Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([F:11])=[C:4]([F:10])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C(OCC)C.C([Li:21])(CC)C>CCCCCC>[F:1][C:2]1[C:7]([Li:21])=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: [Li]C(C)CC
Reactant: Fc1cc(F)c(F)c(F)c1F
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]c1c(F)c(F)c(F)c(F)c1F
Temperature: -65 °C

Procedure:
Inside of a 100 ml volume glass three-neck flask equipped with a 50 mol volume glass dropping funnel, temperature resistor and septum rubber was sufficiently replaced with nitrogen. Into the flask, 5 g (29.8 mmol) of pentafluorobenzene and 30 ml of diethyl ether were charged, of which solution was cooled to -65° C. Thereafter, 14.2 g (34.3 mmol) of 15.5 wt. % hexane solution of sec-butyllithium charged into the dropping funnel were added dropwise while making the inner temperature not to exceed -55° C. After the completion of dropwise addition, the reaction mixture was kept at a temperature of -65°~-55° C. with stirring to give pentafluorophenyllithium. The yield of pentafluorobenzoic acid obtained by blowing of carbon dioxide into the prepared solution of pentafluorophenyllithium was 96.8% by means of gas chromatographic quantitative determination.
Reaction SMILES: C([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5]1)(=O)N.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.C(#[N:44])C>O>[NH2:44][C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5]1
Reactant: CC#N
Reactant: NC(=O)[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: N[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Benzyl N-[(1S,3R)-3-carbamoylcyclohexyl]carbamate, 18d, (9.1 g, 32.9 mmol) was suspended in a mixture of acetonitrile (100 mL) and water (100 mL) and treated with bis(trifluoroacetoxy)iodobenzene (15.5 g, 36.1 mmol). The suspension was allowed to stir at room temperature overnight and was then quenched with 1N HCl (100 mL). After evaporation of the acetonitrile, the acidic aqueous solution was washed with EtOAc (2×150 mL). The pH was adjusted to basic by addition of solid KOH and the resulting emulsion was extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide product 18e (6.2 g, 75% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)[CH:30]=1)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2cnnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2cnnn2)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) and 3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionic acid ethyl ester (Example H15) according to the general procedure K. Obtained as a light red solid (129 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1OC)=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:45][C:46]([F:56])([F:55])C1C=CC(CN)=CC=1>>[Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:46]([F:56])([F:55])[F:45])=[CH:29][CH:28]=1)=[O:24])=[CH:17]2)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Product: C[C@H](Cc1ccc2[nH]c(C(=O)NCc3ccc(C(F)(F)F)cc3)cc2c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1

Procedure:
Prepared analogously to 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(2-methoxybenzyl)-1H-indole-2-carboxamide using 4-trifluoromethylbenzylamine to give the title compound as a pale brown foam.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:10](=[O:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Brc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncccn2)C(=O)C1
Temperature: 25 °C
Yield: 22.1 %

