Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)CCC>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[O:9][N:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: N#Cc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cc(-c2ccccn2)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 100 °C
Yield: 22 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (101 mg, 0.31 mmol), tetrakis(triphenylphosphine) palladium(0) (Pd(PPh3)4, 25 mg, 0.021 mmol) and tri-n-butyl(2-pyridyl)tin in tetrahydrofuran (2 mL) was heated overnight at 100° C. The reaction mixture was cooled and transferred directly onto a flash silica column. Elution with a gradient of hexane:ethyl acetate:chloroform 3:1:4 to 2.5:1:4 followed by trituration with hexane in dichloromethane afforded 22 mg (22%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-pyridyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3): δ −9.12 (s, 1H), 8.88 (d, 1H), 8.78 (d, 1H), 8.64 (s, 1H), 8.61 (s, 1H), 8.26 (d, 1H), 7.89 (m, 3H), 7.51 (m, 1H), 7.40 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1)=[O:2].C1COCC1.[BH4-].[Na+].Cl>CO>[OH:2][CH2:1][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1
Reactant: COC(=O)c1csc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1csc(CO)c1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a mixed liquid of 5.00 g of methyl 5-formylthiophene-3-carboxylate and 50 ml of THF was added 0.67 g of sodium borohydride under ice-cooling. To the reaction solution was added dropwise 5 ml of methanol, followed by stirring for 1 hour under ice-cooling. The reaction solution was added with 1 M hydrochloric acid, extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 4.86 g of methyl 5-(hydroxymethyl)thiophene-3-carboxylate as a pale yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[C:11]([Cl:16])[C:10]=2Cl)=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[Cl:22]C1C=C(CC#N)C=CC=1Cl>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:22])=[C:11]([Cl:16])[CH:10]=2)=[C:4]([C:18]([F:20])([F:21])[F:19])[N:3]=1
Reactant: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)c(C(F)(F)F)n1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc(N)c(-c2ccc(Cl)c(Cl)c2)c(C(F)(F)F)n1

Procedure:
This compound was made in an analogous manner to the compound of Example 4, from 3,4-dichlorophenylacetonitrile (Aldrich) mp. 252°-254.5° C.: TLC (SiO2 ; methanol/chloroform, 1:9) Rf=0.38.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[C:10]([O:11][CH3:12])[CH:9]=[CH:8][CH:7]=3)[N:1]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: COc1cccc(C(N)=O)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cccc2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc12
Temperature: 115 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-3-methoxy-benzamide (700 mg, 4.22 mmol) and 4-(2-hydroxyethoxy)-3,5-dimethyl benzaldehyde (823 mg, 4.22 mmol) in N,N-dimethyl acetamide (10 mL) were added NaHSO3 (58.5 wt %, 841 mg, 4.64 mmol) and p-TSA (160 mg, 0.84 mmol). The reaction mixture was heated at 115° C. for 16 hours, then cooled to room temperature. Solvent was removed under reduced pressure. Water (100 mL) was added and stirred for 1 hour at room temperature. The solid separated was filtered and dried. The solid was further washed with diethyl ether to give crude product 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.2 g (84%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:8].[Cl:20][C:21]1[CH:22]=[C:23]([OH:30])[CH:24]=[N:25][C:26]=1[CH:27]1[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:30][C:23]2[CH:24]=[N:25][C:26]([CH:27]3[CH2:29][CH2:28]3)=[C:21]([Cl:20])[CH:22]=2)=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:8]
Reactant: Oc1cnc(C2CC2)c(Cl)c1
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3cnc(C4CC4)c(Cl)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
