Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:18]([OH:20])=O)[C:7]([C:21]#[N:22])=[C:6]([CH3:23])[NH:5][C:4]=1[CH3:24])#[N:2].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]([CH3:61])[CH2:58][CH2:59][NH2:60]>CN(C=O)C>[C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:18]([NH:60][CH2:59][CH2:58][N:57]([CH3:61])[CH3:56])=[O:20])[C:7]([C:21]#[N:22])=[C:6]([CH3:23])[NH:5][C:4]=1[CH3:24])#[N:2]
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(C(=O)O)c3c2)C(C#N)=C(C)N1
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C(=O)NCCN(C)C)c3c2)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a solution of 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-3-carboxylic acid (300 mg, 0.94 mmol), from Synthetic Example 3, in DMF (5 mL) was added Et3N (476 mg, 4.7 mmol) and HATU (430 mg, 1.13 mmol). The mixture was stirred at rt for 30 min, then N,N-dimethylethylenediamine (167.2 mg, 1.9 mmol) was added. The mixture was kept at rt overnight, and then quenched with water. The reaction mixture was extracted with CH2Cl2, dried, and concentrated. The residue was purified by flash chromatography followed by HPLC to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-N-[2-(dimethylamino)ethyl]-1H-indazole-3-carboxamide (121 mg, 33.7%) (Cpd. No. 103.2, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=8.16 (s, 1H), 7.63 (d, 1H), 7.41 (d, 1H), 4.55 (s, 1H), 3.82 (t, 2H), 3.43 (t, 2H), 3.01 (s, 6H), 2.14 (s, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[N:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:39][C:37]([CH3:40])([CH3:38])[CH2:36][N:33]1[CH:34]=[CH:35][C:31]([NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:29])=[N:32]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)O)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (93.12 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (54.1 mg, 47.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C30H35Cl2N5O2+H [(M+H)+]: 568.2241. found: 568.2246.
Reaction SMILES: F[C:2]1[C:3]([CH3:11])=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:15]1[CH:14]=[C:13]([O:12][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: Cc1cc([N+](=O)[O-])ncc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(Cl)c1
Temperature: 80 °C
Yield: 62.5 %

Procedure:
A mixture of 5-fluoro-4-methyl-2-nitropyridine (0.8 g, 5.12 mmol), 4-hydroxy-2-chloropyridine (0.996 g, 7.69 mmol) and K2CO3 (0.708 g, 5.12 mmol) in DMF (10 mL) was heated at 80° C. for 4 h. The mixture was cooled to RT, poured onto water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 5-((2-chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine (850 mg, 62%) as an off-white solid. MS (ESI) m/z: 266.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.N1CCOCC1.C(N1C[CH2:45][N:44]2[CH2:47][CH2:48][N:49]([CH2:50][CH2:51]CC)P1N(CCCC)CC2)CCC.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([N:49]5[CH2:48][CH2:47][N:44]([CH3:45])[CH2:51][CH2:50]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: CCCCN1CCN2CCN(CCCC)P1N(CCCC)CC2
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: C1COCCN1
Product: CN1CCN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (49 mg, 0.3 mmol), morpholine (130 mg, 1.44 mmol), 2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3]undecane (99 mg, 0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 1 h under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 115 mg of 110 (yield=31%). 1H NMR (CDCl3, 400 MHz): δ8.12-8.10 (m, 1H), 7.58-7.52 (m, 1H), 7.15-7.05 (m, 4H), 6.55 (d, J=9.2 Hz, 1H), 4.25-4.23 (m, 2H), 3.75-3.63 (m, 5H), 3.12-3.10 (m, 2H), 2.93-2.91 (m, 4H), 2.62-2.57 (m, 3H). LC-MS (ESI): m/z=480 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19](O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19]([N:43]=[N+:44]=[N-:45])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(O)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(N=[N+]=[N-])c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
Compound 2 (0.600 g, 1.61 mmol) was dissolved in toluene (15 mL), and diphenylphosphoryl azide (0.696 mL, 3.23 mmol) and DBU (0.483 mL, 3.22 mmol) was added to the solution, followed by stirring at 60° C. for 4 hours. The reaction mixture was diluted with toluene, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain [4-(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)phenyl]phenylmethylazide (0.590 g, yield 92%).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9]OC(OC)OC>C1(C)C(S(O)(=O)=O)=CC=CC=1>[CH3:9][O:8][C:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(OC)OC
Reactant: O=C1CCCCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Product: COC1=CCCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
At 0° C., cycloheptanone (1) (5 cm3, 42.61 mmol, 1 eq.), trimethylorthoformate (5.2 cm3, 46.88 mmol, 1.1 eq.) and anhydrous toluenesulphonic acid (40 mg, 0.213 mmol, 0.05 eq.) were allowed to warm to room temperature and left to stand for 2 days. Crude 1H-NMR spectroscopy indicated formation of the intermediate ketal. Distillation, initially at atmospheric pressure, then at water aspirator pressure (ca. 15 mm/Hg) afforded the product 2 (3.82 g, 71%) as a colourless liquid (b.p. 130-140° C./15 mm/Hg). δH (250 MHz, CDCl3) 1.35-1.55 (4H, m, CH), 1.59-1.74 (2H, m, CH2), 1.97-2.08 (2H, m, CH2), 2.12-2.25 (2H, m, CH2), 3.39 (3H, s, CH3), 4.67 (1H, t, J 7.0 Hz, CH); m/z (CI) 127 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:31])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[NH:1][C:15](=[O:31])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18]
Reactant: Nc1cc(O)ccc1F
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(4-methanesulfonylbenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH2:18][CH3:19])=[CH:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4].[C:20]1([CH3:27])[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][CH:21]=1.B(F)(F)F.O(CC)CC>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH2:18][CH3:19])([C:22]3[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([CH3:27])[CH:21]=3)[CH2:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CC=C(CC)c1ccc2cc(C(=O)OC)ccc2c1
Reactant: Cc1ccccc1O
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc2cc(C(=O)OC)ccc2c1
Yield: 87.3 %

