Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.CN.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[CH3:1][NH:3][S:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: CCN(CC)CC
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Part A: To a mixture of 50 mL of tetrahydrofuran, 15 mL (108 mmol) of triethylamine and 10 mL (116 mmol) of a 40% aqueous methylamine solution at 0 C, was added 15.0 g (72.6 mmol) of 4-methoxy-benzenesulfonyl chloride over a 15 minutes. After 1 hour, the solvents were removed in vacuo, 5% aqueous KHSO4 and ethyl acetate added, the organic layer separated, washed with saturated aqueous sodium bicarbonate, brine, dried with sodium sulfate, filtered and stripped to afford a white solid. This was recrystallized from hot ethyl acetate/hexane to afford 13.4 g of N-methyl-4-methoxybenzenesulfonamide, m/e=202 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:6]1[C:3]2[CH:4]=[C:15]([C:14]([O:18][CH3:19])=[O:17])[S:16][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(C(F)(F)F)cccc2s1
Temperature: 130 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
A mixture of 1.00 g of 2-fluoro-6-(trifluoromethyl)benzaldehyde, 633 mg of methyl thioglycolate, 1.21 g of potassium carbonate and 15 ml of DMF was stirred at 130° C. for 2 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the mixture was extracted with tert-butyl methyl ether three times. The combined organic layers were washed with water and saturated saline, and dried over magnesium sulfate, then, concentrated under reduced pressure, to obtain 480 mg of methyl 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (present condensed ring compound 3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22](Br)[S:21]2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9](=[O:10])[N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[S:21]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(-c3ccccc3)sc2n1)c1ccccc1
Yield: 6 %

Procedure:
Compound A24 was synthesized from compound 12a (0.053 mmol) and phenylboronic acid (0.16 mmol), following the procedure as described for compound A1, to give compound A24 as a white solid in 6% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.40 (s, 9H), 1.82-1.91 (m, 1H), 2.01-2.13 (m, 1H), 2.35-2.42 (m, 1H), 3.13-3.21 (m, 1H), 3.77-3.84 (m, 1H), 4.70-4.72 (m, 1H), 5.46 (d, J=7.08 Hz, 1H), 6.04 (d, J=7.08 Hz, 1H), 7.31-7.46 (m, 11H), 7.63 (s, 1H), 7.89 (s, 1H), 9.88 (brs, 1H); and MS (ESI, EI+) m/z=546.23 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][CH2:6][C:7]([OH:9])=[O:8].O[C:15]([CH3:29])([CH3:28])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=O.C1CCN2C(=NCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][C:6]1[C:7](=[O:9])[O:8][C:15]([CH3:29])([CH3:28])[C:16]=1[C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(O)COc1ccc(F)c(F)c1
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC(=O)C(Oc2ccc(F)c(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A solution of 3,4-difluorophenoxyacetic acid (0.51 g, 2.73 mmol), 2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one (0.5g, 2.1 mmol, Step 3), CMC (1.13 g, 2.73 mmol) and DMAP (15 mg, 0.10 mmol) in dichloromethane (12 ml) was stirred at r.t. for 18 hrs. Then, DBU (0.63 ml, 4.2 mmol) was added and the reaction mixture was refluxed for 3 h. After cooling to r.t. the mixture was extracted with ethyl acetate and washed successively with water, 1 N HCl and brine. The organic layer was dried over MgSO4, filtered and the solvent evaporated under vacuum. The residue was triturated in a mixture of ethyl acetate and hexane affording the title compound as a solid. M.P.: 93-95 ° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:13]([CH3:18])[C:14]([O:16]C)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:13]([CH3:18])[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](C)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of methyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]propionate (1.05 g, 2.89 mmol) in tetrahydrofuran (60 mL) at room temperature is added 1N aqueous sodium hydroxide (8.6 mL, 8.67 mmol). The reaction mixture is stirred for 19 hours at room temperature. The tetrahydrofuran is then evaporated. The remaining residue is acidified with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated to give 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:28][CH2:29][CH:30]1[O:34][N:33]([CH2:35][CH3:36])[C:32](=[O:37])[CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:26])([F:25])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:28][CH2:29][CH:30]4[O:34][N:33]([CH2:35][CH3:36])[C:32](=[O:37])[CH2:31]4)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CCN1OC(CN)CC1=O
Product: CCN1OC(CNC(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C)CC1=O
Yield: 15.9 %

