Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>O>[N:8]1([CH2:2][C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(O)CCl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN1CCCCC1
Reaction time: 48 h

Procedure:
A solution of monochloroacetic acid (9.35 g.) in water (40 ml.) was adjusted to pH 8.0 with a solution of sodium hydroxide (4.0 g.) in water (30 ml.). Piperidine (8.0 ml.) was then added and the mixture was left at room temperature for 2 days and then heated on a steam bath for 2 hr. The solution was then evaporated and the residue was digested with hot ethanol, filtered and the filtrate was evaporated to give piperidinoacetic acid (12.55 g.) as a brown glass.
Reaction SMILES: C([O:8][C:9](=[O:39])[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:38])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[CH2:21]2)[CH:15]=1)([CH3:12])[CH3:11])C1C=CC=CC=1>[Pd].CO>[CH:35]([C:32]1[CH:31]=[CH:30][C:29]([O:28][CH2:27][C:26]([N:22]2[CH2:23][CH2:24][CH2:25][CH:20]([C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[O:13][C:10]([CH3:12])([CH3:11])[C:9]([OH:39])=[O:8])[CH2:21]2)=[O:38])=[CH:34][CH:33]=1)([CH3:37])[CH3:36]
Reactant: CC(C)c1ccc(OCC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(OCC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)O)c3)C2)cc1
Reaction time: 3 h
Yield: 100 %

Procedure:
10% Palladium on carbon (4 mg, 10 wt %) was added to a solution of 2-(3-{1-[(4-Isopropyl-phenoxy)-acetyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid benzyl ester (35 mg, 0.066 mmol) in methanol (2 mL) and the resulting mixture hydrogenated at atmospheric pressure for 3 h. The reaction mixture was filtered through a plug of celite and the celite plug washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure to provide 29 mg (99%) of 2-(3-{1-[(4-Isopropyl-phenoxy)-acetyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid as a clear oil.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.[NH:10]1[CH2:16][CH:15]([OH:17])[CH2:14][NH:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>CCO>[Br:1][C:2]1[C:3]([N:10]2[CH2:16][CH:15]([OH:17])[CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][C:5]([I:8])=[CH:6][CH:7]=1
Reactant: Fc1nc(I)ccc1Br
Reactant: OC1CNCCNC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: OC1CNCCN(c2nc(I)ccc2Br)C1
Yield: 87.2 %

Procedure:
A solution of 3-bromo-2-fluoro-6-iodopyridine (1.00 g, 3.4 mmol), 1,4-diazepan-6-ol (510 mg, 4.4 mmol), and DIPEA (2 mL) in EtOH (6 mL) in a sealed tube was stirred at 100° C. for 20 hours. The reaction mixture was concentrated under reduced pressure to give a residue (1.18 g), which was used for the next step without further purification. MS (ESI) m/z: 398 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])[C@@H:9]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]([C@H:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH3:23])[C@@H:9]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[C@@H](CC(=O)OC(C)(C)C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@@H](CC(=O)O)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Yield: 165.1 %

Procedure:
The product from step (ii) (12 g) was dissolved in DCM (40 mL) and TFA (2 mL) and the reaction mixture stirred for 24 h. The solvents were evaporated to give the subtitle compound 17 g.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1ccccc1CBr
Product: COc1ccccc1CN1CC(=O)N(c2cnn(Cc3c(C)noc3C)c2)C1=O
Yield: 33 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-2-methoxybenzene (199 mg, 1 mmol). Yield: 33%. MS M+H calculated 396.1; found 396.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 uM.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCc2ccc(Cl)cc2)c1

