Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[OH:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:14][N:15]1[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]2[C:19]1=[O:20]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: O=C1c2ccccc2C(=O)N1Oc1cccc(C(F)(F)F)c1
Yield: 88 %

Procedure:
3-Trifluoromethylphenylboronic acid (380 mg, 2.0 mmol) was subjected to the representative coupling procedure with N-hydroxyphthalimide (NHP) as outlined above (method 1). Flash chromatographic purification over silica (40% EtOAc in hexanes) afforded 10 as a white solid (270 mg, 88%). 1H-NMR (500 MHz, CDCl3) δ 7.34-7.38 (m, 1H), 7.40-7.45 (m, 2H), 7.47 (m, J=0.9, 8.1 Hz, 1H), 7.82-7.87 (m, 2H), 7.92-7.97 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 111.6, 117.8, 118.1, 121.4, 122.3, 124.2, 128.8, 130.5, 132.2, 135.1, 159.0, 162.8; LC-MS 309 m/z [MH]+, C15H9F3NO3 requires 309.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].O.O.O.O.O.O.[N+]([O-])([O-])=O.[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.Cl.[OH:26][C:27]1[C:28]([N+]([O-])=O)=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=[O:31]>C1COCC1.O>[OH:26][C:27]1[CH:28]=[C:29]([C:32]([N+:1]([O-:4])=[O:2])=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=[O:31]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1O
Agent: Cl
Agent: [La+3]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])c(C=O)cc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.5 %

Procedure:
3-Hydroxy-4-methoxybenzaldehyde (15.2 g, 0.1 mol) obtained in the same manner as in Reference Example 3 was dissolved in THF (150 ml), to which sodium nitrate (8.5 g, 0.1 mol) and lanthanum nitrate hexahydrate (8.7 g, 0.2 mol) were added, and then a mixture of concentrated hydrochloric acid and water at a ratio of 1:1 (70 ml) was added dropwise over a period of 20 minutes. The mixture was stirred for 40 minutes at room temperature, and the separated organic layer was successively washed with water (50 ml), a saturated aqueous solution of sodium hydrogencarbonate (50 ml), and a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulfate, filtered to remove the desiccating agent, and concentrated under reduced pressure to give a mixture of the title compounds 4a and 4b as pale red crystals (4a:4b=1:1, 13.3 g, yield 67.5%) (Table 2).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:32]([NH2:35])[CH2:33][CH3:34]>O1CCCC1>[CH2:32]([NH:35][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:33][CH3:34]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCN
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCNC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Temperature: -30 °C

