Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13]I>C1COCC1>[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)CI
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@H](C)Cc1cccs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of thiophene (10.6 g, 0.13 mol) in dry THF (100 mL) was cooled to −78° C. under nitrogen. A solution of n-BuLi (28.0 mL, 2.5 M, 70.0 mmol) was then added dropwise. After addition, the reaction mixture was stirred at −78° C. for additional 1 hour, before a solution of (S)-2-methylbutyliodide (10.0 g, 50.5 mmol) in dry THF (20 mL) was added slowly. This mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature slowly and stirred at room temperature overnight. The reaction was quenched by water and the mixture was poured into water (100 mL), and the resulting mixture was extracted with ether (300 mL). The organic layer was washed with water and brine, dried over MgSO4, and concentrated on a rotary evaporator. The residue was subjected to column chromatography on silica gel with hexane as the eluent, leading to a colorless oil as the product (4.27 g, 54.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH2:32]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:43]4[CH2:44][CH2:45][N:40]([CH2:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:41][CH2:42]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: c1ccc(CCN2CCNCC2)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(CCc2ccccc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-phenethylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=620.02 (M+H+); retention time=0.63 minutes.
Reaction SMILES: [CH2:1]([N:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:25])[F:26])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(N)cc1
Yield: 98.1 %

Procedure:
A partial solution of N-isobutyl-4-nitro-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (1.68 g, 4.19 mmol), in EtOH (IMS grade, 50 mL) and water (15 mL) was treated with iron powder (˜325 mesh, 936 mg, 16.76 mmol) and ammonium chloride (896 mg, 16.76 mmol) and heated at reflux for 1 hour. The cooled mixture was filtered through diatomaceous earth washing the filter cake with EtOH and the filtrate concentrated to low volume under vacuum. The residue obtained was diluted with water and extracted into DCM. The combined extracts were dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-75% EtOAc in cyclohexane) gave 4-amino-N-isobutyl-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (1.53 g, 98%). 1H NMR (300 MHz, CDCl3) δ 7.72 (dd, J=7.5, 2.1 Hz, 1H), 7.54-7.39 (m, 4H), 7.14 (d, J=7.7 Hz, 1H), 6.70-6.63 (m, 2H), 3.35 (dd, J=13.5, 8.3 Hz, 1H), 3.15 (dd, J=13.5, 5.3 Hz, 1H), 1.71-1.55 (m, 1H), 0.88 (d, J=6.5 Hz, 3H), 0.77 (d, J=6.7 Hz, 3H). LCMS (m/z, Method A) ES+ 373.1 [M+1]+.
Reaction SMILES: [CH2:1]([NH:8][NH2:9])C1C=CC=CC=1.C(N(CC)CC)C.[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1[CH2:26][C:27](Cl)=[O:28].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][N:8]([C:27](=[O:28])[CH2:26][C:19]1[C:20]([F:25])=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[F:17])[NH2:9]
Reactant: NNCc1ccccc1
Reactant: O=C(Cl)Cc1c(F)ccc(F)c1F
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(N)C(=O)Cc1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.8 %