Procedure:
Mitsunobu coupling of phenol 58 with 4-chlorobenzylalcohol followed by flash chromatography (5 to 30% EtOAc-hexanes gradient) gave 2-(3-(3-(4-chlorobenzyloxy)phenyl)propyl)isoindoline-1,3-dione as a colorless oil. Yield (2.82 g, 71%). 1H NMR (400 MHz, CDCl3) δ 7.79-7.82 (m, 2H), 7.67-7.69 (m, 2H), 7.31-7.38 (m, 4H), 7.15 (t, J=8.0 Hz, 1H), 6.79-6.81 (m, 2H), 6.70-6.73 (m, 1H), 4.99 (s, 2H), 3.72 (t, J=7.2 Hz, 2H), 2.65 (t, J=8.0 Hz, 2H), 2.02 (dddd, J=7.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:21])[C@@H:4]2[CH2:19][C:18](=[O:20])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8].[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C(Cl)Cl>[OH:21][CH:3]1[C@@H:4]2[CH2:19][C:18](=[O:20])[N:5]2[C:6]([C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])=[O:8])=[C:2]1[CH3:1]
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C[C@H]2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C[C@H]2C1O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Pivaloyloxymethyl 2-diazo-3-methyl-1-betaoxoceph-3-em-4-carboxylate (150 mg., 0.42 mmoles) was converted to a methylene chloride solution of pivaloyloxymethyl 2-methyl-1-oxocarbapen-2-em-3-carboxylate by the method of Example 1. Without isolation, and while continuing to maintain the temperature at -78° C., tetrabutylammonium borohydride (26.4 mg., 0.092 mmole) was added and the mixture stirred for 30 minutes. The reaction was quenched with acetic acid (0.58 equivalent), extracted twice with aqueous buffer (pH 7), dried over anhydrous sodium sulfate and filtered to yield a methylene chloride solution of pivaloyloxymethyl 1-hydroxy-2-methylcarbapen-2-em-3-carboxylate [ir (CH2Cl2) 1780, 1745 cm-1 ; Rf 0.25, (4:1 chloroform:ethyl acetate)]. If desired, this product is further isolated by evaporation in vacuo, keeping the temperature as low as possible to minimize degradation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:20]=1.C(O)C.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([OH:13])[C:10]3[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)Sc1ccc(SC)cc1C(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)Sc1ccc(SC)cc1C(O)C2
Reaction time: 1.5 h

Procedure:
17.8 G. of 3-methoxy-8-(methylthio)-dibenzo[b,f]thiepin-10(11H)-one is suspended in 150 ml. of ethanol and reacted with 38 g. of sodium borohydride. The reaction mixture is stirred for 90 minutes, and subsequently treated with water and extracted with ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated, whereby there is obtained 10,11-dihydro3-methoxy-8-(methylthio)-dibenzo[b,f]thiepin-10-ol having a melting point of 122°-124°.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]([NH:20][C:21](=[O:36])[C:22]3[CH:27]=[C:26]([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[Cl:35])=[CH:18][C:17]([C:37](O)=[O:38])=[N:16]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[CH:40]1([NH2:43])[CH2:42][CH2:41]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.B(Cl)(Cl)Cl>CN(C=O)C.O>[Cl:35][C:23]1[CH:24]=[CH:25][C:26]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:27][C:22]=1[C:21]([NH:20][C:19]1[N:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[N:16]=[C:17]([C:37]([NH:43][CH:40]2[CH2:42][CH2:41]2)=[O:38])[CH:18]=1)=[O:36]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2cccc(OCc3ccccc3)c2)n1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: ClB(Cl)Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NC1CC1)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2cccc(O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a solution of 1-(3-(benzyloxy)phenyl)-5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1H-pyrazole-3-carboxylic acid (Example 104, 220 mg, 0.373 mmol) in DMF (5 mL) was added cyclopropylamine (26 mg, 0.448 mmol) and DIPEA (241 mg, 1.87 mmol, 0.325 mL) followed by HATU (213 mg, 0.560 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction was diluted with water (70 mL) and extracted with 2-MeTHF (50 mL). The organic layer was washed with brine (50 mL) dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20-25% EtOAc in DCM and the residue was dissolved in DCM (5 mL). Boron trichloride (1M in DCM, 1.72 mL, 1.72 mmol) was added at 0° C. and the reaction was stirred at this temperature for 40 minutes. The reaction was quenched by the addition of MeOH (1 mL) and stirred for 20 minutes. The reaction was concentrated in vacuo and purified using silica gel column chromatography eluting with 2-6% MeOH in DCM to afford the title compound (103 mg, 79%).
Reaction SMILES: [CH3:1][C@:2]1([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[O:19][C:18](=[O:20])[C:17]2[N:21]=[C:14]([S:15][CH:16]=2)[S:13][CH2:12][CH2:11][N:10]2[C@H:6]([CH2:7][O:8][C:9]2=[O:22])[CH:5]=[CH:4][CH2:3]1.[O:30]1CCCC1>CO>[O:22]=[C:9]1[N:10]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[C:17]([C:18]([OH:19])=[O:20])[N:21]=2)[C@@H:6](/[CH:5]=[CH:4]/[CH2:3][C@@:2]([OH:30])([CH3:1])[CH2:23][CH2:24][CH2:25][C:26]([F:27])([F:29])[F:28])[CH2:7][O:8]1
Reactant: C1CCOC1
Reactant: C[C@@]1(CCCC(F)(F)F)CC=C[C@H]2COC(=O)N2CCSc2nc(cs2)C(=O)O1
Solvent: CO
Product: C[C@](O)(C/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)O)cs1)CCCC(F)(F)F