4-Methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation 26, 0.330 g, 1.168 mmol) was added portionwise over 5 minutes to a suspension of 5-chloro-6-cyclopropylpyridin-3-ol (Preparation 69, 0.214 g, 1.262 mmol) and potassium carbonate (0.32 g, 2.315 mmol) in DMSO (5.0 mL). The mixture was stirred at room temperature for 3 hours, then partitioned between water (20.0 mL) and tert-butyl methyl ether (20.0 mL). The organic layer was further washed with water (2×20.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified with silica gel chromatography eluting with 0 to 5% EtOAc in heptane to yield the title compound as a white solid (0.289 g, 0.668 mmol, 57%):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH2:26])=[CH:21][CH:20]=[CH:19]2.C([O-])(O)=O.[Na+].[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C(Cl)(Cl)Cl>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH:26][C:35](=[O:36])[C:34]1[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=1[F:32])=[CH:21][CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(NC(=O)c5ccccc5F)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 6-(6,7-dimethoxy-quinolin-4-yloxy)-naphthalen-1-ylamine (Step a, 50 mg, 0.14 mmol) and NaHCO3 (38 mg, 0.45 mmol) in CH2Cl2 (1 mL), 2-fluorobenzoyl chloride (18 mL, 0.15 mmol) was added. The reaction was stirred at RT for 20 h. The mixture was taken up into CHCl3 and water, washed with brine, dried with Na2SO4, filtered and concentrated in vacuo. The title compound was purified by column chromatography using 0-100% of a 90:10:1 (CH2Cl2:MeOH: NH4OH) solution as the eluant. M+H 469.1, Calc'd for C28H21FN2O4−468.49.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=1.[OH-].[Li+]>C1COCC1.O>[C:30]([O:29][C:27]([NH:26][CH:20]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[CH:14][CH:15]=1)=[O:28])([CH3:32])([CH3:31])[CH3:33]
Reactant: COC(=O)CCc1ccccc1Oc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccccc2CCC(=O)O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
The ester 61 (0.8 g, 1.65 mmol) was dissolved in THF (10 mL) and diluted with water (10 mL). Lithium hydroxide (0.158 g, 6.6 mmol) was added and the reaction mixture was stirred at room temperature for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×100 mL). The organic layer was washed with water (1×100 mL) and brine (1×100 mL), dried and concentrated to yield the desired acid compound 62 (0.7 g, 97%). 1H NMR (400 MHz, DMSO-d6) 12.1 (s, 1H), 7.31 (dd, J=7.6 and 1.6 Hz, 1H) 7.21 (d, J=8.8 Hz, 2H), 7.18 (d, J=7.6 Hz, 1H), 7.08 (m, 2H), 6.82 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.0 Hz, 1H), 4.52 (m, 1H), 2.88-2.81 (m, 10H), 1.31 (s, 9H)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:24])([F:23])[C:14](=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+].[NH4+].[OH-]>C(Cl)Cl>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:14]([C:13]([F:23])([F:24])[F:12])[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:4]2[OH:6]
Reactant: O=C(Cc1ccccc1)C(F)(F)F
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [NH4+]
Solvent: ClCCl
Product: Oc1c(-c2ccccc2)c(C(F)(F)F)nc2ccc(I)cc12
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (5.20 g, 19.8 mmol), 1,1,1-trifluoro-3-phenylpropan-2-one (3.95 g, 21.0 mmol), and Eaton's reagent (12 mL) in a sealed tube was heated at 100° C. for 2 hours. More 1,1,1-trifluoro-3-phenylpropan-2-one (1.60 g, 8.50 mmol) was added and the mixture was heated for another 2 hours. The reaction was then cooled to room temperature, ice water was added, and the mixture was stirred vigorously for about 20 min. 50% NaOH and conc. NH4OH solution were added until pH was 9. Some gummy dark brown material formed. After the addition of CH2Cl2, the gummy material became fluffy solid. This solid was filtered, washed with water and Et2O, and air dried to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:14]([CH3:26])[C:13](=[O:27])[C:12](C(O)C)=[C:11]3[NH:31]C(=O)C)=[CH:4][CH:3]=1.O1CCOCC1.Cl>CCOC(C)=O>[NH2:31][C:11]1[C:10]2[C:15](=[N:16][C:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)[N:14]([CH3:26])[C:13](=[O:27])[CH:12]=1