Procedure:
To 1-Boc-3-oxopiperazine 3a (390 mg, 1.95 mmol) in DMF (5 mL) at 0° C. was added NaH (60% in oil, 97 mg, 2.44 mmol). The reaction was stirred at 0° C. for 25 min before a solution of 2-bromopyrimidine 1i (465 mg, 2.92 mmol) in DMF (2 mL) was added. The reaction was slowly warmed up to room temperature overnight. To the reaction mixture was added H2O, and the resulting mixture was extracted with EtOAc. The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 3% MeOH/CH2Cl2) gave 3b as yellow oil (120 mg).
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH:14]1([C:17]2[N:22]=[C:21]([C:23]3[NH:40][C:26]4=[N:27][C:28]([N:31]5[CH2:36][CH2:35][CH2:34][C@@H:33]([C:37](O)=[O:38])[CH2:32]5)=[CH:29][CH:30]=[C:25]4[N:24]=3)[CH:20]=[CH:19][N:18]=2)[CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH:14]1([C:17]2[N:22]=[C:21]([C:23]3[NH:40][C:26]4=[N:27][C:28]([N:31]5[CH2:36][CH2:35][CH2:34][C@@H:33]([C:37]([N:4]6[CH2:5][CH2:6][C@H:2]([F:1])[CH2:3]6)=[O:38])[CH2:32]5)=[CH:29][CH:30]=[C:25]4[N:24]=3)[CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1
Reactant: F[C@H]1CCNC1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1)N1CC[C@H](F)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
(S)-3-Fluoropyrrolidine (175 μmol) was added to a vial followed by N,N-dimethylformamide (200 μL), triethylamine (35 μL, 250 μmol) and (R)-1-(2-(2-cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (200 μL, 50 μmol, 0.25 M in N,N-dimethylformamide) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (250 μL, 100 μmol, 0.4 M solution in N,N-dimethylformamide). The reaction mixture was shaken at 50° C. for 16 h. The solvent was evaporated by Speedvac and the residue was purified via preparative HPLC to afford the title compound. MS API-ES+ (M+H) 436; HPLC retention time 2.521 min (Method C).
Reaction SMILES: Cl.C1(C(=[N:15][C:16]2[S:20][CH:19]=[N:18][C:17]=2[C:21]([O:23][CH3:24])=[O:22])C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:15][C:16]1[S:20][CH:19]=[N:18][C:17]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ncsc1N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ncsc1N
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Aqueous 3N HCl (1 mL) was added to a solution of methyl 5-(diphenylmethyleneamino)thiazole-4-carboxylate (1.22 g, 3.81 mmol) in THF (5 mL). The reaction mixture was stirred for 1 h and the white solid which had formed was isolated by filtration to give methyl 5-aminothiazole-4-carboxylate (0.527 g, 2.72 mmol, 71%). Retention time (min)=0.422, method [7], MS (ESI) 159.0 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:33](=[O:43])[N:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:35])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:36]([N:34]([CH3:35])[C:33]([C@@H:9]1[CH2:10][C@@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][NH:8]1)=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1
Yield: 94.3 %

Procedure:
19176 B73: A solution of 9.68 g (16.33 mmol) (2S,4R)-2-(Benzyl-methyl-carbamoyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 33 ml CH2Cl2 was treated at −20° C. with 36 ml TFA, warmed up to RT during 5.5h and kept over night at 0° C.. The reaction was evaporated and treated with aqueous saturated NaHCO3 solution/EtOAc (3×), the organic phase was dried (Na2SO4) and evaporated to give 7.59 g (95%) (2S,4R)-4-Tritylsulfanyl-pyrrolidine-2-carboxylic acid benzyl-methyl-amide, MS: 493 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.[Pt]=O.C(O)C>[CH2:14]([N:17]([CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1)[CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CCCNCCC
Agent: O=[Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: c1ccccc1
Product: CCCN(CCC)C1CCc2ccc(OC)cc2C1
Yield: 69.8 %

