Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[CH3:20][C:21]1[N:22]=[N:23][S:24][C:25]=1[C:26]([NH:28][NH2:29])=O>>[CH3:20][C:21]1[N:22]=[N:23][S:24][C:25]=1[C:26]1[O:15][C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)=[N:29][N:28]=1
Reactant: N#Cc1ccc2c(ccn2CC(=O)O)c1C(F)(F)F
Reactant: Cc1nnsc1C(=O)NN
Product: Cc1nnsc1-c1nnc(Cn2ccc3c(C(F)(F)F)c(C#N)ccc32)o1

Procedure:
Synthesized as described in Example 35C from [5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 4-methyl-1,2,3-thiadiazole-5-carbohydrazide: MS (ES) m/z 391 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:14]([NH2:24])[C:15]1[CH:23]=[CH:22][C:21]2[O:20][CH2:19][O:18][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[CH2:19]1[O:20][C:21]2[CH:22]=[CH:23][C:15]([CH2:14][NH:24][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:16][C:17]=2[O:18]1
Reactant: CSc1ccc2ncnc(Cl)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CSc1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 83.4 %

Procedure:
4.12 g (0.0196 mol) of 4-chloro-6-methylthioquinazoline, 3.70 g (0.0245 mol) of piperonylamine and 3.50 g (0.0330 mol) of sodium carbonate were mixed with 100 ml of isopropyl alcohol. The obtained mixture was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from chloroform/n-hexane to give 5.32 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]#[N:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:27]=1.[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O.[Zn+2].[Br-].[Br-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12]([N:11]=3)=[CH:13][CH:14]=[C:15]([C:25]3[NH:30][N:29]=[N:28][N:26]=3)[CH:16]=4)=[CH:7][C:6]=2[CH:27]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)N(C)c1nc2cc(C#N)ccc2nc1-c1cc2cc(F)ccc2o1
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N(C)c1nc2cc(-c3nnn[nH]3)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 130 °C
Reaction time: 48 h
Yield: 36.9 %

Procedure:
To a solution of 2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carbonitrile (150 mg, 0.42 mmol) in DMSO (30 ml) and water (2 ml) was added ZnBr2 (46.9 mg, 0.21 mmol) and NaN3 (81.3 mg, 1.25 mmol), and the resulting mixture was stirred for 48 h at 130° C. The reaction mixture was quenched with water (100 ml) and adjusted to pH 3 with HCl (2N), extracted with ethyl acetate (4×60 ml), and the organic layers combined and concentrated in vacuo to give the residue, which was purified by silica gel column chromatography (12% methanol in dichloromethane) to afford 3-(5-fluorobenzofuran-2-yl)-N-methyl-N-(propan-2-yl)-7-(1H-tetrazol-5-yl)quinoxalin-2-amine as a yellow solid (62.6 mg, 37%).
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7](=[O:21])[C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[C:9]=1[F:20])([CH3:5])[CH3:4].S(Cl)(Cl)=O.[H-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[F:20][C:9]1[C:10]([C:16]([F:17])([F:18])[F:19])=[C:11]([F:15])[C:12]([F:14])=[CH:13][C:8]=1[C:7]1[O:21][CH2:5][C:3]([CH3:4])([CH3:2])[N:6]=1
Reactant: CC(C)(CO)NC(=O)c1cc(F)c(F)c(C(F)(F)F)c1F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)COC(c2cc(F)c(F)c(C(F)(F)F)c2F)=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
A solution of 5.81 g (18.4 mmol) of N-(2-hydroxy- 1,1-dimethylethyl)-2, 4,5-trifluoro-3-(trifluoromethyl)benzamide in 100 mL of chloroform at 0° C. was treated dropwise with 5 mL of thionyl chloride. The mixture was allowed to warm to room temperature overnight. The solution was concentrated to a yellow oil which was dissolved in 20 mL of DMF and treated with 0.8 g (21.6 mmol) of 60% sodium hydride. This reaction mixture was stirred at room temperature for 18 hours, then poured into 50 mL of dilute NaHCO3. The solution was extracted with ethyl acetate; the organic phase was washed with water and dried over magnesium sulfate. Concentration in vacuo gave an orange oil which was chromatographed on silica, eluting with 2% methanol in chloroform, to give 2.62 g of a yellow oil.
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[C:22]1([CH3:31])[C:23]([N:28]=[C:29]=[O:30])=[CH:24][CH:25]=[CH:26][CH:27]=1>O1CCCC1>[CH3:31][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1
Reactant: Cc1ccccc1N=C=O
Reactant: C#CCN1CCCc2ccc(O)cc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN1CCCc2ccc(OC(=O)Nc3ccccc3C)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (250 mg, 1.34 mM) and triethylamine (0.2 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, o-tolyl isocyanate (250 mg/ml, 2.01 mM) was added at once and then the reaction mixture was further stirred for 48 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:19) to give 10a as solid. Yield: 300 mg, 70.13%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH3:38][N:39]([CH3:49])[C:40](=[O:48])[CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][C:40]([N:39]([CH3:49])[CH3:38])=[O:48])[CH2:47][CH2:46]3)=[O:28])[C@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 709.3 [(M+H)+]
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=N)OCC)[CH:19]=1.C([O-])(=O)C.[Na+]>C(O)C>[N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:24]([C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)=[N:15][C:10]=3[CH:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=N)c1cccnc1
Reactant: CC(c1ccc(N)c(N)c1)n1ccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccc2[nH]c(-c3cccnc3)nc2c1)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 5.05 parts of 4-[1-(1H-imidazol-1-yl)ethyl]-1,2-benzenediamine, 6.45 parts of ethyl 3-pyridinecarboximidate dihydrochloride, 4.27 parts of sodium acetate and 80 parts of absolute ethanol was stirred first for 16 hours at room temperature and for 1 hour at reflux. The reaction mixture was evaporated. There were added successively 50 parts of water and ammonium hydroxide. The product was filtered off, washed with water and 2-propanol and crystallized from ethanol. The product was filtered off and dried, yielding 5.1 parts (70%) of 5-[1-(1H-imidazol-1-yl)ethyl]-2-(3-pyridinyl)-1H-benzimidazole; mp. 253.7° C. (compound 189).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=[O:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH:23]=O>N1CCCCC1.C(O)C>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH:23]=[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.5 %