Procedure:
to a solution of 44.64 parts of benzyloxycarbonyl-D-alanine in 276 parts of tetrahydrofuran is added 2.02 parts of N-methylmorpholine. The resulting solution is cooled to about -30° C. and 25.4 parts of isobutyl chloroformate is added with stirring. After stirring for about 5 minutes, 13.0 parts of n-propylamine is added and the mixture stirred for a further 10 minutes. The mixture is cooled overnight and then concentrated under reduced pressure to a syrup. This residue is dissolved in methylene chloride and washed successively with 2 M potassium carbonate, water, twice with 1 M hydrochloric acid and finally, twice with water. After drying over anhydrous magnesium sulfate the solution is concentrated under reduced pressure. The residue is diluted with 180 parts of ethyl ether and cooled to 5° C. The resulting crystals are filtered, washed with ether and dried to give benzyloxycarbonyl-D-alanine n-propylamide, melting at about 116.5°-120° C.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:36]=2)(C(OCC=C)=O)[C:22]([O:24]CC=C)=[O:23])=[CH:15][CH:14]=1)#[N:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:22]([CH:21]([CH2:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:18][CH:17]=1)[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:36]=1)([OH:24])=[O:23]
Reactant: C=CCOC(=O)C(CCc1ccc(C#N)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COC(=O)c1ccc(CC(CCc2ccc(C#N)cc2)C(=O)O)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A solution of 41.8 ml (0.3 mol) of triethylamine and 8.6 ml (0.23 mol) of formic acid in 500 ml of dioxane is added to a solution of 43.5 g (0.09 mol) of diallyl 2-[2-(4-cyanophenyl)ethyl]-2-(4-methoxycarbonylbenzyl)malonate, 1.67 g (0.01 mol) of triphenylphosphine and 410 mg of palladium acetate in 505 ml of dioxane at room temperature. The reaction mixture is then stirred at 10° C. for 2 hours. After conversion is complete, the reaction solution is cooled and the solvent is removed in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 50:1). 25 g (74 mmol, 82% yield) of a colourless solid are obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[C:21]([CH2:30][CH:31]=O)=[CH:22][C:23]([O:28][CH3:29])=[C:24]([CH:27]=1)[C:25]#[N:26].C([BH3-])#N.[Na+]>CO>[F:19][C:20]1[C:21]([CH2:30][CH2:31][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:18]=[CH:17][C:12]4[C:13](=[O:16])[O:14][CH2:15][C:11]=4[CH:10]=3)[CH2:2][CH2:3]2)=[CH:22][C:23]([O:28][CH3:29])=[C:24]([CH:27]=1)[C:25]#[N:26]
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: COc1cc(CC=O)c(F)cc1C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)c(F)cc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (94 mg, 0.33 mmol) and 5-fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile (58 mg, 0.30 mmol) in methanol (3.0 mL) at 0° C. was added sodium cyanoborohydride (29 mg, 0.47 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 5-fluoro-2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 424.3 [M+1]+. (0.068 μM)
Reaction SMILES: Cl[C:2]1[C:11]2=[N:12][N:13]([CH2:25][CH2:26][CH3:27])[C:14]([N:15]([CH2:23][CH3:24])C(=O)OC(C)(C)C)=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:28]>>[CH2:23]([NH:15][C:14]1[N:13]([CH2:25][CH2:26][CH3:27])[N:12]=[C:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:3]=[C:2]2[NH2:28])[CH3:24]
Reactant: N
Reactant: CCCn1nc2c(Cl)nc3ccccc3c2c1N(CC)C(=O)OC(C)(C)C
Product: CCCn1nc2c(N)nc3ccccc3c2c1NCC