Procedure:
Cool a solution of 6-(1-ethyl-propenyl)naphthalene-2-carboxylic acid methyl ester (0.74 g, 2.75 mmol) and o-cresol (2.0 mL, 19.4 mmol) in CH2CL2 (20 mL) to −78° C.; dropwise add BF3-OEt2 (1.22 mL, 9.6 mmol). Remove the cooling bath and stir the reaction at RT for 16 h. Quench the reaction with ice water; then dilute with EtOAc (200 mL). Wash the resulting mixture twice with brine, dry over Na2SO4, filter, and concentrate the filtrate. Purify the product using medium pressure silica gel chromatography (100% hex to 25:75 EtOAc:hex) to give the title compound as a white solid (0.87 g, 87%). MS (ES) in/e 363 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([CH:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C)C=O>[CH2:12]([C:19]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.2 %

Procedure:
To a stirred solution of p-nitrobenzyl chloride (15 g) and diethyl benzylmalonate (22 g) in N,N-dimethylformamide (150 ml) was added NaH (60% in oil, 3.8 g). After stirring at room temperature for 2 days, the reaction mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate. The ethyl acetate layer was washed with aqueous citric acid solution, water, saturasted aqueous sodium hydrogen carbonate solution and brine, and dried (MgSO4). The organic solvent was evaporated off and the residual oil was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:6, v/v) gave diethyl benzyl-4-nitrobenzylmalonate (24 g, 71%) as crystals. Melting point: 70-71°C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][C:20]#[CH:21])[CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[O:24][CH3:25]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:21]#[C:20][CH2:19][C:17]2[CH:16]=[C:15]([O:22][CH3:23])[C:14]([O:24][CH3:25])=[C:13]([O:12][CH3:11])[CH:18]=2)=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: C#CCc1cc(OC)c(OC)c(OC)c1
Product: COc1cc(CC#Cc2c(C)nc(N)nc2N)cc(OC)c1OC
Yield: 85.3 %

Procedure:
2,4-Diamino-5-iodo-6-methylpyrimidine (250 mg) was allowed to react with 1,2,3-Trimethoxy-5-(prop-2-ynyl)benzene (412 mg) as per the general procedure to afford 2,4-Diamino-5-(3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)-6-methylpyrimidine as a white powder (280 mg, 85%): Rf=0.31 (9:1, CHCl3:MeOH); mp=164-166° C.; 1H NMR (DMSO-d6) δ 6.72 (s, 2H), 6.42 (s, 2H), 3.85 (s, 2H), 3.76 (s, 6H), 3.63 (s, 3H), 2.24 (s, 3H); 13C NMR (DMSO-d6) δ 165.0, 164.3, 159.7, 152.8, 135.9, 132.8, 105.0, 96.3, 89.3, 75.8, 60.0, 55.8, 25.7, 21.7; HRFAB[M+Li]335.1679 (calculated C17H20N4O3Li: 335.1695).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12](F)[C:11]=3[F:20])[CH:5]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([F:20])=[C:12]([NH:30][C@H:28]([C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=4)[CH3:29])[CH:13]=[CH:14][C:15]=3[N+:16]([O-:18])=[O:17])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Temperature: 160 °C
Yield: 70 %

