Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[OH-:16].[Na+].Cl>CO>[O:9]([CH2:8][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:16])[CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [OH-]
Reactant: Clc1cc(COc2ccccc2)ccn1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=c1cc(COc2ccccc2)cc[nH]1
Temperature: 170 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-4-(phenoxymethyl)pyridine (2.34 g, 10.68 mmol) in anhydrous methanol (30 mL) in a steel bomb was added sodium hydroxide (3.20 g, 80.11 mmol). The reaction mixture was stirred at 170° C. for 16 hours, cooled to 0° C. and neutralized with cold concentrated hydrochloric acid, followed by the addition of methanol (10 mL) and filtration. The filtrate was concentrated in vacuo and the residue was washed with methanol and hexane. The title compound was obtained as a colorless solid in 93% (2 g): 1H NMR (300 MHz, CDCl3) δ 13.00 (br s, 1H), 7.35-7.25 (m, 3H), 6.99-6.90 (m, 3H), 6.64 (s, 1H), 6.34 (d, J=6.6 Hz, 1H), 4.93 (s, 2H); MS (ES+) m/z 202.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])=[CH:5][C:3]=1[NH2:4].[CH3:23][O:24][C:25]1[N:30]=[C:29](S(C)(=O)=O)[N:28]=[C:27]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:26]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[N:12]([CH3:21])[C:11]2=[O:22])=[CH:5][C:3]=1[NH:4][C:29]1[N:28]=[C:27]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:26]=[C:25]([O:24][CH3:23])[N:30]=1
Reactant: COC(=O)COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(OC)nc(Nc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 15.5 %

Procedure:
To a mixture of 400 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 360 mg of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylsulfonylpyrimidine and 2 ml of N,N-dimethylformamide, 196 mg of potassium carbonate was added, and the mixture was stirred for 5 hours at 80° C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 98 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenylamino}-6-methoxy-4-(methoxycarbonyl)methoxypyrimidine [present compound 1-67].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.CN.[CH3:17][N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:18][CH3:17])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
A solution of 5-fluoro-2-nitrobenzoic acid (0.550 g, 2.97 mmol), methylamine hydrochloride (0.241 g, 3.56 mmol), TBTU (0.954 g, 2.97 mmol), and DIPEA (1.15 g, 8.91 mmol) in DCM (10.0 mL) was stirred at rt for 30 minutes. The reaction was quenched with saturated NaHCO3 (10 mL) and extracted with DCM (15 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield a yellow semi-solid. 1H NMR (CDCl3, 400 MHz): δ=3.06 (d, J=5.05 Hz, 3H), 7.20-7.26 (m, 1H), 8.16 (dd, J=8.84, 4.55 Hz, 1H). MS (ES+): m/z 199.05 [MH+] (TOF, polar).