Procedure:
7-Methoxy-2-tetralone (35.1 g, 0.20 mole) was dissolved in dry benzene (1000 ml) and put in a 2000 ml three neck-flask. To this solution was added dipropylamine (109 ml, 0.80 mole) and p-toluenesulfonic acid monohydrate (34 g, 0.2 mole). This mixture was refluxed under nitrogen with continuous water removal for 48 hr. The benzene was replaced by ethanol (600 ml, anhydrous) and the solution was hydrogenated in a 2 liter pressure bottle over platinum oxide (1.0 g) under 2 atmospheres of pressure at room temperature for 2.5 hr. The solution was filtered through cellulose powder and concentrated. Benzene was added to the filtrate. The organic solution was basified with 10% sodium hydroxide, washed with water and extracted with 5% hydrochloric acid. The aqueous solution was basified with 10% sodium hydroxide and extracted with diethyl ether. The organic extract was dried and evaporated to give a brown liquid (36.5 g) of N,N-dipropyl-7-methoxy-1,2,3,4-tetrahydro-2-naphthylamine. A sample was purified by chromatography through a column of silica gel using 2% methanol-chloroform mixture as eluant. The hydrochloride salt was prepared and crystallized from methanol and diethyl ether: mp 152-157° C., and Anal. Calcd for C17H28NOCl.1/2H2O:C, 66.53%;H, 9.45%;N, 4.56%; and Found:C, 66.39%;H, 9.40%;N, 4.39%.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[N:4][C:5]([CH3:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:13][C:14]([F:25])([F:24])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OC(C)C)=O)(C(OC(C)C)=O)=[N-]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[N:4][C:3]=1[O:12][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:14]([F:13])([F:25])[F:24]
Reactant: Cc1nc(O)c(Br)cc1[N+](=O)[O-]
Reactant: OC(c1ccc(F)cc1)C(F)(F)F
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(OC(c2ccc(F)cc2)C(F)(F)F)c(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 6 h
Yield: 62.5 %

Procedure:
To a stirred suspension of 3-bromo-6-methyl-5-nitro-pyridin-2-ol (0.10 g, 0.43 mmol) in THF (3 mL), 2,2,2-trifluoro-1-(4-fluorophenyl)ethanol (0.13 g, 0.64 mmol, 1.5 equiv) and triphenylphosphine (0.17 g, 0.64 mmol, 1.5 eq) were added at room temperature under inert atmosphere (Ar). To this mixture, DIAD (diisopropyl diazodicarboxylate) (0.13 mL, 0.64 mmol, 1.5 eq) was added dropwise over 10 minutes while keeping the temperature below 40° C. The reaction mixture was stirred for 6 h under heating at 60° C. After this time, TLC indicted that the starting material had been consumed and the reaction mixture was allowed to reach room temperature before quenching with water (10 mL). The water phase was extracted with ethyl acetate (3×15 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give a brown residue, which was purified by combiflash column chromatography (silica gel, heptane/ethyl acetate, v/v=95/5). Fractions containing the pure compound were collected and concentrated in vacuo to give the title compound (0.11 g, 62% yield) as a yellow oil.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Br.Br.[NH2:12][C:13]1[C:17]([NH2:18])=[CH:16][S:15][CH:14]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[N:27]=[C:28]=[S:29]>C1COCC1>[NH2:12][C:13]1[C:17]([NH:18][C:28]([NH:27][C:21]2[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=2[Cl:19])=[S:29])=[CH:16][S:15][CH:14]=1
Reactant: Cc1cccc(Cl)c1N=C=S
Reactant: Nc1cscc1N
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1NC(=S)Nc1cscc1N

Procedure:
was obtained in a similar manner to the method specified in Example 6a) by reacting a mixture prepared from 0.74 g (=1.01 ml) of N-ethyl-N,N-diisopropylamine in 40 ml of THF, 0.8 g of 3,4-diaminothiophene dihydrobromide and 0.473 g of 2-chloro-6-methylphenyl isothiocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:15](Cl)=[O:16])[CH2:7][CH2:6]2.[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23]C(=O)C1C=CC=CC=1>>[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:15]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)=[O:16]
Reactant: COc1cc2c(cc1OC)CN(C(=O)Cl)CC2
Reactant: O=C(NCCCCO)c1ccccc1
Product: COc1cc2c(cc1OC)CN(C(=O)NCCCCO)CC2
Yield: 67 %