Procedure:
3.22 g (26.4 mmol) of benzyl hydrazine together with 4.4 ml (1.2 eq) of triethylamine and 0.16 g of DMAP (0.05 eq) were initially charged in 50 ml of dichloromethane, and 5.5 g of 2,3,6-trifluorophenylacetyl chloride in 50 ml of dichloromethane were then slowly added dropwise at 0° C. The mixture was then stirred at room temperature overnight, and ammonium chloride solution was added. The organic phase was separated off, dried and concentrated. Purification by column chromatography gave 6.2 g of 2,3,6-trifluorophenylacetic acid 1-methylhydrazide.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1.[CH2:33]([O:40][CH:41]1[CH:46]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:45]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:44]([CH2:63][O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[O:43][C:42]1=[O:72])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>C1COCC1>[S:28]1[C:24]([CH2:23][C:15]2[CH:14]=[C:13]([C:42]3([OH:72])[C@H:41]([O:40][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C@@H:46]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C@@H:45]([O:55][CH2:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C@@H:44]([CH2:63][O:64][CH2:65][C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[O:43]3)[C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]1=2
Reactant: Brc1cc(Cc2cc3ccccc3s2)cc2ccccc12
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2cc(Cc3cc4ccccc4s3)cc3ccccc23)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
Under a nitrogen atmosphere, an n-butyllithium hexane solution (1.6 M, 1.58 ml, 2.53 mmol) was added dropwise to a solution of 2-(4-bromonaphthalen-2-ylmethyl)-benzo[b]thiophene (0.81 g, 2.29 mmol) in anhydrous THF (15 ml) at −78° C. over five minutes. The reaction mixture was stirred at −78° C. for 5 minutes, and then a solution of 3,4,5-trisbenzyloxy-6-benzyloxymethyltetrahydropyran-2-one (1.36 g, 2.52 mmol) in anhydrous THF (10 ml) was added dropwise thereto at −78° C. and the reaction solution was stirred at −78° C. for 2 hours. To the obtained reaction mixture was added a saturated ammonium chloride aqueous solution and the mixture was extracted with diethyl ether and the organic layer was washed with a saturated sodium chloride aqueous solution, and then dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure and the obtained residue was purified by silica gel flash column chromatography [n-hexane:ethyl acetate (10:1)] to obtain the title compound (1.4 g, 75%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])=[C:7]([C:13]2[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=2)[CH:8]=1)=[O:30]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1ccnn1C
Yield: 73.3 %

Procedure:
4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) was treated with 2,4-difluorophenyl isocyanate (12.4 μL, 0.1 05 mmol) in a similar manner as described in Example 1.2 to afford Compound 141 as a white solid in 73.3% yield. LCMS m/z (%)=416 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 8.95 (s, 1H), 8.46 (s, 1H), 8.08-8.02 (m, 1H), 7.45-7.42 (m, 2H), 7.37 (d, J=2.7 Hz, 1H), 7.33-7.27 (m, 1H), 7.12 (d, J=8.95 Hz, 1H), 7.05-6.98 (m, 1H), 6.24 (d, J=2.7 Hz, 1H), 4.03 (t, J=5.80 Hz, 2H), 3.67 (s, 3H), 2.54 (t, J=5.73 Hz, 2H), 2.12 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([S:8]([N:11]2[C:15]3[CH:16]=[C:17]([C:24]([OH:26])=O)[CH:18]=[C:19]([C:20]([F:23])([F:22])[F:21])[C:14]=3[O:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1>>[CH2:37]([O:36][C:34](=[O:35])[C:33]1[CH:39]=[CH:40][C:30]([NH:29][C:24]([C:17]2[CH:18]=[C:19]([C:20]([F:22])([F:23])[F:21])[C:14]3[O:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:27][CH3:28])(=[O:9])=[O:10])[C:15]=3[CH:16]=2)=[O:26])=[CH:31][CH:32]=1)[CH3:38]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2c1cc(C(=O)O)cc2C(F)(F)F
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cc3c(c(C(F)(F)F)c2)OCN3S(=O)(=O)c2cc(Cl)ccc2OC)cc1

