Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Cl.O1CCC[CH2:5]1.Cl[C:10]1[S:11][C:12]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Cl:20])[C:13]=2[N:14]=1.[Cl-].[NH4+]>C(OCC)C.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:15]1[C:13]2[N:14]=[C:10]([CH3:5])[S:11][C:12]=2[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: Fc1cc(Cl)c2nc(Cl)sc2c1
Reactant: C1CCOC1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Mg]Cl
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1nc2c(Cl)cc(F)cc2s1
Reaction time: 2 h
Yield: 49.6 %

Procedure:
67 ml of a solution of methyl magnesium chloride in tetrahydrofuran (3M; 0.2 mol) were added dropwise to a solution of 22 g (0.1 mol) of 2,4-dichloro-6-fluorobenzothiazole and 3.3 g (5 mmol) of dichlorobis(triphenylphosphine)nickel in 100 ml of diethyl ether. After stirring had been carried out for 2 hours, the mixture was poured onto saturated aqueous ammonium chloride solution. The desired product was extracted with diethyl ether, after which the combined organic phases were washed with water, dried over magnesium sulfate and finally evaporated down. 10 g of the desired product were obtained by crystallization from petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]([O:32][Si](C)(C)C)=[CH:28][CH2:29][CH2:30][CH3:31]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:28]([CH2:29][CH2:30][CH3:31])[C:27]([O:26][CH3:25])=[O:32])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CCCC=C(OC)O[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCC(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (158 mg, 0.5 mmol) and (1-methoxypent-1-enyloxy)trimethylsilane (16 mmol) which was prepared using General Silyl Ketene Acetal Method A in 10 mL of dry DCM was added TiCl4 (0.5 mL of 1.0 M DCM solution, 0.5 mmol) and then stirred 1 h. The reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2× EtOAc. The organic layers were dried over MgSO4, filtered, concentrated and purified on SiO2 by MPLC using a EtOAc/hexane gradient to give 160 mg (77% yield) of methyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)pentanoate. MS found: (M+H)+=417.
Reaction SMILES: O[Li].O.[Cl:4][C:5]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:6]=1[CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][CH:14]([C:19]([NH:21][C:22]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[O:30][CH3:31])=[O:20])[C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=1.Cl>C1COCC1.O>[Cl:4][C:5]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:6]=1[CH2:7][O:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][CH:14]([C:19]([NH:21][C:22]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[O:30][CH3:31])=[O:20])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1
Reactant: COC(=O)C(Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)Nc1c(OC)cccc1OC
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1NC(=O)C(Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.3 %

Procedure:
LiOH.H2O (120 mg, 2.9 mmol) was added to a solution of the compound of Example 1 (0.98 g, 1.9 mmol) in THF (10 ml) and water (5 ml) and the reaction stirred at room temperature for 1.5 h, then acidified to pH1 with 10% hydrochloric acid and extracted with DCM (2×25 ml). The combined organic layers were dried (MgSO4) and the solvent evaporated in vacuo to give a white foam that was triturated with DCM/Et2O to give the title compound as a white solid (0.52 g, 54%). δH (DMSO d6) 9.09 (1H, br s, NH), 7.58-7.44 (3H, m, Ar—H), 6.98 (2H, d, J 8.4 Hz, Ar—H), 6.65 (2H, d, J 8.4 Hz, Ar—H), 5.20 (2H, s, CH2OAr), 3.69 (6H, s, OMe), 3.69 (1H, m, CHCH2) and 3.05 (2H, m, CHCH2). m/z (ESI, 60V) 504, 506 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:6][C:7](=[S:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[CH:5]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[NH:6][C:7](=[S:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[C:9]=1[CH3:10])[CH3:2]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1=C(C(C)O)C(c2ccc(C#N)cc2)NC(=S)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{5-Acetyl-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}benzonitrile (Example 1; 100 mg, 0.24 mmol) is dissolved in 3 ml methanol, and sodium borohydride (10 mg, 0.26 mmol) is added. After stirring at room temperature for 1 h, the crude mixture is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10) to give the product as a 1.6:1-mixture of the two diastereomers.