Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[S:3]([CH:6]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[CH2:7][CH:8](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:32]1([C:38]2[CH:43]=[CH:42]C=[C:40]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:39]=2[OH:50])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[F:27][C:26]([F:28])([F:29])[S:23]([CH:6]([S:3]([C:2]([F:31])([F:30])[F:1])(=[O:5])=[O:4])[CH2:7][C:8]1[C:40]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:39]([OH:50])[C:38]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:43][CH:42]=1)(=[O:24])=[O:25]
Reactant: Oc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: O=S(=O)(C(CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: O=S(=O)(C(Cc1ccc(-c2ccccc2)c(O)c1-c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reaction time: 9 h
Yield: 97 %

Procedure:
1,1,3,3-Tetrakis(trifluoromethylsulfonyl)propane [4] (157.3 mg, 0.28 mmol) was added to an acetonitrile (0.25 ml) solution of 2,6-diphenylphenol (61.9 mg, 0.25 mmol) at room temperature. After 9 hours of stirring, it was purified by Kugelrohr distillation (120° C./3 mmHg) thereby obtaining 4-(2,2-bis(trifluoromethylsulfonyl)ethyl-2,6-diphenylphenol [1n] with a yield of 97% (130.7 mg, 0.24 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2)[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[O:26][C:27]=1[CH3:28]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[O:26][C:27]=1[CH3:28])[C:11]([CH3:16])=[CH:10]2)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc2[nH]c(C)cc2c1)OCC
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Product: CCOC(=O)C(Cc1ccc2c(c1)cc(C)n2Cc1nc(-c2ccccc2Cl)oc1C)OCC

Procedure:
In analogy to the procedures described in examples. 36a) and 36b), rac-2-ethoxy-3-(2-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 5) was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-1H-indol-5-yl}-2-ethoxy-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:17])[N:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[C:11]#[N:12])=[O:5])C.[OH-].[Na+]>CO>[C:13]([C:9]1[C:10]([C:11]#[N:12])=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH3:17])[N:8]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1c(C#N)c(C(C)(C)C)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(C)(C)C)c(C#N)c1C(=O)O

Procedure:
Using the procedure for Example A, Step B above, the title compound was prepared from 5-tert-butyl-4-cyano-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (prepared as described in the previous step, 610 mg, 2.59 mmol) and 1.0 N aqueous NaOH (4.00 mL, 4.00 mmol) in MeOH (10 mL). The title compound was obtained as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 4.17 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[OH:23])[CH:10]=1)=O.N.CO>ClCCl>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]#[C:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[OH:23])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(NCCCc1cccc(C#CC2CCCCC2O)c1)C(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NCCCc1cccc(C#CC2CCCCC2O)c1

Procedure:
Deprotection of 2,2,2-trifluoro-N-(3-(3-((2-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamide followed by flash chromatography (10% (7N NH3/MeOH)/dichloromethane) gave 2-((3-(3-aminopropyl)phenyl)ethynyl)cyclohexanol as an orange oil. Yield (0.606 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.16-7.26 (m, 3H), 7.08-7.12 (m, 1H), 3.48-3.56 (m, 1H), 2.71 (t, J=7.2 Hz, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.38-2.46 (m, 1H), 2.01-2.10 (m, 2H), 1.64-1.82 (m, 7H), 1.40-1.52 (m, 1H), 1.16-1.40 (m, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:12]([S:14]Cl)=[O:13]>C1COCC1>[C:1]1([N:7]2[C:8](=[O:9])[NH:10][C:12](=[O:13])[S:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)Nc1ccccc1
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n(-c2ccccc2)s1
Yield: 13.8 %