Procedure:
tert-Butyl 4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl(ethyl)carbamate (718 mg, 1.85 mmol) and methanolic ammonia (25 mL of a 7 M solution) were heated in a steel Parr vessel in a 150° C. oven for 17 h. The reaction mixture was concentrated, treated with 2 M sodium carbonate and extracted with chloroform. The combined organic layers were dried (magnesium sulfate), filtered, concentrated, and purified by prep HPLC (silica cartridge, eluting with CMA in chloroform). The product was recrystallized from acetonitrile to afford 272 mg of N1-ethyl-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine as white crystals, mp 193-194° C. MS (APCI) m/z 270 (M+1)+; Anal. Calcd for C15H19N5: C, 66.89; H, 7.11; N, 26.00. Found: C, 66.65; H, 7.20; N, 26.19.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[CH:15][N:14]([C:17]3[S:18][C:19]([C:29](O)=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:21]=3)[C:13]=2[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:34](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>O.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[CH:15][N:14]([C:17]3[S:18][C:19]([C:29]([NH2:34])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:21]=3)[C:13]=2[CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Reactant: O=C(O)c1sc(-n2cnc3ccc(OCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)c1sc(-n2cnc3ccc(OCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a mixture of 3.3 g (7.16 mmole) of 2-(6-benzyloxy-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid (I.25b), 20 mL of dimethylformamide and 3.26 g (8.59 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) was added 0.759 g (14.52 mmole) of ammonium chloride followed by 3.74 mL (21.48 mmole) of ethyldiisopropylamine. The mixture was stirred at ambient temperature for 1 hour and then diluted with 500 mL of water. The suspension was stirred for 30 minutes. The precipitate was collected by filtration to afford 3.2 g of 2-(6-benzyloxy-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide as an off-white solid (I.25c).
Reaction SMILES: B.C1COCC1.[C:7]([O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[CH2:20][CH2:19]2)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:7]([O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([OH:25])[CH2:20][CH2:19]2)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Oc1ccc2c(c1)CCC2=O)c1ccccc1
Agent: B
Solvent: C1CCOC1
Product: O=C(Oc1ccc2c(c1)CCC2O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BH3.THF (1 M solution in THF, 773.8 mL, 773.8 mmol) was added dropwise to a stirred mixture of the product of Step B (195 g, 773.8 mmol) in anhydrous THF at 0° C. under nitrogen, and the reaction mixture was stirred at rt overnight. The mixture was cooled to 0° C. and carefully quenched with methanol (500 mL). Cooling bath was removed, and the solution was stirred until bubbling stopped. The solvent was evaporated under reduce pressure. The residue was purified by column chromatography on silica gel (EtOAc:PE=1:10) to give the title compound. 1H-NMR (400 MHz, CDCl3): δ 8.19-8.22 (m, 2H), 7.62-7.66 (m, 1H), 7.52 (t, J=7.6 Hz, 2H), 7.45 (d, J=8.1 Hz, 1H), 7.06-7.10 (m, 2H), 5.25 (t, J=6.1 Hz, 1H), 3.05-3.12 (m, 1H), 2.81-2.89 (m, 1H), 2.49-2.58 (m, 1H), 1.96-2.04 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[C:3]([N:40]2[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]2)=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:11]3=[N:12][CH:13]=2)[CH:7]=1.FC1C=C(C2C=C3C(C4C=NN(CC5C=CC=C(F)C=5)C=4)=CNC3=NC=2)C=NC=1N1CCNCC1>CO.Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:31])=[O:32])[C:11]3=[N:12][CH:13]=2)[CH:5]=[N:4][C:3]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cl
Agent: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5cnc(N6CCNCC6)c(F)c5)cc34)cn2)c1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCNCC5)c(F)c4)cnc32)cc1
Yield: 72.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-fluoro-5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (step 1 product of example 173) (550 mg, 0.758 mmol) was deprotected in methanol/HCl in dioxane (5/5 ml) to afford 342 mg (72% yield) of the titled compound. MS: m/z=626.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11](S(C)(=O)=O)[C:10]([CH3:17])([CH3:16])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH2:27][OH:28])[CH:22]=[C:23]([F:26])[C:24]=1[F:25].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:16][C:10]1([CH3:17])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=[C:2]([O:28][CH2:27][C:21]3[CH:22]=[C:23]([F:26])[C:24]([F:25])=[C:19]([F:18])[CH:20]=3)[CH:3]=[C:4]2[NH:11]1
Reactant: OCc1cc(F)c(F)c(F)c1
Reactant: CC1(C)Cn2c(cc(Cl)nc2=O)N1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Cn2c(cc(OCc3cc(F)c(F)c(F)c3)nc2=O)N1

Procedure:
To a solution of 7-chloro-2,2-dimethyl-1-(methylsulfonyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (180 mg, 0.648 mmol) and (3,4,5-trifluorophenyl)methanol (210 mg, 1.30 mmol) in N,N-dimethylformamide (DMF) (3.5 mL) was added K2CO3 (269 mg, 1.94 mmol). The reaction mixture was sealed in a microwave vial and irradiated with a microwave using initial normal to 100° C. for 1 h. Purification via MDAP afforded the title product as a white solid.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].Cl[CH:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[CH:11]=1)[C:7]([OH:9])=[O:8]>C(O)C>[S:1]([CH:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[CH:11]=1)[C:7]([OH:9])=[O:8])[C:2]#[N:3]
Reactant: COc1ccc2cc(C(Cl)C(=O)O)ccc2c1
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2cc(C(SC#N)C(=O)O)ccc2c1
Reaction time: 15 h