Procedure:
4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (0.3 g) (prepared according to WO 2009/080250) was coupled with the amine obtained in Step D (0.12 g) as described in Example 12, Step C to afford the title product as a beige solid (62 mg, mixture of diasteroisomers). LCMS (Method F) 2.02 min, M+H 542/544.
Reaction SMILES: [F:1][C:2]([F:49])([P:45]([OH:48])([OH:47])=[O:46])[C:3]1[CH:44]=[CH:43][C:6]([CH2:7][C:8]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:42])([F:41])[P:37]([OH:40])([OH:39])=[O:38])=[CH:32][CH:31]=2)([C:19]([O:21]CC2C=CC=CC=2)=[O:20])[C:9]([O:11]CC2C=CC=CC=2)=[O:10])=[CH:5][CH:4]=1>C(O)=O.CO.Cl[Pd]Cl>[F:42][C:36]([F:41])([P:37]([OH:40])([OH:39])=[O:38])[C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:49])[P:45]([OH:48])([OH:47])=[O:46])=[CH:44][CH:43]=2)([C:19]([OH:21])=[O:20])[C:9]([OH:11])=[O:10])=[CH:31][CH:32]=1
Reactant: O=C(OCc1ccccc1)C(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)C(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Solvent: O=CO
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)C(=O)O
Reaction time: 24 h
Yield: 66.6 %

Procedure:
A mixture of the product of Example 2 (0.2 g), PdCl2 and a few drops of HCO2H in 20 mL of MeOH was shaken under 50 psi of H2 for 24 h. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was lyopholized to give 0.1 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([CH3:33])([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH3:32][CH:17]1[N:16]2[C:21]([CH2:22][O:23][C:24]3[C:15]2=[CH:14][C:13]([NH:12][C:10]2([CH3:33])[CH2:11][NH:8][CH2:9]2)=[C:26]([C:27]([F:29])([F:30])[F:28])[CH:25]=3)=[N:20][NH:19][C:18]1=[O:31]
Reactant: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CNC4)cc3N21
Yield: 44 %

Procedure:
A solution of 3-methyl-3-(4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.010 g, 0.021 mmol) in DCM (1 mL) and TFA (0.25 mL) was stirred for 1 h at ambient temperature. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Table 3, Method 10) to give 4-methyl-6-(3-methyl-azetidin-3-ylamino)-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a white solid (0.0045 g, 44%). LC/MS (Table 1, Method 4) Rt=1.441 min; MS m/z: 370 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][CH:29]([CH3:31])[CH3:30])[N:22]=3)=[CH:19][N:20]=2)=[CH:11][C:10]=1[CH2:32][CH3:33])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[CH2:32]([C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][CH:29]([CH3:30])[CH3:31])[N:22]=3)=[CH:19][N:20]=2)[CH:13]=[C:14]([CH3:15])[C:9]=1[OH:8])[CH3:33]
Reactant: CCc1cc(-c2ncc(-c3cc(C)nc(NC(C)C)n3)o2)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(-c2ncc(-c3cc(C)nc(NC(C)C)n3)o2)cc(C)c1O
Reaction time: 18 h
Yield: 97.7 %

Procedure:
To a solution of {4-[2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-oxazol-5-yl]-6-methyl-pyrimidin-2-yl}-isopropyl-amine (27 mg, 61 μmol) in THF (2 mL) and MeOH (2 mL), 10% Pd/C is added (50 mg). The reaction mixture is stirred under H2 atmosphere for 18 h, and is filtered through celite. The filtrate is evaporated to give 2-ethyl-4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-oxazol-2-yl]-6-methyl-phenol (21 mg) as a yellow oil; LC-MS: tR=0.88 min, [M+H]+=353.03.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>>[O:10]=[C:9]1[C:8]2[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6](=[O:11])[N:1]1[CH2:2][C:3]([OH:5])=[O:4]
Reactant: NCC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C(O)CN1C(=O)c2ccccc2C1=O