Reaction SMILES: C([O:8][C:9]1[CH:33]=[C:12]2[N:13]=[C:14]([NH:23][N:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]2[N:10]=1)C1C=CC=CC=1.[H][H]>CO.C(Cl)Cl.[Pd]>[OH:8][C:9]1[CH:33]=[C:12]2[N:13]=[C:14]([NH:23][N:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]2[N:10]=1
Reactant: [H][H]
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(OCc4ccccc4)cc3n2)c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(O)cc3n2)c1
Yield: 68.9 %

Procedure:
There was dissolved N-(2-benzyloxy-7-morpholin-4-yl-pyrazolo[1,5-a]-pyrimidin-5-yl)-N′-(3-methyl-benzylidene)-hydrazine (50.7 mg, 0.115 mM) in a mixed solvent of methanol/methylene chloride (1:2) (3 mL), then 10% palladium on carbon (10.1 mg) was added to the solution and the mixture was stirred for 3 hours in a hydrogen gas atmosphere. The reaction liquid was filtered, the solvent was distilled off, and the resulting residue was purified by the reversed phase HPLC and then subjected to a desalting operation to thus give the title compound (27.8 mg, yield: 69%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24]I)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:26]#[N:27].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][C:26]#[N:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccccc2)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CC#N)N(C(=O)OCc2ccccc2)C1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-iodomethyl-4-t-butyldimethylsilyloxypyrrolidine (110 g) in dry dimethylformamide (300 ml), sodium cyanide (10.29 g) was added, and the resultant mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hypochlorite solution and aqueous sodium chloride solution in order and dried over magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give (2R,4R)-1-benzyloxycarbonyl-2-cyanomethyl-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:32][C:31]([F:34])([F:33])[C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([C:2]([F:36])([F:1])[F:35])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][CH:42]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:43][CH2:44]3)[CH:17]=[C:18]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[C:9]=2[C:8]1=[O:27]
Reactant: O=C1c2c(-c3ccc(Cl)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CCN(C2CCNCC2)C1
Product: O=C1c2c(-c3ccc(Cl)cc3)cc(N3CCC(N4CCCC4)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 55.5 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (70.2 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-chlorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (67.4 mg, 56%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19](=[O:21])[NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(C)(C)C.Br[CH2:24][C:25](=O)[CH2:26][CH3:27].C(OCC)C>CC#N>[CH2:26]([C:25]1[N:20]=[C:19]([C@@H:8]([NH2:7])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[O:21][CH:24]=1)[CH3:27]
Reactant: CCC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=O
Solvent: CCOCC
Solvent: CC#N
Product: CCc1coc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C

Procedure:
A mixture of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl ester, 1, (10 g, 32.3 mmol) and 1-bromo-2-butanone (90%, 4.1 mL, 36 mmol) in CH3CN (500 mL) is refluxed for 18 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to the solution and the precipitate which forms is removed by filtration and is used without further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[CH3:10][O:11][NH2:12]>CO>[CH3:10][O:11][N:12]=[C:5]1[CH2:6][CH2:7][NH:2][CH2:3][CH2:4]1
Reactant: O=C1CCNCC1
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C1CCNCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 3.84 g (25.00 mmol) 4-piperdinone hydrochloride and 2.51 g (30.00 mmol) O-methylhydroxylamine hydrochloride in 50 mL of MeOH was stirred for 8 hours at 60° C. and then evaporated down in vacuo. The residue was stirred with saturated aqueous potassium carbonate solution and the aqueous phase was extracted with DCM. The combined organic phases were dried over sodium sulfate, evaporated down in vacuo, and dried. Yield: 2.80 g (87% of theoretical); C6H12N2O (M=128.172); calc.: molpeak (M+H)+: 129; found: molpeak (M+H)+: 129; HPLC-MS: 1.44 minutes (method C).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[F:25][C:26]([F:32])([F:31])[S:27](Cl)(=[O:29])=[O:28].O.Cl>N1C=CC=CC=1>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][S:27]([C:26]([F:32])([F:31])[F:25])(=[O:29])=[O:28])[CH:4]=2)[NH:8][CH:7]=1