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:10][CH2:9][N:8]([C:11](=[O:26])[C@H:12]([NH:24][CH3:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:7][CH2:6]1)=[O:4].C(OC([NH:41][C:42]([CH3:50])([CH3:49])[CH2:43]/[CH:44]=[CH:45]/[C:46](O)=[O:47])=O)(C)(C)C>>[CH3:1][NH:2][C:3]([C:5]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:10][CH2:9][N:8]([C:11](=[O:26])[C@H:12]([N:24]([C:46](=[O:47])/[CH:45]=[CH:44]/[CH2:43][C:42]([NH2:41])([CH3:50])[CH3:49])[CH3:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CNC(=O)C1(Cc2ccccc2)CCN(C(=O)[C@@H](Cc2ccc3ccccc3c2)NC)CC1
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Product: CNC(=O)C1(Cc2ccccc2)CCN(C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)/C=C/CC(C)(C)N)CC1

Procedure:
4-Benzyl-1-((2R)-2-methylamino-3-(2-naphthyl)propionyl)piperidine-4-carboxylic acid methylamide (360 mg; 0.82 mmole) was coupled to (2E)-5-(tert-butyloxycarbonylamino)-5-methyl-2-hexenoic acid using the same coupling procedure as in step D. Removal of the N-terminal Boc group was performed as in step D but at −10° C. The crude product was purified on a RP-18-Seppak® (5 g; Waters) using a gradient from 0.1% TFA in water/acetonitrile 100/0 to 0.1% TFA in 60/40 water/acetonitrile to afford 306 mg of the title compound as a trifluoroacetate.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:13][C:14]([C:16]2([NH:31]C(=O)OC(C)(C)C)[CH2:21][CH2:20][N:19]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1>C(Cl)Cl>[NH2:31][C:16]1([C:14]([NH:13][C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11][OH:12])=[O:15])[CH2:17][CH2:18][N:19]([C:22]2[C:23]3[CH:30]=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: ClCCl
Product: NC1(C(=O)N[C@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
HCl (4M in dioxane) (0.378 mL, 1.51 mmol) was added to (R)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 42) (0.160 g, 0.30 mmol) in DCM (3 mL). The resulting suspension was stirred at 20° C. for 3 hours. The reaction mixture was evaporated. The crude product was purified by preparative HPLC (Waters XTerra C18 column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (R)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.051 g, 39.3%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2Cl)(=[O:15])=[O:14]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:21]1[C:20]2[C:25](=[C:16]([S:13]([CH3:12])(=[O:14])=[O:15])[CH:17]=[CH:18][CH:19]=2)[N:24]=[CH:23][CH:22]=1
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Reactant: CS(=O)(=O)c1cccc2c(Cl)ccnc12
Product: Cc1[nH]c2ccc(Cl)cc2c1-c1ccnc2c(S(C)(=O)=O)cccc12

Procedure:
The sub-title compound was prepared by the method of Example 40 step a, using 5-chloro-2-methyl-1H-indole and 8-methanesulphonyl-4-chloroquinoline.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.CC#N.O>[CH2:1]([O:8][C@H:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CCCCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Ester 31 (1.3 g, 3.73 mmol) was dissolved in THF/MeOH/CH3CN mixture (v/v/v, 1/1/1, 90 mL). Lithium hydroxide monohydrate (235 mg, 5.6 mmol) as a solution in water (30 mL) was added, and the mixture stirred overnight. The solvent amount was reduced in vacuo to about 30 mL. To the remaining aqueous solution was added 1 M hydrochloric acid to bring the pH down to 3. The aqueous layer was extracted with diethyl ether (3×40 mL). The combined organic extracts were dried over sodium sulfate. The drying agent was removed by filtration, and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (40 g RediSep column, eluting with a gradient of 0% through 50% ethyl acetate/hexanes over 40 min, 40 mL/min) to give the product 33 (990 mg, 79%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.30-7.05 (m, 5H), 4.51 (s, 2H), 3.90-3.80 (m, 1H), 2.58-2.45 (m, 2H), 1.80-1.60 (m, 2H), 1.50-1.20 (m, 18H), 0.85 (t, J=5.8 Hz, 3H).