Procedure:
(G1a) irradiating a reaction product of glycine (a) and phthalic anhydride (b) with microwaves to produce 2-(1,3-dioxoisoindolin-2-yl)acetic acid (compound 1a);
Reaction SMILES: CC(C)(O[C:5]([NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:9]1=[O:24])=[O:6])C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:50][C:51]1[CH:60]=[C:59]2[C:54]([C:55]([N:62]3[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]3)=[CH:56][C:57]([NH2:61])=[N:58]2)=[CH:53][CH:52]=1>>[C:18]1([O:17][C:15]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:8]([NH:7][C:5]([N:65]3[CH2:66][CH2:67][N:62]([C:55]4[C:54]5[C:59](=[CH:60][C:51]([Cl:50])=[CH:52][CH:53]=5)[N:58]=[C:57]([NH2:61])[CH:56]=4)[CH2:63][CH2:64]3)=[O:6])[C:9]2=[O:24])=[O:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)Oc2ccccc2)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)Oc4ccccc4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, (3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-carboxylic acid, phenyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 537 (M++1). 1H NMR (CDCl3,) δ 1.56˜2.08 (m, 5H), 2.16–2.24 (m, 1H), 3.14 (m, 4H), 3.54 (dd, 1H), 3.68 (m, 4H), 4.54 (br.dd, 1H), 4.84 (br.s, 2H), 4.90 (ddd, 1H), 5.80 (d, 1H), 6.15 (s, 1H), 7.16˜7.22 (m, 3H), 7.27 (m, 1H), 7.41 (m, 2H), 7.62 (d, 1H), 7.72 (d, 1H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f23) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13](CC3C=NC=CC=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([C:31]3SC=C[CH:35]=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3].[CH3:37][O:38][C:39]1[CH:44]=CC(S(Cl)(=O)=O)=[CH:41][CH:40]=1>>[CH3:37][O:38][C:39]1[CH:44]=[CH:35][C:31]([S:28]([N:10]2[CH2:9][C:8]3[CH:36]=[C:4]([C:2]#[N:3])[CH:5]=[CH:6][C:7]=3[NH:13][CH2:12][C@H:11]2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:29])=[O:30])=[CH:41][CH:40]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Agent: Cl
Product: COc1ccc(S(=O)(=O)N2Cc3cc(C#N)ccc3NC[C@H]2Cc2ccccc2)cc1

Procedure:
The title compound was prepared from Compound A of Example 23 and 4-methoxyphenylsulfonyl chloride following the procedure of Compound B of Example 23.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[I:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2>S(=O)(=O)(O)O>[I:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2c(I)cccc2N1
Agent: O=S(=O)(O)O
Product: O=C1Cc2c(ccc([N+](=O)[O-])c2I)N1
Reaction time: 1 h

Procedure:
A mixture of concentrated sulfuric acid (0.73 mL) and concentrated nitric acid (0.14 mL) was added slowly to a solution of 1,3-dihydro-4-iodo-2H-indol-2-one (0.5 g, 1.93 mmol) (see T. Fukuyama, supra, and Kende, supra) in concentrated sulfuric acid (6 mL) at −5° C. with stirring. The mixture was stirred for an additional 15 min at −5° C. then poured into ice. After standing for 1 h, solid was collected by filtration and washed with water, and dried in a vacuum oven to give 1,3-dihydro-4-iodo-5-nitro-2H-indol-2-one. (Yield 0.46 g, 78%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.[Cl-]>C(Cl)Cl.O>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NCCCn1ccnc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 14.9 g of chloroacetyl chloride in 25 ml of methylene chloride was added to a stirred solution of 15.0 g of 1-(3-aminopropyl)imidazole in 75 ml of methylene chloride at 0° C. The rate of addition was controlled to keep the reaction temperature below 15° C. During the course of the reaction a brown gummy viscous oil separated out of solution. Approximately two-thirds of the way through the addition, 50 ml of 20% NaOH was added to the mixture, and the oil went into solution. After the addition was completed, the mixture was stirred at room temperature for 15 minutes. The water layer was removed, the organic layer was dried over MgSO4 and filtered, and the solvent was removed under vacuum to give a yellow oil. The oil was dissolved in 30 ml of water and the pH was adjusted to approximately 3.0. Analysis for organic chloride indicated dimerization and/or trimerization had occurred.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:38](=[O:39])[CH2:37][O:36][CH3:35])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: COCC(=O)Cl
Product: COCC(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, methoxyacetyl chloride.
Reaction SMILES: C([O:9][CH:10]1[CH2:14][CH:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11]1)(=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[O:15]([CH:13]1[CH2:14][CH:10]([OH:9])[CH:11]=[CH:12]1)[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(OC(=O)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC1C=CC(O)C1
Yield: 9.1 %