Procedure:
To the solution of phenyl-urea (13.0 g, 95.48 mol) in THF (100 mL) was slowly added chlorocarbonyl sulfenylchloride (13 mL, 148.85 mmol) at RT. The reaction mixture was refluxed overnight, the volatiles removed in vacuo yielded 2-phenyl-1,2,4-thiadiazolidine-3,5-dione as a white solid (4.0 g, 20%). 1H NMR (DMSO-d6): δ 12.49 (s, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.43 (t, J=7.6 Hz, 2H), 7.27 (t, J=7.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([NH:22]C(=O)OC(C)(C)C)[CH2:21][CH2:20]C3)=[O:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:30][CH3:31].CC1C=CC(OC2N=CC(NC(C3(NC(=O)OC(C)(C)C)CC3)=O)=CC=2)=CC=1OC>>[NH2:22][C:18]1([C:16]([NH:15][C:12]2[CH:13]=[N:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:30][CH3:31])[CH:4]=3)=[CH:10][CH:11]=2)=[O:17])[CH2:21][CH2:20]1
Reactant: COc1cc(Oc2ccc(NC(=O)C3(NC(=O)OC(C)(C)C)CCC3)cn2)ccc1C
Agent: COc1cc(Oc2ccc(NC(=O)C3(NC(=O)OC(C)(C)C)CC3)cn2)ccc1C
Product: COc1cc(Oc2ccc(NC(=O)C3(N)CC3)cn2)ccc1C

Procedure:
The title compound (58 mg) was made in a similar fashion to the preparation of Intermediate 102 replacing 1,1-dimethylethyl (1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}cyclobutyl)carbamate with 1,1-dimethylethyl (1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}cyclopropyl)carbamate (Intermediate 104, 80 mg)
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1ccccc1Cl
Product: Nc1nnc(-c2ccccc2Cl)c(-c2ccccc2)n1
Yield: 45.5 %

Procedure:
6-(2-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (103 mg, 45%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 2-chlorophenylboronic acid (0.125 g, 0.80 mmol) according to the general procedure of Example 1.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:37])[C:19]([OH:36])([C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][C:30](=[O:33])[N:29]([CH3:34])[C:28]=4[CH:35]=3)[C:20]([F:23])([F:22])[F:21])=[C:14]([Cl:38])[CH:13]=2)[CH:8]=[CH:7][C:6]=1[F:39])C.[Li+].[OH-].Cl>O1CCCC1.CO>[Cl:38][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[CH:18]([CH3:37])[C:19]([OH:36])([C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH3:34])[C:28]=2[CH:35]=1)[C:20]([F:22])([F:21])[F:23])[O:11][C:9]1[CH:8]=[CH:7][C:6]([F:39])=[C:5]([CH:10]=1)[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)c1cc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(c1ccc(Oc2ccc(F)c(C(=O)O)c2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 81.2 %

Procedure:
To a solution of 5-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-phenoxy}-2-fluoro-benzoic acid ethyl ester (23 mg, 0.04 mmol) in tetrahydrofuran (0.085 ml) and methanol (0.085 ml) was added a 1 M aqueous LiOH solution (0.08 ml, 0.08 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 2.5 h. The mixture was cooled in an ice bath and acidified using 1 M aqueous HCl. The mixture was concentrated. To the residue, water was added, extracted twice with AcOEt, the organic phases were washed with water, dried (MgSO4) and concentrated to give the title compound (18 mg) as a white solid. MS (m/e, ISP neg. ion)=552.2 [M−H+].
Reaction SMILES: CO[C:3]([CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:7]=2[C:6]1=[O:18])=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1(C)C(C)=CC=CC=1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:3]([CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:7]=2[C:6]1=[O:18])=[O:4]
Reactant: COC(=O)C1CCOc2cc(Cl)c(Cl)cc2C1=O
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccn1)C1CCOc2cc(Cl)c(Cl)cc2C1=O
Temperature: 25 °C
Yield: 14 %

