Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][C:3]1=[O:13].C(N(CCC)CCC)CC.[C:24]1([CH:30]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:40][CH2:39][CH2:38][CH2:37][N:34]2[CH2:33][CH2:32][N:31]([CH:30]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:36][CH2:35]2)=[N:4][C:3]1=[O:13]
Reactant: Cn1c(=O)nc(Cl)c2ccccc21
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CCCN(CCC)CCC
Solvent: C1COCCO1
Product: Cn1c(=O)nc(NCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.4 %

Procedure:
To a suspension of 1-methyl-4-chloro-2(1H)quinazolinone (4 g), tri(n-propyl)amine (7.2 g) and dioxane (20 ml) was added 3-[4-(diphenylmethyl)piperazin-1-yl]propylamine (3.5 g) and the mixture was stirred for 1.5 hours at ambient temperature. The reaction mixture was concentrated in vacuo and to the residue was added water. After the aqueous layer was made basic with 1N potassium hydroxide aqueous solution, the mixture was extracted twice with chloroform. The chloroform layer was washed with 0.2N potassium hydroxide aqueous solution, with water and with saturated sodium chloride aqueous solution respectively, dried over anhydrous magnesium sulfate and then concentrated in vacuo. After the residue was dissolved in toluene, remaining tri(n-propyl)amine was removed by evaporation in vacuo. This procedure was carried out further twice and then the residual oil was purified by subjecting to a column chromatography on silica gel (70 g) using 2% methanol in chloroform for elution to give a crystal, which was recrystallized from a mixture of ethyl acetate and hexane to give 1-methyl-4-[ 3-{4-(diphenylmethyl)piperazin-1-yl}propylamino]-2(1H)-quinazolinone (2.4 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1.CCN(C(C)C)C(C)C>CCO>[N:18]1[C:17]2[NH:21][CH:22]=[CH:23][C:16]=2[C:15]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Yield: 88.6 %

Procedure:
A mixture of (R)-tert-butyl pyrrolidin-3-ylcarbamate (250 mg, 1.34 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (206 mg, 1.34 mmol) and DIPEA (0.35 mL, 2.01 mmol) in EtOH (3 mL) was stirred at reflux temperature for 16 hours. The volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (15 mL), and filtered. The filtrate was washed with brine (3×5 mL), dried over anhydrous Na2SO4, and concentrated to give the title compound (360 mg, 88% yield). MS (m/z): 304 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:27]=2)=[CH:4][C:3]=1[O:28][CH3:29].[Li+].[OH-].O.Cl>CO.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:27]=2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)c1ccc(-c3ccc(O)c(OC)c3)cc1N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(C(=O)O)cc2NC3=O)ccc1O
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A mixture of Example 12 (80 mg, 0.2 mmol) and LiOH (24 mL, 1 mmol) in methanol (10 mL), THF (10 mL), and water (10 mL) was heated to reflux overnight, cooled to room temperature, and adjusted to pH <5 with concentrated HCl. The solid was collected by filtration to provide 55 mg of the desired product. MS (DCI) m/e 377 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 12.65 (s, 1H), 9.89 (s, 1H), 9.28 (s, 1H), 8.33 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.52 (dd, J=8.1, 1.6 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.17-7.20 (m, 2H), 7.04-7.10 (m, 2H), 6.88 (d, J=8.1 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([OH:28])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([O:28][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(O)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(OCC(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A suspension of 5-[4-(benzyloxy)phenyl]-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrazole (1.5 g), 1-bromo-2-methylpropane (2.76 g) and anhydrous potassium carbonate (1.67 g) in DMF (10 ml) was added stirred at 100° C. for 1 hour. The mixture was poured into ice water and extracted with AcOEt. The organic layer was washed with H2O, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=30% to give 5-[4-(benzyloxy)phenyl]-3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazole (1.64 g) as a solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:38][CH:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]1>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([CH2:38][CH:39]5[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:46])[CH2:41][CH2:40]5)[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C2
Temperature: 75 °C
Yield: 13.2 %

