Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:12]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13]1)=[N:10][OH:11].[OH-].[K+].O.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]([CH:12]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13]3)=[N:10][O:11][C:2]=2[CH:7]=1
Reactant: ON=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1ccc2c(C3CCN(Cc4ccccc4)C3)noc2c1
Yield: 74.8 %

Procedure:
A mixture of (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime (10.8 g, 34.2 mmol), potassium hydroxide (10 g), water (100 ml), and ethanol (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the solution was cooled and ethanol was removed on a rotary evaporator. The aqueous mixture was diluted with water (100 ml) then extracted with dichloromethane (500 ml). The organic solution was washed with brine and dried over anhydrous MgSO4. The solution was concentrated to an oil (9.8 g). The crude product was purified by flash chromatography over a silica gel column. The product thus obtained weighed 4.46 g (44%) as a light yellow oil. The oily product was dissolved in ethanol, and then treated with a solution of fumaric acid (1.73 g, 1.0 eq) in ethanol. Crystallization took place slowly with the addition of isopropyl ether. Recrystallization from ethanol (15 ml) gave 4.6 g of 6-fluoro-3-[1-(phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazole fumarate as white crystals, m.p.=142°-144° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[C:10]([CH2:17][CH3:18])([CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH3:15][NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH2:17][CH3:18])[CH3:16]
Reactant: [H][H]
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1NC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCCC1NC

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.7 g) and 1-benzyl-4-methylamino-3-ethyl-3-methyl piperidine (6 g, 24.39 mmol) in methanol (60 ml) was stirred in hydrogen atmosphere (1 atm.) at 60° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-methylamino-3-ethyl-3-methylpiperidine. Yield 2.5 g (66%), C9H20N2, m/z 157 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[S:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:14][C:10]=2[C:9](=O)[NH:8][N:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:25])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:25])=[C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[S:12][C:11]=12)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1n[nH]c(=O)c2cc(-c3ccc(F)cc3)sc12
Product: CCOC(=O)c1nnc(Cl)c2cc(-c3ccc(F)cc3)sc12
Temperature: 90 °C

Procedure:
A mixture of 2-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-thieno[2,3-d]pyridazine-7-carboxylic acid ethyl ester (0.2 g, mmol) in phosphorous oxychloride (3 mL) was heated at 90° C. for 3 hours, cooled and evaporated to dryness. To the residue was added ice and ethyl acetate and then basified over potassium carbonate solid. The organic layer was separeted, washed with water, brine and dried over sodium sulfate. The organic layer was evaporated to dryness and the residue was purified by flash chromatography (silica gel, 5% acetone/hexane) to obtain 4-chloro-2-(4-fluorophenyl)-thieno[2,3-d]pyridazine-7-carboxylic acid ethyl ester as a solid (0.12 g). MS: m/z=338 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C@@H:23]2[C@@H:28]3[CH2:29][C@@H:25]([CH:26]=[CH:27]3)[C@@H:24]2[C:30]([NH2:32])=[O:31])=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:33]1[O:36][C@@H:34]1[CH3:35].C(=O)([O-])[O-]>CO>[Cl:1][C:2]1[C:3]([NH:22][C@@H:23]2[C@@H:28]3[CH2:29][C@@H:25]([CH:26]=[CH:27]3)[C@@H:24]2[C:30]([NH2:32])=[O:31])=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19]([CH2:33][C@H:34]([OH:36])[CH3:35])[CH2:18][CH2:17]4)[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cnn(C5CCNCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: C[C@@H]1CO1
Agent: O=C([O-])[O-]
Solvent: CO
Product: C[C@@H](O)CN1CCC(n2cc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cn2)CC1
Reaction time: 8 h