Procedure:
A mixture of 5-carboxy-2-oxindole (88.5 mg), indole-2-carbaldehyde (87 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (1 drop) in ethanol (3 mL) was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was filtered and acidified with 2N hydrochloric acid. The resulting solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven to give 60 mg (40% yield) of 3-(1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid as a mustard-colored solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][CH3:14])[C:6](=[O:15])[CH2:5]2.[CH3:16][O:17][C:18]([C@@H:20]1[O:22][CH2:21]1)=[O:19].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:19])[C@H:20]([OH:22])[CH2:21][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][CH3:14])[C:6](=[O:15])[CH2:5]2
Reactant: COC(=O)[C@H]1CO1
Reactant: CCCN1C(=O)Cc2cc(N)cc(F)c21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCN1C(=O)Cc2cc(NC[C@@H](O)C(=O)OC)cc(F)c21

Procedure:
5-Amino-7-fluoro-1-propyl-1,3-dihydro-indol-2-one (0.300 g, 1.44 mmol), methyl (2R)-glycidate (0.147 g, 1.44 mmol) and lithium trifluoromethanesulfonate (0.220 g, 1.44 mmol) in acetonitrile (5 ml) are heated at 90° C. for 8 hours. The reaction is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (5% methanol/dichloromethane) to give the title compound as a yellow solid. HPLC r.t. 4.03 min; MS for C15H19FN2O4 m/z 311.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([O:11]C(C)(C)C)=O)[C:5]([OH:7])=[O:6])[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(C(F)(F)F)=O.[CH3:38][CH:39]([C@H:41]([NH2:60])C(OCCOCN1C2NC(N)=NC(=O)C=2N=C1)=O)[CH3:40]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:38][CH:39]([C@H:41]([NH2:60])[C:9]([NH:8][C@H:4]([C:5]([OH:7])=[O:6])[CH:2]([CH3:1])[CH3:3])=[O:11])[CH3:40]
Reactant: CC(C)[C@H](N)C(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
Boc-VAL, DCC, DMF, 0° C., 1 hr, ii) DMAP, DMF, 18 hrs, rt iii) TFA, 0° C., 30 min, iv) Boc-Val, DCC, DMF, 0° C., 1 hr, v) TEA, rt, vi) adding Boc-Val amino acid anhydride (step iv) to the neutralized Val-ACV (step v), 5 hrs, rt, vii) TFA, 0° C., 30 min.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31](=[O:34])(=[O:33])[NH2:32])=[CH:21][CH:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>N1C=CC=CC=1>[C:35]([NH:32][S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:7]2=[O:17])=[CH:20][CH:21]=1)(=[O:33])=[O:34])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Solvent: c1ccncc1
Product: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.8 %

