRL 40,201) and of 16.75 ml (0.232 mol) of thionyl chloride is heated to the reflux temperature for 10 minutes. After having taken up the reaction mixture in benzene, filtered the solution in the presence of carbon black and evaporated the solvent, 16 g of an orange-coloured oil are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([I:19])=[CH:14][C:13]=2[CH3:20])=[C:6]2[C:10]=1[C@@H:9]([OH:11])[CH2:8][CH2:7]2.O[C:22]1[CH:35]=[CH:34][C:25]2[C@H:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][O:28][C:24]=2[CH:23]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:13]([CH3:20])=[CH:14][C:15]([I:19])=[CH:16][C:17]=2[CH3:18])=[C:6]2[C:10]=1[C@H:9]([O:11][C:22]1[CH:35]=[CH:34][C:25]3[C@H:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][O:28][C:24]=3[CH:23]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1cc(I)cc(C)c1-c1ccc(F)c2c1CC[C@@H]2O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(I)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from (S)-7-fluoro-4-(4-iodo-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-ol and (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 3 of Intermediate 1. LC (method 8): tR=1.08 min; Mass spectrum (ESI+): m/z=595 [M+Na]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[N:3]=1.[CH2:15]([Mg]Cl)[CH:16]([CH3:18])[CH3:17]>C1COCC1.CN1C(=O)CCC1>[CH3:14][C:9]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:3]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: CC(C)C[Mg]Cl
Reactant: Cc1ccc(C)n1-c1cccc(Cl)n1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cccc(CC(C)C)n1

Procedure:
The product from Example 12b (1.0 g, 4.84 mmol) was treated with 2.0 M isobutylmagnesium chloride (2.90 mL, 5.81 mmol) in 30 mL THF and 3 mL NMP at room temperature under a N2 atmosphere. Added Fe(acac)3 (85 mg, 0.242 mmol) and stirred at room temperature for 18 h. During the course of the reaction two additional charges of Grignard reagent and catalyst were added. The reaction was quenched by pouring into 5% acetic acid and extracting with ether. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound that was purified by silica gel column chromatography eluting with 10% EtOAc/hexane to give (620 mg, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[CH3:13][O:14][C:15](=[O:27])[CH:16]([NH2:26])[CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([O:24][CH3:25])[CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([NH:26][C:10](=[O:11])[CH2:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([O:24][CH3:25])[CH2:22][CH2:23]1
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Reactant: COC(=O)C(N)CC1CCN(OC)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CC1CCN(OC)CC1)NC(=O)Cc1cc(C)ccc1C
Reaction time: 0.5 h

Procedure:
2,5-Dimethylphenylacetyl chloride (2.1 g, 11.5 mmol) was added dropwise to a mixture of 2-amino-3-(1-methoxy-piperidin-4-yl)-propionic acid methyl ester (1.7 g, 7.8 mmol) and K2CO3 (2.1 g, 15.2 mmol) in 50 mL of THF at room temperature. After the addition, the mixture was stirred for 0.5 h and diluted with 50 ml of water. The mixture was extracted with EtOAc five times and the combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel. Yield: 1.2 g of 2-[2-(2,5-dimethyl-phenyl)-acetylamino]-3-(1-methoxy-piperidin-4-yl)-propionic acid methyl ester as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[N+:19]([C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33])([O-:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH:17][S:32]([C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=1[N+:19]([O-:21])=[O:20])(=[O:33])=[O:34])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in the preceeding examples but using 2-(2,4-dichlorophenyl)-3-amino-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2-nitro-4-trifluromethylbenzenesulfonylchloride, the title com-pound was obtained in a similar yield:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][OH:26])=[NH:24])=[C:21]([F:29])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:47](OC1C=CC=CC=1)=[O:48]>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=2)[S:15][C:16]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]2[NH:24][C:47](=[O:48])[O:26][N:25]=2)=[C:21]([F:29])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N=C(NO)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CCCOCc3ccccc3)cc2F)no1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 0.62 g of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-N-hydroxy-benzamidine in 17 mL of dichloromethane at 0° C., under argon, were added 0.23 mL of pyridine and 154 μL of phenyl chloroformate. The reaction mixture was stirred for 10 min at 0° C. followed by 1 h at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was taken up into 10 mL of acetonitrile under argon and 0.165 mL of 1,4-diazabicyclo[5.4.0]undec-7-ene (DBU) was added. The reaction mixture was stirred at room temperature overnight then warmed to 40° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up into dichloromethane and a 1M aqueous solution of NaH2PO4 was added. The aqueous layer was separated and extracted three times with dichloromethane. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 770 mg of crude product as a yellow powder. Purification by column chromatography on silica gel (heptane 1/ethyl acetate 1) gave 150 mg followed by column washing with 100% MeOH gave 320 mg of the title compound. In total, 470 mg of 3-{4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-[1,2,4]oxadiazol-5-one as white powder was obtained.