Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[N:14]1([C:8]([C:7]2[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N2CCOCC2)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
To a solution of 3-(methoxycarbonyl)benzoic acid (200 mg, 1.11 mmol) in DCM (10 mL) were added morpholine (200 mg, 2.30 mmol) and TEA (300 mg, 2.96 mmol) and the resulting solution was stirred for 10 min at 20° C. To the mixture was added HATU (500 mg, 1.31 mmol) and the reaction mixture was stirred at 20° C. for 1 h. The mixture was concentrated and the residue was purified via column chromatography to obtain the title product (250 mg, Yield 90.5%). LCMS (m/z): 250.1 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[CH:23]([CH3:27])[N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:21]5)[C:12]=3[O:14][CH:15]([F:17])[F:16])[C:7](=[O:47])[C:6]([C:48]([O:50]CC)=[O:49])=[CH:5]2)[CH2:3][CH2:2]1.Cl>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[CH:23]([CH3:27])[NH:22][CH2:21]5)[C:12]=3[O:14][CH:15]([F:17])[F:16])[C:7](=[O:47])[C:6]([C:48]([OH:50])=[O:49])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(-c3ccc4c(c3)CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C4C)ccc2c1=O
Agent: Cl
Solvent: CCO
Product: CC1NCc2cc(-c3ccc4c(=O)c(C(=O)O)cn(C5CC5)c4c3OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
In 4 ml of ethanol was suspended 1.00 g of ethyl (-)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2-tritylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, followed by adding thereto 0.26 ml of 6N hydrochloric acid, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, after which 0.75 ml of a 5N aqueous sodium hydroxide solution was added to the filtrate and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 16 ml of water, followed by filtration. Carbon dioxide was bubbled into the filtrate and the crystals were collected by filtration to obtain 0.56 g of light-yellow (-)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: C([Cl:4])(=O)C.C(O)C.[F:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:23]=1>C(OCC)(=O)C>[ClH:4].[F:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:23]=1
Reactant: CC(=O)Cl
Agent: Fc1cccc2c(CCNCc3cccc(OCC(F)(F)C(F)F)c3)c[nH]c12
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add acetyl chloride (2.4 mL, 33.8 mmol) dropwise to anhydrous ethanol (50 mL) and stir the solution for 10 min at ambient temperature and add to a solution of N-(2-(7-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine (12.0 g, 30.1 mmol) in ethyl acetate. Concentrate the resulting solution under reduced pressure to give a yellow solid. Recrystallize the yellow solid from ethyl acetate/ethanol/diethyl ether to give the title compound: mp 142–143° C. MS(m/e): 399 (M+1), 397 (M−1). Calculated for C20H19F5N2O.HCl: Calcd: C, 55.24; H, 4.64; N, 6.44. Found: C, 55.44; H, 4.66; N, 6.46.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:12][C@H:13]3[CH2:18][O:17][C@H:16]([CH2:19][OH:20])[C@@H:15]([OH:21])[CH2:14]3)=[N:9][C:5]2=[N:6][C:7]=1I.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1)#[CH:23].C(N(C(C)C)CC)(C)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:12][C@H:13]3[CH2:18][O:17][C@H:16]([CH2:19][OH:20])[C@@H:15]([OH:21])[CH2:14]3)=[N:9][C:5]2=[N:6][C:7]=1[C:23]#[C:22][C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][CH:25]=1
Reactant: C#Cc1ccc(C(C)(C)O)cc1
Reactant: OC[C@H]1OC[C@H](Oc2nc3nc(I)c(Cl)cc3[nH]2)C[C@@H]1O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)c1ccc(C#Cc2nc3nc(O[C@H]4CO[C@H](CO)[C@@H](O)C4)[nH]c3cc2Cl)cc1