Procedure:
(1S,2S,3R,4R)-3-[6-Chloro-2-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Compound LVII above) (100 mg, 0.2 mmol) was combined with (R)-(−)-propylene oxide (25.6 mg, 0.442 mmol) and MP-Carbonate (140 mg, 0.442 mmol) in methanol (10 mL) and stirred in a sealed tube overnight. The product was filtered and the filtrate concentrated to afford a solid which was purified via reverse phase chromatography (Gilson) to afford following extractive neutralization of fractions and concentration the title compound as a white solid. 1H NMR (d-chloroform): 14.01 (br s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.69 (s, 1H), 7.13 (br s, 1H), 6.83 (s, 1H), 6.37 (1, 2H), 6.15 (d, J=9 Hz, 1H), 5.25 (t, J=9 Hz, 1H), 4.26 (m, 1H), 3.89 (m, 1H), 3.22 (d, J=10 Hz, 1H), 3.11 (s, 1H), 2.99 (d, J=10 Hz, 1H), 2.86 (s, 1H), 2.81 (m, 2H), 2.66-2.13 (m, 7H), 2.03 (m, 2H), 1.61 (d, J=10 Hz, 1H), 1.22 (d, J=7 Hz, 3H). MS: 510.9 (M+H). HPLC retention time: 1.59 minutes (G Method).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][NH:5][C:4](=[O:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21].O>CS(C)=O>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[CH:6]=[C:7]([CH3:8])[C:2](=[O:1])[NH:3][C:4]1=[O:9]
Reactant: ClCCCCBr
Reactant: Cc1c[nH]c(=O)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn(CCCCCl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
10.1 g (80.0 mmol) of 4-hydroxy-5-methylpyrimidin-2(1H)-one (thymine) in 300 ml of dimethyl sulfoxide (DMSO) and 11.1 g (80.0 mmol) of K2CO3 were stirred at room temperature for 1 hour. Then 13.7 g (80.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to the mixture, and the reaction mixture was then stirred at room temperature for 5 hours. Water was added to the reaction mixture, and it was then extracted with ethyl acetate. The aqueous phase was then neutralized and extracted with methylene chloride. Drying of the organic phase, removal of the desiccant by filtration and evaporation of the solvent to dryness in vacuo resulted in 7.1 g of the title compound
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH3:12])[C:5]=1[O:13][CH3:14])[CH2:2][CH3:3].[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>>[C:15]([C:8]1[CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]([O:13][CH3:14])=[C:6]([CH2:10][CH2:11][CH3:12])[CH:7]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)Cl
Reactant: CCCc1cccc(CCC)c1OC
Product: CCCc1cc(C(=O)CC)cc(CCC)c1OC

Procedure:
2,6-Di-n-propylanisole and propionyl chloride were treated in the same way as in step (a) of Example 30 to give 4-propionyl-2,6-di-n-propylanisole.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][C:24](=[O:26])[CH3:25])[CH:19]=2)[CH:14]=1)=O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.O1CCCC1.[OH-].[Na+]>O>[CH2:2]([C:1]1[S:36][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][C:24](=[O:26])[CH3:25])[CH:19]=3)[CH:14]=2)=[N:10][N:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)NNC(=O)c1ccc2cc(OC(C)=O)ccc2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCc1nnc(-c2ccc3cc(OC(C)=O)ccc3c2)s1
Yield: 97.9 %

Procedure:
In a 100 ml-round-bottomed flask, 3.00 g (8.42 mM) of N-heptanoyl-N'-(6-acetoxy-2-naphthoyl)hydrazine, 3.83 g (9.47 mM) of Lawesson's reagent and 40 ml of tetrahydrofuran were placed, followed by refluxing for 1 hour under stirring. After the reaction, the reaction mixture was cooled on an iced water bath and poured into a solution of 3.00 g of sodium hydroxide in 250 ml of iced water to precipitate a crystal. The crystal was recovered by filtration and washed with water to obtain 2.92 g of 2-hexyl-5-(6-acetoxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 97.9 %).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:16][C:17]([C:19]2([NH:34]C(=O)OC(C)(C)C)[CH2:24][CH2:23][N:22]([C:25]3[C:26]4[CH:33]=[CH:32][NH:31][C:27]=4[N:28]=[CH:29][N:30]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C:19]1([C:17]([NH:16][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:18])[CH2:20][CH2:21][N:22]([C:25]2[C:26]3[CH:33]=[CH:32][NH:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH2:23][CH2:24]1
Reactant: CCN(CC)CC[C@H](NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CC[C@H](NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
(S)-1-(4-Chlorophenyl)-N3,N3-diethylpropane-1,3-diamine (Intermediate 60) (119 mg, 0.49 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (179 mg, 0.49 mmol) and DIPEA (0.259 mL, 1.48 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (207 mg, 0.54 mmol) was added and the resulting solution was stirred at 50° C. for 2 hours. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 10% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-(diethylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (189 mg, 65.5%) as a colourless gum. (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-(diethylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (189 mg, 0.33 mmol) was dissolved in DCM (5.00 mL) and TFA (1 mL) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford crude product which was triturated with diethyl ether to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-(diethylamino)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (70.0 mg, 29.3%) as a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:32][C:33]1[S:34][CH:35]=[N:36][N:37]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]([NH:32][C:33]1[S:34][CH:35]=[N:36][N:37]=1)=[O:18])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nncs1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Yield: 78.9 %

