Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([CH:19]3[CH2:22][O:21][CH2:20]3)[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:31]1[C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[N:34]=[C:30]1[CH3:29])=[N:3][C:4]=2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4COC4)CC3)n(C)c2n1
Yield: 23.1 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-(4-oxetan-3-yl-piperidin-1-ylmethyl)-9H-purine (100 mg, 0.25 mmol), 2-methyl-1H-benzoimidazole (38 mg, 0.29 mmol), Pd2dba3 (6 mg, 0.006 mmol), Xphos (12 mg, 0.025 mmol) and cesium carbonate (121 mg, 0.37 mmol) in DMF (2 mL) was purged with argon gas then subjected to microwave irradiation at 145° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 99:1 to 98:2) to afford 446 as a white solid (29 mg, 23%). LCMS (Method I): RT=2.37 min, M+H+=503. 1H NMR (CDCl3, 400 MHz) δ 8.09 (m, 1 H); 7.72 (m, 1 H); 7.39 (m, 2 H); 4.76 (dd, J=7.9, 6.0 Hz, 2 H); 4.46 (t, J=6.0 Hz, 2 H); 4.35 (m, 4 H); 3.90-3.84 (m, 7 H); 3.78 (s, 2 H); 2.96 (m, 5 H); 2.80-2.71 (m, 1 H); 2.22 (m, 2 H) and 1.69 (m, 5 H)
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[OH:16])([O-:5])=[O:4]>CC(O)=O>[Br:1][C:8]1[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[OH:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(Br)c1O
Temperature: 40 °C
Reaction time: 65 h

Procedure:
4.0 g of bromine in 7.3 mL of AcOH was added dropwise to a solution of 4.0 g of 2-nitro-4-trifluoromethyl-phenol and 300 mg FeCl3 in 23.1 mL of AcOH at 0° C. Reaction was then heated at 40° C. for 1.5 h. and then allowed to stir for 65 h at rt. Solvent was then removed, placed solid back into EtOAc, filtered through celite and concentrated in vacuo. 5 g of title compound was collected.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([O:18]CC)(=O)[CH2:11][C:12]([O:14]CC)=O>>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH2:11][C:10]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1])=[O:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1cccc(Cl)c1Cl
Product: O=C(CC(=O)Nc1cccc(Cl)c1Cl)Nc1cccc(Cl)c1Cl
Temperature: 170 °C
Reaction time: 8 h

Procedure:
100 mmol 2,3-dichloroaniline and 50 mmol diethyl malonate were put together and stirred at overnight 170° C. The formed ethanol was distilled off directly (100 mmol≡6.6 mL) on a stream of nitrogen. N1,N3-di(2,3-dichloro-phenyl)-malonamide was formed as one solid block. The reaction was cooled and EtOAc was added. The product had to be crushed with a mortar, because it resembled very hard brick. The crushed material was stirred in EtOAc and filtered. EtOAc added was added twice and the mixture was stirred and filtered each time. 14.7 g N1,N3-di(2,3-dichloro-phenyl)-malonamide was obtained (yield 75.0%, purity 98.4%)
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: COc1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(-c2n[nH]c3ncnc(N)c23)cc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 13.7 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g, 3.83 mmoles) in DMF (12 ml), ethanol (7 ml) and water (7 ml), 3-Fluoro-4-methoxyphenyl boronic acid (0.781 g, 4.59 mmoles) and sodium carbonate (2.03 g, 19.15 mmoles) were added and the system is degassed for 30 min. Tetrakis triphenylphosphine Palladium (0.872 g, 0.754 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.136 g, 14% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.53 (s, 1H), 8.19 (s, 1H), 7.45 (m, 2H), 7.33 (t, J=8.6 Hz, 1H), 3.89 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].C(OC(=O)C)(=O)C>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]2[C:7]([O:15][C:13](=[O:14])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
3-Nitrophthalic anhydride was prepared from 3-nitrophthalic acid and acetic anhydride by the same procedure given for its 4-nitro isomer in Example 2. The yield of recrystallized product was 17.85 g (92.5%); m.p. 163°-164°C, whose percent elemental analysis of C, 49.79; H, 1.57; N, 7.22 is in excellent agreement with the theoretical values.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[O:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([C:2]3[CH:3]=[CH:4][C:5]4[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=4[CH:16]=3)=[CH:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2SCC1
Reactant: [O-]B([O-])Oc1ccc(N2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2SCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.70 g), 4-morpholinophenyl borate (581.3 mg) and potassium carbonate (0.65 g) in toluene/ethanol/water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphine palladium (0.14 g), and the mixture was refluxed for 20 hours and then cooled. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/dichloromethane=1:4) to give yellow crystals of methyl 7-(4-morpholinophenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (664.4 mg).