Procedure:
A mixture of (2R,3 S,5R)-5-((6-chloro-5-iodo-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol (50 mg, 0.120 mmol), 2-(4-ethynylphenyl)propan-2-ol (28.2 mg, 0.176 mmol), Pd(Ph3P)4 (13.58 mg, 0.012 mmol), copper(I) iodide (2.237 mg, 0.012 mmol) and diisopropylethylamine (0.062 ml, 0.360 mmol) in dioxane (2 ml) was charged in a reaction tube. Then the tube was sealed and N2 was bubbled through for 5 min. The mixture was heated at 80 C for 2 h, and then concentrated. The resulting residue was purified on reverse phase HPLC eluting with 10-70% CH3CN/H2O with TFA as an additive to give the title compound. LC-MS m/e=458.35 (M+H)+ (Rt 1.70/4.0 min); 1H NMR δ (ppm) (CD3OD): 7.83 (s, 1H), 7.58-7.54 (m, 4H), 5.13 (septet, 1H, J=5 Hz)), 4.34 (ddd 1H, J=12, 5, 2 Hz), 3.89 (dd, 1H, J=12, 2 Hz), 3.64 (dd, 1H, J=12, 6 Hz)), 3.61 (dd, 1H, J=12, 5 Hz), 3.37 (t, 1H, J=11 Hz), 3.19-3.15 (m, 1H), 2.77-2.73 (m, 1H), 1.70 (dd, 1H, J=23, 12 Hz), 1.55 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[S:10][N:9]=2)=[CH:4][CH:3]=1.[F:16][C:17]1[C:22]([F:23])=[C:21](O)[CH:20]=[CH:19][C:18]=1[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:21]3[CH:20]=[CH:19][C:18]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:17]([F:16])[C:22]=3[F:23])=[C:11]([CH3:15])[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Reactant: Cc1snc(-c2ccc(Cl)cc2)c1CO
Product: Cc1snc(-c2ccc(Cl)cc2)c1COc1ccc(CCC(=O)O)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling ((3-(4-chlorophenyl)-5-methylisothiazol-4-yl)methanol and ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=7.1 Hz, 2H), 7.42 (d, J=7.0 Hz, 2H), 6.90 (m, J=5.6 Hz, 1H), 6.72 (m, J=5.6 Hz, 1H), 4.98 (s, 2H), 2.96 (m, 2H), 2.68 (m, 2H), 2.62 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:17][C:18](=[O:25])[CH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[N:17]1[C:18](=[O:25])[CH:19]=[C:20]2[S:21][CH:22]=[CH:23][N:24]2[C:31]1=[O:32]
Reactant: Cc1c(NC(=O)Cc2nccs2)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2sccn2c1=O
Temperature: 110 °C
Yield: 34 %

Procedure:
A mixture of N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(thiazol-2-yl)acetamide (0.45 g, 1.26 mmol) and CDI (0.815 g, 5.02 mmol) in toluene (6.5 mL) was heated at 110° C. for 2 h. The cooled mixture was partitioned between EtOAc and water. The organic layer was washed with brine, and the combined aqueous layers were extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with 70% EtOAc-hexanes, to give slightly impure 6-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione as a tan solid (34% yield). The material was used without further purification. Mass spectrum m/z 385 (M+H)+.
Reaction SMILES: [C:1]([O:6]C)(=O)[C:2]([CH3:4])=[CH2:3].CC(C)(O)C#[N:11].[S:14](=[O:18])(=[O:17])([OH:16])[OH:15]>>[S:14]([OH:18])([OH:17])(=[O:16])=[O:15].[C:1]([NH2:11])(=[O:6])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: CC(C)(O)C#N
Agent: O=S(=O)(O)O
Product: C=C(C)C(N)=O

Procedure:
Heretofore, an α,β-unsaturated carboxylic acid ester, for example, methyl methacrylate, has been produced by treating acetone cyanohydrin with concentrated sulfuric acid to form methacrylamide sulfate and esterifying it with methanol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:39])([CH2:36][CH2:37][CH3:38])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[C:25]=3[F:33])=[CH:20][C:19]([CH3:34])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:39])([CH2:36][CH2:37][CH3:38])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[C:25]=3[F:33])=[CH:20][C:19]([CH3:34])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(OC)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(OC)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
rac-{1-[({7-[(2,6-Difluoro-3-methoxybenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]-pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 125A) in 4 ml of dichloromethane was admixed with 3 ml of trifluoroacetic acid. The resulting solution was stirred at room temperature for 3 h. After the reaction had ended, the solvent was drawn off under reduced pressure and the residue was purified by preparative HPLC chromatography (Method 21), which gave 10 mg (11% of theory, over 2 stages) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOCC>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(F)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of 3-fluorophenol (2.24 g, 20.0 mmol) in DMF (40 mL) is added potassium carbonate (3.03 g, 22.0 mmol) and ethyl bromoacetate (2.34 mL, 21.0 mmol), and the mixture is stirred at 70° C. for 18 h. The mixture is cooled to RT, Et2O is added, and the mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is vacuum distilled to give 3.2 g of the product 432.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[N:5]1>O>[Br:1][C:7]1[C:6]([C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])=[N:5][N:4]([CH3:3])[CH:8]=1
Reactant: BrBr
Reactant: Cn1ccc(C(F)(F)C(F)(F)C(F)(F)F)n1
Solvent: O
Product: Cn1cc(Br)c(C(F)(F)C(F)(F)C(F)(F)F)n1
Reaction time: 1 h

