Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1([CH3:37])[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:33]3[C:27]4[O:26][C:25]([CH3:37])([CH3:24])[CH2:29][C:28]=4[CH:30]=[CH:31][CH:32]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: CC1(C)Cc2cccc(C(=O)O)c2O1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: CC1(C)Cc2cccc(C(=O)NC[C@@H]3C[C@@H]4C[C@@H]4N3C(=O)c3nc(N)sc3-c3cccc(F)c3)c2O1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2,2-dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid. LC-MS (basic): tR=0.87 min; [M+H]+=507.2.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].CC#N.CCN(CC)CC.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:24]([O:23][C:19](=[O:22])/[CH:20]=[CH:21]/[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])[CH3:25]
Reactant: Cc1ccncc1Br
Reactant: C=CC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cnccc1C
Yield: 43.6 %

Procedure:
A mixture of 2.0 g (12 mmol) of 3-bromo-4-methylpyridine, 2.5 mL of CH3CN, 3.2 mL (23 mmol) of Et3N, 5.8 g (58 mmol) of ethyl acrylate, and 0.095 g (0.12 mmol) of PdCl2(dppf).CH2Cl2 is stirred in an evacuated and sealed pressure tube at 125° C. for 1 h. The mixture is concentrated and purified by flash chromatography (5-60% EtOAc in hexanes) to provide 1.0 g (47%) of (E)-3-(4-methyl-pyridin-3-yl)-acrylic acid ethyl ester as a dark oil. This material is stirred in 2 mL of toluene with 0.70 mL (6.0 mmol) of benzyl bromide at 60° C. overnight. The resulting precipitate is filtered and washed with toluene to provide 1.4 g (4.0 mmol) of the benzyl pyridinium bromide as a white powder. To this material in 20 mL of EtOH at 0° C. is added 0.30 g (8.0 mmol) of NaBH4 in portions over 30 minutes. The mixture is stirred for 90 min, concentrated by half, dissolved in CH2Cl2, washed twice with water and once with brine, dried over Na2SO4, filtered, and concentrated. Flash chromatography (5-50% EtOAc in hexanes) provides 0.42 g (1.5 mmol) of (E)-3-(1-benzyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-acrylic acid ethyl ester as a yellow oil. This material is stirred in 3 mL of EtOH with 42 mg of Pd/C under an H2 atmosphere overnight. The vessel is evacuated with N2, filtered through diatomaceous earth, and concentrated to provide 208 mg of I-031 as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH2:17])[N:3]=1.[CH:18]([NH2:22])([CH2:20][CH3:21])[CH3:19]>>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH:22][CH:18]([CH2:20][CH3:21])[CH3:19])=[N:3][C:4]=3[NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCC1
Reactant: CCC(C)N
Product: CCC(C)Nc1nc(N)c2ncn(C3CCCCC3)c2n1

Procedure:
Reaction of 2-chloro-9-cyclohexyl-9H-adenine with sec.-butylamine according to the procedure of Example 1 affords the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16]([O:18]CC)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:23][NH2:24]>>[CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16]([NH:24][CH3:23])=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: CN
Product: CNC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 110 °C

Procedure:
A mixture of ethyl 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate (100 mg, 0.33 mmol) and methyl amine (40% aq, 2.5 ml) was heated at 100-120° C. for 3-4 h. The reaction mixture was evaporated to dryness and the residue was purified by on neutral alumina chromatography eluting with methanol-dichloromethane gradient to obtain 10 mg of 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-N-methylpropanamide.
Reaction SMILES: C([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:7][C:6]([O:16]C(=O)C)=[CH:5]1)(=O)C.N#N.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[OH:16][C:6]1[CH:7]=[C:8]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[NH:4][CH:5]=1
Reactant: CC(=O)Oc1cc(-c2ccc(Cl)cc2)n(C(C)=O)c1
Agent: N#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1c[nH]c(-c2ccc(Cl)cc2)c1
Temperature: -8 °C
Reaction time: 0.5 h