Procedure:
By operating as in Example 25, 140 milligrams (0.44 mmol) of 3-benzoyloxy-5-t-butyldimethylsiloxycyclopent-1-ene was held in anhydrous ether with 30 milligrams (0.79 mmol) of lithium aluminum hydride for one hour at room temperature under a nitrogen atmosphere, following which the mixture was heated under reflux for 30 minutes. Thereafter the aftertreatment was carried out as in Example 25, and the resulting crude product was separated by preparative thin-layer chromatograph (silica gel 2mm, hexane:ethyl acetate = 4:1) to obtain 85 milligrams (0.04 mmol, 91%) of 3-t-butyldimethylsiloxy-5-hydroxycyclopent-1-ene.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=1)=[O:9].O1[CH2:41][CH2:40]OCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12]([N:11]2[CH2:41][CH2:40][N:7]([CH3:6])[CH2:8][CH2:10]2)[N:11]=1)=[O:9]
Reactant: C1COCCO1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(S(C)(=O)=O)ncc1-c1ccccc1
Product: CN1CCN(c2ncc(-c3ccccc3)c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)CC1
Reaction time: 16 h
Yield: 96.2 %

Procedure:
To a solution of 0.3 g (0.58 mmol) 2-methanesulfonyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml dioxan 0.16 ml (1.45 mmol) 1-methyl-piperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml H2O. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 140:10:1) to give 0.15 g (48%) 2-(4-methyl-piperazin-1-yl)-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a off-white solid, m.p. 162.0-162.8°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2].[NH2:21][CH2:22][C@@H:23]([C:25]1[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=1)[OH:24]>>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:21][CH2:22][C@H:23]([OH:24])[C:25]3[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)/C=C/c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from (E)-3-[4-(4-oxo-piperidine-1-yl)-phenyl]-acrylic acid ethyl ester (which was obtained in Example 169) (0.27 g, 1.0 mmol) and N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) (0.27 g, 1.1 mmol) according to the prodedure shown for Example 180 to give 0.40 g of yellow solid; m.p. 103-106° C.; 1H NMR (DMSO-d6) δ 1.24 (t, 3H), 1.20-1.45 (m, 2H), 1.75-1.95 (m, 2H), 2.55-2.95 (m, 5H), 2.92 (t, 3H), 3.67-3.85 (m, 2H), 4.14 (q, 2H), 4.46-4.50 (m, 1H), 6.34 (d, 1H), 6.96 (d, 1H), 6.79-7.05 (m, 3H), 7.05 (d, 1H), 7.17 (d, 1H), 7.56 (d, 2H); MS (ES) m/z: 504.0 (MH+).
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:11]>>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1)=[O:11]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Product: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Yield: 101.4 %

Procedure:
Prepared from commercially available ethyl difluoroacetate (14.49 g, 117 mmol) and commercially available 4-(trifluoromethyl)acetophenone (15.36 g, 80 mmol) as described in example C.1 step 1 to give 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (21.60 g, 101%) as a light brown oil. MS (ISN) 265.0 [(M−H)−].
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12](Cl)=[O:13])[CH2:8]2.[CH3:15][O:16][C:17](=[O:31])[C@@:18]([CH3:30])([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[NH2:19].C(N(CC)CC)C>C1COCC1>[CH3:15][O:16][C:17](=[O:31])[C@@:18]([CH3:30])([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[NH:19][C:12]([O:11][CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)=[O:13]
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)[C@](C)(N)Cc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@](C)(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
To a stirred solution of 2-adamantylchloroformate (0.965 g, 4.5 mmol) in dry THF (10 mL) was added a solution of α-methyl-D-tryptophan methyl ester (0.928 g, 4 mmol) in dry THF (20 mL) followed by a solution of triethylamine (0.808 g, 8 mmol) in dry THF (20 mL) dropwise. After 15 minutes, the reaction mixture was filtered, the solvent removed in vacuo and column chromatographed using 2% MeOH:98% CH2Cl2 as eluant to yield the title compound (1.42 g, 89%) as a syrup. IR (film) 1740-1695 b.r cm-1 ; NMR (CDCl3) δ1.50-1.60 (2H, m), 1.67 (3H, s), 1.70-2.10 (12H, m), 3.38 (1H, d, J =14.5Hz), 3.50-3.60 (1H, br.s), 3.68 (3H, s), 4.86 (1H, br.s), 5.28 (1H, br.s), 6.93 (1H, d, J 2.4Hz); 7.04-7.10 (2H, m), 7.33 (1H, d, J 8.2Hz) 7.54 (1H, d, J 7.8Hz), 8.18 (1H, br.s).