Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][CH:19]([CH3:21])[CH3:20])[N:11]=2)[CH2:3]1.[OH-:22].[Na+].OO>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]([NH2:17])=[O:22])=[CH:14][N:13]=[C:12]([NH:18][CH:19]([CH3:21])[CH3:20])[N:11]=2)[CH2:3]1
Reactant: [OH-]
Reactant: CC(C)Nc1ncc(C#N)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)Nc1ncc(C(N)=O)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
4-((1R,3R,4R)-3-Hydroxy-4-methylcyclohexylamino)-2-(isopropylamino)pyrimidine-5-carbonitrile (0.38 g, 1.313 mmol) was dissolved in DMSO (5 mL). To this solution was added a 50% aqueous sodium hydroxide solution (0.103 ml, 1.970 mmol) and a 30% aqueous hydrogen peroxide solution (0.101 ml, 0.985 mmol) at room temperature. Then the reaction mixture was stirred at 50° C. for 1 h. After that, the reaction mixture was poured into ice water (15 mL) and the resulting mixture was stirred for 1 h. The resulting precipitate was filtered and washed with water to afford 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(isopropylamino)pyrimidine-5-carboxamide (0.210 g, 0.683 mmol, 52% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 0.94 (d, J=6.40 Hz, 4H) 1.12 (d, J=5.91 Hz, 9H) 1.65 (dd, J=13.29, 2.95 Hz, 1H) 1.92 (br. s., 1H) 2.15 (br. s., 1H) 2.97 (br. s., 1H) 3.81-4.14 (m, 2H) 4.55 (d, J==5.41 Hz, 1H) 6.70-7.02 (m, 1H) 8.34 (br. s., 1H) 8.92 (br. s., 1H); MS (ESI) m/z 308.0 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.OS(O)(=O)=O.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[N+:20]([C:5]1[CH:4]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:8]=[CH:7][C:6]=1[CH2:9][C:10]([OH:12])=[O:11])([O-:22])=[O:21]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-trifluoromethylphenyl acetic acid (2.5 g, 12.25 mmol) in 8 mL of glacial acetic acid at 0° C. under an anhydrous atmosphere was added 5 mL of fuming H2SO4 (11% SO3) (caution!) followed by cautious addition of 90% HNO3 (3.5 mL, 73.14 mmol) within 10 min. The reaction mixture was then stirred at room temperature for 2 h and poured into ice-water. The resulting solid was filtered and washed with cold deionized water to give the desired product after drying as off-white solid, 2.5 g (82%); 1H NMR (200 MHz, CDCl3) δ4.02 (s, 2H), 7.41 (d, J=8.0 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 8.28 (s, 1H). The product was used directly into the following reactions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[H-].[Na+].Cl[CH2:19][C:20](=O)[CH3:21]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[C:11]2[C:20]([CH3:21])=[CH:19][O:15][C:10]=2[CH2:9]1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2ccccc2F)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccccc1F)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2-fluorophenyl)cyclohexane-1,3-dione (mp180-181° C.; 1.03 g) in DMF (20 ml) was added 60% sodium hydride (0.22 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 150° C. overnight (14 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2-fluorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:5]=[C:11]=[O:13]
Reactant: NCc1ccccc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C=NCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 232.7 %

Procedure:
To a solution of 2-chlorobenzylamine (1.0 g, 7.06 mmol) in a mixture of CH2Cl2 and H2O (10 mL/10 mL), triphosgene (838 mg, 2.82 mmol) and NaHCO3 (1.78 g, 21.2 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. Then the reaction mixture was partitioned between CH2Cl2 and water. The combined organic layers are dried over MgSO4 and filtered. The solvent was evaporated to give the desired product (1.1 g, 93%). EI-MS m/z 168.7 (M+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:20]4[CH:25]=[CH:24][N:23]=[C:22](F)[CH:21]=4)=[N:13][N:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=34)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:30][CH:27]([CH3:29])[CH3:28])[CH:21]=4)=[N:13][N:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=34)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: CC(C)N
Reactant: Fc1cc(-c2nn3ccccc3c2-c2ccnc(NC3CC3)n2)ccn1
Product: CC(C)Nc1cc(-c2nn3ccccc3c2-c2ccnc(NC3CC3)n2)ccn1
Yield: 80.7 %