Reactant: CC(=O)Nc1c(C(C)O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1c(=O)cc(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21

Procedure:
The product of Example 3 (21 mg) was combined with 2.8 mL of 1,4-dioxane and 1 mL 1M aqueous HCl. After 15 hours at room temperature the reaction was diluted with EtOAc and washed with water followed by saturated aqueous NaHCO3 solution before drying (Na2SO4). The concentrated residue was purified by preparative TLC (silica gel) eluted with EtOAc affording the title compound. HPLC/MS: 430.0 (M+1), 432.0 (M+3); Rt=3.77 min.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12].[SH-:13].[Na+].[OH-].[Na+].Cl>O.CN(C)C=O>[Cl:1][C:2]1[C:7]([SH:13])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12]
Reactant: [SH-]
Reactant: Clc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
Hexachlorobenzene (25.0 g, 0.088 mol) was added to 50 mL of dimethylformamide followed by the addition of 7.4 g (0.096 mol) of 73% sodium hydrosulfide and 7.9 mL (0.079 mol) of 40% aqueous sodium hydroxide. The stirred reaction mixture was heated to 85° C. for 3.0 hr, cooled to room temperature, and poured into 200 mL of water. After 10 min of stirring, the insoluble material was removed by filtration, and the filtrate acidified with 15 mL (0.18 mol) of concentrated aqueous hydrochloric acid. The resulting precipitate was collected by filtration, washed with 100 mL of water, and dried in vacuo giving 22.8 g, 92% of theoretical, of pentachlorothiophenol.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]2[CH:15]=1)=[O:5].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Mg]Cl.Cl.O>C1COCC1.C(OCC)C.C(OCC)(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([CH:15]=[C:6]([C:4]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH3:17])=[O:5])[N:7]=2)[CH:10]=1
Reactant: CON(C)C(=O)c1cn2cc(Cl)ccc2n1
Reactant: Cc1ccccc1[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccccc1C(=O)c1cn2cc(Cl)ccc2n1
Temperature: -4 °C
Reaction time: 3 h

Procedure:
To a solution of 0.144 g of N-methoxy-N-methyl-6-chloroimidazo[1,2-a]pyridine-2-carboxamide in 3 mL of THF cooled to −4° C. is added dropwise a solution of 1.5 mL of a 2M solution of 2-methylphenylmagnesium chloride in ethyl ether. The reaction mixture is stirred for 3 hours at −4° C. 3 mL of 1N hydrochloric acid, 8 mL of water and 40 mL of ethyl acetate are added. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered, evaporated to dryness under reduced pressure, and then purified on a column of silica, eluting with a 90/10 mixture by volume of dichloromethane and ethyl acetate. The fractions containing the product are combined and concentrated to dryness under reduced pressure to give 0.034 g of (6-chloroimidazo[1,2-a]pyridin-2-yl)(2-methylphenyl)methanone in the form of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].ClCl.C(Cl)(Cl)[Cl:16]>CC(O)=O>[Cl:16][C:11]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: ClC(Cl)Cl
Agent: ClCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)c2c(c1)CCN2

Procedure:
To a solution of 5-nitroindoline (0.5 g, 3.1 mmol) in 15 mL of AcOH was added a solution of Cl2 in ACOH dropwise until 30% of starting material was consumed. The reaction mixture was concentrated in vacuo, yielding an oil which was subjected to column chromatography (CHCl3, neat) to provide 0.23 g (1.2 mmol) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1)[CH3:2].C(O)=[O:19]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:19])[CH3:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: C#Cc1ccc(C[C@H](OC)C(=O)OCC)cc1
Reactant: O=CO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(C(C)=O)cc1)OC