Reaction SMILES: [CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17](OC)[C:18]([CH:20]=2)=[O:19])[C:13]2[C:12]([O:24][CH3:25])=[C:11]([O:26][CH3:27])[C:10]([O:28][CH3:29])=[CH:9][C:8]=2[CH2:7][CH2:6]1)=[O:3].C1(C)C=C[C:33]([S:36](O)(=O)=O)=CC=1.CS>>[CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([S:36][CH3:33])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([O:28][CH3:29])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=[O:3]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC)c(=O)cc1[C@@H](NC(C)=O)CC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CS
Product: COc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1[C@@H](NC(C)=O)CC2
Temperature: -30 °C
Reaction time: 240 h

Procedure:
In a glass autoclave cooled at -30° C there were charged 34.0 g of colchicine, 6.7 g of p-toluene-sulfonic acid and 208 g of methylmercaptan. The temperature is raised up to +20° C, which causes the internal pressure of the autoclave to reach about 3 atmospheres. The reaction mixture is maintained under stirring for 10 days in the absence of light. The methylmercaptan in excess is distilled off between 20° and 40° C and the residue is treated by 670 ml of chloroform. The solution thus obtained is filtered and the filtrate is neutralized using hydrogen sodium carbonate after having added thereto 270 ml of water. The aqueous phase is separated and extracted three times with fresh chloroform. The chloroform extracts are combined, dried and evaporated. The solid residue (43 g) is dissolved in 150 ml of ethyl acetate and a few thiocolchicine crystals (obtained in a preliminary experiment) are introduced into the solution in order to initiate the crystallization. 16.0 g of thiocolchicine are collected in this manner. The mother-liquors are evaporated to give 21 g of an impure product which is subjected to a purification step by column chromatography using neutral alumina (activity I) as absorbent and chloroform as eluant. 7.1 g are thus recovered. The total amount of the desired product is 23.1 (yield: 65 %). Said yields may be improved by chromatographic purification of the above crystallization mother-liquors. The product melts at 192° C and has a specific rotation [α]D20 equal to -229° (in chloroform; concentration: 0.524 gr/l).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][CH2:18][CH:19]=[O:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][CH2:18][CH2:19][OH:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)c1nc(COCC=O)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1nc(COCCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
In ethanol (6 ml)was dissolved 220 mg (0.59 mmol)of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-ylmethoxy]acetaldehyde (24a), followed by addition of 45 mg (1.2 mmol)of sodium borohydride, and the mixture was stirred for 15 minutes. The reaction mixture was weakly acidified with acetic acid. A saturated aqueous sodium hydrogen carbonate solution was added to neutralize again, and the mixture was extracted with methylene chloride. The extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was fractionated by silica gel chromatography (ethyl acetate). The product was recrystallized from n-hexane to give 144 mg of 2-{[5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methoxy}ethanol (25a)(yield 65%). mp 89-90° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH3:2].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl.C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C@@H:5]1[CH2:9][C@@H:8]([O:10][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-CBZ-trans-4-hydroxy-L-proline ethyl ester (5.6 g, 19 mmol) and anhydrous pyridine (4.6 mL, 4.5 g, 57 mmol) in CHCl3 (30 mL) was added p-toluenesulfonyl chloride (7.2 g, 38 mmol) in one portion. After stirring at room temperature for 72 h, the reaction was diluted with CH2Cl2 (70 mL) and pyridine removed by repeated extraction with 10% HCl (4×10 mL). The organic layer was dried (MgSO4) and concentrated to a golden oil which was purified