Procedure:
At 40° C., 3.27 g (20.45 mmol) of bromine are added dropwise to a solution of 4.65 g (18.59 mmol) of 1-methyl-3-heptafluoropropyl-1H-pyrazole in 18 ml of water and the reaction mixture is afterstirred firstly at 60° C. for 1 hour and then at room temperature for 18 hours. The aqueous phase is extracted three times with dichloromethane and the organic phase is dried over sodium sulphate. The dichloromethane is distilled off at reduced pressure on a rotary evaporator. This gives 5.75 g (77.85% of theory) of 1-methyl-3-heptafluoropropyl-4-bromo-1H-pyrazole as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(C)[CH:27]=CC=C[CH:23]=1.COC(C)=C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@@H:10]([C:11]([O:13][CH3:14])=[O:12])[O:15][C:22]1([CH3:27])[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1
Reactant: COC(=O)[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 120 °C
Yield: 36 %

Procedure:
147.5 mg (0.50 mmol) of methyl (2S,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate and 2.5 cm3 of anhydrous toluene are introduced, under an argon atmosphere, into a 10 cm3 round-bottomed flask equipped with a magnetic stirrer system. 10 grains of 4 Å molecular sieve, 188.5 μl (144.2 mg, 2.0 mmol) of 2-methoxypropene and 12.5 mg (0.05 mmol) of pyridinium p-toluenesulphonate are then added to the suspension obtained. The mixture is allowed to react for 1 hour at a temperature in the region of 20° C. and is then heated to 120° C. and allowed to react at this temperature for 2 hours. The resulting dark-brown reaction mixture is cooled to a temperature in the region of 20° C. 60 cm3 of dichloromethane are added. The organic phase is washed with 5 cm3 of a saturated aqueous sodium hydrogen-carbonate solution, 3 times with 5 cm3 of water and then once with 5 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulphate. After filtration and concentration to dryness under reduced pressure, a residue is obtained which is chromatographed on a column of silica gel, eluting with an ethyl ether/hexane (15/85 by volume) mixture. There are obtained, with a yield of 36%, 60 mg (0.18 mmol) of (4S,5S)-3-t-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:11]3=[N:12][C:13]=2[C:14]2[CH:15]=N[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:4][CH:3]=1.B(O)(O)[C:37]1C=CC(C)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:37])=[CH:20][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)nc3)c(-c3ccc(C)nc3)nc21
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)nc3)c(-c3ccc(C)cc3)nc21
Temperature: 150 °C

Procedure:
A mixture of ethyl 7-(3-chloro-2-(6-methylpyridin-3-yl)-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl) heptanoate (Example 5, step 1) (86 mg, 0.206 mmol), p-tolylboronic acid (56.1 mg, 0.413 mmol) and 2M sodium carbonate (0.309 ml, 0.619 mmol) were combined in a microwave vial. Dioxane (2 ml) was added and the flask was sealed and deoxygenated by evacuation/N2 purge (×3). Pd(Ph3P)4 (47.7 mg, 0.041 mmol) was added and the mixture was de-oxygenated by evacuation/N2 purge (×3) and heated at 150° C. for 3 hours using microwave radiation. The mixture was diluted with water and extracted with EtOAc (×2). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to a give a brown gum. The crude product was loaded onto an Isolute® SCX-2 cartridge and eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions were concentrated under reduced pressure and further purification by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]([C:13]2[N:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:4]=1.I[Si](C)(C)C>>[F:20][CH:2]([F:1])[C:3]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]([C:13]2[N:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:4]=1
Reactant: CCOC(=O)c1cn(-c2ncc(F)cn2)nc1C(F)F
Agent: C[Si](C)(C)I
Product: O=C(O)c1cn(-c2ncc(F)cn2)nc1C(F)F
Temperature: 90 °C

Procedure:
A mixture of ethyl 3-(difluoromethyl)-1-(5-fluoropyrimidin-2-yl)-1H-pyrazole-4-carboxylate (50 mg) and iodotrimethylsilane (1.0 mL) is heated at 90° C. for 4 h. The mixture is concentrated under vacuum, quenched with ice, and sodium metabisulfite is added until the aqueous solution becomes colorless. The mixture is then extracted with EtOAc (3×10 mL) and dried over anhydrous MgSO4. The dried extract is filtered and concentrated under vacuum to afford the title compound as white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[C@H:13]([CH3:15])[NH2:14])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:20][C:21](=[O:32])/[CH:22]=[CH:23]/[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:19].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37]>C1C=CC=CC=1>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].[C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[C@H:13]([CH3:15])[NH:14][C@H:22]([C:21]([O:20][CH2:18][CH3:19])=[O:32])[CH2:23][C:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:31])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)/C=C/C(=O)c1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: O=C(O)/C=C\C(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](CC(=O)c1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 59.5 %