Reactant: NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(CNS(=O)(=O)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A suspension of 2-[2-(5-aminomethyl-1H-indol-3-yl)ethyl]-1H-isoindole-1,3(2H)-dione, hemisulphate, hydrate (1.10 g) in pyridine (40 ml) was cooled in an icebath and treated dropwise with trifluoromethanesulphonyl chloride (0.5 ml). The mixture was stirred at room temperature for 5.5 h, further trifluoromethanesulphonyl chloride (0.5 ml) being added after 4.75 h, and water (10 ml) was added. After 10 minutes the solution was acidified with hydrochloric acid (2N) and extracted into ethyl acetate (4×100 ml). The combined extract was washed with sodium carbonate (2N; 100 ml), dried (magnesium sulphate) and evaporated to dryness, affording a yellow-brown foam (1.2 g). This was purified by chromatography on a silica column (Merck Kieselgel 60; 22 g) eluted with ethyl acetate, affording title material as a yellow-brown solid (0.91 g), m.p. 176°-8°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C.C[O-].[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:15]
Reactant: CCCCCCCCO
Reactant: COC(=O)Cc1cc(O)c(C(C)(C)C)cc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)Cc1cc(O)c(C(C)(C)C)cc1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
Into a 200-ml four-necked flask, were charged 23.6 g of methyl (2-methyl-4-t-butyl-5-hydroxyphenyl)acetate, 13.0 g of octylalcohol and 0.5 g of sodium methoxide. The mixture was allowed to react at 120° C. for 2 hours, and then at 140° to 150° C. under a reduced pressure of 20 mmHg for 5 hours. During the course of this reaction, along with the progress of reaction 1.5 g of sodium methoxide was added in three equal portions. After completion of the reaction, the reaction mixture was cooled to 80° C., neutralized with glacial acetic acid, then dissolved in toluene, washed with water, dried over anhydrons sodium sulfate, and freed from the solvent under reduced pressure to obtain 29.4 g (88% yield) of viscous octyl 2-methyl-4-t-butyl-5-hydroxyphenylacetate.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1.[CH:17]([C:20]([N:23]=[C:24]=[O:25])(C)[CH3:21])(C)C>>[CH:20]([NH:23][C:24](=[O:25])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])=[CH:7][CH:8]=1)([CH3:21])[CH3:17]
Reactant: CC(C)C(C)(C)N=C=O
Reactant: CC(C)=CCOc1ccc(OCCO)cc1
Product: CC(C)=CCOc1ccc(OCCOC(=O)NC(C)C)cc1

Procedure:
Following the procedure of Example 9, 2[4-(3-methyl-2-butenoxy)phenoxy]ethanol and isopropyl isopropyl isocyanate are reacted together to give O-2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl N-isopropylcarbamate, MS, m/e 307 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:11]([CH3:12])=[C:10]([CH3:13])[S:9][C:8]=2[F:14])[N:5]=[C:4]([OH:15])[CH:3]=1.[C:16](Cl)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([NH:1][C:2]1[N:6]([C:7]2[C:11]([CH3:12])=[C:10]([CH3:13])[S:9][C:8]=2[F:14])[N:5]=[C:4]([OH:15])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: Cc1sc(F)c(-n2nc(O)cc2N)c1C
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(O)nn1-c1c(F)sc(C)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Then, the obtained pyrazole derivative was dissolved in 50 mL of toluene, and to this solution, 6.0 g of acetyl chloride was added, followed by reflux with heating for 12 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, the residue was dissolved in 30 mL of ethanol, and 20 mL of a 25mass % ammonia water was added, followed by stirring at room temperature for 30minutes. The solvent was distilled off under reduced pressure, and the obtained solid was washed with diisopropyl ether to obtain 5.2 g of 5-acetylamino-1-(2-fluoro-4-methyl-5-methylthiophenyl)-3-hydroxypyrazole in the form of pale yellow crystals (melting point: 204-205° C.).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]([CH3:26])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH:21]([NH:24][CH3:25])[CH2:20]3)=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:29][N:30]([CH3:35])[CH2:31][C:32](O)=[O:33]>>[CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C:32](=[O:33])[CH2:31][N:30]([CH3:35])[CH3:29])[CH2:20]3)=[CH:15][CH:14]=2)[CH3:26])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)N(C)c2ccc(N3CCC(NC)C3)cc2)cc1