Procedure:
10 g of N-benzyloxycarbonyl-DL-valine, 4.1 g of triethylamine, 150 ml of chloroform, 4.4 g of ethyl chlorocarbonate and 4.1 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 1(i) to obtain 10.5 g (yield: 79%) of 2-(N-benzyloxycarbonyl-DL-valylamino)-1,3,4-thiadiazole as white crystals having a melting point of 162°-164° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=1[CH3:38])=[O:5])C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:38][C:30]1[CH:31]=[C:32]([C:33]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:34])[CH:36]=[CH:37][C:29]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]2[CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1[nH]c2c(-c3ccc(C(=O)O)cc3C)cccc2c1CCCOc1cccc2ccccc12
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCOCC2)ccc1-c1cccc2c(CCCOc3cccc4ccccc34)c(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 98D (75 mg) and morpholine (32 mg) in dichloromethane (2 mL) was added 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (58 mg) and DMAP (38 mg). The mixture was stirred at room temperature overnight and concentrated. The concentrate was diluted with ethyl acetate (150 mL), washed with 5% HCl, water and brine and dried (Na2SO4), filtered and concentrated. The concentrate was dissolved in THF (4 mL), methanol (2 mL) and water (2 mL). LiOH.H2O (100 mg) was added to the mixture and the mixture was stirred overnight. The mixture was concentrated, the concentrate was acidified with 5% HCl and extracted with ethyl acetate. The extract was washed with brine and dried (Na2SO4), filtered and concentrated. The concentrate was purified by reverse phase HPLC (C-18, 30 to 100% acetonitrile/water/0.1% TFA). 1H NMR (300 MHz, DMSO-d6) δ 12.95 (m, 1H), 10.79 (s, 1H), 8.25 (m, 1H), 7.87 (m, 1H), 7.71 (d, 1H), 7.35-7.57 (m, 6H), 7.27 (s, 1H), 7.08 (m, 2H), 6.90 (d, 1H), 4.21 (t, 1H), 3.64 (m, 8H), 3.37 (t, 2H), 2.26 (t, 2H), 2.07 (s, 3H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-])=[O:4].[O-]CC.[Mg+2].[O-]CC.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>CO.O1CCCC1>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])=[O:4]
Reactant: O=C(O)c1cccs1
Reactant: COC(=O)CC(=O)[O-]
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+2]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
In 200 mL of methanol, was dissolved 8.90 g (75.4 mmol) of monomethyl malonate, and the resulting solution was mixed with 4.30 g (37.5 mmol) of magnesium ethoxide, followed by stirring for 4 hours at room temperature. The reaction solution was concentrated and the residue was dried under reduced pressure. In 150 mL of tetrahydrofuran, was dissolved 4.80 g (37.5 mmol) of 2-thiophenecarboxylic acid and the resulting solution was mixed with 6.69 g (41.2 mmol) of carbonyldiimidazole, followed by stirring for 1 hour. The reaction solution was added to a dry magnesium salt and stirred at room temperature for 21 hours. The reaction solution was concentrated; the residue was mixed with 150 mL of 1.5 N hydrochloric acid, extracted with ethyl acetate, and washed with an aqueous sodium hydrogencarbonate solution and then saturated sodium chloride water. The resultant was dried over sodium sulfate anhydride, filtered, and concentrated. The residue was distilled (0.06 mmHg, 87) to give 5.95 g (32.3 mmol, 86.1%) of methyl 2-thiophenecarbonylacetate as an anhydrous liquid. Similarly to Example 133, 2.52 g (8.28 mmol, 81.2%) of yellow crystals were obtained from 5.95 g (32.2 mmol) of methyl 2-thiophenecarbonylacetate by recrystallization from methanol.
Reaction SMILES: [OH:1][CH:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[C:16]([NH:26][C@H:27]([C:31](O)=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:16]([NH:26][C@H:27]([C:31]([O:1][CH:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: COc1ccc(COC(=O)C(C)O)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C(C)OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methoxybenzyl 2-hydroxypropionate (4.2 g, 20 mmole), N-CBZ-L-valine (5.02 g, 20 mmole) and DMAP (0.24 g, 2 mmole) in 100 ml dichloromethane was added a solution of DCC (4.54 g, 22 mmole) and the mixture was stirred overnight at room temperature. The mixture was cooled to 5° C. and the urethane was filtered. The filtrate was evoporated and the product was isolated by silica gel column chromatography. Yield: 7.9 g
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C.C(#N)C>[CH:19]([N:3]1[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]1=[O:1])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc[nH]c(=O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1ccn(C(C)C)c(=O)c1
Temperature: 60 °C
Yield: 25.8 %