Procedure:
6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (4-hydroxy-butyl)-amide (25B) is prepared from 25A as described for 1D.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:20])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-bromo-3-methylbenzoic acid (8.6 g, 40.0 mmol) in CH2Cl2 was added DMF (0.4 mL), followed by oxalyl chloride (3.7 mL, 42 mmol) slowly over 10 minutes by syringe. The reaction was stirred for 1 hour at room temperature, and then concentrated to give the title compound.
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[N:20]=[CH:19][C:18]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[OH-].[K+].Cl>C(Cl)Cl>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[C:18]1[CH:19]=[N:20][C:12]([C:10]2[NH:2][C:1](=[O:3])[C:4]([CH:5]([CH3:7])[CH3:6])([CH3:8])[N:9]=2)=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: CC(C)C(C)(NC(=O)c1ncc(C2OCCO2)cc1C(=O)O)C(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)C1(C)N=C(c2ncc(C3OCCO3)cc2C(=O)O)NC1=O
Yield: 3 %

Procedure:
2-[(1-Carbamoyl-1,2-dimethylpropyl)carbamoyl]-5-(1,3-dioxolan-2-yl)nicotinic acid (4.19 g, 0.019 mol) and 15% potassium hydroxide is heated at 80° C. for 1 hour. The reaction mixture is acidified to pH 3 with concentrated hydrochloric acid and methylene chloride is added. The methylene chloride layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oil. The oil is chromatographed using silica gel and methylene chloride with increasing percentage of ether as eluent to give the title compound as a pale yellow solid (0.19 g, 5%), mp 156° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[C:10]2[N:6]([CH2:7][CH2:8][CH2:9]2)[C:5](=[O:12])[CH:4]=1>CC(C)=O>[O:12]=[C:5]1[CH:4]=[C:3]([CH:2]=[O:1])[CH:11]=[C:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2
Reactant: O=c1cc(CO)cc2n1CCC2
Solvent: CC(C)=O
Product: O=Cc1cc2n(c(=O)c1)CCC2
Yield: 101.3 %

Procedure:
A solution of 7-(hydroxymethyl)-2,3-dihydro-5(1H)-indolizinone (237 mg, 1.44 mmol) in acetone (12 ml) was treated with IBX (603 mg, 2.16 mmol) and heated at reflux for 1 h. The mixture was then evaporated, dissolved in dichloromethane and filtered, redissolved in dichloromethane and filtered again to provide the slightly impure desired product (238 mg, 101%)
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[CH:36][CH:35]=4)=[N:18][CH:19]=[C:20]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]4)[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[CH:36][CH:35]=3)=[N:18][CH:19]=[C:20]([CH2:22][N:23]3[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]3)[CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(C)=O)cc3)n2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cc1
Yield: 73.6 %

Procedure:
A solution of N-(4-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)phenyl)acetamide (0.140 g, 0.186 mmol) in trifluoroacetic acid (Aldrich) (1.383 mL, 18.62 mmol) and trifluoromethane sulfonic acid (TCI) (0.494 mL, 5.59 mmol) was stirred at rt in a sealed tube for 1 h. The reaction mixture was first neutralized with sat. NaHCO3 then extracted with CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (120 g, 4% MeOH in DCM) to give the product as a yellow solid (0.070 g). m/z (ESI, +ve ion) 512.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 11.85 (s, 1H); 8.72 (s, 1H); 8.28 (d, J=0.73 Hz, 1H); 7.68 (s, 2H); 7.48 (d, J=8.48Hz, 2H); 7.12 (br. s., 1H); 5.43 (br. s., 2H); 3.53 (s, 2H); 3.26 (br. s., 4H); 2.78 (s, 3H); 2.59 (s, 7H); 2.19 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([C:23]#[C:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[N:32]=[C:33]([C@@H:36]5[CH2:40][C@H:39]([CH3:41])[CH2:38][N:37]5C(OC(C)(C)C)=O)[NH:34][CH:35]=4)=[CH:27][CH:26]=3)=[CH:22][C:16]=2[N:15]=1)=O)(C)(C)C.[ClH:49].O1CCOCC1>CO>[ClH:49].[CH3:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#[C:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]5[N:32]=[C:33]([C@@H:36]6[CH2:40][C@H:39]([CH3:41])[CH2:38][NH:37]6)[NH:34][CH:35]=5)=[CH:29][CH:30]=4)=[CH:22][C:16]=3[N:15]=2)[CH2:10]1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(C#Cc4ccc5[nH]c([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)nc5c4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1CN[C@H](c2nc(-c3ccc(C#Cc4ccc5[nH]c([C@@H]6C[C@H](C)CN6)nc5c4)cc3)c[nH]2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (2S,4S)-2-[4-[4-[2-[2-[(2S,4S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]ethynyl]phenyl]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (56 mg, 0.086 mmol) in methanol (2 mL) is added 4M HCl/dioxane (430 uL, 1.72 mmol). The mixture is stirred at rt for 3 hours. Removal of the solvent under vacuum gives 2-[(2S,4S)-4-methylpyrrolidin-2-yl]-5-[2-[4-[2-[(2S,4S)-4-methylpyrrolidin-2-yl]-1H-imidazol-4-yl]phenyl]ethynyl]-1H-benzimidazole HCl salt. The crude is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:13].[OH-].[K+].[C:16](=S)=[S:17]>C(O)C>[CH2:11]([S:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:13][C:16]([SH:17])=[N:1][C:2]=2[CH:7]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: CCS(=O)(=O)c1ccc(O)c(N)c1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc2oc(S)nc2c1