Procedure:
A sample of N-acetyl-3-acetoxyl-5-p-chlorophenylpyrrole (16) (2.8 g; 0.01 mol) was deoxygenated for ten minutes with a stream of N2. The solids were then dissolved in deoxygenated methanol (30 mL) which was then chilled to -8° C. At once was added a cold deoxygenated solution of NaOH (1.6 g; 0.04 mol) in 20 mL H2O, which solution was then heated briefly to 15° C. and then immediately cooled to -5° C.; after 25 minutes the clear solution was treated with a cold deoxygenated solution of citric acid (4.2 g; 0.02 mol) in 15 mL H2O. The temperature rose briefly to 5° C. After 0.5 hr. stirring at -5° C., the solids were collected by filtration and washed with cold deoxygenated H2O. The pale green product was dried under vacuum at room temperature over P2O5 for several days (1.3 g; 68%); TLC Rf=0.19 (CHCl3 :EtOH, 9:1); IR (KCl) showed no evidence for C=O absorption.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][OH:22])[C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][OH:22])[C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CO)c1ccc(OCc2ccccc2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(CO)C(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl 2-(4-benzyloxy-3-methoxyphenyl)-3-hydroxy-propionate (1.29 g; 3.29 mmol; from step (iii) above) in THF (12.5 mL) was added a solution of LiOH (0.273 g; 6.75 mmol) in H2O (5 mL), and the mixture was stirred at room temperature for 2.5 hours. The resultant mixture was partially concentrated, water (25 mL) was added, the mixture was washed with two portions of CH2Cl2, made acidic with HCl/aq (2M), and extracted with 3 portions of CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), and evaporated to yield 10.55 g (quant.) of a yellow powder. Purity 83.2%. 1H-NMR (400 MHz; MeOH): δ 7.41 (d, 2H); 7.32 (m, 4H); 6.94 (d, 2H); 6.82 (dd, 1H); 5.06 (s, 2H); 4.04 (m, 1H); 3.83 (s, 3H); 3.70 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([N:48]2[CH2:53][CH2:52][N:51]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:50][CH2:49]2)=[CH:40][C:41]([O:45][CH2:46][CH3:47])=[C:42]([NH2:44])[CH:43]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(O)C(F)(F)F.CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:42]3[CH:43]=[C:38]([CH3:37])[C:39]([N:48]4[CH2:53][CH2:52][N:51]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:50][CH2:49]4)=[CH:40][C:41]=3[O:45][CH2:46][CH3:47])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 54.4 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (2.9 g, 5.7 mmol) and (5-methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (2.0 g, 5.7 mmol) in trifluoroethanol (100 mL) was added p-toluene sulfonic acid (2.2 g, 11 mmol), and the vial was sealed and heated to 80° C. overnight. The reaction was then cooled to rt and excess 0.5 M NaOMe in MeOH was added. The solution was transferred to a roundbottom flask and silica was added. The solvent was removed on a rotovap and the product purified on a 120 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound 2.5 g, 3.1 mmol, 54% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 9.33 (d, J=6.7 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J=5.4 Hz, 1H), 8.02 (s, 1H), 7.73-7.70 (m, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.53 (s, 1H), 7.43-7.31 (m, 2H), 7.23 (d, J=8.6 Hz, 1H), 7.16 (t, J=8.0 Hz, 2H), 6.92 (t, J=6.6 Hz, 1H), 6.71 (s, 1H), 6.56 (d, J=5.1 Hz, 1H), 4.23 (q, J=7.2 Hz, 2H), 4.04 (q, J=7.0 Hz, 2H), 3.33-3.25 (m, 2H), 3.03 (s, 3H), 2.84-2.78 (m, 4H), 2.74 (t, J=6.6 Hz, 2H), 2.63-2.46 (m, 4H), 2.11 (s, 3H), 1.40 (t, J=6.8 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H). MS (ESI) m/z=811 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.[OH-].[NH4+].[Cl-].[Na+]>[Zn].C1(C)C=CC=CC=1>[CH2:12]([O:11][C:9]([CH2:8][C:7]1[CH:2]=[N:3][C:4]([C:14]([CH3:15])([CH3:17])[CH3:16])=[N:5][CH:6]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cc1cnc(C(C)(C)C)nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cnc(C(C)(C)C)nc1
Yield: 77 %