Procedure:
Reaction of 3-(5-chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carboxylic acid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave 4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester. Light yellow solid, MS (ISP)=584.9 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:47][N:48]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:64][C:65]4[N:70]=[CH:69][C:68](O)=[CH:67][CH:66]=4)[CH:62]=3)[N:57]=[CH:56][N:55]=2)=[N:49]1>C(Cl)(Cl)Cl.O1CCCC1>[CH3:47][N:48]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:64][C:65]4[N:70]=[CH:69][C:68]([O:1][CH2:2][CH2:3][CH:4]5[CH2:8][CH2:7][CH2:6][N:5]5[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:67][CH:66]=4)[CH:62]=3)[N:57]=[CH:56][N:55]=2)=[N:49]1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(O)cn4)cc23)n1
Reactant: CC(C)(C)OC(=O)N1CCCC1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCCC5CCCN5C(=O)OC(C)(C)C)cn4)cc23)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
Tert-butyl 2-(2-hydroxyethyl)pyrrolidine-1-carboxylate (260 mg, 1.2 mmol), triphenyl phosphine (310 mg, 1.2 mmol) and diethyl azodicarboxylate (0.19 mmol, 1.2 mmol) were added to a tetrahydrofuran solution (6 ml) of 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (200 mg, 0.60 mmol) obtained in Example 6, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with chloroform, the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=96:4) and amine-type silica gel column chromatography (hexane:ethyl acetate=50:50) to obtain tert-butyl 2-(2-{[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethyl)pyrrolidine-1-carboxylate (290 mg, yield: 90.5%) as a pale yellow amorphous solid.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][CH:20]=[N:21]2)=[C:17](Cl)[N:16]=1>CS(C)=O>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][NH:21]2)=[C:17]([O:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:16]=1
Reactant: Oc1ccccc1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1nc(Oc2ccccc2)c2nc[nH]c2n1
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
Potassium t-butoxide (J. T. Baker, 7.3 g, 64.8 mmol) was added to a solution of phenol (Mallinckrodt, 15.2 g, 162 mmol) in 50 mL anhydrous DMSO. After stirring for 30 minutes, 2-amino-6-chloropurine (Sigma, lot #69F4064. 5.5 g, 32.4 mmol) was added and the mixture stirred for 6 days at 100° C. The reaction was poured onto ice and extracted with EtOAc. The solvents were removed in vacuo and the resultant oil applied to a silica gel column. Elution with CHCl3 /MeOH (95:5, v/v) followed by combination and evaporation of appropriate fractions gave 1.6 g (7.0 mmol, 22%) of product. mp=228° C.
Reaction SMILES: CCCP(=O)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:39]2[CH2:40][CH2:41][N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=3)[CH2:37][CH2:38]2)=[O:14])=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCN(c3ccccn3)CC2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4 mg, 0.7 mmol), 1-(2-pyridyl)piperazine (Aldrich, Buchs, Switzerland; 114.3 mg, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is purified by column chromatography on silica gel, eluent 5-10% methanol in dichloromethane, to give the title compound as a solid. 1H-NMR (400 MHz, DMSO-d6, δ): 2.31 (s, 3H); 3.35-3.74 (m, 8H); 6.65 (ddd, 1H); 6.79 (d, 1H); 7.13 (dd, 1H); 7.32 (d, 1H); 7.44 (d, 1H); 7.49-7.56 (m, 2H); 7.69 (m, 1H); 8.11 (m, 1H); 8.40 (m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.06 (s, 1H); 9.24 (m, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][NH2:15].O>CCCCO>[F:11][C:10]([F:12])([F:13])[C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:15][N:14]=[C:4]2[NH2:5]
Reactant: NN
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 25 °C

Procedure:
2-Fluoro-5-trifluoromethyl-benzonitrile (2.66 g) was dissolved in n-BuOH (51 ml) prior to the addition of NH2NH2.H2O (1.02 ml). The solution was heated to reflux for 30 min. After cooling to rt, the solution was concentrated and CH2Cl2 was added. The organic layer was washed with H2O, brine, dried, filtered, and concentrated in high vacuum to give 5-trifluoromethyl-1H-indazol-3-ylamine (2.25 g): 1H NMR (DMSO, δppm, 300 mHz) 5.70 (s, br, 2H), 7.40 (dd, 2H), 8.20 (s, 1H), 11.90 (s, br, 1H).
Reaction SMILES: [CH2:1]([O:9][CH:10]([CH3:15])[CH2:11][CH2:12][CH2:13][OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[OH-].[Na+].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:14][CH2:13][CH2:12][CH2:11][CH:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:15])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CCCCCCCCOC(C)CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCOC(C)CCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.08 h
Yield: 78.2 %

Procedure:
7 g of 4-octyloxypentanol, 4.34 g of p-toluenesulfonyl chloride, 1.8 g of pyridine and 10 ml of benzene were stirred under N2 stream at room temperature for 22 hours. Thereafter, 6.5 ml of hot conc. NaOH aqueous solution was added to the reaction mixture and stirred for 5 min. Then, the mixture was poured into cold 10%-hydrochloric acid and extracted with hexane. The hexane layer was washed successively with cold 5%-hydrochloric acid, saturated NaHCO3 aqueous solution and water and dried with anhydrous MgSO4. After removing the solvent by distillation, the product was treated with alumina column (hexane) to obtain 6.6 g of 4-octyloxypentyl p-toluenesulfonate.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.Cl.[CH2:15]([NH:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>C(O)C>[CH2:15]([N:22]1[C:5](=[O:7])[CH2:4][CH2:3][C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: NNCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1CCC(c2ccccc2)=NN1Cc1ccccc1
Yield: 12.1 %

