Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Br:16])=[CH:11][C:10]=2[Br:17])=[O:5])C.[NH2:19][CH:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:16][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([Br:17])[CH:11]=1)[N:8]=[C:7]([NH:19][CH:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:15]2
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)c1cc2cc(Br)cc(Br)c2nc1Cl
Product: O=C(O)c1cc2cc(Br)cc(Br)c2nc1NC(Cc1ccccc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 6,8-dibromo-2-chloro-quinoline-3-carboxylic acid ethyl ester is reacted with DL-phenylalanine to provide the title compound in good yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][O:15][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CC[C@](CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Product: COc1cc(C(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 2.5.2 using (S)-(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1.351 mmol) and methanesulfonyl chloride (0.14 mL, 1.81 mmol) to give the title compound: Rf=0.27 (silica gel, ethyl acetate).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1)#[N:2].[Cl:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[CH:28]([CH3:47])[C:29]([C:35]1[CH:46]=[CH:45][C:38]2[N:39]([CH3:44])[C:40](=[O:43])[N:41]([CH3:42])[C:37]=2[CH:36]=1)([OH:34])[C:30]([F:33])([F:32])[F:31]>CN(C1C=CN=CC=1)C.C(#N)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][C:22]=1[CH:28]([CH3:47])[C:29]([C:35]1[CH:46]=[CH:45][C:38]2[N:39]([CH3:44])[C:40](=[O:43])[N:41]([CH3:42])[C:37]=2[CH:36]=1)([OH:34])[C:30]([F:33])([F:31])[F:32])[O:27][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:1]#[N:2])=[CH:10][CH:9]=1
Reactant: CC1(C)OB(c2ccc(OCC#N)cc2)OC1(C)C
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(c1ccc(Oc2ccc(OCC#N)cc2)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Copper(II)acetate (26 mg), 4-cyanomethoxy-phenylboronic acid pinacol ester (CAS Reg. No. 475272-13-0, 38 mg), and DMAP (30 mg) were added to a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 85, 20 mg) in acetonitrile (3 ml). The mixture was stirred with molecular sieves under air atmosphere for 4 h at 80° C., and then filtered over Celite concentrated to an oil. The residue was purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (24 mg) as a white solid. MS (m/e)=546.1 [M+H+].
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)CCC.Cl[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=1>C1(C)C=CC=CC=1>[F:45][C:42]1[CH:43]=[CH:44][C:39]([C:6]2[N:7]=[CH:8][N:9]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]=2)=[N:40][CH:41]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Fc1ccc(Cl)nc1
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)nc1
Temperature: 25 °C
Yield: 34 %

Procedure:
To the solution of 4-Tributylstannyl-1-trityl-1H-imidazole (1.00 g, 1.67 mmol) in toluene (10 ml) added 2-Chloro-5-fluoropyridine (0.31 g, 2.38 mmol) and tetrakis(triphenylphoshine)palladium (0) (0.19 g, 0.17 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at reflux under argon overnight. The reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was purified on silica gel using 30% diethyl ether in hexanes to isolate 4-(5-Fluoro-2-pyridyl)-1-trityl-1H-imidazole (0.23 g) as a clear oil.
Reaction SMILES: [OH:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].CN(C)C=O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[OH:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([O:7][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: CC(O)CCC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.2 %

Procedure:
80 g (0.57 mol) of sodium 4-hydroxypentanoate and 184.1 g (0.57 mol) of tetrabutylammonium bromide are suspended in 1.2 liters of abs. dimethyl formamide and the suspension is stirred for 15 minutes at room temperature. Then 67.8 ml (0.57 mol) of benzyl bromide are added dropwise and the reaction mixture is stirred for 15 hours at room temperature. The solution so obtained is diluted with water and extracted three times with ether. The organic phases are washed once with water and once with brine. The combined organic phases are dried over MgSO4, filtered and concentrated by evaporation. Distillation of the residue gives 63.1 g of benzyl 4-hydroxypentanoate of b.p. 139°-140° C./2.10-2 torr as a colourless oil.
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[S:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH2:42][CH2:43][C:44](O)=[O:45]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:44](=[O:45])[CH2:43][CH2:42][C:38]5[S:37][CH:41]=[CH:40][N:39]=5)[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reactant: O=C(O)CCc1nccs1
Product: CC(OC(=O)CCc1nccs1)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 62 %

