Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][C:51]1[C:55]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)=[C:54]([CH3:63])[O:53][N:52]=1>CN(C=O)C>[CH3:50][C:51]1[C:55]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)=[C:54]([CH3:63])[O:53][N:52]=1
Reactant: Cc1noc(C)c1-c1cccc(N)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4c(C)noc4C)c3)c(=O)oc12
Temperature: 25 °C
Yield: 78.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(3,5-dimethyl-isoxazol-4-yl)-phenylamine (0.012 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.020 g of product in 80% yield: LCMS (ESI) m/z 391 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=1.[Cl:22]NC(=O)CCC(N)=O>CC(O)=O>[Cl:22][C:10]1[C:11]([OH:13])=[N:12][C:7]([S:6][CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([Cl:1])[CH:3]=2)=[N:8][C:9]=1[NH:14][C@H:15]([CH3:18])[CH2:16][OH:17]
Reactant: C[C@H](CO)Nc1cc(O)nc(SCc2cccc(Cl)c2)n1
Reactant: NC(=O)CCC(=O)NCl
Solvent: CC(=O)O
Product: C[C@H](CO)Nc1nc(SCc2cccc(Cl)c2)nc(O)c1Cl
Reaction time: 3 h

Procedure:
The product of Example 3 (0.22 g) was dissolved in AcOH (10 ml), N-chlorosuccinamide (90 mg) added and stirred for 3 h. The volatiles were removed under reduced pressure and the residue purified by reverse phase HPLC with gradient elution in acetonitrile/0.02M ammonium hydroxide (90% to 50% aqueous phase) to yield the title product as a white solid. Yield 0.1 g.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)O1.[NH2:23][C:24]1[C:25]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]3)=[N:26][C:27](Br)=[CH:28][N:29]=1>>[NH2:23][C:24]1[N:29]=[CH:28][C:27]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3([C:20]#[N:21])[CH2:16][CH2:17][CH2:18][CH2:19]3)=[CH:13][CH:14]=2)=[N:26][C:25]=1[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]2
Reactant: Nc1ncc(Br)nc1-c1ccc2c(c1)CCNC2=O
Reactant: CC1(C)OB(c2ccc(C3(C#N)CCCC3)cc2)OC1(C)C
Product: N#CC1(c2ccc(-c3cnc(N)c(-c4ccc5c(c4)CCNC5=O)n3)cc2)CCCC1
Yield: 44 %

Procedure:
General method A was applied to 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopentanecarbonitrile (149 mg, 0.5 mmol) and 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (180 mg, 0.5 mmol) to give 1-(4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)phenyl)cyclopentanecarbonitrile as a yellow solid (89 mg, 0.22 mmol, 44% yield) after purification by preparatory reverse phase HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (s, 1H), 8.02 (d, J=8.3 Hz, 3H), 7.96 (d, J=8.0 Hz, 1H), 7.72-7.78 (m, 1H), 7.70 (s, 1H), 7.57 (m, J=8.5 Hz, 3H), 3.38-3.45 (m, 2H), 2.99 (t, J=6.4 Hz, 2H), 2.37-2.46 (m, 2H), 2.03-2.16 (m, 2H), 1.84-1.94 (m, 4H); MS (EI) m/z=410.5 [M+1]+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29](=[O:35])[N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH:27]=2)[NH:22][C:21]=1[C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([Cl:43])[CH:37]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:33]([N:30]([CH2:31][CH3:32])[C:29]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([Cl:43])[CH:37]=1)=[C:20]2[CH2:19][CH2:18][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:35])[CH3:34]
Reactant: CCN(CC)C(=O)c1ccc2[nH]c(-c3cc(Cl)cc(Cl)c3)c(CCN(CCCCc3cccnc3)C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCN(CC)C(=O)c1ccc2[nH]c(-c3cc(Cl)cc(Cl)c3)c(CCNCCCCc3cccnc3)c2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 71.6 %