Procedure:
By the same procedure as the reaction of Example 8 using the compound 64-1 (Less polar) instead of the compound 7 and using a mixture of tetrahydrofuran and methanol instead of methanol, the title compound having the following physical data was obtained.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].Cl[C:7]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[CH:10]=[C:9]([Cl:17])[N:8]=1>CO>[NH2:4][CH2:3][CH2:2][CH2:1][NH:5][C:7]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[CH:10]=[C:9]([Cl:17])[N:8]=1
Reactant: NCCCN
Reactant: Clc1cc2nccnc2c(Cl)n1
Solvent: CO
Product: NCCCNc1nc(Cl)cc2nccnc12

Procedure:
A solution of propane-1,3-diamine (890 mg, 12 mmol) and 5,7-dichloropyrido[4,3-b]pyrazine (600 mg, 3 mmol) in methanol (10 mL) was stirred at room temperature for 4 hours. The volatiles were evaporated, and the residue was purified by chromatography to afford the title compound. MS (m/z): 238 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11](O)[CH2:10][CH2:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=[O:18]>>[C:1]1([C:7]2[CH2:12][CH2:11][C:10](=[O:18])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1CCC(O)CC1c1ccccc1
Product: O=C1CC=C(c2ccccc2)CC1

Procedure:
The phenyl-4-hydroxycyclohexanone produced in step (2), on mixing with a strong acid such as trifluoroacetic acid at moderate (room) temperature, yields 4-phenyl-3-cyclohexen-1-one. The thus produced compound (without isolation) is reduced at the 3-position of the cyclohexane ring, (e.g., with hydrogen in the presence of a catalyst such as palladium on charcoal) to yield 4-phenylcyclohexanone.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23].Cl[CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:25][CH2:26][C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23]
Reactant: O=C(CCCl)N1CCOCC1
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CCC(=O)N4CCOCC4)CC3)c2n1
Temperature: 90 °C
Reaction time: 48 h
Yield: 63.2 %