Procedure:
In analogy to Example 5, 150 mg (0.29 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-1 3-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using 3-(2-thiazolyl)propionic acid and, after workup and purification, 119 mg (62%) of the title compounds were obtained as a colourless foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:17])[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[OH:9])[CH:2]=1.[CH:18]([Mg]Br)=[CH2:19].[Cl-].[NH4+]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:17])([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[OH:9])[CH:18]=[CH2:19])[CH:2]=1
Reactant: O=C(c1cccnc1)C(O)c1ccccc1Cl
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)(c1cccnc1)C(O)c1ccccc1Cl
Reaction time: 3 h

Procedure:
A solution of 13 g (0.0531 mol) of 1-(pyrid-3-yl)-2-(2-chlorophenyl)-2-hydroxyethanone in tetrahydrofuran (THF) was added dropwise to a freshly prepared solution of 0.18 mol of vinylmagnesium bromide in 80 ml of THF at room temperature. Stirring was carried out for three hours at room temperature, after which the solution was hydrolyzed by adding ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The collected organic phases were dried over Na2SO4 and then filtered, and the filtrate was evaporated down. The crude product was stirred with methyl tert-butyl ether, filtered off under suction and dried to give a product of melting point 110°-112° C.
Reaction SMILES: [CH2:1]([S:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[O:6])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCCCS(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)CCCC)n1
Temperature: 100 °C

Procedure:
A mixture of 5.2 g. 3-butylsulphinyl-1,2,4-triazole, 6.0 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate distilled under reduced pressure to remove solvent. Finally the residue was maintained at 100° C./0.5 mm. for 30 minutes in order to remove all traces of volatile material from the product. The product, 1-diallylcarbamoyl-3-n-butylsulphinyl-1,2,4-triazole, was obtained as an oil, nD26 1.5277. Elemental analysis satisfactory.
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][C:6]=2[C:5]=1[C:12]([O:14]C)=O)=[C:2]=[S:3].[CH3:16][C:17]1[N:21]([CH2:22][CH2:23][CH2:24][NH2:25])[CH:20]=[N:19][CH:18]=1>>[CH3:16][C:17]1[N:21]([CH2:22][CH2:23][CH2:24][N:25]2[C:12](=[O:14])[C:5]3[C:6]4[CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:20]=[N:19][CH:18]=1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCC2
Reactant: Cc1cncn1CCCN
Product: Cc1cncn1CCCn1c(=S)[nH]c2sc3c(c2c1=O)CCC3

Procedure:
The compound was synthesized starting from methyl 5,6-dihydro-2-isothiocyanato-4H-cyclopenta[b]thiophene-3-carboxylate (0.10 g, 0.42 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.058 g, 0.42 mmol) as described above.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([C:2]2[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C(O)c1ccc(-c2cccc(Cl)c2)o1

Procedure:
5-Bromo-2-furoic acid (1 g, 5.8 mmol) was coupled to 3-chloro-phenylboronic acid (683 g, 4.4 mmol) acid using Method F to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]([NH2:28])[CH3:27])=[C:16]([F:29])[CH:15]=1.C(N(CC)CC)C>C(#N)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]([NH:28][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:11])=[O:10])[CH3:27])=[C:16]([F:29])[CH:15]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(N)c1ccccc1-c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)c1
Yield: 103.3 %