Procedure:
To a solution of {2-[2-(3,5-dichlorophenyl)-5-diethylcarbamoyl-1H-indol-3-yl]ethyl}-(4-pyridin-3-yl-butyl)carbamic acid tert-butyl ester (63 mg in 3 mL methylene chloride) at 0° C. was added 0.15 mL anisole followed by 0.76 miL trifluoroacetic acid and the mixture stirred at 0° C. After 1.5 hours, an additional charge of 0.5 mL trifluoroacetic acid was added and stirring continued for another hour at which time the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:6.5:1) gave the title compound (38 mg). m/e=537 (M)
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:46])[C:14]([CH3:45])([CH3:44])[CH2:15][NH:16][C:17]([C:19]1[C:20]([OH:43])=[C:21]2[C:26](=[CH:27][N:28]=1)[N:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24](=[O:36])[C:23]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[CH:22]2)=[O:18])(C)(C)C>C(Cl)Cl>[CH2:29]([N:25]1[C:26]2[C:21](=[C:20]([OH:43])[C:19]([C:17]([NH:16][CH2:15][C:14]([CH3:45])([CH3:44])[C:13]([OH:46])=[O:12])=[O:18])=[N:28][CH:27]=2)[CH:22]=[C:23]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:24]1=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O)C(=O)O
Reaction time: 2 h
Yield: 59.6 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a mixture of 3-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-2,2-dimethyl-propionic acid tert-butyl ester (22 mg, 0.042 mmol) and CH2Cl2 (3 mL), and the resulting mixture was stirred for 2 h. Solvent was evaporated in vacuo, and the residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 11.8 mg of the title compound as a light yellow solid. MS: (+) m/z 472.34 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:18](O)[CH3:19]>CCOCC.CN(C)C=O>[C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O:10][CH2:18][CH3:19])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
Phenylmalonic acid (13.5 g, 0.07 mol) in dry ether (40 mL) was treated with thionyl chloride (8.92 g, 5.4 mL, 0.07 mol) and one drop of N,N-dimethylformamide. The mixture was heated at 40°-50° C. for 3 hours. The clear solution was evaporated under reduced pressure to remove any residual thionyl chloride. The oily residue was redissolved in dry ether (40 mL), the solution was treated with ethanol (0.075 mol, 4.1 mL) and refluxed for 2 hours. The reaction mixture was cooled to room temperature and washed with water. The organic layer was extracted with saturated solution of sodium bicarbonate until alkaline. The combined extracts were washed with ether and the aqueous layer was acidified with 5N HCl to pH 1. The precipitated oil was extracted with CH2Cl2 (50 mL×3). The combined extracts were washed with water (50 mL×4) and dried over anhydrous MgSO4. The oily product crystallized on standing.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:32][C:22]([C:21]2[CH:25]=[CH:26][C:18]([C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:5]4[C:4]([NH:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:11][CH2:12]3)=[O:17])=[N:19][CH:20]=2)=[O:24])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: NC1CCCC1
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC3CCCC3)cn2)CC1
Yield: 76 %

Procedure:
By the same procedure as described in the example 24, the synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using cyclopentylamine. And then, the product was recrystallized with isopropanol and ether to give a desired compound.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.C(N(CC)CC)C.[C:35]1([C:41]2[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[B-]C#N.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[C:41]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:48]=[CH:47][C:44]([CH2:45][N:17]2[CH2:18][CH2:19][CH2:20][N:14]([CH2:13][C:2]3([CH3:1])[O:6][C:5]4=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]4[CH2:3]3)[CH2:15][CH2:16]2)=[CH:43][CH:42]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: O=C([O-])O
Agent: [B-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC1(CN2CCCN(Cc3ccc(-c4ccccc4)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
A mixture of tert-butyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-homopiperazin-1-carboxylate prepared in Example 645 (346 mg, 0.91 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). To the solution, triethylamine (0.27 ml, 1.96 mmol) was added. The solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml). To the solution, 4-phenylbenzaldehyde (496 mg, 2.72 mmol), sodium cyanotrihydroborate (171 mg, 2.72 mmol) and acetic acid (0.17 ml, 2.72 mmol) were added in this order followed by stirring at room temperature overnight. The reaction mixture was poured into a saturated sodium hydrogencarbonate solution, then extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=5/1) to afford 2-[4-(biphenyl-4-ylmethyl)homopiperazin-1-ylmethyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (251 mg, yield 62%) as a white powder.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=2)[C:9]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])=[O:10])[CH:5]=[CH:4][N:3]=[CH:2]1.[BH4-].[Na+]>C(O)C.O>[CH3:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[CH:9]([C:8]1[CH:20]=[CH:21][CH:22]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=1)[OH:10]
Reactant: Cc1cc(C)c(C(=O)c2cccc(-n3ccnc3)c2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(C(O)c2cccc(-n3ccnc3)c2)c(C)c1
Temperature: 56 °C
Reaction time: 20 h
Yield: 84.4 %

Procedure:
To a suspension of 16 g of 3-(1-imidazolyl)-2',4',6'-trimethylbenzophenone in 90 ml of ethanol is added a solution of 3.4 g of sodium borohydride in 30 ml of water. After stirring at 56° C. for 20 hours, the reaction mixture is poured into ice-cold water. The precipitate is filtered off and recrystallized from a mixture of dioxane and water to give 13.6 g of α-(2,4,6-trimethylphenyl)-3-(1-imidazolyl)benzenemethanol as white crystals, melting at 191°-193° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]2[S:18][CH2:17][NH:16][C:15]2=[O:19])[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:4])[CH3:3]>O1CCCC1.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:13][CH:14]2[S:18][CH2:17][NH:16][C:15]2=[O:19])[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: Cc1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(CC2SCNC2=O)cc(C(C)(C)C)c1O
Yield: 17.7 %