Procedure:
A solution of N-cyclopropyl-4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (206 mg, 0.595 mmol) in isopropylamine (3 mL, 35.2 mmol) was heated at 150° C. in a steel bomb for 16 hours. The excess isopropylamine was removed under a stream of nitrogen. The crude material was triturated with ether to provide N-cyclopropyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine (185 mg, 80%) as a tan solid. 1H NMR (CDCl3) δ 8.60 (d, 1H), 8.51 (d, 1H), 8.14 (m, 2H), 7.32 (t, 1H), 6.93 (t, 1H), 6.80 (d, 1H), 6.62 (s, 1H), 6.55 (d, 1H), 5.62 (br, 1H), 4.60 (d, 1H), 3.87 (m, 1H), 2.85 (m, 1H), 1.29 (d, 3H), 1.22 (d, 3H), 0.86 (m, 2H), 0.63 (m, 2H); MS m/z 386 (M+1).
Reaction SMILES: [K].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[O:9][C:5]=2[CH:4]=1.[C:20]([CH:22]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])[C:23](=[O:27])[CH:24](Cl)[CH3:25])#[N:21].O>CN(C)C=O>[C:20]([CH:22]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])[C:23](=[O:27])[CH:24]([O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:8]2[O:9][C:5]3[CH:4]=[C:3]([Cl:2])[CH:19]=[CH:18][C:6]=3[N:7]=2)=[CH:16][CH:15]=1)[CH3:25])#[N:21]
Reactant: CC(Cl)C(=O)C(C#N)c1ccc(Cl)cc1Cl
Reactant: Oc1ccc(Oc2nc3ccc(Cl)cc3o2)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3o2)cc1)C(=O)C(C#N)c1ccc(Cl)cc1Cl
Temperature: 100 °C
Yield: 46.9 %