Procedure:
To a solution of 41.4 mg (0.0834 mmole) of 5-n-butyl-2-(2-chlorophenyl)-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step B) in 1 ml of dry pyridine stirred at room temperature under argon was added 97 μl (117 mg, 0.836 mmole) of benzoyl chloride. The resulting solution was stirred at room temperature for 12 hours and then treated with saturated NaH2PO4 solution. The mixture was extracted 3× with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was flash chromatographed twice on silica gel (elution with 6-7% MeOH in CH2Cl2 containing 0.2-0.4% concd. NH4OH) to give 30 mg (60%) of the title compound as a white solid; satisfactory purity by TLC in 94:6:0.2 CH2Cl2 --MeOH-concd. NH4OH; mass spectrum (FAB) m/e 601 (M+1)+.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]=[C:14]([CH:5]2[CH:6]([C:11]([OH:13])=[O:12])[CH:7]3[CH2:10][C:4]2([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]3)[OH:15])=[CH:18][CH:19]=1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: Nc1ccc(O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=Nc1ccc(O)cc1

Procedure:
A solution of 101 g of allylbicylo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride and 54.5 g of 4-aminophenol in 155 g of toluene is heated to boiling point, and the water formed during imidation is separated in a Hahn stillhead.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37](O)=[O:38])=[CH:33][CH:32]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:78][CH2:79][C:80]([NH:82][C@@H:83]([C:91]([OH:93])=[O:92])[CH2:84][CH:85]1[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]1)=[O:81]>CN(C=O)C>[Si:1]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH:22]=2)[C@@H:13]1[C:31]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([NH:78][CH2:79][C:80]([NH:82][C@@H:83]([C:91]([OH:93])=[O:92])[CH2:84][CH:85]2[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]2)=[O:81])=[O:38])=[CH:40][CH:41]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)O)cc1)c1ccc(F)cc1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)NCC(=O)N[C@H](CC2CCCCC2)C(=O)O)cc1)c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 0.08 h

Procedure:
{4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 8) (25.1 mg, 0.040 mmol) was dissolved in DMF (1 ml, dry). N-methylmorpholine (13 μl, 121 mmol) was added and the reaction mixture was stirred at 30° C. for five minutes. TBTU (20.1 mg, 0.063 mmol) was added and the reaction mixture was stirred at 30° C. for 1 hour. Glycyl-3-cyclohexyl-D-alanine (12.5 mg, 0.055 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was purified with preparative HPLC on a C8 column. A gradient from 10 to 100% MeCN in 0.1M NH4OAc buffer was used as eluent. Most of the MeCN was removed under reduced pressure. The residue was diluted with water and lyophilised to give the title compound, M/z: 921 (M−1).
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=O)[CH:12]=[N:13][CH:14]=1.O>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH:12]=[N:13][CH:14]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)S(=O)N=Cc1cncc(Br)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 101.4 %

Procedure:
To a solution of 2-methyl-propane-2-sulfinamide (11 g, 91 mmol) and 5-bromo-3-pyridine-carboxaldehyde (14 g, 75 mmol) in dichloromethane (500 mL) is added titanium isopropoxide (43 g, 150 mmol). The reaction is then heated at reflux (bath temperature=60° C.) for 4 hours. The resultant mixture is cooled to room temperature and poured into a stirred mixture of diatomaceous earth (50 g) and water (150 mL). The slurry is stirred for 10 min and then filtered. The organic layer from the filtrate is washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo affords 2-methyl-propane-2-sulfinic acid 1-(5-bromo-pyridin-3-yl)-methylideneamide as a yellow solid (22 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[N:6][NH:5][C:4](=[S:9])[C:3]=1[C:10]#[N:11].C([O-])(=O)C.[Na+].Cl[CH2:18][C:19]#[N:20]>C(O)C.CC(O)C>[NH2:11][C:10]1[C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[N:5][C:4]=2[S:9][C:18]=1[C:19]#[N:20]
Reactant: Cc1n[nH]c(=S)c(C#N)c1C
Reactant: N#CCCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCO
Product: Cc1nnc2sc(C#N)c(N)c2c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The 5,6,-dimethyl-3-thioxo-2,3-dihydropyridazine-4-carbonitrile (99 mg, 0.60 mmol) was stirred in ethanol (6.0 mL). Sodium acetate (50 mg, 0.60 mmol) and chloroacetonitrile (0.040 mL, 0.60 mmol) were added and the mixture was stirred at ambient temperature for 90 minutes. The mixture was then diluted with IPA, stirred for 15 minutes, and filtered. The solute was concentrated in vacuo, and the resulting solid was dried overnight at 60° C. in a vacuum oven to give the product. LC/MS: RT=0.38 min., m/z=205 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:23][C:24](OC(C)=O)=[O:25]>>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH:16][C:24](=[O:25])[CH3:23])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Product: CC(=O)Nc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylpyrimidine-4,5-diamine (350 mg, 1.19 mmol, 1.0 eq) and Ac2O (12 mL) was stirred at rt for 3 h and concentrated. The residue was dissolved in MeOH (3 mL). Sat. aqueous NaOH was added dropwise until pH=12 and stirred for 10 minutes. The final mixture was concentrated and purified by silica gel chromatography (hexane/EtOAc=10:1 as eluent)) to obtain target product N-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-phenylpyrimidin-5-yl)acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](=[O:14])[CH3:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C(C1C2C(=CC=C(OC(F)(F)F)C=2)N([CH2:32][C:33]([OH:35])=[O:34])C=1)(=O)C>>[C:12]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH2:32][C:33]([OH:35])=[O:34])[CH:8]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: COc1ccc2c(C(C)=O)c[nH]c2c1
Product: COc1ccc2c(C(C)=O)cn(CC(=O)O)c2c1