Procedure:
A solution of 0.28 g of the compound of Example 17 in 30 ml of tetrahydrofuran was hydrogenated at 60 pounds per square inch in the presence of 1.12 g of 5% palladium on carbon overnight at 60° C. The reaction mixture was filtered and evaporated to dryness. The resulting residue was dissolved in 3.5 ml of a 1:1.5 ethyl acetate/hexane solution and loaded onto a silica gel chromatography column. Elution with 40% ethyl acetate in hexane produced fractions which, upon evaporation to dryness, provided 0.05 g of title compound. m.p. 64°-68° C.
Reaction SMILES: [C:1]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([CH:18]=[O:19])[C:9]([CH:15]([CH3:17])[CH3:16])=[N:10][C:11]=1[CH:12]([CH3:14])[CH3:13])(OCC)=[O:2].[CH2:27]([Li])[CH2:28][CH2:29][CH3:30]>C(OCC)(=O)C.CCCCCC>[CH:15]([C:9]1[C:8]([CH2:18][OH:19])=[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:6]([CH:1]([OH:2])[CH2:27][CH2:28][CH2:29][CH3:30])=[C:11]([CH:12]([CH3:13])[CH3:14])[N:10]=1)([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCC(O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and n-butyllithium, according to the procedures described in Example 93. 1H NMR (300 MHz, CDCl3): δ 7.16 (m, 4 H), 4.49 (m, 1 H), 4.31 (d, J=5.5 Hz, 2 H), 3.74 (septet, J=6.6 Hz, 1 H), 3.42 (septet, J=6.6 Hz, 1 H), 1.88 (m, 1 H), 1.58 (d, J=3.3 Hz, 1 H), 1.18 (m, 18 H), 0.821 (t, J=4.1 Hz, 3 H). FAB-MS: calcd for (C23H32NFO2) 373, found 374 (M+H). Anal. Calcd for C23H32NO2F: C, 73.96; H, 8.64; N, 3.75; F, 5.09. Found: C, 73.81; H, 8.60; N, 3.58; F, 5.02. mp 166-168° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][C:17]2[C:18]([F:27])=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH3:26])=[CH:20]3)[CH:11]=1)C1C=CC=CC=1>CS(O)(=O)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:27][C:18]1[C:17]([O:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([CH2:9][OH:8])[CH:11]=2)=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[C:21]([CH3:26])[NH:22]2
Reactant: Cc1cc2c(F)c(Oc3cc(COCc4ccccc4)ncn3)ccc2[nH]1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc2c(F)c(Oc3cc(CO)ncn3)ccc2[nH]1
Temperature: 100 °C

Procedure:
In a 20 mL microwave vial is placed 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole (2.59 g, 7.13 mmol) in methane sulfonic acid (15 ml) and the solution is heated in a microwave reactor at 100° C. for 5 min. The reaction is then diluted with 250 mL EtOAc and saturated aqueous NaHCO3. The aqueous layer is washed with EtOAc (4×100 mL). The organic phases are combined, washed with (2×150 mL) water, followed by (1×60 mL brine), dried over Na2SO4, and concentrated in vacuo. The residue is purified via FCC (0-20% MeOH/DCM) to give the title compound. MS (ESI) m/z 274.1 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:16](Br)[CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH2:16]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCn1c2ccccc2c2ccccc21

Procedure:
A suspension of 100 g (0.6 mol) of carbazole in 200 ml of toluene is heated under reflux, with stirring. After cooling to 95°, first 26.8 g (0.12 mol) of triethylbenzylammonium chloride and then a solution of 169.8 g of KOH in 180 ml of water are added. The temperature thereby drops to 65°. 205.6 g (1.5 mol) of butyl bromide are now added in the course of 5 minutes, with vigorous stirring, whereupon the temperature rises to 92°. The mixture is kept under reflux for a further 10 minutes, all the carbazole dissolving. The aqueous phase is then removed. .The toluene phase is washed with a little water, dried over Na2CO3 and evaporated in vacuo. The oily residue is dissolved in 300 ml of warm hexane and the solution is clarified. On cooling, the product crystallizes in beige-coloured crystals of melting point 50°-52°.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([O:27][CH3:28])=[CH:16][N:15]=2)=[N:6]1.[C:33](=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([N:20]([CH3:33])[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([O:27][CH3:28])=[CH:16][N:15]=2)=[N:6]1
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1N(C)c1ccncc1
Temperature: 190 °C
Reaction time: 18 h