Reaction SMILES: N#N.Br[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:12]=2)[C:7](=[O:20])[N:6]([CH3:21])[CH:5]=1.[CH2:22]([S:24]([NH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:25])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][N:6]1[CH:5]=[C:4]([C:32]2[CH:33]=[C:28]([NH:27][S:24]([CH2:22][CH3:23])(=[O:25])=[O:26])[CH:29]=[CH:30][CH:31]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:12]=2)[C:7]1=[O:20]
Reactant: Cn1cc(Br)c2cc(-c3ccccn3)ccc2c1=O
Reactant: CCS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1cccc(-c2cn(C)c(=O)c3ccc(-c4ccccn4)cc23)c1
Reaction time: 0.08 h
Yield: 3.9 %

Procedure:
For 5 min, N2 was bubbled through a mixture of 4-bromo-2-methyl-6-pyridin-2-ylisoquinolin-1-one (48.1 mg, 0.153 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (35.0 mg, 0.153 mmol), Pd(dppf)Cl2 (22.3 mg, 0.03 mmol) and aqueous 1M K3PO4 (0.38 mL, 0.38 mmol, 1 M) in dioxane (5 mL) which was then microwaved at 80° C. for 20 min. Purification by silica gel chromatography (PE:EA=3:1 to 1:2) followed by preparative HPLC gave the title compound (2.5 mg, 3.9%) as a white solid. 1H NMR (Methanol-d4, 400 MHz) δ 8.69 (d, J=8.4 Hz, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.23 (d, J=1.2 Hz, 1H), 8.15-8.22 (m, 1H), 8.10 (dd, J1=8.4 Hz, J2=1.6 Hz, 2H), 7.65-7.62 (m, 1H), 7.50-7.45 (m, 3H), 7.38-7.30 (m, 2H), 3.71 (s, 3H), 3.16 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H). LCMS: 420.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH2:24]([C:26]1[O:30][N:29]=[C:28]([CH3:31])[C:27]=1[C:32](O)=[O:33])[CH3:25]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:32]([C:27]3[C:28]([CH3:31])=[N:29][O:30][C:26]=3[CH2:24][CH3:25])=[O:33])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: CCc1onc(C)c1C(=O)O
Product: CCc1onc(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 5-ethyl-3-methyl-isoxazole-4-carboxylic acid. LC-MS (basic): tR=0.80 min; [M+H]+=470.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[Li].C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C>C1COCC1>[F:13][C:9]1[CH:8]=[C:7]([CH:6]2[CH2:2][CH2:3][CH2:4][NH:5]2)[CH:12]=[CH:11][CH:10]=1
Reactant: Fc1cccc(C=NCCCCl)c1
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: [Li]
Solvent: C1CCOC1
Product: Fc1cccc(C2CCCN2)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In step 9-2, 3-chloro-N-(3-fluorobenzylidene)propan-1-amine (9-1) (53 g, 266 mmol) was added at −78° C. to a solution of lithium granules (5.5 g, 800 mmol) and 4,4′-di-tert-butylbiphenyl (5.7 g, 21 mmol) in THF (50 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 2 hours then quenched with water and the temperature was allowed to rise up to 20° C. The solids were removed by filtration and the mother liquor was reduced using a rotary evaporator. The resulting residue was reconstituted in ethyl acetate, the organic washed with 1N HCl (3×25 mL) and the aqueous layer was extracted with ethyl acetate. The aqueous layer was then neutralized with 1N NaOH solution and the aqueous layer was extracted with ethyl acetate (3×100 mL). The organic layer was dried with sodium sulfate and the solvent was removed to yield 2-(3-fluorophenyl)pyrrolidine (9-2) as a light yellow oil. m/z=165.2 [M+1].