Reactant: CN(C)CC(=O)O
Product: CCCCOc1ccc(C(=O)N(C)c2ccc(N3CCC(NCC(=O)CN(C)C)C3)cc2)cc1

Procedure:
4-Butoxy-N-methyl-N-[4-(3-methylaminopyrrolidin-1-yl)phenyl]benzamide was reacted with N,N-dimethylglycine by method E. This resulted in the product with the molecular weight of 466.63 (C27H38N4O3); MS (ESI): 467 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C@@H:7]2[CH2:8][C@@H:4]([CH:5]=[CH:6]2)[N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[BH4-].[Na+].Cl>O1CCCC1.O>[OH:1][CH2:2][C@@H:7]1[CH2:8][C@H:4]([NH:3][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:5]=[CH:6]1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H]2C=C[C@@H]1C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of (1S,4R)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (part a of this example, 95.50 g, 0.456 mole) in tetrahydrofuran (500 ml)-water (50 ml) was added over 10 minutes to a vigorously stirred solution of sodium borohydride (Aldrich, 21.96 g, 0.580 mole as 99%) in water (100 ml). The temperature was maintained below 35° C. After 2 hours, the solution was cooled to maintain the temperature below 25° C. while concentrated hydrochloric acid (50 ml) was added over 10 minutes. Additional water (100 ml) was added to dissolve solid and the solution was extracted with toluene (4×300 ml). The combined organic layers were washed with 9:1 saturated sodium sulfate/saturated sodium carbonate (200 ml) and dried (sodium sulfate). Evaporation of solvents under reduced pressure left a colorless syrup which crystallized on stirring with hexanes (200 ml) to provide title compound as a fine white powder (87.16 g, 90%), m.p. 72–73° C.; 1H-NMR (DMSO-d6) δ 6.78 (d, J=7.6 Hz, 1H), 5.80 and 5.60 (two m, 2H), 4.58 (t, J=5.25 Hz, 2H), 4.45 (m, 1H), 3.35 (m overlapping water), 2.60 (m, 1H), 2.30 (m, 1H), 1.38 (s, 9H), 1.20 (m, 1H); [α]58920+2.80° (c 5.0, methanol).
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]([CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[CH3:25])[N:20]=[C:19]([Cl:32])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C>CO.Cl>[Cl:32][C:19]1[N:20]=[C:21]([N:24]([CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[CH3:25])[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CN(Cc1ccco1)c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: CO
Product: CN(Cc1ccco1)c1nc(Cl)nc(NN)c1F
Reaction time: 5 h
Yield: 25.2 %

Procedure:
Tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(2-furanylmethyl)(methyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (7.1439 g, 12.51 mmol) was dissolved in MeOH (65 mL) and HCl (4M in 1,4-dioxane) (65 mL). The reaction mixture was left to stir 5 hours, evaporated and purified by RP-HPLC to provide 2-chloro-5-fluoro-N-(2-furanylmethyl)-6-hydrazino-N-methyl-4-pyrimidinamine as an orange solid (0.8561 g). LCMS: (M+H)+=272.1.
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:38])[O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH:9]3[NH:16][C:17]([C:19]3[CH:20]=[N:21][N:22]([C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=4)[C:23]=3[S:24][CH2:25][CH2:26][CH3:27])=[O:18])[CH2:7]1)[CH2:13]2>CO>[F:38][CH:4]([F:3])[O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH:9]3[NH:16][C:17]([C:19]3[CH:20]=[N:21][N:22]([C:28]4[CH:37]=[CH:36][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)[C:23]=3[S:24][CH2:25][CH2:26][CH3:27])=[O:18])[CH2:7]1)[CH2:13]2
Reactant: CCCSc1c(C(=O)NC2C3CC4CC2CC(OC(F)F)(C4)C3)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC2C3CC4CC2CC(OC(F)F)(C4)C3)cnn1-c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