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (Example 3) (147 mg, 0.37 mmol) and triethyamine (52 μL, 0.37 mmol) in DMF (3 mL, anhydrous) was added tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (103 mg, 0.37 mmol). The reaction mixture was stirred at 75° C. until LCMS indicated reaction was complete. Solvent was then removed in vacuo. Purified by prep. HPLC (high pH) to afford a brown solid (28.9 mg, 0.049 mmol, 13%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:33].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:33])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCCl
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(OC(F)(F)F)cc1
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(OC(F)(F)F)cc1

Procedure:
Subsequent chlorination (70° C.; 4h30) of 3-ethyl-8-[2-(4-trifluoromethoxy-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.200 g; 2.731 mmol), and purification by FC (DCM/MeOH=50/1) afforded 1-chloro-3-ethyl-8-[2-(4-trifluoromethoxy-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (0.810 g; 63%). LC-MS: tR=1.08 min.; [M+H]+=473.97 g/mol.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([O:25][CH3:26])=[CH:20][C:19]=3[OH:27])(O)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(O)(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([O:25][CH3:26])=[CH:20][C:19]=3[OH:27])[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1F
Agent: COc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1F

Procedure:
Following the procedure as described in PREPARATION 3B, and making non-critical variations using 1-(diphenylmethyl)-3-(5-fluoro-2-hydroxy-4-methoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(5-fluoro-2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one was obtained (73%): 1H NMR (300 MHz, CDCl3) δ 9.33-8.84 (br, 1H), 7.41-7.25 (m, 9H), 7.22-7.04 (m, 4H), 6.92 (s, 1H), 6.71 (d, J=7.7 Hz, 1H), 6.64 (d, J=12.2 Hz, 1H), 6.56-6.49 (m, 1H), 5.09 (s, 1H), 3.84 (s, 3H); MS (ES+) m/z 440.1 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>ClCCl.N1C=CC=CC=1>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=2)=[O:13])=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc1
Yield: 56 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-aminophenyl methyl sulfone (2.00 g, 11.7 mmol) in 16 mL of pyridine. The crude product was recrystallized from acetonitrile-DMF to yield 2.0 g of the title compound, mp 236°-238° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:24][CH3:25])[CH:3]=1.[S:26]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][S:26]4(=[O:33])=[O:32])=[CH:3][C:4]=3[O:24][CH3:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=S1(=O)CCCCN1
Reactant: COc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Product: COc1cc(N2CCCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Yield: 74.2 %

Procedure:
Using (4-bromo-2-methoxyphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (404 mg) described in Preparation Example 252 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (340 mg) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:39])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([CH3:38])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:35]1[CH:36]=[C:31]([C:27]2[CH:26]=[C:25]([C:23]3[CH2:22][C:21](=[O:39])[NH:20][C:9]4[CH:10]=[C:11]([C:16]([F:18])([F:19])[F:17])[C:12]([CH2:14][CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[CH:32]=[C:33]([CH3:38])[N:34]=1
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M208) (155 mg, 0.28 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (72 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([SH:10])=[C:7]([CH3:11])[C:6]=2[CH:12]=1.Cl[C:14]1[N:15]=[N:16][C:17](OC)=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10][C:17]3[N:16]=[N:15][CH:14]=[CH:19][CH:18]=3)=[C:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: COc1ccc(Cl)nn1
Reactant: Cc1c(S)oc2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Sc2cccnn2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution containing 5-chloro-2-mercapto-3-methyl benzofuran (10 mmol, 1.98 g and 3-chloro-6-methoxy pyridazine (10 mmol, 1.44 g) in dimethylformamide (DMF, 10 mL) was added potassium carbonate (20 mmol, 2.76 g) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with H2O (200 mL), the precipitated yellow solid was collected and the solid was purified by silica gel chromatography (eluent: hexanes:EtOAc::9:1) to obtain 6-(5-chloro-3-methyl-benzofuran-2-sulfenyl)-pyridazine (93%, 2.87 g); mp 131° C.-134° C.
Reaction SMILES: CO[CH:3](OC)[CH2:4]Cl.O.Cl.[C:10]([O:16]CC)(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>N1C=CC=CC=1>[CH3:14][C:12]1[O:13][CH:3]=[CH:4][C:11]=1[C:10]([OH:16])=[O:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(CCl)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1occc1C(=O)O
Temperature: 0 °C