Procedure:
To a stirred mixture of 5-amino-6-chloro-2-ethyl-N-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridine-8-carboxamide (Example 4, Step 4, 400 mg, 1.19 mmol) and 4-(3-chloro-propanoyl)morpholine (G. Mattalia,; C. Serafini; U. Bucciarelli, Farmaco, Ed. Sci., 1976, 31, 457-67., 529 mg, 2.98 mmol) in N,N-dimethylformamide (5 mL) were added potassium carbonate (576 mg, 4.17 mmol) and sodium iodide (446 mg, 2.98 mmol). After stirring at 90° C. for 48 h, the reaction mixture was cooled to room temperature. The mixture was evaporated and the obtained residue was partitioned between dichloromethane (30 mL) and water (20 mL). The mixture was extracted with dichloromethane (2×30 mL). The combined extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Flash column chromatography (NH-silica gel) of the residue eluting with dichloromethane/methanol (100:1 to 20:1) afforded a yellow amorphous powder, which was crystallized from ethyl acetate/ethanol to give 359 mg (63%) of the title compound as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.[OH-].[K+].[CH3:17]I.O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:14]=[CH:13][N:12]([CH3:17])[N:11]=1
Reactant: CI
Reactant: COc1ccccc1Nc1cc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Nc1ccn(C)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The pyrazole from Example 5 (b) (4.0 g) was added to a mixture of crushed potassium hydroxide pellets (4.7 g) in dry dimethylsulphoxide, which had previously been stirred for 5 minutes under nitrogen at room temperature. After stirring for 0.75 hours, methyl iodide (3.1 g) was added to the red solution and stirring was maintained for a further 0.75 hours. The reaction mix was poured into water, extracted with ethyl acetate, the organic layer washed, dried, evaporated and chromatographed to give a light brown oil.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N:11]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1n[nH]c2ccccc12
Reactant: C1CNCCN1
Product: c1ccc2c(N3CCNCC3)n[nH]c2c1
Temperature: 250 °C

Procedure:
A neat mixture of 3-chloroindazole (15.72 g, 0.103 mol) and piperazine (46.00 g, 0.534 mol) was heated at 250° C. for 14 h in a stainless steel sealed vessel Upon cooling to room temperature, the viscous residue was partitioned between 1.0 N aqueous NaOH and methylene chloride. The organic layer was dried over magnesium sulfate, filtered, and the filtrate treated with 4.1 N HCl in dioxane which resulted in the precipitation of both products as a greenish-yellow gummy residue. The gum was collected and taken up in water where it was observed that the disubstituted piperazine precipitated out of solution. The precipitate was filtered off and the filtrate was concentrated in vacuo to give exclusively the monosubstituted piperazine, 3-piperazin-1-yl-1H-indazole, as a green foam. Yield, 19.03 g (77%). MS (APCI): 203 [M+H]+, 201 [M-H]−.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1>C(N(CC)CC)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)C(Cl)=NNc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: CC(=O)C(=NNc1ccc(Cl)cc1)Sc1ccc(Cl)cc1
Yield: 96 %

Procedure:
The reaction of 4.47 g of 1-chloro-1-[(4-chlorophenyl) hydrazono]-2-propanone with 3.43 g of 4-chlorothiophenol and 3.36 ml of triethylamine as Example 11 yielded 6.3 g of 1-[(4-chlorophenyl)thio]-1-[(4-chlorophenyl)hydrazono]-2-propanone, mp 164°-167° C.
Reaction SMILES: C([O:3][C:4](=[O:15])/[C:5](/[CH3:14])=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])C.[OH-].[K+]>C(O)C.O.CCOCC>[OH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1/[CH:6]=[C:5](\[CH3:14])/[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)/C(C)=C/c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: C/C(=C\c1ccccc1O)C(=O)O

Procedure:
To a solution of 35.5 g of (E)-3-(2-hydroxy-phenyl)-2-methyl-acrylic acid ethyl ester in 600 ml of ethanol, a solution of 10.66 g of potassium hydroxide in 500 ml of water was dropped in. After refluxing for 5 hours, another 5.0 g of potassium hydroxide was put in and the mixture was refluxed for another 19 hours. Then the reaction mixture was cooled down, diluted with ether and washed to pH 4 with HCl 2N and water. The organic phase was dried, filtered and evaporated to dryness. The resulting colourless crystals were not further purified.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]1[C:47]([C:51](O)=[O:52])=[N:48][NH:49][N:50]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:51]([C:47]2[C:46]([CH3:45])=[N:50][NH:49][N:48]=2)=[O:52])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1n[nH]nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]nc1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reaction time: 8 h
Yield: 28.2 %