Procedure:
4.84 g (20 mmoles) of (S)-alanyl-(S)-proline-t-butylester are dissolved in 40 ml of dry benzene and 4.08 g (20 mmoles) of E-ethyl-3-benzoyl-acrylate are added at room temperature under stirring. After one hour stirring at room temperature the solvent is evaporated off under reduced pressure, the residue is dissolved in 20 ml of ethyl acetate and 2.32 g (20 mmoles) of maleinic acid are added. The precipitated crystals are filtered off after one hour standing and washed with 20 ml of ethyl acetate. 6.7 g (60%) of product are obtained with a melting point of 109°-110° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH3:21])[CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH3:21])[CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(Cc1ccncc1)C(=O)Nc1ccc(N)cc1
Reaction time: 8 h

Procedure:
To a mixture of 5.72 gms. (0.02 mole) of 1-(p-nitrophenyl)-3-methyl-3-(4-pyridylmethyl)urea (see U.S. Pat. No. 3,700,678), 200 ml. of ethanol and 65 ml. of hydrazine hydrate there is added with stirring 0.5 gms. of 5 percent palladium-on-carbon in 50 ml. of ethanol. The resulting mixture is allowed to stand overnight at room temperature and then is refluxed for 2 to 3 hours. The hot reaction mixture is then filtered and the filtrate evaporated to remove solvent. The residue is 1-(p-aminophenyl)-3-methyl-3-(4-pyridylmethyl)urea.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].S(=O)(=O)(O)O.[CH:36](=O)[CH2:37][CH2:38][CH3:39]>>[CH2:36]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCC=O
Reactant: COc1ccc(-c2[nH]c(-c3ccc(N)cc3)nc2C(=O)Nc2nccs2)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCNc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(OC)cc3)[nH]2)cc1

Procedure:
2-(4-Aminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (1.0 g) obtained in Example 48, sodium borohydride (0.13 g), 4N sulfuric acid (0.2 ml) and butyraldehyde (0.3 ml) were treated in the same manner as in Example 72 to give 2-(4-butylaminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (1.1 g). This was converted to hydrochloride to give 2-(4-butylaminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide hydrochloride (0.20 g), melting point 250° C. or above.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:28][CH2:27]2)=[CH:22][C:21]=1[F:29])=[O:9])=C>CO.ClCCl>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:28][CH2:27]2)=[CH:22][C:21]=1[F:29])=[O:9]
Reactant: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Solvent: CO
Solvent: ClCCl
Product: O=C(NOCCO)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Yield: 71.4 %

Procedure:
8-(4-Cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (2-vinyloxy-ethoxy)-amide (56 mg, 0.14 mmol) was dissolved in methanol and loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. The eluent was collected and concentrated to give a residue. The residue was subjected to flash chromatography (Si-PPC, gradient 0% to 20%, methanol in dichloromethane) to afford the title compound as a pale yellow solid (37 mg, 71%). LCMS (method A): RT=6.40 min, [M+H]+=371. 1H NMR (CH3OH-d4): 8.20 (1 H, d, J=0.71 Hz), 7.67-7.65 (1 H, m), 7.17-7.11 (1 H, m), 6.94-6.87 (2H, m), 6.73 (1 H, d, J=7.38 Hz), 6.39 (1 H, s), 4.00-3.97 (2 H, m), 3.75-3.72 (2 H, m), 1.98-1.89 (1 H, m), 1.04-0.98 (2 H, m), 0.73-0.68 (2 H, m).
Reaction SMILES: [C:1]1(=O)[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].P(=O)(O)(O)O>O>[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1[NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:16]=1
Reactant: O=C1CCCCCN1
Agent: Nc1ccccc1N
Agent: O=P(O)(O)O
Solvent: O
Product: NCCCCCc1nc2ccccc2[nH]1
Temperature: 100 °C

Procedure:
170 g (1.5 mols) of caprolactam and 215 g (2 mols) of o-phenylene diamine are melted in a nitrogen atmosphere. 10 g of 85 % by weight phosphoric acid (the remaining 15 % by weight being water) are run into the melt with stirring, at 100°C and the heating is continued, 28 g of water distilling off over a period of 2 hours at an internal temperature of 170 to 250°C. The reaction mixture is then subjected to fractional distillation, initially in a water jet vacuum and subsequently in an oil pump vacuum. After the first distillate of excess o-phenylene diamine, 247 g (81 % of the theoretical) of 2-(5'-aminopentyl)-benzimidazole are obtained in the form of a yellowish-brown solidifying in crystalline form with a boiling point of 210° to 215°C at 0.05 Torr, and a melting point of 101°C.