Procedure:
135 mg of 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)-pyrimidin-4-amine (2-18-1, 0.316 mmol, 1. eq.) were dissolved in 3 ml of 1-methylpyrrolidin-2-one and 514 mg of cesium carbonate (1.58 mmol, 5 eq.) were added. The reaction mixture was stirred at 190° C. bath temperature for 18 hours. After cooling at room temperature the mixture was partitioned between water and butan-2-one. The phases were separated and the aqueous layer was extracted twice with butan-2-one. The combined organic layers were washed with brine and dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography and preparative TLC to yield 10.9 mg (0.02 mmol, 7.2%) of the analytically pure target compound.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](/[C:23](/[CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24]\[C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O=O.[H][H]>>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([CH:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(/C(=C\C(N)=O)C4CCCC4)c3)ncnc21
Reactant: [H][H]
Agent: O=O
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC(N)=O)C4CCCC4)c3)ncnc21
Temperature: 25 °C

Procedure:
General screening procedure for asymmetric hydrogenation using the substrate, (Z)-(4-(1-(3-amino-1-cyclopentyl-3-oxoprop-1-enyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (10) to afford optically enriched product, (4-(1-(3-amino-1-cyclopentyl-3-oxopropyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-11 or (S)-11): A 300 mL-volume autoclave with glass vial (20 mL) was charged with the substrate (10), the catalyst (metal, ligand, and catalyst precursor), and oxygen-free solvent (4-6 mL) under nitrogen. This autoclave was charged with hydrogen gas to the desired pressure and stirred at room temperature or heated with oil bath. After hydrogen gas was released, the reaction mixture was concentrated under reduced pressure. The residue was purified by eluting through a silica gel pad using a mixture of ethyl acetate and methanol (v/v=9/1) to afford product, (4-(1-(3-amino-1-cyclopentyl-3-oxopropyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-11 or (S)-11), for chemical conversion (HPLC and chiral HPLC), LC/MS and NMR spectroscopy and enantiomeric excess (% ee by chiral HPLC) determination.
Reaction SMILES: [Cl:1]Cl.[Cl:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].O>C(O)(=O)C>[Cl:1][C:12]1[CH:13]=[C:8]([S:5]([CH2:4][Cl:3])(=[O:6])=[O:7])[CH:9]=[CH:10][C:11]=1[OH:14]
Reactant: O=S(=O)(CCl)c1ccc(O)cc1
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(CCl)c1ccc(O)c(Cl)c1
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
14.2 g (0.2 mole) of chlorine was passed into a solution of 41.5 g (0.2 mole) of 4-chloromethylsulphonylphenol in 200 ml acetic acid at 20° C. The mixture was stirred for a further 10 minutes and the solvent was then stripped off under reduced pressure. 100 ml of water were added to the residue and after crystallization the product was filtered off. 44.8 g (93% of theory) of 2-chloro-4-chloromethylsulfonylphenol were obtained in the form of a beige powder of melting point 108° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:27])[C:13]=3[NH:17][C:18](=[O:26])[CH2:19][CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:8]=2)[CH2:3]1.[CH3:28][C:29]([Si:32]([CH3:38])([CH3:37])[O:33][CH2:34][CH:35]=O)([CH3:31])[CH3:30]>>[Cl:27][C:12]1[C:13]([NH:17][C:18](=[O:26])[CH2:19][CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][CH2:35][CH2:34][O:33][Si:32]([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:38])[CH3:37])[CH2:3]1)[CH:16]=[CH:15]2
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: N[C@H]1CCN(c2ccc3c(NC(=O)CCC4CCCC4)c(Cl)ccc3n2)C1
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCN(c2ccc3c(NC(=O)CCC4CCCC4)c(Cl)ccc3n2)C1

Procedure:
Prepared according to the method of example 50(a), using N-[2-[(3S)-3-amino-1-pyrrolidinyl]-6-chloro-5-quinolinyl]-cyclopentanepropanamide (Example 62) (300 mg) and [[(1,1-dimethylethyl)dimethylsilyl]oxy]-acetaldehyde (133 μl). Purification (SiO2, methanol:dichloromethane 3:97 as eluant) gave the sub-title compound as a solid (200 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[ClH:33].[N:34]1([CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Reactant: O=C(O)CCCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCCN3CCCCC3)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C

Procedure:
A mixture of 2.4 g. (6.06 mm.) of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, 1.35 g. (6.06 mm.) of δ-piperidinovaleric acid hydrochloride and 1.30 g. (6.30 mm.) of dicyclohexylcarbodiimide in 100 ml. of methylene chloride are stirred at room temperature for 5 hours. The reaction mixture is cooled overnight in the refrigerator and the by-product of dicyclohexylurea removed by suction filration. The mother liquor is evaporated and the residue dissolved in a mixture of methylene chloride/cyclohexane and allowed to stand in the cold for 2 hours. Gravity filtration separates the small amount of solid which appears, and the solvents are removed using a rotary evaporator. Crystallization from methylene chloride/diethyl ether yields the desired product.