Procedure:
A mixture of 5-cyclopropyl-N-(2,3-difluoro-6-nitrophenyl)-1H-pyrazol-3-amine (Method 85; 0.400 g, 1.43 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.209 g, 1.50 mmol, and DIEA (0.373 ml, 2.14 mmol) in n-BuOH (3 ml) was heated in a sealed tube at 160° C. for 8 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=4:1) to give the title compound as an orange solid (0.40 g, 70%). NMR (400 MHz) 11.95 (s, 1H), 8.74 (s, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.43 (t, J=7.0 Hz, 2H), 7.25 (d, J=6.4 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 6.26 (t, J=8.6 Hz, 1H), 5.63 (s, 1H), 4.78 (m, 1H), 1.84 (m, 1H), 1.48 (d, J=6.8 Hz, 3H), 0.91 (m, 2H), 0.66 (m, 2H). MS: Calcd.: 399; Found: [M+H]+ 400.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:12]=[CH:11][N:10](S(C3C=CC(C)=CC=3)(=O)=O)[C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.O.[OH-].[Li+]>O1CCCC1.O>[Br:1][C:2]1[C:3]2[CH:12]=[CH:11][NH:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cn(C)c(=O)c32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(Br)c2cc[nH]c2c1=O
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of Example 1e (7 g, 18.36 mmol) and lithium hydroxide monohydrate (3.08 g, 73.4 mmol) in tetrahydrofuran (50 mL) and water (20 mL) was heated at 80° C. overnight. After cooling to ambient temperature, the reaction mixture was poured into 300 mL of water. The resulting solid was collected by vacuum filtration to give the title compound (3.92 g, 17.26 mmol, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[C:27]([O:30][C@H:31]1[CH2:36][C:35](=[O:37])[O:34][C:32]1=[O:33])(=[O:29])[CH3:28].C(O)(=O)C>C1C=CC=CC=1>[C:27]([O:30][C@@H:31]([CH2:36][C:35]([NH:26][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][CH2:19]2)[N:11]=3)=[C:2]([F:1])[CH:3]=1)=[O:37])[C:32]([OH:34])=[O:33])(=[O:29])[CH3:28]
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CC(=O)O[C@H]1CC(=O)OC1=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)O[C@@H](CC(=O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (70 mg, 0.194 mmol) and (S)-(−)-2-acetoxysuccinic anhydride (34 mg, 213 μmol) was added benzene (1.9 mL) and acetic acid (55 μl, 0.968 mmol) before it was stirred at 80° C. for 1 h. The reaction mixture was concentrated before the regioisomers were separated via SFC (Column: Chiralpak IC, Mobile Phase: liquid CO2/40% MeOH) to give (2S)-2-acetoxy-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)phenylamino)-4-oxobutanoic acid. MS (ESI) m/z: Calculated: 519.1; Observed: 520.1 (M++H).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)[N:7]=[C:6]([CH2:17][CH3:18])[C:5]=1[C:19]#[N:20])[CH3:2].B(Br)(Br)Br.O>C(Cl)Cl>[CH2:21]([N:3]([CH2:1][CH3:2])[C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:7]=[C:6]([CH2:17][CH3:18])[C:5]=1[C:19]#[N:20])[CH3:22]
Reactant: CCc1nn(-c2ccc(OC)cc2)c(N(CC)CC)c1C#N
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCc1nn(-c2ccc(O)cc2)c(N(CC)CC)c1C#N
Yield: 97.4 %

Procedure:
The 5-(diethylamino)-3-ethyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (39 mg, 0.13 mmol) from above was dissolved in CH2Cl2 (5 mL) and BBr3 (1 M solution in DCM, 1 mL, 1.0 mmol) was added and stirred over night. CH2Cl2 and water were added and the phases were separated, the aqueous phase was again extracted with EtOAc/CH2Cl2 (1:1). The solution was dried using a phase separator and concentrated under reduced pressure. Purification using preparative HPLC gave 5-(diethylamino)-3-ethyl-1-(4-hydroxyphenyl)-1H-pyrazole-4-carbonitrile (36 mg, 97%).
Reaction SMILES: [C:1](=[O:21])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>CN(C=O)C>[CH3:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][N:43]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH3:10])[CH2:8][CH2:9]3)=[O:21])[CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(C(=O)OCC3CCN(C)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.4 %