Temperature: 100 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To (2S)-3-(4-Ethynyl-phenyl)-2-methoxy-propionic acid ethyl ester (36 Mg, 0.15 mmol) (Example 29, Step A) were added 4 ml of formic acid. The solution was stirred for 1 hour at 100° C. and then cooled to room temperature. The mixture was taken up with methylene chloride and the solution was washed with water, sodium carbonate, and water, dried (MgSO4) and the solvent was evaporated under vacuum. Obtained a brown liquid (0.035 g, 95%). 1H-NMR (200.15 MHz, CDCl3): δ 7.43 (d, 1H, J=73), 7.12 (d, 1H, J=7.3), 4.18 (q, 2H, J=7.0), 3.97 (dd, 1H, J=7.3, 5.6), 3.32 (s, 3H), 3.06 (s, 1H), 3.03 (d, 1H, J=2.4 Hz), 2.56 (s, 2H), 1.22 (t, 3H, J=7.25).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:16]([F:18])[F:17])=[N:8][N:9]([CH3:15])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:15][N:9]1[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH:16]([F:18])[F:17])=[N:8]1
Reactant: CCOC(=O)c1c(C(F)F)nn(C)c1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(F)F)c(C(=O)O)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
N-Methyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (0.5 g, 1.84 mmol) in ethanol (3 ml) was admixed gradually with an 8N aqueous sodium hydroxide solution (0.7 ml) and stirred at room temperature for 3 h. The solvent was removed by rotary evaporation; the residue was taken up in water (10 ml) and extracted with diethyl ether (10 ml). Acidification to pH 1 with 1M HCl was followed by extraction with ethyl acetate (3×10 ml). The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed by rotary evaporation. N-Methyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid (0.44 g, 1.80 mmol, 98%) was isolated as a yellowish solid.
Reaction SMILES: [CH2:1]([C:8]([NH2:11])(C)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C(O)C(C)(N)C)C=CC=CC=1.[IH:24]>>[C:2]1([CH2:1][CH:8]([NH2:11])[CH2:9][I:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(N)Cc1ccccc1
Reactant: I
Agent: CC(C)(N)C(O)c1ccccc1
Product: NC(CI)Cc1ccccc1
Yield: 31 %

Procedure:
There are many possible methods for hydrogenating the hydroxyl group at benzyl position of APPD. For example, U.S. Pat. No. 3,084,099 issued to Hays et al. describes a method of preparing 1-benzyl-iso-propyl amine from 1phenyl-2-methyl-2-amino-propanol by hydrogenation in 57% hydriodic acid with red phosphorous. However, the strongly acidic condition of this system may induce iodination of other hydroxyl groups. In fact, the hydrogenation of APPD in the above conditions produced 1-phenyl-2-amino-3-iodopropane instead of phenylalaninol, as disclosed in Japanese Patent 3910914. Other approaches were made by two independent groups, Boerner et al. prepared D-phenylalaninol from L(+)-APPD by 4 steps with a total yield of 31% (Pharmazie 45, 531 (1990)). On the other hand, the hydrogenation of L(+)-APPD in the presence of sulfuric acid was found to give D-phenylalaninol (D-PAO)in 73-85% yield (Hashizume, Japanese Patent 63255254). It is obvious that the latter is quite cost-effective. However, in this process, it is necessary to use excess amounts of base to neutralize the reaction mixture for the recovery of D-PAO because an excess amount of sulfuric acid is used. When the pH of the reaction mixture is adjusted to above 11, large amounts of salts are produced and some of them, including small amount of D-PAO, are precipitated. This phenomenon makes the work-up process very complicated. Furthermore, it makes it impossible to derivatize phenylalaninol into desired forms such as N-terminal blocked phenylalaninols without isolation of phenylalaninol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.O=P(Cl)(Cl)Cl.[NH2:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]1[NH:19][C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[N:26]=1
Reactant: Nc1cccnc1N
Reactant: COc1ccc(C(=O)O)c(OC)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3cccnc3[nH]2)c(OC)c1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