Procedure:
To a solution of 300 ml. of anhydrous ethanol and 0.15 moles of sodium thiocyanate is added 0.12 moles of α-chloro-6-methoxy-2-naphthylacetic acid and stirred for 15 hours. The reaction mixture is filtered and washed with absolute ethanol. The filtrate is evaporated to dryness, the residue is dissolved in 250 ml. of ether and washed several times with water. The ether is then dried and evaporated to dryness to obtain α-thiocyanato-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7])=[C:2]=[O:3].Cl.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>O1CCCC1>[F:30][C:16]([F:15])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]1[CH2:24][CH2:25][N:26]([C:2]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])=[O:3])[CH2:27][CH2:28]1
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: FC(F)(F)c1ccccc1C1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1NC(=O)N1CCC(c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
A solution of methyl 2-isocyanatobenzoate (10.00 g, 56.4 mmol) in tetrahydrofuran (30 ml) was slowly added to a solution of 4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (14.3 g, 53.8 mmol, Sigma) and triethylamine 99% (8.99 ml, 64.5 mmol) in tetrahydrofuran (120 ml) at 0° C. The mixture was removed from the cooling bath and stirred at room temperature for 15 min, at which time LC/MS analysis indicated that the reaction was complete. EtOH (75 ml) and aqueous LiOH (2N, 95 ml) were then added, and the solution was stirred for 6 h at room temperature. Subsequently, aqueous HCl (2N, 150 ml) was added, and the resulting mixture was extracted with EtOAc (2×600 ml). The EtOAc extract was dried over MgSO4 and concentrated to an off-white solid. Recrystallization from EtOAc yielded 14.0 g (66%) of 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxamido) benzoic acid as a white solid, which was homogeneous by analytical high-performance liquid chromatography (>99%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:24]([C:25]#[C:26][Si](C)(C)C)[CH2:23][CH2:22][C@H:17]1[C:18]([O:20]C)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCOCC1.Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:24]([C:25]#[CH:26])[CH2:23][CH2:22][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-((trimethylsilyl)ethynyl)-L-prolinate (1.24 g, 2.83 mmol) in dioxane (12 mL) at room temperature was added a solution of 2 M lithium hydroxide (3 mL, 6.0 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction was diluted with 1 M HCl solution (50 mL), and the aqueous mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to provide the titled compound.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][CH:22]([CH2:36][CH3:37])[C@@H:23]([C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:26]=1)[OH:24]>>[CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:21][C@H:22]([C:23]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]=2)=[O:24])[CH2:36][CH3:37])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1
Reactant: CCC(N)[C@H](O)c1nc(-c2ccccc2)no1
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1)C(=O)c1nc(-c2ccccc2)no1

Procedure:
Similarly prepared according to the general procedure given for Example 43 above but using (R)-2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid and (S)-2-amino-1 (3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol; MS: 497 (MH+).
Reaction SMILES: [CH:1](O)=O.[NH:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([N:17]2[CH2:31][C:20]3=[C:21]4[N:26]([N:27]=[C:19]3[CH2:18]2)[C:25]([CH3:28])=[C:24]([Cl:29])[C:23]([CH3:30])=[N:22]4)=[O:16])[CH2:5]1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[Cl:29][C:24]1[C:23]([CH3:30])=[N:22][C:21]2[N:26]([N:27]=[C:19]3[CH2:18][N:17]([C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][CH:6]4[CH2:7][N:4]([CH3:1])[CH2:5]4)=[O:16])[CH2:31][C:20]3=2)[C:25]=1[CH3:28]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CNC1)C3
Reactant: O=CO
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CN(C)C1)C3
Yield: 21.4 %