Procedure:
3-Methoxybenzenesulfonyl chloride (331 mg, 1.6 mmol) was added to a solution of 1-(4′-chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethylamine (400 mg, 1.6 mmol) and triethylamine (246 μL, 1.7 mmol) in acetonitrile. The reaction was mixed at room temperature for 24 hours, afterwhich the acetonitrile was removed in vacuo. The remaining solid was dissolved in dichloromethane and purified by preparative liquid chromatogrpahy on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-50% methyl tert-butyl ether in hexane (35 min), to afford the the desired product (694 mg, 99%) as a white solid;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:17][C:10]=12.[CH:41](=O)[CH3:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH2:41]([N:21]1[CH2:20][CH2:19][CH:18]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25]([C:27]4[C:28](=[O:40])[N:29]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)[N:30]=[CH:31][CH:32]=4)=[O:26])=[CH:3][C:2]=3[F:1])[CH:15]=2)[CH2:23][CH2:22]1)[CH3:42]
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(C4CCNCC4)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Yield: 2.9 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-(piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 154, Step C, 43.4 mg, 0.0776 mmol), acetaldehyde (17.1 mg, 0.388 mmol), NaBH(OAc)3 (82 mg, 0.388 mmol) and THF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford crude product. The crude product was further purified with preparative HPLC to afford product (1.3 mg, 2.14%). LRMS (APCI neg): >97% purity, 254 nm, m/e 587 (M). 1H NMR (400 MHz, CD3OD) δ 8.41 (d, 1H), 8.36 (d, 1H), 8.31 (d, 1H), 8.03 (dd, 1H), 7.67 (m, 2H), 7.49 (m, 1H), 7.39 (t, 1H), 7.29 (m, 3H), 6.62 (d, 1H), 2.60 (q, 2H), 2.32 (m, 2H), 2.19 (m, 2H), 1.94 (m, 1H), 1.18 (t, 3H), 0.90 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][C:3]=1[C:30](OCC)([O:34]CC)[O:31][CH2:32][CH3:33].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][C:3]=1[C:30]([O:31][CH2:32][CH3:33])=[O:34]
Reactant: CCOC(OCC)(OCC)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of 4-[7-chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (375 mg, 0.677 mmol) in acetone (8 mL) and water (2 mL) was added p-toluenesulfonic acid monohydrate (321 mg, 1.69 mmol). The reaction mixture was stirred at room temperature for 2 hours, then quenched with ice water. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, then concentrated in vacuo to remove the majority of the acetone. The resultant mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (29:1 dichloromethane:methanol) provided ethyl 7-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylate (175 mg, 54%) as a brown solid. Rf 0.08 (29:1 dichloromethane:methanol); 1H NMR (400 MHz, CDCl3) δ 8.36 (d, 1H), 8.09 (d, 1H), 7.82 (d, 1H), 7.65 (m, 2H), 7.14 (t, 2H), 6.30 (d, 1H), 5.19 (d, 1H), 4.46 (q, 2H), 4.32 (m, 1H), 2.06 (m, 2H), 1.77–1.21 (m, 9H); MS m/z 480 (M+1).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[N:11]([CH3:30])[C:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[N:14]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CI.[H-].[Na+].[C:35](=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:35][N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8]([C:10]1[N:11]([CH3:30])[C:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[N:14]=1)=[O:9]
Reactant: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-cyclohexyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxamide (15 mg, 0.033 mmol) from Example 36, (Method A) and methyl iodide (0.003 mL, 0.049 mmol) in DMF (2 mL) was added sodium hydride (60% in mineral oil, 2 mg, 0.049 mmol). The mixture was stirred at rt for 2 hr and then poured into aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (0.5 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]2=[O:17])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)CC)C.C(Cl)Cl>>[C:18]([O:17][C:9]1[CH2:10][C:11]([CH3:15])([CH3:16])[CH2:12][C:13](=[O:14])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)cc1
Reactant: CCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)OC1=C(c2ccc(C)cc2)C(=O)CC(C)(C)C1
Yield: 71 %