Procedure:
To methyl 2-oxo-1H-pyridine-4-carboxylate (700 mg, 4.57 mmol) in dry DMF (4.4 mL) was added finely ground K2CO3 (2.53 g, 18.3 mmol) followed by 2-iodopropane (914 μL, 9.14 mmol). The mixture was heated at 60° C. (external) for 1 h. The mixture was diluted with acetonitrile (10 mL) and was filtered. The filtrate was evaporated onto Celite and was purified by column chromatography (0-100% EtOAc/DCM) to give methyl 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (230 mg). ESI-MS m/z calc 195.1. found 196.3 (M−1)−. Retention time: 1.09 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[N:6]=[CH:5]2.[N:15]1[N:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]3)[C:19]=12.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[N:15]1[N:16]=[CH:17][N:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:28][CH2:27][C@H:26]([NH:29][C:12]([C:7]4[N:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=5)[N:8]=4)=[O:14])[CH2:25]3)[C:19]=12
Reactant: N[C@H]1CCN(c2nccn3cnnc23)C1
Reactant: Cc1ccc2nc(C(=O)O)ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(C(=O)N[C@H]3CCN(c4nccn5cnnc45)C3)ncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a solution of 6-methylquinazoline-2-carboxylic acid (0.040 g, 0.21 mmol, 1.2 eq) and (S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-amine (0.49 g, 0.18 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.10 mL, 0.7 mmol, 4 eq) and HATU (0.075 g, 0.20 mmol, 1.1 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)—N-(1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-yl)-6-methylquinazoline-2-carboxamide (0.028 g, 0.07 mmol, 42%). 1H NMR (400 MHz, DMSO) δ 9.62 (s, 1 H), 9.31 (t, J=3.9 Hz, 1 H), 8.08-8.00 (m, 2 H), 8.00-7.92 (m, 1 H), 7.85 (d, J=5.1 Hz, 1 H), 7.29 (d, J=5.0 Hz, 1 H), 4.82-4.70 (m, 1 H), 4.70-3.60 (br, 4 H), 2.56 (s, 3H), 2.40-2.20 (br, 2 H); MS: (ES) m/z calculated for C19H18N8O [M+H]+ 375.2, found 375.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([F:12])[C:5]=1[F:13].[Br:15][C:16]1[N:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH3:24])[NH:18][C:17]=1[CH:25]=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:18]2[C:17]([CH:25]=[O:26])=[C:16]([Br:15])[N:20]=[C:19]2[CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([F:12])[C:5]=1[F:13]
Reactant: COC(=O)c1ccc(CBr)c(F)c1F
Reactant: CCCCc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(Br)c(C=O)n1Cc1ccc(C(=O)OC)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
4-bromomethyl-2,3-difluorobenzoic acid methyl ester (3.5 g, 13.2 mmol), 5-bromo-2-butyl-3H-imidazole-4-carbaldehyde (3.1 g, 13.2 mmol) and potassium carbonate (1.8 g, 13.2 mmol) were combined and dissolved in DMF (20 mL, 300 mmol). The mixture was stirred at room temperature overnight. The mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The crude reaction was purified by silica gel chromatography (0-50% EtOAc:hexanes) to obtain 4.16 g of intermediate (8a) as a yellow solid. MS m/z: [M+H+] calcd for C17H7BrF2N2O3, 416.23; found 417.1. 1H-NMR (CDCl3): 9.68 (1H, s), 7.64 (1H, t), 6.55 (1H, t), 5.64 (2H, s), 3.95 (3H, s), 2.63 (2H, t), 1.69 (2H, m), 1.36 (2H, m) 0.90 (3H, t).
Reaction SMILES: O1C[CH2:5][N:4]([CH:7]=[O:8])[CH2:3]C1.CNC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([C:25]3[CH:26]=[C:27]4[C:31](=[C:32](C(O)=O)[CH:33]=3)[NH:30][N:29]=[CH:28]4)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][C:14]=1[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(#N)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([C:25]3[CH:26]=[C:27]4[C:31](=[C:32]([C:7]([N:4]([CH3:5])[CH3:3])=[O:8])[CH:33]=3)[NH:30][N:29]=[CH:28]4)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][C:14]=1[CH3:37]
Reactant: Cc1cc(-c2ncccc2-c2cc(C(=O)O)c3[nH]ncc3c2)ccc1F
Reactant: O=CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(-c2ncccc2-c2cc(C(=O)N(C)C)c3[nH]ncc3c2)ccc1F