Procedure:
A mixture 4-chloro-5-ethoxycarbonylmethyl-2-(2-methylprop-2-yl)pyrimidine (18 g), toluene (180 cm3), zinc dust (36 g) and 3 molar ammonium hydroxide solution saturated with sodium chloride (180 cm3) was heated at 100° C. for 120 hours. After cooling and filtering to remove the solid component the organic phase was separated, the aqueous phase washed with ethyl acetate and the washings combined with the organic phase. After washing the organic phase with water and drying over anhydrous magnesium sulphate the solvents were removed by evaporation under reduced pressure and the residual oil (16 g) was subjected to purification by column chromatography using a silica column eluted with dichloromethane to yield 5-ethoxycarbonylmethyl-2-(2-methylprop-2-yl)pyrimidine (12 g) as a yellow oil.
Reaction SMILES: C(O)[C@H]1[O:7][CH:6]([OH:8])[C@H:5]([OH:9])[C@@H:4](O)[C@@H]1O.O.C1C=C2C(C[C@H](N)C(O)=O)=CNC2=CC=1.[O:29]=[CH:30][C@@H:31]([C@H:33]([C@@H:35]([C@@H:37]([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])[OH:32].C(O)[C@H]1O[C@H](OC[C@H]2OC(O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>>[C:6]([O-:8])(=[O:7])[C@H:5]([CH3:4])[OH:9].[O:29]=[CH:30][C@@H:31]([C@H:33]([C@@H:35]([C@@H:37]([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])[OH:32]
Reactant: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OC[C@H]1O[C@H](OC[C@H]2OC(O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Product: C[C@H](O)C(=O)[O-]

Procedure:
The benchmark for the SSF fermentation was set by the fermentation with glucose syrup (DE 98) as substrate. The SSF study was started with a maltodextrine preparation from Roquette Freres (Glucidex™ 12, DE 11-14) and successfully finished. Two glucoamylase preparations were extensively tested: AMG E™ from Novozymes (glucoamylase with high debranching activity) and Optimax™ 7525 HP from Genencor (glucoamylase/pullulanase). A typical SSF fermentation on pure maltodextrines was free of residual sugars within 2 days. The main residual sugars present were glucose and isomaltose, however, at a consistently lower concentration than in comparable cultures that received DE 98 glucose syrup as substrate. Maltose concentrations were low (<50 mg/i) in contrast to comparable DE 98 cultures running at pH 6.4-6.6. A considerable amount of maltose was introduced in the fermentation with the addition of Glucidex 12. The fact that maltose could be fermented at low pH was a significant finding. The fermentation yield (mol (S)-lactate produced per mol glucose consumed) was slightly higher than 100%. Organic acids in sugar free SSF broth were analyzed and levels were comparable with Bacillus coagulans fermentations at pH 6.4-6.6. Below pH 5.55 the SSF fermentation was relatively slow. At pH 5.90 a 50% increase in total residual sugar was observed compared to cultures running between pH 5.55-5.75. Similar results were obtained using the crude liquefied starch. In the final stage, successful SSF experiments were performed with crude liquefied starch hydrolysates. There was no difference observed between the SSF fermentation on purified maltodextrines and the liquefied starch from the Cargill Refinery regarding fermentation time. Both SSF fermentations finished in 30-40 hours. Cultures containing crude liquefied starch or maltodextrin as substrate typically contained 180-200 g/l of (S)-lactic acid. The enantiomeric purity of the lactic acid was better than 99.5%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Br[CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)C=O>[CH2:34]([O:33][C:31]([C:30]1[N:26]=[C:25]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[N:4]2)[S:27][CH:29]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
A mixture of 0.45 g (1.17 mmol) of the starting material I, 0.46 g (2.36 mmol) of ethyl bromopyruvate and 7 ml of dimethylformamide was stirred at 80° C. for 30 min. After cooling the precipitated crystals were filtered off, washed with ethanol and dried to yield 0.41 g (85%) of the title compound; Mp.: 242-243° C.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[CH3:12][NH2:13]>O>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([NH:13][CH3:12])[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: CN
Solvent: O
Product: C=CCC1=C(C)C(NC)CC1=O
Reaction time: 1 h
Yield: 96.3 %