Procedure:
Using the procedure described in Example III and starting with 3.00 g (0.0130 mol) of 2-(4'-methylphenyl)-5,5-dimethyl-1,3-cyclohexanedione, 1.59 g (0.0098 mol) of octanoyl chloride, 2.63 g (0.0260 mol) of triethylamine, and 30 mol of methylene chloride, 2.5 g (71% yield) of a clear, colorless oil was obtained as the desired product.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:34]([C:35]#[C:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[CH:33][N:13]([C@@H:14]2[O:32][C@H:22]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[C@@H:16]([O:17][CH2:18][N:19]=[N+:20]=[N-:21])[CH2:15]2)[C:12](=[O:45])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([NH:9][C:10]1[C:34]([C:35]#[C:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:42])([F:41])[F:43])=[CH:33][N:13]([C@@H:14]2[O:32][C@H:22]([CH2:23][OH:24])[C@@H:16]([O:17][CH2:18][N:19]=[N+:20]=[N-:21])[CH2:15]2)[C:12](=[O:45])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)C[C@@H]1OCN=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: [N-]=[N+]=NCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material (15) (140 mg, 0.22 mmol) was dissolved in THF (7.5 ml). TBAF (1M soln. in THF, 0.25 ml) was added slowly and stirred for 2 h at room temperature. Volatile material removed under reduced pressure to yield a brown gel that was purified by flash chromatography (EtOAc:DCM 7:3) to yield the desired product (16) as a light coloured crystalline solid (0.9 g, 76%). 1H NMR (d6 DMSO): δ 2.16 (m, 1H, H-2′), 2.22 (m, 1H, H-2′), 3.70 (d, 1H, J=11.5 Hz, H-5′), 3.75 (d, 1H, J=11.3 Hz, H-5′), 4.01 (m, 1H, H-4′), 4.10 (m, 1H, CH2NH), 4.23 (m, 1H, H-3′), 4.76 (s, 2H, CH2S), 5.32 (s, 1H, 5′ OH), 5.99 (m, 1H, H-1′), 7.37 (m, 2H, Ph), 7.50 (m, 2H, Ph), 7.81 (d, 1H, J=7.35 Hz, Ph), 7.95 (s, 1H, H-6), 9.78 (br s, 1H, NHCH2), 12.64 (br s, 1H, NH). Mass (−ve electrospray) calcd for C22H20F3N7O6 535.44, found 534.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]=[CH:17][C:18]#[N:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH:16]=[CH:17][C:18]#[N:19])(=[O:15])=[O:14])=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc(S(=O)(=O)C=CC#N)cc1
Reaction time: 48 h

Procedure:
23 grams (0.2 mol) of methanesulfonyl chloride (CH3SO2Cl) are dissolved in 600 milliliters of chloroform, and 42 grams (0.2 mol) of 3-(4-aminobenzenesufonyl)acrylonitrile, prepared as described in copending application Ser. No. 228,410 filed Feb. 22, 1972, are added with stirring and cooling in an ice bath followed portionwise by a solution of 16 g (0.2 mol) of pyridine in 200 ml of pyridine. The reaction mixture is allowed to reach room temperature and is thereafter left at about 20° C for about 48 hours. The solution is filtered and then washed with water, a 5% solution of HCl in water, a 5% sodium bicarbonate solution in water, and water, in sequence.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:18]([O:17][C:15]([NH:14][C@H:10]1[C@@H:11]([CH3:13])[CH2:12][NH:8][CH2:9]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Yield: 87.8 %

Procedure:
A suspension of 1-benzyl-cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (5.37 g) and 10% palladium-on-charcoal (2.70 g) in ethanol (50 ml) was shaken with hydrogen were absorbed under elevated pressure (100 kg/cm2) at room temperature for 22 hours. The catalyst was removed by filtration and the filtrate was evaporated to give the title compound (3.25 g). The compound was gradually solidified at room temperature.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:25]I>ClCCl.C(Cl)(Cl)Cl>[I:25][CH2:3][CH:2]1[CH2:1][C:4]2[C:5]3[C:6](=[N:7][CH:8]=[N:9][C:10]=3[CH:11]=[C:12]([O:16][CH3:17])[C:13]=2[O:14][CH3:15])[N:18]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: II
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccccc3)c12
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-phenyl-amine (0.12 g, 0.37 mmol) (from Example 15, Step E, supra) in dichloromethane (20 mL) was added I2 (0.24 g, 1.87 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with chloroform (100 mL), and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.05) as eluent to give the desired 5-iodomethyl-7,8-dimethoxy-4-phenyl-5,6-dihydro-4H-1,3,4-triaza-phenalene as a pale yellow solid. (Yield 0.11 g, 66%).