Procedure:
was prepared from 1-(6-methoxy-1H-indol-3-yl)-ethanone [99532-52-2] in a similar manner as described in step B and C of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Brown solid. MS: 248 [M+H]+, 517 [2M+Na]+; tR (HPLC conditions k): 2.30 min.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH:4]([OH:28])[C@@H:5]([NH:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH3:7])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:5]([CH2:6][CH3:7])[CH:4]([OH:28])[C:2]([CH3:29])([CH3:3])[CH3:1]
Reactant: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)C(O)C(C)(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of (3RS,4S)-2,2-dimethyl-4-(trityl-amino)-hexan-3-ol (0.47 g, 1 eq, 1.21 mmol) in DCM (10 mL) under an argon atmosphere at room temperature, was added CF3COOH (5 mL) dropwise, and the solution was stirred at this temperature for 1 h. The solvent was evaporated in vacuo, the residue was precipitated: from Et2O (3 mL) with hexane (20 mL) with stirring to give a yellow oil. The solvent was decanted from the oil, and the oil was washed-with hexane (20 mL) and dried in vacuo to afford the title compound as a light yellow oil. Yield: 0.18 g (99%). (53% de 3R,4S: 47% de 3S,4S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.86-0.99 (m, 3H, NH2CH(CH2 CH3)CH(C(CH3)3)OH), 1.25-1.30 (m, 9H, NH2CH(CH2CH3) CH(C(CH3)3OH), 1.20-1.67 (m, 2H, NH2CH(CH2CH3)CH(C(CH3)3)OH), 3.14 (m, 1H, NH2CH(CH2CH3) CH(C(CH3)3)OH), 3.38 (m, 1H, NH2CH(CH2CH3) CH(C(CH3)3)OH, 3.64 (m, 1, NH2CH(CH2CH3)CH(C(CH3)3)OH), 7.41, 7.73 & 8.44 (3×bs, 2H, NH2CH(CH2CH3) CH(CH(CH3)2)OH).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7].[OH-].[K+]>CCO>[C:18]1([C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9][C:8]=2[C:6]([NH:5][CH2:4][C:3]([OH:24])=[O:2])=[O:7])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CNC(=O)c1ncc2ccccc2c1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1ncc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
A mixture of [(4-Phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid methyl ester (144 mg, 0.45 mmol), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at ambient temperature for 18 h before the solvent was evaporated in vacuo. The residue was dissolved in water. The pH of the solution was adjusted to 3-4 by addition of concentrated aqueous HCl. The solution was then extracted with EtOAc (2×25 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a yellowish solid (127 mg); MS-(+)-ion: M+1=307.1.
Reaction SMILES: [OH:1][C:2]([C:22]([F:25])([F:24])[F:23])([CH3:21])[CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH3:20].C(Cl)Cl>[Pd].O>[OH:1][C:2]([C:22]([F:25])([F:24])[F:23])([CH3:21])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH3:20]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CC(C)(O)C(F)(F)F)cc12
Agent: [Pd]
Solvent: ClCCl
Solvent: O
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCC(C)(O)C(F)(F)F)cc12

Procedure:
Obtained from the title compound of Example 96 by a procedure similar to that described in Example 2, but using 10% palladium on charcoal as catalyst, as a foam. Rf 0.40 (SS 7). Found: C,59.55; H,6.86; N,7.10. C19H25F3N2O; 0.17 CH2Cl2 ; H2O requires C,59.55; H,7.13; N,7.25%. LRMS: m/z 355.0 (M+1)+.