Procedure:
2-Allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g) was dropwise added to a 40% aqueous solution of monomethylamine (60 g) in the same flask as used in Example 1 at a temperature of 10° to 20° C. for 1 hour. At the same temperature, the reaction mixture was kept for 1 hour. After completion of the reaction, monomethylamine and water were evaporated off under reduced pressure. The residue was extracted with dichloromethane, and the solvent was evaporated off from the organic layer to obtain 2-allyl-3-methyl-4-methylamino-2-cyclopentenone (15.9 g). Yield, 96%. nD23 1.5090.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[CH3:23][O:22][C:20](=[O:21])[CH2:19][O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 4-trifluoromethyl-phenol (10.000 g; 61.687 mmol), potassium carbonate (9.377 g; 67.856 mmol), and methyl bromoacetate (5.67 ml; 61.687 mmol) in acetone (250 ml) was heated at reflux for 1 h30. Filtration, concentration to dryness under reduced pressure, and purification by FC (DCM) afforded (4-trifluoromethyl-phenoxy)-acetic acid methyl ester as a colorless oil (14.100 g; 98%). LC-MS: tR=0.95 min.; [M+H]+: no ionisation.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1)#[CH:2].I[C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][S:24]([N:23]1[C:22]2[C:21](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:2]=[C:1]1[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Nc1ccccc1I
Reactant: C#Cc1ccc(OCCCN2CCN(C)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(CCCOc2ccc(-c3cc4ccccc4n3S(C)(=O)=O)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
The mixture of 1-ethynyl-4-(3-(4-methylpiperazino)propoxy)benzene (230 mg, 0.89 mmol), 2-iodo-N-(methanesulfonyl)aniline (0.89 mmol, 296 mg), Cul (17 mg, 0.089 mmol), Pd(PPh3)2Cl2 (32 mg, 0.045 mmol) and triethylamine (0.5 mL) in DMF (5 mL) was stirred at 80° C. for overnight. After concentration, water (20 mL) was added and extracted by methlene chloride (3×20 mL). The organics was concentrated and purified by column chromatography afforded the title compound (260 mg): 1H NMR (CDCl3, 400 MHz) δ 8.05 (d, 1H, J=8.8 Hz), 7.55 (d, 1H, J=2.1 Hz), 7.50 (td, 2H, J=8.8,2.1 Hz), 7.32 (d, 1H, J=2.1 Hz), 7.30 (d, 1H, J=2.1 Hz), 6.96 (td, 2H J=2.1, 8.8 Hz), 6.60 (d, 1H, J=0.5 Hz), 4.08 (t, 2H, J=6.3 Hz), 2.74 (s, H), 2.55 (m, 10H), 2.33 (s, 3H), 2.02 (quintet, 2H, J=6.3 Hz); EIMS m/z 462 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:28])=[N:25][CH:26]=3)[CH2:16][CH:17]([CH3:18])[CH3:19])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN
Reactant: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)O)nc3)c(C)o2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.6 %

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (0.9 g), methyl 5-aminopyridine-2-carboxylate (0.5 g), sodium carbonate (0.5 g) and sodium iodide (0.9 g) in N,N-dimethylacetamide (20 mL) was stirred at 80° C. for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (6 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridine-2-carboxylic acid. To the obtained 5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridine-2-carboxylic acid (395 mg) were added ethyl β-alaninate hydrochloride (184 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg), hydroxybenzotriazole monohydrate (184 mg), triethylamine (168 μL) and N,N-dimethylformamide (10 mL) was added. The obtained mixture was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (171 mg, 35%) as an amorphous compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=2)[CH:19]=[N:18]1>O1CCOCC1.CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:26][C:22]4[CH:21]=[C:20]5[C:25](=[CH:24][CH:23]=4)[NH:17][N:18]=[CH:19]5)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCCCO
Solvent: C1COCCO1
Product: c1cc(Nc2cc(C3CC3)[nH]n2)nc(Nc2ccc3[nH]ncc3c2)n1
Temperature: 100 °C
Yield: 5.3 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.8 5 mmol, 1 equiv.) and 1H-indazol-5-amine (340 mg, 2.55 mmol, 3 equiv.) in 1,4-dioxane (1 ml) and n-BuOH (0.5 ml) was heated to 100° C. The mixture was allowed to react overnight (about 15 hr). The mixture was filtered under reduced pressure to afford title compound N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1H-indazol-5-yl)pyrimidine-2,4-diamine (Compound 13) (44.5 mg, 15.8%) as solid. LC-MS (m/z)=333.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.44 (s, J=17.7 Hz, 2H), 0.82 (t, J=17.7 Hz, 2H), 1.758 (s, 1H), 6.02 (s, 1H), 6.41 (s, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.56 (d, J=9 Hz, 1H), 7.92 (d, J=6.6 Hz, 1H), 8.04 (d, J=9.6 Hz, 2H), 9.71 (s, 1H), 10.38 (s, 1H), 11.77 (s, 1H), 13.05 (s, 1H).