Procedure:
To a solution of 4-oxo-4-phenylbutanoic acid (1.0 g) in ethanol (28 mL) were added benzylhydrazine hydrochloride (1.1 g) and sodium acetate (4.2 g) at room temperature, and the mixture was heated under reflux overnight. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.18 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.CCN(CC)CC.[CH2:27]([O:34][C:35](Cl)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([O:34][C:35]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](N)C2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](NC(=O)OCc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
A solution of compound 17 (4.37 g, 16.72 mmol) in THF (30 mL) was cooled to 0° C. and treated successively with Et3N (4.6 mL, 3.38 g, 33 mmol) and benzylchloroformate (2.8 mL, 3.42 g, 20 mmol). The reaction mixture was allowed to stir for 2 hrs at 0° C., quenched by adding an aqueous saturated NH4Cl solution (30 mL) and extracted with EtOAc. The extract was dried over Na2SO4, filtered and concentrated. Crude product was purified by flash chromatography using 30% EtOAc in hexanes as an eluent to provide title compound 115 (3 g, 45% yield). LRMS (ESI): (calc) 396.20 (found) 397.2 (MH)+.
Reaction SMILES: N[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.N(OCCC(C)C)=O.[I:39]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[I:39][C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1
Reactant: II
Reactant: CCCn1c(N)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: CC(C)CCON=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(I)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of 2-Amino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (prepared as given in Example 13) (0.169 g, 0.41 mmol), isoamyl nitrite (0.2 ml, 1.5 mmol), iodine (83 mg, 0.32 mmol) was taken in THF (5 ml) and stirred for 2 hours at 80° C. Reaction mixture was cooled and saturated solution of Na2S2O3 was added and extracted with ethyl acetate (3×5 ml). The organic layer was washed with brine (10 ml), dried over Na2SO4 and evaporated to obtain 2-Iodo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (93 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]([C:30]([F:33])([F:32])[F:31])=[CH:18][C:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)=[O:20])[CH:13]=[C:14]([Cl:16])[CH:15]=1.O>N1C=CC=CC=1>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([C:19](=[O:20])[CH:18]=[C:17]([C:12]3[CH:11]=[C:10]([Cl:9])[CH:15]=[C:14]([Cl:16])[CH:13]=3)[C:30]([F:33])([F:31])[F:32])=[CH:22][CH:23]=2)=[N:7][CH:6]=1
Reactant: O=C(Cl)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Reactant: Nc1ncc(Cl)cn1
Solvent: c1ccncc1
Solvent: O
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(C(=O)Nc2ncc(Cl)cn2)cc1
Reaction time: 2.5 h
Yield: 50.5 %

Procedure:
To a solution of 0.5 g of 2-amino-5-chloropyrimidine in 20 mL of pyridine, 0.5 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)benzoic acid chloride was poured at room temperature and the mixture was stirred for 2.5 hours. After that, water was added to the reaction solution that was extracted with ethyl acetate, an organic layer was washed with water and diluted hydrochloric acid and then dehydrated and dried with saturated saline followed by anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified using silica gel column chromatography that was eluted with ethyl acetate-hexane (5:2) followed by crystallization from a mixed solvent of hexane and a small amount of ethyl acetate to obtain 0.31 g of aimed product as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[C:33]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)#[N:34]>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:38]3[CH2:39][CH2:40][CH:35]([C:33]#[N:34])[CH2:36][CH2:37]3)[CH:32]=[CH:31][CH:30]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2nc(-c3ccc(C4(C(F)(F)F)CC4)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: N#CC1CCNCC1
Product: Cc1cc(-c2nc(-c3ccc(C4(C(F)(F)F)CC4)cc3)no2)nn1Cc1cccc(N2CCC(C#N)CC2)c1

Procedure:
Analogously to the process described in Example 9, 50 mg (0.099 mmol) of the compound from Example 2A and 22 mg (0.199 mmol) of 4-cyanopiperidine were used to obtain 23 mg (43% of theory) of the title compound.