Procedure:
A mixture of Example 104 (112 mg; 0.25 mmol; 1 eq.), paraformaldehyde (68 mg; 0.76 mmol; 3.00 eq.) and sodium triacetoxyborohydride (107 mg; 0.50 mmol; 2 eq.) in DCE (5 mL) was stirred at reflux for 2 hours. 1M NaOH was added and extracted several times with EtOAc. The combined organics were dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (22 mg, 21%) as a white solid. 1H NMR (CDCl3) δ 7.40-7.33 (m, 2H), 7.11-7.05 (m, 1H), 6.73-6.69 (m, 1H), 5.03-5.01 (m, 2H), 4.97-4.89 (m, 1H), 4.61-4.60 (m, 2H), 4.16-4.10 (m, 2H), 3.34-3.28 (m, 2H), 2.91 (s, 2H), 2.85 (s, 1H), 2.69 (s, 1H), 2.62 (s, 2H), 2.51 (s, 3H). HPLC (max plot) 98%, Rt 1.92 min. UPLC/MS: (MS+) 412.4 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)[CH2:3][CH2:2]1.CC(O)=O.C(O[C:41]1(O[Si](C)(C)C)[CH2:43][CH2:42]1)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:27]([N:23]1[CH:22]=[C:21]2[C:25]([CH:26]=[C:18]([C:10]3[CH:9]=[C:8]([CH:4]4[CH2:5][CH2:6][CH2:7][N:1]([CH:41]5[CH2:43][CH2:42]5)[CH2:2][CH2:3]4)[N:16]4[C:11]=3[C:12]([NH2:17])=[N:13][CH:14]=[N:15]4)[CH:19]=[CH:20]2)=[N:24]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ncnn2c(C3CCCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncnn2c(C3CCCN(C4CC4)CC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 17 h
Yield: 49.2 %

Procedure:
To a solution of 7-azepan-4-yl-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.20 mmol) in MeOH (2 mL) containing 3 Å molecular sieves was added AcOH (112 μL, 2.00 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (236 μL, 1.18 mmol) and sodium cyanoborohydride (55 mg, 0.88 mmol). The reaction was stirred at 60° C. for 17 h. Aqueous NaOH (1N, 15 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 40% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 47 mg (50%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1 H), 7.58 (s, 1 H), 7.48 (d, 1 H), 7.28 (s, 1 H), 6.97-7.07 (m, 5 H), 6.84 (dd, 1 H), 6.27 (s, 1 H), 5.34 (s, 2 H), 3.04-3.15 (m, 1 H), 2.56-2.64 (m, 1 H), 2.44-2.53 (m, 2 H), 1.27-1.77 (m, 6 H), 0.07-0.14 (m, 2 H), −0.03-0.05 (m, 2 H); ES-MS m/z 478.33 [M+H]+, HPLC RT (min) 2.10.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.Br[CH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1C#N.[H-].[Na+].[Li+].[Br-]>CN(C=O)C.CS(C)=O>[CH2:11]([N:7]1[CH:2]=[CH:3][C:4](=[O:9])[NH:5][C:6]1=[O:8])[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:13]=1
Reactant: N#Cc1ccccc1CBr
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=c1ccn(Cc2ccccc2)c(=O)[nH]1
Yield: 54 %

Procedure:
In accordance with this process, 6-Chlorouracil (1) is alkylated with 2-(bromomethyl)benzonitrile in the presence of NaH and LiBr in a mixture of DMF-DMSO to produce the N-benzyluracil derivative (2) in 54% yield. Compound (2) is further alkylated with iodomethane and NaH in DMF/THF to give the 1,3 disubstituted uracil (3) in 72% yield. Subsequent displacement of chlorouracil (IV) with 3(R)-aminopiperidine dihydrochloride in the presence of either NaHCO3 in hot methanol or K2CO3 in aqueous isopropanol provides alogliptin (4), which is isolated as the corresponding benzoate salt by treatment with benzoic acid in ethanol. The overall yield of this three-stage process is ˜20-25%. One of the disadvantages of above described process is the difficulty to separate and purify mixtures of solvents with high boiling point (for example, DMF/DMSO) for recycling. Another disadvantage is the usage of hazardous materials such as sodium hydride, which requires anhydrous solvents as a reaction media.