Procedure:
HATU (0.092 g, 0.241 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), 5-methyl-2H-1,2,3-triazole-4-carboxylic acid (0.022 g, 0.177 mmol) and DIPEA (0.042 mL, 0.241 mmol) in DMF (2 mL). The resulting solution was stirred overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and evaporated to a residue. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.0191 g, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.51 (s, 1H), 7.79 (d, 1H), 7.69 (t, 1H), 7.46-7.51 (m, 2H), 7.44 (d, 1H), 7.30 (t, 1H), 4.36 (d, 2H), 2.15 (s, 3H). LCMS: m/z 420.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)=[O:4].[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][NH:19][C:12](=[O:14])[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:18])[F:17])=[CH:16][CH:15]=2)[CH:22]=1
Reactant: NCc1cccnc1
Reactant: O=C(O)C=Cc1ccc(NC(=O)C(F)(F)F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccc(NC(=O)C(F)(F)F)cc1)NCc1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
A solution of 4-(trifluoroacetylamino)cinnamic acid (1.30 g) and 3-(aminomethyl)pyridine (540 mg) in 20 ml dimethylformamide was mixed with 0.9 ml diethyl cyanophosphate and subsequently with 0.8 ml triethylamine on ice, and then stirred at room temperature for 4 hours. The solid precipitated from water was then filtered, washed with water, and dried by heating under reduced pressure to give N-(3-pyridylmethyl)-4-[(trifluoroacetyl)amino]cinnamamide (1.61 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15](C(O)=O)=[N:14][CH:13]=[CH:12][N:11]3[CH:19]=2)=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[Na+].[Na+].CCOCC>O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nccn2cc(-c3ccc(F)cc3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2cn3ccncc3n2)cc1
Temperature: 100 °C
Yield: 36.3 %

Procedure:
A mixture of 2-(4-fluorophenyl)imidazo[1,2-a]pyrazine-8-carboxylic acid (Preparation #C.1, 18.9 g, 66.1 mmol) and 1M of hydrogen chloride in water (500 mL) was heated to about 100° C. for about 2 h. The reaction mixture was cooled to ambient temperature and solid Na2CO3 (50.0 g) was added cautiously portion-wise to raise the pH to about 8-9. The resulting brown solid was collected washing with water (4×80 mL). The product in the filtrate was extracted with EtOAc (3×200 mL). In addition the solid was dissolved in EtOAc (1 L) and filtered from insoluble material. The combined organic extracts were washed with water (3×200 mL) and brine (150 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to yield a brown solid. The solid was stirred with Et2O (8×150 mL); the insoluble solid was filtered each time until no product remained in the insoluble material. The Et2O was evaporated to yield a brown solid, which was dissolved in EtOAc (25 mL) and purified by silica chromatography using the EtOAc as eluent to yield an orange/brown solid (5.12 g, 34.8%): LC/MS (Table 1, Method g) Rt=2.10 min; MS m/z: 214.1 (M+H)+.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6][N:5]=1)=O.[OH-].[Na+].CN(C)C(=[O:32])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[OH:32][C:4]1[N:9]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6][N:5]=1
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)c1cnc(S(C)=O)nc1NCc1ccc(OC)c(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(O)nc1NCc1ccc(OC)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of a whole amount of 2-methylsulfinyl-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 68-(1)) in tetrahydrofuran 6 ml is dropped 2N aqueous sodium hydroxide solution 1.32 ml under ice cooling over a 2 minite period and the reaction mixture is stirred at the same temperature for 30 minutes. Further tetrahydrofuran 8 ml and N,N-dimethylacetamide 6 ml are added thereto and the mixture is stirred under ice cooling for 30 minites. Thereto are added water 5 ml and N,N-dimethylacetamide 2 ml and the mixture is stirred under ice cooling for one hour. The reaction mixture is acidified with an aqueous 10% citric acid solution and diluted with water, extracted twice with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is separated by silica gel chromatography (silica gel 20 g, solvent; chloroform:ethyl acetate=5:1→chloroform:isopropanol=30:1) to give 2-hydroxy-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine as a slightly yellowish crystalline powder, 618 mg. mp 195-197° C.