Reaction SMILES: C(O[C:9]1[CH:14]=[C:13](OCC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1>CO.[Pd]>[CH:23]([C:12]1[CH2:13][CH2:14][CH2:9][CH:10]([C:26]([N:28]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[C:33]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)[CH:34]=3)[CH2:29]2)=[O:27])[CH:11]=1)([CH3:25])[CH3:24]
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(N4CCN(C)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C1=CC(C(=O)N2Cc3ccc(N4CCN(C)CC4)cc3C2)CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-[5-(4-methyl-piperazin-1-yl)-1,3-dihydro-isoindol-2-yl]-methanone (8.61 g, 15.0 mmol) and 10% Pd/C (1.0 g) in methanol (200 mL) was stirred vigorously under a hydrogen atmosphere (˜1 atm) for 18 h at ambient temperature. The mixture was filtered through a plug of Celite and reduced in vacuo to give a purple oil. This residue was purified by column chromatography using an eluant of DMAW120 to give the title compound as its acetate salt. This salt was taken up in MeOH (30 mL) and to the solution was added saturated HCl in EtOAc (20 mL). This mixture was stirred at ambient for 2 h and the solid formed collected by filtration and dried in vacuo to give the title compound as its hydrochloride salt (2.64 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH2:30][O:31][CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([CH2:30][O:31][CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cc1nc(Cl)ccc1COCC(C)(C)O
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1COCC(C)(C)O

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 1-[(6-chloro-2-methylpyridin-3-yl)methoxy]-2-methylpropan-2-ol (110 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[C:20]([CH3:22])[N:19]=[C:18](Cl)[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:24][CH3:25])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>CN1CCCC1=O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:26]5[CH:30]=[CH:29][N:28]=[CH:27]5)[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:24][CH3:25])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(-c3cc(C)nc(Cl)c3)nc(=O)c1-2
Reactant: c1c[nH]cn1
Solvent: CN1CCCC1=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cc(C)nc(-n4ccnc4)c3)nc(=O)c1-2
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(2-chloro-6-methyl-4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one (0.30 g, 0.84 mmol), imidazole (0.06 g, 0.9 mmol) and N-methyl-2-pyrrolidinone (10 ml) was refluxed for 60 hours. The mixture was cooled to room temperature, filtered through a plug of celite and the plug was rinsed with methanol. The solvent was removed in vacuo and the residue was washed with ethanol and the solution was filtered. The filtrate was treated with charcoal, filtered, and the solvent was removed in vacuo. The residue was triturated with ether and a dark solid was collected by filtration. The product was recrystallized from ether/methanol to afford 0.018 g (10%) of 1-cyclopentyl-3-ethyl- 6-[2-(1-imidazolyl)-6-methyl-4-pyridyl]pyrazolo[3,4-d]pyrimidin-4-one.1/4 hydrate as a beige powder, m.p. 277°-278° C.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([C:18](O)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(S(F)(F)([F:37])(CC)N)C>C(Cl)Cl>[CH2:1]([N:13]1[N:17]=[N:16][C:15]([C:18]([F:37])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCS(N)(F)(F)(F)CC
Reactant: CCCCCCCCCCCCn1nnc(C(O)(C(=O)OCC)c2ccccc2)n1
Solvent: ClCCl
Product: CCCCCCCCCCCCn1nnc(C(F)(C(=O)OCC)c2ccccc2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A solution of 2-dodecyl-α-hydroxy-α-phenyl-2H-tetrazole-5-acetic acid, ethyl ester (0.45 g, 1.08 mmole) in CH2Cl2 (2 mL) was added dropwise to a -78° C. solution of diethyl amino sulfur trifluoride (DAST, J. Org. Chem. 1975;(40):574:578, 0.15 mL, 1.1 mmole) in CH2Cl2 (1 mL) under dry nitrogen. The mixture was stirred for 60 minutes at -78° C. before the cooling bath was removed and the solution allowed to warm to room temperature, where it was stirred an additional 3 hours. The mixture was poured into ice water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with brine (50 mL) and dried. Filtration and concentration produced an oil which was flash chromatographed (silica gel, 7:1 hexane-ethyl acetate) to afford 0.3 g (66%) of the title compound as an oil.