Procedure:
(1-Methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 1; 4.30 g, 14.6 mmol) was dissolved in DMF (50 mL). DIPEA (8.91 mL, 51.1 mmol) and 4-(3-methylphenyl)piperazine dihydrochloride (3.64 g, 14.6 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (500 mL) and then washed sequentially with 1 M aq NaOH solution (6×200 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (150 mL) and methyl isocyanate resin (1.0 g) was added and the reaction mixture shaken for 14 h, filtered and then concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-(3-methylphenyl)piperazine-1-carboxylate (0.65 g, 13.3%) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:5][N:4]=[C:3]1SC.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:5][N:4]=[C:3]1[N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CSc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)n1C
Reactant: C1CCNC1
Product: Cc1nc(-c2cnc(N3CCCC3)n(C)c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
A solution of Example C3 (0.087 g, 0.207 mmol) in pyrrolidine (1.75 mL, 21.31 mmol) was heated at 100° C. in a sealed vessel overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM). The material was treated with MeCN, sonicated and the resulting solid collected via filtration and dried to afford 3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidin-4(3H)-one (62 mg, 67%). 1H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.58 (m, 4H), 3.45 (s, 3H), 2.35 (s, 3H), 1.87 (m, 4H); MS (ESI) m/z: 444.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]=3[C:6]3[C:14]2=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=3)=[CH:26][CH:25]=1
Reactant: Cc1cccc2c3c([nH]c12)CCCC3=O
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: Cc1cccc2c3c(n(Cc4ccc(F)cc4)c12)CCCC3=O
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
8-Methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.1967 g, 0.99 mmol) is added to a slurry of pentane-washed NaH (0.0449 g, 0.0011 mol) in DMF (2 mL). After stirring for 30 min, p-fluorobenzyl bromide (0.15 mL, 0.0012 mol) is added. Starting material is still present after 3 h, so additional p-fluorobenzyl bromide (0.015 mL, 0.12 mmol) is added and the mixture is stirred overnight. The mixture is then partitioned between aq. sodium bicarbonate and ethyl acetate and the organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (75 mL) using methanol/dichloromethane (2/98). The impure fractions are rechromatographed on silica gel (60 mL) using methanol/dichloromethane (2/98). The pure fractions are combined and recrystallized from ethyl acetate/hexane/dichloromethane to give 0.1021 g (34%) of the title compound; mp 154-155° C.; MS (ESI+) for C20H18FNO m/z 308.2 (M+H)+; IR (drift) 1635, 1602, 1539, 1510, 1462, 1449, 1414, 1226, 1159, 835, 826, 801, 786, 756, 747 cm−1; 1H NMR (CDCl3) δ2.21, 2.51, 2.59, 2.81, 5.55, 6.87, 6.98, 7.17, 8.23. Anal. Calcd for C20H18FNO: C, 78.15; H, 5.90; N, 4.56. Found: C, 77.72; H, 5.95; N, 4.64.
Reaction SMILES: Cl[C:2]1[C:3]2[N:12]([CH3:13])[N:11]=[C:10]([CH3:14])[C:4]=2[N:5]=[C:6]([CH2:8][CH3:9])[N:7]=1.[NH2:15][CH2:16][CH:17]([OH:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][N:12]1[C:3]2[C:2]([NH:15][CH2:16][CH:17]([OH:19])[CH3:18])=[N:7][C:6]([CH2:8][CH3:9])=[N:5][C:4]=2[C:10]([CH3:14])=[N:11]1
Reactant: CC(O)CN
Reactant: CCc1nc(Cl)c2c(n1)c(C)nn2C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc(NCC(C)O)c2c(n1)c(C)nn2C
Temperature: 25 °C
Reaction time: 60 h
Yield: 76 %

Procedure:
A mixture of 10.5 g (0.05 mol) of 7-chloro-5-ethyl 1,3-dimethylpyrazolo[4,3-d]pyrimidine (Ex. 11) 7.5 g (0.1 mol) of 1-amino-2-propanol and 8 ml of triethylamine in 75 ml of methylene dichloride is stirred at room temperature for 60 hours and filtered. The hygroscopic solid is stirred in 50 ml of saturated sodium bicarbonate solution to give 9.5 g (76%) of 1-[1,3-dimethyl-5-ethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]amino-2-propanol, a hemihydrate melting at 116°-119° C. from ethyl acetate-pet ether.