Procedure:
7,8-Dichloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid methyl ester (0.2 mmol) and 2-aminopyridin (0.2 mmol) were dissolved in 1 ml xylene. Reaction was performed by microwave irradiation for one hour at 150° C. The solution obtained from this reaction was cooled to room temperature and extracted by 2 mol/l hydrochloric acid and ethyl acetate. The ethyl acetate extract was dried over sodiumsulfate and the solvent removed in vacuo. The remaining residue was purified via HPLC (Chromolith prep. RP18, Solvent A water:acetonitrile 90:10+0.1% formic acid, solvent B: water:acetonitrile 10:90+0.1% formic acid, flow: t=0 min 25 ml/min, t=1 min 50 ml/min, gradient: t=0 min 10% B, t=1 min 10% B, t=2 min 10% B, t=2.2 min 20% B, t=7.5 min 50% B, t=7.6 min 100% B, t=8.5 min 100% B). After evaporation of the solvent in vacuo 7,8-Dichloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid pyridine-2-ylamide was obtained as a white powder in a yield of 14%. LC-MS: 1.9 min, 351.0 (MH+), 1H-NMR: (DMSO-d6, 500 MHz): □ [ppm]: 10.543 (s, 1H), 8.304 (s, 1H), 8.135 (d, 1H, J=8.1 Hz), 7.809 (t, 1H, J=7.6 Hz), 7.758 (s, 1H), 7.524 (s, 1H), 7.114 (s, 1H), 4.652 (m, 1H, J=2.8 Hz), 4.360 (t, 1H, J=8.9 Hz), 4.042 (m, 1H, J=4.9 Hz), 2.512 (m, 2H, J=1.8 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]2[N:4]([N:5]=[C:6]([CH2:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:45])[CH:21]([O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:37])[CH3:36])=[CH:31][C:30]=4[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=3)[NH:7]2)[N:3]=1.[Br:46]N1C(=O)CCC1=O>O1CCCC1.ClCCl>[Br:46][C:9]1[C:2]([CH3:1])=[N:3][N:4]2[C:8]=1[NH:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:45])[CH:21]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH2:38][CH3:39])([CH3:36])[CH3:37])=[CH:31][C:30]=3[C:40]([CH2:43][CH3:44])([CH3:42])[CH3:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:18]=1)=[N:5]2
Reactant: CCCCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(CCCc2nn3nc(C)cc3[nH]2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(CCCc2nn3nc(C)c(Br)c3[nH]2)cc1
Reaction time: 0.5 h

Procedure:
In a mixture of 100 ml of tetrahydrofuran and 500 ml of dichloromethane was dissolved 50.0 g of 6-methyl-2-(3-(4-(2-(2,4-di-tert-amylphenoxy)octaneamido)phenyl)propyl)-1H-pyrazolo(1,5-b)(1,2,4)triazole (J). Thereto, 13.8 g of N-bromosuccinimide was added at room temperature, and stirring was continued for 30 minutes. The resulting reaction mixture was washed with 500 ml each of water for three times, and dried over anhydrous magnesium sulfate. An oily substance obtained by removing the solvent from the reaction mixture by distillation under reduced pressure was fractionated by chromatography on a column of silica gel (eluting solvent; hexane-ethyl acetate (3/1) mixture), and the eluate was concentrated and evaporated to dryness. Thus, the desired intermediate (K), 7-bromo-6-methyl-2-(3-(4-(2-(2,4-di-tert-amylphenoxy)octaneamido)phenyl)propyl)-1H-pyrazolo(1,5-b)(1,2,4)triazole, was obtained. Yield: 49.3 g (87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:13][CH2:14][C:15](=O)[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][C:15]1[C:6]2[C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[S:13][CH:14]=1
Reactant: COC(=O)CC(=O)CSc1cc(OC)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: COC(=O)Cc1csc2cc(OC)cc(C(F)(F)F)c12