Reaction SMILES: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H]([O:16][C:17]3[CH:22]=[C:21]4[O:23][C:24]([C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30](O)[CH:29]=5)=[CH:25][C:26](=[O:27])[C:20]4=[C:19]([OH:37])[CH:18]=3)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O.[C:44](=O)([O-])[O-:45].[K+].[K+].IC.C(OCC)(=O)C>CN(C)C=O.ClCCl>[OH:37][C:19]1[CH:18]=[C:17]([OH:16])[CH:22]=[C:21]2[C:20]=1[C:26](=[O:27])[CH:25]=[C:24]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:45][CH3:44])[CH:29]=1)[O:23]2
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3o2)cc1O
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(=O)c3c(O)cc(O)cc3o2)cc1OC
Temperature: 90 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
1 kg of 3′,5,7-trihydroxy-4′-methoxy flavone-7-rutinoside and 454 g of potassium carbonate were dissolved in dimethylformamide at 10° C., which was heated and stirred at 90° C. for 8 hours. The reaction solution was cooled to room temperature. To the solution was added 1 kg of iodomethane, followed by stirring at room temperature for 12 hours. Upon completing the reaction, 50 L of mixed solution of ethyl acetate and dichloromethane (3:2) was added thereto. The resultant solution was stirred for 30 minutes and then filtered. 5.2 L of methanol and 5 kg of conc. hydrochloric acid were added to the filtered solid, followed by heating to reflux at 65° C. for 8 hours. The reaction mixture was cooled down to room temperature. The precipitated solid were collected by filtration and washed with a small amount of methanol to give a desired compound (yellow solid, 426 g, yield: 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH2:10][C:11](OCC)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(O)C.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)c(Cl)c1
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
In 2.4 liters of ethanol, 119 g (0.46 mole) of ethyl 3-(3,4-dichlorophenyl)-3-oxopropionate were dissolved. To the resulting solution, 115 ml (0.68 mole) of ethyl orthoformate and 4.4 g (2.28 mmol) of p-toluenesulfonic acid were added, followed by heating under reflux for 8 hours. The reaction mixture was poured into 1 liter of a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate (700 ml, three times). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was dissolved in 800 ml of tetrahydrofuran. The resulting solution was added dropwise to a suspension of 25.9 g (0.68 mole) of lithium aluminum hydride in 4 liters of tetrahydrofuran over 1 hour under ice-cooling. After stirring at 0° C. for 2 hours, 250 ml of water and 125 ml of a 10% aqueous solution of sodium hydroxide were added and the mixture was stirred at room temperature for a further 1 hour. The reaction mixture was filtered through Celite. The filtrate was poured into 1 liter of a saturated aqueous solution of sodium chloride, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A residue was dissolved in 500 ml of chloroform. Under ice-cooling, 500 ml of 50% trifluoroacetic acid were added dropwise to the resulting solution over 30 minutes and the mixture was stirred for 30 minutes. The reaction mixture was diluted with 300 ml of methylene chloride. The organic layer was washed with water and a saturated aqueous solution of sodium bicarbonate and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (eluting solvent: n-hexane: ethyl acetate=9:1), whereby 46 g of the title compound were obtained as white crystals.