2M aqueous sodium hydroxide (2.050 mL, 4.10 mmol) was added in one portion to methyl 4-[4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]-5-propylsulfanylpyrazol-1-yl]benzoate (Intermediate#95) (459 mg, 0.82 mmol) in methanol (10 mL). The resulting mixture was stirred at 20° C. for 18 hours and then a further 4 hours at 55° C. The reaction mixture was concentrated and diluted with water (50 mL), and washed with ether (20 mL). The aqueous solution was adjusted to pH 3 with 2M HCl and extracted with EtOAc (2×25 mL), and the combined extracts washed sequentially with water (2×20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 4-[4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]-5-propylsulfanylpyrazol-1-yl]benzoic acid (284 mg, 63.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[C:7]([OH:31])=[N:8][N:9]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=2[Cl:30])[C:10]=1[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])=[O:5].[H-].[Na+].S(OCC)(O[CH2:42][CH3:43])(=O)=O.O>CS(C)=O>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[C:7]([O:31][CH2:42][CH3:43])=[N:8][N:9]([C:22]2[C:23]([Cl:30])=[CH:24][C:25]([Cl:29])=[CH:26][C:27]=2[Cl:28])[C:10]=1[N:11]1[C:12](=[O:21])[C:13]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]2[C:15]1=[O:16])=[O:5]
Reactant: O=C(c1ccccc1Cl)c1c(O)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N1C(=O)c2ccccc2C1=O
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N2C(=O)c3ccccc3C2=O)c1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 0.55 g (1.0 mmol) of the compound of Step C in 10 mL of dry dimethyl sulfoxide was treated portionwise with 36 mg (1.5 mmol) of sodium hydride and the resulting mixture was stirred for 30 minutes at room temperature. Then 0.21 mL (0.25 g, 1.61 mmol) of diethyl sulfate was added and the reaction mixture was stirred for one hour at room temperature. The reaction mixture was poured into water and the product was extracted into ethyl acetate. The extracts were washed with water and dried with brine and magnesium sulfate, and evaporated to a gum. The product was crystallized from boiling ethanol to give the product (230 mg, 40%) as fine crystals, m.p. 215-216° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:17]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[C:2]=2[CH3:1])=[O:18])[CH:22]=[CH:23][C:24]=1[O:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)#[N:27]
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cc(N)ccc1OCCCN1CCOCC1
Product: Cc1c(C(=O)Nc2ccc(OCCCN3CCOCC3)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 42.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (1.0 g) synthesized according to Starting Material Synthesis Example 88 and 5-amino-2-(3-morpholinopropoxy)benzonitrile (0.9 g), the title compound (0.75 g) was obtained, melting point: 172–174° C.
Reaction SMILES: [CH2:1]([C:4]([CH2:11][CH2:12][CH3:13])([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].C1(C)C=CC=CC=1.[OH-].[Na+:22]>CO>[CH2:11]([C:4]([CH2:1][CH2:2][CH3:3])([CH2:8][CH2:9][CH3:10])[C:5]([O-:7])=[O:6])[CH2:12][CH3:13].[Na+:22]
Reactant: CCCC(CCC)(CCC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCC(CCC)(CCC)C(=O)[O-]
Reaction time: 4 h
Yield: 89.5 %

Procedure:
In a flask equipped with a dropping-funnel and a mechanical stirrer were placed 30 g (0.161 mol) of pure tri-n-propylacetic acid prepared as described above and 75 g of toluene. The mixture was stirred until dissolution after which a hot solution of 6.45 g of sodium hydroxide in 30 g of Methanol was added through the dropping-funnel. To the solution thus obtained was added 1g of CECA WSL black after which the whole was refluxed for 1 hour while being stirred. The black was filtered off and the residual mixture was distilled by adding little-by-little through the dropping-funnel 88 g of toluene to prevent the mixture from forming a mass. Distillation was suspended when the temperature at the head of the column reached 105°C, after which the mixture was cooled to room-temperature The precipitate which formed was centrifuged out and rinsed twice with 20 g of acetone. It was then dried in a rotatory evaporator at 80°C for 2 hours and then at 105°C under atmospheric pressure in a ventilated drying-oven for 4 hours. In this way, 30 g of sodium tri-n-propylacetate were obtained which represents a yield of 89.5%.