Procedure:
Methyl 4-((3-methoxy-5-(trifluoromethyl)phenyl)sulfanyl)-3-oxobutanoate (810 mg) was added to Eaton's reagent (1994 μl) at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was subjected to silica gel column chromatography (EtOAc/hexane) to give methyl(6-methoxy-4-(trifluoromethyl)-1-benzothiophen-3-yl)acetate as a crude product (604 mg). The product was used to the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH:19](O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O.O>C(OCC)(=O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH:19]([Cl:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)CCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
In a mixture of 200 ml of ethyl acetate and 12 g of pyridine is dissolved 11.5 g of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxybutyrate, and 5 ml of thionyl chloride is added to the solution, followed by refluxing with stirring for 1 hour. After cooling, 500 ml of water and 100 ml are added to the reaction solution, followed by extraction. The extract is washed with 0.1N hydrochloric acid and water successively, dried over anhydrous magnesium sulfate and treated with activated carbon. The ethyl acetate is evaporated off to give 10.5 g of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorobutyrate pale yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[O:30]1[CH2:35][CH2:34][N:33](C2C=C(C=CC=2)N)[CH2:32][CH2:31]1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([N:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)[CH:21]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1cccc(N2CCOCC2)c1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(N2CCOCC2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-morpholinoaniline in step 1. MS: 412.5 (M+H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH:7]=[C:8]1[N:12]([CH3:13])[CH2:11][CH2:10][S:9]1>C(O)C>[C:4]([N:7]=[C:8]1[N:12]([CH3:13])[CH2:11][CH2:10][S:9]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: CN1CCSC1=N
Solvent: CCO
Product: CC(=O)CC(=O)N=C1SCCN1C
Temperature: 25 °C

Procedure:
A solution of 13 g. of diketene in 100 ml. of ethanol was added dropwise to an ice-cold solution of 18 g. of 2-imino-3-methylthiazolidine in 100 ml. of ethanol. The mixture was allowed to warm spontaneously to room temperature and then evaporated to dryness. The residue was triturated with ether, collected on a filter and dried in a dessicator to give 2-acetoacetylimino-3-methylthiazolidine, m.p. 43°-45° C.
Reaction SMILES: [F:1][C@:2]([C:14]([F:17])([F:16])[F:15])([CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=[O:4].[H][H]>CCOCC>[F:1][C@:2]([C:14]([F:15])([F:17])[F:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=[O:4]
Reactant: CCCCCC=CC[C@@](F)(C(=O)O)C(F)(F)F
Reactant: [H][H]
Solvent: CCOCC
Product: CCCCCCCC[C@@](F)(C(=O)O)C(F)(F)F
Yield: 84.4 %