by silica gel flash chromatography (gradient elution, using 1:1, 2:1 ethyl ether-petroleum ether) to yield 8.2 g (98%) of pure 2 as a colorless oil: TLC Rf 0.27 (3:3:1 ethyl ether-petroleum ether-CH2CL2); [α]24D -29° (c 1.5, CHCl3); 1H NMR (250 MHz, CDCl3 δ 7.79-7.74 (m, 2 H), 7.37-7.26 (m, 7 H), 5.18-5.00 (m, 3H, phCH2 and H-4), 4.44 (app q, J=7.5 Hz, 1 H, H-2), 4.19-3.99 (q, J=7.1 Hz, 2H, CO2CH2CH3, two rotamers), 3.76-3.60 (m, 2 H, H-5), 2.62-2.38 (m, 1 H, H-3), 2.45+2.43 (s, 3 H, PhCH3), 2.23-2.08 (m, 1 H, H-3), 1.25+1.08 (t, J=7.1 Hz, 3 H, CO2CH2CH3); 13C NMR (75.5 MHz, CDCl3) δ 171.59, 171.39, 154.12, 153.64, 145.10, 135.96, 135.81, 133.14, 133.08, 129.88, 129.86, 128.25, 128.17, 127.85, 127.60, 127.48, 78.66, 78.00, 67.14, 67.11, 61.25, 61.17, 57.39, 57.07, 52.25, 51.87, 36.99, 35.86, 21.41, 13.84, 13.69; IR (CHCl3) 1740, 1705, 1420, 1355, 1175 cm-1 ; LRMS (EI, 70 eV) m/e 447 (M+, 0.23), 374 (2), 202 (2), 158 (24), 91 (100); HRMS (EI, 40 eV) m/e 447.1337 (447.1351 calcd for C22H25NO7S).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a solution of 0.400 g (1.76 mmol) of 4-acetyl-piperidine-1-carboxylic acid tert-butyl ester in ethanol (3 mL) is added 0.134 g (3.52 mmol) of sodium borohydride. The mixture is stirred at room temperature for 1 hour then a saturated aqueous solution of ammonium chloride is added to consume excess reactants. The mixture is washed with ethyl acetate and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.390 g (96.6%) of 4-(1-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2]CCOC1C=C2C(=CC=1)NC=C2.[CH2:15]([O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([NH2:30])=[O:29])[CH:23]=[C:22]2[N:31]=[C:32]=[O:33])[CH:16]=C>>[N:31]([C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([O:18][CH2:15][CH2:16][O:2][CH3:1])[CH:20]=2)[N:24]([C:28]([NH2:30])=[O:29])[CH:23]=1)=[C:32]=[O:33]
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: COCCOc1ccc2[nH]ccc2c1
Product: COCCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O

Procedure:
was prepared from 5-(2-methoxy-ethoxy)-1H-indole using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([Cl:9])=[CH:6][C:7]=1[NH2:8].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18].Cl>[OH-].[Na+]>[Cl:9][C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[C:10]([F:13])([F:11])[F:12])[NH:1][C:17](=[O:18])[C:16](=[O:20])[NH:8]2
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(C(F)(F)F)cc2[nH]c1=O
Temperature: 25 °C

Procedure:
A mixture of 3,4-diamino-6-chlorobenzotrifluoride (185 mg, 0.88 mmol) and oxalic acid dihydrate (117 mg, 0.93 mmol, used as received)in 2N HCl (4 mL) was refluxed at 170°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed twice by cold water (2×2 mL), collected by filtration, and dried at 60° C. with reduced pressure for 2 h, affording 180 mg of crude title compound (77.3%) as a light yellow powder. The crude product was dissolved in 1N NaOH (6 mL) and filtered. The filtrate was acidified to pH=6, affording 138 mg of title compound. It was recrystallized from DMSO/H2O twice to give 102 mg of pure compound (43.9%) as yellow microcrystals. mp: >360° C. (dec. from 295° C.). IR (KBr, cm-1) 3425, 3200, 1731, 1706, 1625; 1400. 1H NMR (DMSO-d6): δ7.274 (s, 1H); 7.478 (s, 1H); 12.145 (s, 2H). HRMS: calcd for C9H4ClF3N2O2 (M+) m/z: 263.9912; found: 263.9919.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3]1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3]1
Reactant: COC(=O)c1cc(-c2ccccc2)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1C(=O)O
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
Methyl 1-methyl-3-phenylpyrazole-5-carboxylate (3 g) was dissolved in a mixed solvent of ethanol (20 ml) and water (20 ml) and sodium hydroxide (0.7 g) was added. The mixture was stirred at a refluxing temperature for 30 min. Ethanol was evaporated and to the residue was added dilute hydrochloric acid. The obtained solid was recrystallized from aqueous methanol solution to give the title compound (0.8 g), melting point: 189° C.