Procedure:
100 mmol 1-amino-5-ethylsulfonyl-2-hydroxybenzene were dissolved in 200 ml of ethanol and 150 ml of carbon disulfide. 120 mmol of potassium hydroxide was added and the mixture refluxed over night. The solvent was evaporated, the residue treated with 1 M hydrochloric acid, extracted with ethyl acetate and dried. Evaporation gave the crude product which was recrystallized from ethyl acetate to yield the title compound as yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:19]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10](=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:25]
Reactant: Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)Nc1c(C)cc(Cl)cc1C(=O)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step A from (2-amino-5-chloro-3-methyl-phenyl)-phenyl-methanone and methyl 3-chloro-3-oxopropanoate. Brown oil. MS (ESI): 346.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N:17]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>O.CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:8][S:23]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:25])=[O:24])[CH:5]=[N:6][CH:7]=1
Reactant: Oc1cncc(Br)c1
Reactant: O=S(=O)(Cl)N1CCOCC1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(Oc1cncc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is charged with 5-bromo-pyridin-3-ol (0.310 g, 1.78 mmol), potassium phosphate (0.982 g, 4.63 mmol) and acetone (10 mL), and morpholine-4-sulfonyl chloride (0.529 g, 2.85 mmol) is added dropwise at 0° C. The mixture is stirred at room temperature overnight. Saturated NaHCO3 in water (1 mL) is added and the mixture is concentrated in vacuo. The residue is purified on silica gel chromatography eluting with a 9:1 to 4:1 heptane-ethyl acetate gradient to give morpholine-4-sulfonic acid 5-bromo-pyridin-3-yl ester. MS (ESI) m/z 322.9 and 324.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([NH:15]C(OCC2C=CC=CC=2)=O)[C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[NH2:15][C:10]1[C:9](=[O:26])[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])[C:13]([CH3:14])=[CH:12][CH:11]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
ter-Butyl-2-[3-[(benzyloxy)carbonyl]amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate (preparation 4) (5 g, 13 mmol) was dissolved in ethyl acetate (70 ml), treated with 10% Pd on carbon catalyst (400 mg) and stirred under a hydrogen atmosphere (2 psi, room temperature, 3 hr). The catalyst was removed by filtration, and the solvent evaporated to dryness to give the desired product as a cream solid (3.08 g, 99%). 1H NMR (CDCl3) δ 1.40 (s, 9H), 2.20 (s, 3H), 4.00 (s, br, 2H), 4.70 (s, 2H), 5.90 (d, 1H), 6.45 (d, 1H). LRMS m/z=239.5 (M+1)+.