Procedure:
In 120 ml of ether was dissolved 10 g (39 mmol) of (R)-2-fluoro-2-(trifluoromethyl)-4-decenoic acid, and 3 g of activated carbon having 5% palladium supported thereon was added to the above-obtained solution. The resulting mixture was vigorously stirred under an atmospheric-pressure hydrogen atmosphere for 96 hours. Subsequently, the reaction mixture was filtered through Celite, and the solvent was removed under reduced pressure, thereby obtaining 8.5 g of (R)-(+)-2-fluoro-2-(trifluoromethyl)decanoic acid having the physical properties as mentioned hereinbefore, in a yield of 85%.
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:9][C:10]([NH:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:43]=[CH:44][CH:45]=1)[CH2:20][CH2:21][NH:22][C:23]1[C:24](=[O:42])[N:25]([CH2:31][C:32]([O:34]CC2C=CC=CC=2)=[O:33])[C:26]([CH3:30])=[C:27](Cl)[N:28]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>[Pd].C(#N)C>[C:5]([O:9][C:10]([NH:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:43]=[CH:44][CH:45]=1)[CH2:20][CH2:21][NH:22][C:23]1[C:24](=[O:42])[N:25]([CH2:31][C:32]([OH:34])=[O:33])[C:26]([CH3:30])=[CH:27][N:28]=1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: Cc1c(Cl)nc(NCCc2cccc(COCCNC(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC#N
Product: Cc1cnc(NCCc2cccc(COCCNC(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Ammonium formate (425 mg, 6.74 mmol) and 10% palladium on charcoal (200 mg) was added to a solution of benzyl 2-[3-{[3-({2-[(tert-butoxycarbonyl)amino]ethoxy}methyl)phenethyl]amino}-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 106) (392 mg, 0.67 mmol) in acetonitrile (10 ml), and the reaction stirred at room temperature overnight. The reaction mixture was filtered through Whatman® fibre, and the filtrate concentrated under reduced pressure. The residue was suspended in dichloromethane, basified using I N NaOH solution, and re-acidified to pH 4, using 1N hydrochloric acid. This solution was extracted with ethyl acetate (3×), and the combined organic extracts dried over MgSO4 and evaporated under reduced pressure to give the title compound as a white foam, (180 mg, 58%).
Reaction SMILES: [Si]([O:8][C@H:9]([C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([NH:55][CH:56]=[O:57])[CH:49]=1)[CH2:10][NH:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:27][CH2:26]2)=[O:22])=[C:15]([CH3:47])[CH:14]=1)(C(C)(C)C)(C)C.F.F.F.C(N(CC)CC)C>ClCCl>[CH:56]([NH:55][C:50]1[CH:49]=[C:48]([C@@H:9]([OH:8])[CH2:10][NH:11][CH2:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([NH:20][C:21]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32](=[O:46])[NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:27][CH2:26]3)=[O:22])=[C:15]([CH3:47])[CH:14]=2)[CH:53]=[CH:52][C:51]=1[OH:54])=[O:57]
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Agent: F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylamino]methyl}-2,5-dimethylphenylcarbamoyl)-ethyl]piperidin-4-yl ester (238 mg, 0.30 mmol) in dichloromethane (3.0 mL) was added triethylamine trihydrofluoride (147 μL, 0.90 mmol). This mixture was stirred at room temperature overnight and then the mixture was concentrated under reduced pressure. The residue was purified by prep-RP-HPLC (gradient: 2 to 50% acetonitrile in water with 0.05% TFA). The appropriate fractions were collected and combined and lyophilized to give biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester as the ditrifluoroacetate salt (50 mg, 97% purity). LPLC (2-90) Rt=2.76; [M+H+] found 680.8.
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@H:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:14]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:13][C@@H:10]2[CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(=[CH:52][P:53](=[O:68])([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[O:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[O:61]([P:53]([O:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)([CH:52]=[CH:11][C@H:10]1[O:13][C@H:14]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:9]1[O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:68])[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: O=C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: O=P(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Product: O=P(C=C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)(Oc1ccccc1)Oc1ccccc1

Procedure:
An 880 mg portion of 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose was dissolved in 6 ml of dry toluene and treated with 1.11 g of diphenyl triphenylphosphoranylidenemethylphosphonate at reflux temperature for 36 hours. Purification by chromatography, eluting with hexane:ethyl acetate afforded 660 mg of the desired compound.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>CS(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)[C@H](Cc1ccccc1)Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
L-Phenylalanine (8.3 g, 0.05 mol) and 4.8 g (0.025 mol) of 2,5-dichloronitrobenzene were dissolved in 40 ml of anhydrous dimethyl sulfoxide (DMSO), and the stirred solution was heated to 80° C. under an argon atmosphere. Potassium tert.-butylate (4.2 g, 0.025 mol), dissolved in 30 ml of DMSO, was added dropwise in the course of 40 minutes. Stirring was continued for 3 hours at 80 to 90° C., the mixture was allowed to cool, and unreacted phenylalanine was removed by filtration with suction and washed with water. The collected alkaline filtrates were extracted twice using diethyl ether to remove unreacted dichloronitrobenzene. The mixture was then acidified using glacial acetic acid and extracted several times using ethyl acetate, and the extracts were dried over magnesium sulfate and evaporated.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][C:38]([C:41]#[N:42])=[N:39][CH:40]=2)O1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[N:37][C:38]([C:41]#[N:42])=[N:39][CH:40]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1(C)OB(c2cnc(C#N)nc2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3cnc(C#N)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (Peak 2, Example 49, Step 7) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (Frontier, Cat. No. C2065). LCMS (M+H)+: m/z=442.2.