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[N:10]=[C:6]2[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:19][C:18]1[C:11]([N:9]2[CH:8]=[C:7]3[C:2]([NH:21][C:22]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=4)=[N:3][CH:4]=[C:5]([F:20])[C:6]3=[N:10]2)=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]
Reactant: Cc1cc(N)ncn1
Reactant: N#Cc1cccc(F)c1-n1cc2c(Br)ncc(F)c2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(F)cccc4C#N)cc23)ncn1
Temperature: 150 °C
Yield: 51.7 %

Procedure:
A mixture of 2-(4-bromo-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-3-fluorobenzonitrile (85 mg, 0.25 mmol), 4-amino-6-methylpyrimidine (31 mg, 0.28 mmol), Pd2(dba)3 (12 mg, 0.013 mmol), Xantphos (15 mg, 0.026 mmol) and cesium carbonate (166 mg, 0.51 mmol) in dioxane (1.8 mL) was de-gassed and purged with nitrogen and the reaction mixture was heated at 150° C. in a sealed vial for 30 minutes. The resultant mixture was diluted with dioxane and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography (10-100% ethyl acetate in cyclohexane) to afford the title compound as a brown solid (47 mg, 51% yield). LCMS (Method C): RT=2.25 min, m/z: 364 [M+H+].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:18][OH:19])[CH2:15][CH:16]=[CH2:17])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH:16]=[CH2:17])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: C=CCC(CO)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(COS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A solution of methanesulphonyl chloride (2.3 g) in dichloromethane (10 ml) was added to an ice-cooled solution of 4-(3,4-dichlorophenyl)-5-hydroxypent-1-ene (4.3 g) (see Preparation 22) and triethylamine (2.5 g) in dichloromethane (50 ml) over 10 minutes. The mixture was stirred for a offer 30 minutes before being washed sequentially with water (3×25 ml) and brine (25 ml), then dried over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave 4-(3,4-dichlorophenyl)-5-(methanesulphonyloxy)pent-1-ene (5.4 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCCCC1.ClC(OC)=O.Cl.[CH3:32][O:33][NH:34][CH3:35]>C(Cl)Cl>[CH3:32][O:33][N:34]([CH3:35])[C:16]([C@@H:13]1[CH2:12][CH2:11][C@H:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:15][CH2:14]1)=[O:18]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(=O)O)CC1
Agent: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CON(C)C(=O)[C@H]1CC[C@@H](CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of cis-4-{[(tert-butoxycarbonyl)amino]methyl}-cyclohexanecarboxylic acid (18.53 g, 72.0 mmol) and N-methylpiperidine (21.9 ml, 17.8 g, 180 mmol) in methylene chloride (360 ml) under nitrogen cooled in an ice-bath was adde dropwise methyl chloroformate (6.13 ml, 7.48 g, 79.2 mmol). The solution was stirred 15 minutes with cooling, and O,N-dimethylhydroxylamine hydrochloride (8.43 g, 86.4 mmol) was added. The mixture was stirred 18 hours while warming from ice-bath temperature to ambient temperature. The mixture was washed with 10% citric acid solution (100 ml), saturated sodium carbonate solution (100 ml), water (100 ml), and brine (100 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give crude product (15.30 g, 71%) as a yellow oil. The crude product was purified by flash column chromatography on silica gel, eluting with a gradient of 50:50 to 75:25 ethyl acetate/hexane to give tert-butyl [(cis-4-{[methoxy(methyl)amino]carbonyl}cyclohexyl)methyl]carbamate (13.76 g, 64%) as a pale yellow oil. 1H NMR (CDCl3) 4.61 (1H, br s), 3.68 (3H, s), 3.17 (3H, s), 3.11 (2H, t, J 6.5 Hz), 2.79 (1H, m), 1.75 (3H, m), 1.68-1.52 (6H, m), 1.44 (9H, s).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.Cl.[NH2:28][CH:29]([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(=O)([O-])[O-].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:28][CH:29]([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Reactant: CC(N)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CNC(C)C(=O)OC(C)(C)C)cc2C)ncn1
Reaction time: 18 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with tert-butyl 2-aminopropanoate hydrochloride (227.1 mg; 1.24 mmol) and polymer supported carbonate (150 mg) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 18 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 2-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylbenzylamino)propanoate which was used directly without any further purification. The residue was taken up into DCM (4.5 ml) and TFA (0.5 ml) added. After stirring at RT for 2 hours the solvent was removed in vacuo. The residue was taken up into dilute HCl and precipitated by basification to pH 3-4. The solid was removed by filtration, washed with water and dried to give the title compound as a white solid (85 mg, 71%).