Ex-76A: To a suspension of 2,4-dimethoxybenzoic acid (0.36 g, 2 mmol) and 8 ml of POCl3 in a 50 ml of a round-bottom flask, 2,3-diaminopyridine (0.22 g, 2 mmol) was added. The mixture was heated to reflux for 4 hours and then cooled to room temperature. The reaction mixture was then concentrated to remove most of the POCl3. The residue was carefully treated with 1N HCl at 0° C. using a water-ice bath, then neutralized with NaOH (50%). The off-white solid was filtered to give 2-(2,4-dimethoxy-phenyl)-3H-imidazo[4,5-b]pyridine (0.44 g, 88%). 1H-NMR (DMSO-d6) δ 8.28–8.36 (m, 2H), 7.97 (d, J=8 Hz, 1H), 7.21–7.25 (m, 1H), 6.80 (s, 1H), 6.78 (d, J=9 Hz, 1H), 4.05 (s, 3H), 3.91 (s, 3H). HRMS (ES+) Calcd. for C24H19N3O5: 430.1403. Found: 430.1414.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:22][CH2:23][C:24]#[N:25]>CN(C)C=O.C(OCC)(=O)C>[CH3:12][C:11]1([CH3:13])[C:8]([CH3:9])([CH3:10])[O:7][B:6]([C:4]2[CH:3]=[N:2][N:1]([CH2:22][CH2:23][C:24]#[N:25])[CH:5]=2)[O:14]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C
Temperature: 90 °C

Procedure:
Pyrazole-4-boronic acid pinacol ester (1 g, 1 equiv, 5.15 mmol) was dissolved in dimethylformamide (15 mL) followed by the addition of Cs2CO3 (0.86 g, 1.5 equiv, 7.73 mmol) and 3-chloropropionitrile (1.1 equiv, 5.67 mmol, 0.44 mL). The mixture was heated at 90° C. overnight. The reaction was diluted with ethyl acetate and washed with water (3×) and brine (3×). The organic phases was concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to return the title compound (0.11 g, 9%). 1H NMR (500 MHz, DMSO): δ 1.26 (12H, s), 3.07 (2H, t), 4.40 (2H, t), 7.65 (1H, s), 8.04 (1H, s). MS m/z 248 (M+H+)+.
Reaction SMILES: C(C=N[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][CH2:27][CH2:28][OH:29])[CH:21]=2)[C:16]([F:30])=[CH:15][N:14]=1)(O)=O.[NH2:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35]>>[OH:36][CH:33]([CH2:34][OH:35])[CH2:32][NH:31][C:28]([CH:27]=[N:26][C:11]1[CH:6]=[C:7]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][CH2:27][CH2:28][OH:29])[CH:21]=3)[C:16]([F:30])=[CH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=1)=[O:29]
Reactant: O=C(O)C=Nc1ccccc1Nc1ncc(F)c(Nc2cccc(NCCO)c2)n1
Reactant: NCC(O)CO
Product: O=C(C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(NCCO)c3)n2)c1)NCC(O)CO

Procedure:
In like manner to the preparation of N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine, N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine and 1-amino-2,3-propanediol were reacted to give N2-[3-[N-(2,3-dihydroxypropyl)amino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 12.86 min.; purity: 90.0%; MS (m/e): 486.40 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[C:34](Cl)([O:36][C:37](=O)[O:38]C(Cl)(Cl)Cl)Cl.C(=O)([O-])O.[Na+]>ClCCl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:37]([O:36][CH3:34])=[O:38])[CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C(N1CCC(c2cccnc2)C1)N1CCNc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)N1CCN(C(=O)N2CCC(c3cccnc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
0.25 g of 1-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoxaline, 8.1 ml of dichloromethane and 0.3 ml of diisopropylethylamine are placed in a 50 ml round-bottomed flask under a nitrogen atmosphere. 0.12 g of triphosgene is added at 0° C. and then the reaction mixture is left stirring at ambient temperature for three hours. 0.5 ml of diisopropylethylamine and 0.33 ml of methanol are subsequently added and the reaction mixture is stirred for twenty-four hours. A saturated aqueous sodium hydrogencarbonate solution and dichloromethane are added. The aqueous phase is extracted three times with dichloromethane. The organic phases are combined, washed with water and with a saturated aqueous sodium chloride solution and dried over sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol 95/5 mixture. 0.112 g of methyl 4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-3,4-dihydroquinoxaline-1(2H)-carboxylate is obtained.