Procedure:
A first reaction mixture of chloroacetaldehyde dimethylacetal (300 g), water (400 mL) and 36% hydrochloric acid (40 mL) was stirred and brought to reflux. When the first reaction mixture became homogenous, it was cooled and added to a stirred solution of ethyl acetoacetate (260 g) and pyridine (500 mL) and left stirring at ambient temperature for 72 hours, to produce a second reaction mixture. The organic layer was then separated from the second reaction mixture and the aqueous layer was diluted with water and then extracted with methylene chloride. The combined organics were washed with 2N hydrochloric acid, followed by removal of the solvent. The residue was treated with a solution of sodium hydroxide (80 g) in water (700 mL) and ethanol (100 mL), to produce a third reaction mixture. After refluxing for 1 hour the third reaction mixture was poured into ice/water and acidified with hydrochloric acid. A cream colored precipitate formed. This precipitate was collected on a filter, washed with water and dried to give 2-methyl-3-furancarboxylic acid, 180 g. 100 g of the 2-methyl-3-furancarboxylic acid was added in portions to thionyl chloride (500 mL) and refluxed for 3 hours. Excess thionyl chloride was then distilled off to produce a residue. The residue was distilled using a water pump, to give 2-methyl-3-furanylcarboxylic chloride, bp. 62° C., 100 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:26])([F:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][N:16]=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[F:26][C:8]([F:7])([F:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1
Reactant: FC(F)(F)c1ccccc1C1=NCCc2ccccc21
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1C1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.5 %

Procedure:
Under cooling in a dry ice-acetone bath, lithium aluminum hydride (1.03 g) was added to THF (30 mL) to make a suspension. A solution of 1-[2-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline (6.22 g) in THF (30 mL) was added dropwise to the suspension under an argon atmosphere. The reaction solution was stirred at room temperature for 15 hours. The reaction liquid was cooled in ice and then a saturated aqueous Rochelle salt solution (1.5 mL) was added to stop the reaction. The liquid was stirred at room temperature for 1 hour and magnesium sulfate and celite were then added thereto. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 1-[2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline (5.42 g).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[N:9][CH:8]=[C:7]([N:11]2[CH:15]=[C:14]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:13]=[C:12]2[CH3:25])[N:6]=1)C=C.C1([SiH3])C=CC=CC=1.O>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]([C:17]#[C:16][C:14]2[N:13]=[C:12]([CH3:25])[N:11]([C:7]3[NH:6][C:5](=[O:4])[CH:10]=[N:9][CH:8]=3)[CH:15]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: C=CCOc1cncc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)n1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: O
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cncc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A solution of 75 mg (0.214 mmol) 2-Allyloxy-6-[4-(3-chloro-phenylethynyl)-2-methyl imidazol-1-yl]-pyrazine in 5 ml of methylene chloride was degassed with argon. Then 0.052 ml (0.428 mmol) of phenyl silane and 2.5 mg (0.002 mmol) of tetrakis(triphenyl-phosphine)palladium were added and the mixture was stirred for 1 h at room temperature. Then water (1 ml) was added and the mixture was vigourously stirred for 5 min., diluted with 10 ml of methylene chloride and the organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The obtained solid was triturated with benzene to remove impurities (triphenylphosphine oxide), filtered and dried to yield 30 mg (0.097 mmol, 45%) of the title compound as a white crystalline solid, MS: m/e=311.1, 313.1 (M+H+)
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[H][H]>[Pd]>[CH:3]([OH:4])([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1]
Reactant: [H][H]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Product: OC(C(F)(F)F)C(F)(F)F
Yield: 90 %