Procedure:
5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N,N-dimethyl-1H-indazole-7-carboxamide was prepared analogous to the preparation of 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-7-yl)(morpholino)methanone by the reaction of dimethyl amine (0.55 mL, 1.1 mmol, 2M in THF) with 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylic acid (100 mg, 0.28 mmol), HBTU (140 mg, 0.36 mmol), NEt3 (57 mg, 0.08 mL, 0.57 mmol) in acetonitrile (4 mL). Extractive work-up followed by preparative HPLC purification and neutralization procedure as discussed previously provided desired 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N,N-dimethyl-1H-indazole-7-carboxamide as a white solid. 1H NMR (DMSO-d6): δ 13.05 (s, 1H), 8.63 (dd, 1H, J=1.7 and 4.7 Hz), 8.13 (s, 1H), 7.87 (dd, 1H, J=1.4 and 7.6 Hz), 7.81 (s, 1H), 7.46 (dd, 1H, J=4.7 and 7.6 Hz), 7.32 (d, 1H, J=7.3 Hz), 7.02-6.98 (m, 1H), 6.95-6.89 (app m. 2H), 2.93 (br s, 3H), 2.57 (br s, 3H), 2.09 (s, 3H).19F NMR (DMSO-d6): δ −118.91. LCMS: rt 4.63 min (A), purity 97%, MS (m/e) 375 (MH+).
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1>CN(C=O)C>[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:9]=[N:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:14][CH:13]=1
Reactant: CSc1ccc(S)cc1
Reactant: O=Cc1ccncc1Cl
Solvent: CN(C)C=O
Product: CSc1ccc(Sc2cnccc2C=O)cc1
Temperature: 65 °C
Yield: 110.3 %

Procedure:
3-Chloroisonicotinaldehyde [prepared according to R. B. Moffett et al., J. Heterocycl. Chem. 1979, 16, 1459] (550 mg, 3.9 mmol), 4-methylsulfanyl-benzenethiol (732 mg, 4.7 mmol) potassium carbonate (700 mg, 5.1 mmol) and DMF (10 mL) were combined and the mixture was heated together at 65° C. for 2 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to give the title compound (1.124 g) as a yellow oil. The 1H NMR spectrum showed the material to be of sufficient purity (90-95%) to be used without further purification; δH (CDCl3, 300 MHz) 2.52 (3H, s), 7.28 (2H, d), 7.40 (2H, d), 7.64 (1H, d), 8.39 (1H, s), 8.61 (1H, d), 10.42 (1H, s); MS m/z (ES−) 260 (M−H+).