Procedure:
Approximately 100cc of Pd/C catalyst is packed into a ½″ diameter pipe reactor. Approximately 1 g/min of the hexafluoroacetone and 500cc/min hydrogen gas is fed into the reactor at atmospheric pressure and 180° C. Hexafluoro-2-propanol is produced in greater than 90% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)OC(C)(C)C)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
Tert-butyl 4-bromophenylcarbamate (5.5 g, 20.21 mmol) was dissolved in THF, Lithium aluminum hydride (2.301 g, 60.63 mmol) was added and it was stirred at 60° C. overnight. Then it was quenched by EA, followed by H2O, concentrated and CH2Cl2 and 1M NaOH was added in, washed with CH2Cl2, extracted with CH2Cl2, dried over Na2SO4, concentrated, purified by flash chromatography (PE: EA=40:3) to give 2.1 g yellow oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:31]1([NH:36][C:37]([NH2:39])=[NH:38])[CH2:35][CH2:34][CH2:33][CH2:32]1.CC(C)([O-])C.[K+].CCOCC>O1CCCC1.O>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:39]=[C:37]([NH:36][CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[N:38]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N=C(N)NC1CCCC1
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
To a solution of (2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (3.5 g, 8.9 mmol) in tetrahydrofuran (36 mL, 0.25 M) was added N-cyclopentylguanidine hydrochloride (1.89 g, 11.6 mmol), followed by solid potassium tert-butoxide (2.6 g, 23.2 mmol) in two portions. The resultant solution was heated to reflux for 23 hours. Upon cooling to room temperature, ether was added followed by water. The organics were washed with brine, and the aqueous layer was extracted with ether. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (3.7 g, 91%) as an off white solid. 1H NMR (CDCl3): δ 7.97 (d, 1H), 7.68 (d, 1H), 7.59 (dd, 2H), 7.27 (t, 1H), 7.10 (t, 2H), 6.24 (d, 1H), 5.99 (d, 1H), 5.96 (d, 1H), 5.01 (d, 1H), 4.28 (m, 1H), 3.97 (m, 1H), 2.12–1.99 (m, 4H), 1.79–1.44 (m, 12H); 13C NMR (CDCl3) δ 163.12 (d, JCF=246.6 Hz), 162.09, 161.53, 156.67, 152.15, 142.66, 141.09, 131.46 (d, JCF=8.0 Hz), 129.92 (d, JCF=3.1 Hz), 128.39, 115.45(d, JCF=21.3 Hz), 108.68, 107.13, 105.15, 90.13, 53.84, 52.87, 33.50, 33.30, 24.05, 23.70; 19F NMR (CDCl3) δ −113.49; MS m/z 457 (M+1); Anal. Calcd for C27H29FN6: C, 71.03; H, 6.40; N, 18.41. Found: C, 71.20; H, 6.37; N, 18.52.
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)([CH3:4])=[O:3].[I:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C.[I-]>ClCCl>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][C:16]([NH:17][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:25]([I:24])[CH:26]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: CP(C)(=O)CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1I
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CP(C)(C)=O)CC3)c(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-({4-[(dimethylphosphoryl)methyl]piperazin-1-yl}methyl)-5-(trifluoromethyl)aniline (yellow solid, 3.66 mmole, 1.0 eq.) was dissolved in 15 mL anhydrous dichloromethane. 3-Iodo-4-methylbenzoyl chloride (1.58 grams, 5.64 mmole, 1.54 eq.) was added in one portion. At 0° C., under N2 protection, diisopropylethyl amine (2.4 mL, 14.0 mmole, 3.8 eq.) was added dropwise in 3 minutes. The reaction mixture was stirred at 0° C. under N2 for 30 minutes. It was then evaporated to remove most of the volatile components. The residue was purified via column chromatography (elution sequence: 100% dichloromethane—1% MeOH/dichloromethane/sat.NH3—10% MeOH/dichloromethane/sat.NH3), 40 mg of light yellow color oil was obtained and identified as the desire iodide. MS (LC/MS): 592.3 [M-].
Reaction SMILES: [C:1]1([S:7][C:8](Cl)(Cl)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=C[N:14]=1>C(N)=O>[C:1]1([S:7][C:8]2[CH:16]=[CH:17][CH:18]=[CH:13][N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)(Cl)Sc1ccccc1
Reactant: Brc1ccccn1
Solvent: NC=O
Product: c1ccc(Sc2ccccn2)cc1
Temperature: 75 °C
Yield: 81 %

Procedure:
A solution of phenyl(trichloromethyl)sulfane (0.25 g, 1.099 mmol) in formamide (16.40 ml), was degassed with nitrogen and treated with 2-bromopyridine (0.115 ml, 1.209 mmol). The reaction solution was heated at 75° C. overnight. Gas Chromatography-Mass Spectrometry (GCMS) indicates a yield of 81% of 2-(phenylthio)pyridine, and a 7% byproduct of disulfide.