Procedure:
2.70 Grams of a potassium salt of 4-(6-chloro-2-benzoxazolyloxy)phenol and 2.48 g of 1-cyano-1-(2,4-dichlorophenyl)-3-chloro-2-butanone were refluxed in 50 ml of N,N-dimethylformamide under heat at 100° C. for 4 hours. The reaction mixture was added to water, and after the mixture was subjected to extraction with chloroform, the extract was concentrated. The residue was separated and purified by column chromatography to give 2.05 g of a compound No. 176 which was a light yellow solid (melting point 93°-94° C.). The yield was 46.9%. The compound No. 176 was analyzed, and the results are shown in Tables 1 to 23.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14](/[CH:17]=[N:18]/[S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([Mg]Cl)[CH:26]=[CH2:27].N#N>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]([NH:18][S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:27][CH:26]=[CH2:25])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](=O)/N=C/[C@H]1CC[C@H](CCOCc2ccccc2)CC1
Reactant: C=CC[Mg]Cl
Agent: N#N
Solvent: ClCCl
Product: C=CCC(N[S@](=O)C(C)(C)C)[C@H]1CC[C@H](CCOCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of (R,E)-N-((trans-4-(2-(benzyloxy)ethyl)cyclohexyl)methylene)-2-methylpropane-2-sulfinamide in DCM (65 mL) was added allylmagnesium chloride (2M in THF, 5.87 mL, 11.74 mmol) dropwise under N2. The resulting mixture was stirred at 0° C. for 1 h and quenched by addition of saturated NH4Cl solution, separated. The aqueous phase was extracted with EtOAc and combined organic phase were washed with brine, dried over Na2SO4. Purification by flash column chromatography (eluent: 20% EtOAc in hexanes) gave the product (2.57 g, 100%). LC/MC: 392.1 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].[C:21]([O:27][CH2:28]I)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].O>CN(C=O)C>[CH3:23][C:22]([CH3:25])([CH3:24])[C:21]([O:27][CH2:28][N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:6][C:7]1=[O:12])=[O:26]
Reactant: CC(C)(C)C(=O)OCI
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCN1C(=O)CC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.0 g of 6-bromo-3,4-dihydro-4,4-dimethylquinolin-2(1H)-one was dissolved in 10 ml of dry DMF, 3.85 g of cesium carbonate were added and 953 mg of iodomethyl pivalate were added dropwise while cooling with water, and the mixture was stirred at room temperature for 4 hours. The experiment was left to stand at room temperature overnight. Then a further 0.4 ml of iodomethyl pivalate was added at room temperature and the mixture was stirred at room temperature for a further 2 hours. (According to TLC and LC-MS, there is still reactant in the reaction solution). 50 ml of water were added, the mixture was extracted three times with 50 ml each time of ethyl acetate. The combined organic phases were dried over MgSO4, then concentrated under reduced pressure and purified on silica gel with the n-heptane/ethyl acetate solvent mixture as a linear gradient of 100% n-heptane=>100% ethyl acetate. This gave 700 mg of 6-bromo-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl 2,2-dimethylpropionate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27][CH2:28]S([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45]C[NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27][CH:28]3[CH2:45][C:40]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:46]([NH2:48])=[O:47])[CH2:41][CH2:42][NH:43]3)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(OC)cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(OC)cc(C(=O)N2CCC(CCC3CC(C(N)=O)(c4ccccc4)CCN3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
The method of example 3.3 was used with 2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.96 mmol) and 4-phenylpiperidine-4-carboxylic acid amide hydrochloride (1.06 mmol) to prepare the title compound. Chromatography on silica gel eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and then 10% methanol in dichloromethane gave the title compound:
Reaction SMILES: C([O:8][C:9]([C:11]1[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=1)=[O:10])C1C=CC=CC=1.C1CCCCC=1>C(O)C.[Pd]>[F:21][C:18]([F:19])([F:20])[C:12]1[C:11]([C:9]([OH:10])=[O:8])=[CH:16][N:15]=[CH:14][N:13]=1
Reactant: O=C(OCc1ccccc1)c1cnc(Cl)nc1C(F)(F)F
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: O=C(O)c1cncnc1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 2-chloro4-trifluoromethyl-5-pyrimidine carboxylic acid benzyl ester in cyclohexene (3 mL, 30 mmole) and ethanol (9 mL) was treated with 10% palladium on carbon and the resulting mixture was heated to reflux for 1 h. The mixture was cooled to room temperature and filtered through a pad of Celite and concentrated to give a quantitative yield of a gummy, off-white solid. LR ES MS (C6H3F3N2O2): 191 (M−H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH:11]=1)([O-])=O.[H][H]>[Pd].C(O)C>[CH3:18][C:12]1([CH3:19])[CH2:13][C:14]([CH3:16])([CH3:17])[CH2:15][CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:11]1
Reactant: [H][H]
Reactant: CC1(C)C=C(c2ccccc2[N+](=O)[O-])CC(C)(C)C1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccccc2N)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 78 h

Procedure:
A mixture of 1-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (130.0 g, 501.3 mmol), 10% palladium on carbon (13.0 g, wet) and ethyl alcohol (1820 mL) was placed in a flask, then the inside of the flask was replaced with hydrogen, and the mixture was stirred for 78 hours at room temperature under a hydrogen atmosphere at atmospheric pressure. Reaction was repeated two more times on the same scale as above, by the same procedure under the same reaction conditions. The three reaction mixtures were combined and subjected to the following treatment.
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[C:11]2[C:20]([CH3:23])=[N:21][S:22][C:10]=2[C:9]=1[OH:24])=[O:7])CCC.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[OH:24][C:9]1[C:10]2[S:22][N:21]=[C:20]([CH3:23])[C:11]=2[C:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[N:13][C:8]=1[C:6]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:7]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(-c2cnccn2)c2c(C)nsc2c1O
Product: Cc1nsc2c(O)c(C(=O)NCC(=O)O)nc(-c3cnccn3)c12

Procedure:
The title compound was synthesized in analogy Example 3 from 7-hydroxy-3-methyl-4-pyrazin-2-yl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and glycine: MS (m/z) 346.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(O)c(Cl)c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(O)c(Cl)c1

Procedure:
46.2 g (0.273 mol) of 3-chloro-4-hydroxy-benzaldehyde, 104 g (1 mol) of malonic acid, 140 ml of pyridine and 4 ml of piperidine are heated to 100° C for 2 hours, whilst stirring. The volatile constituents are distilled off under reduced pressure at 80° C and the residue is stirred with 800 ml of water. The resulting crystals are filtered off and recrystallised from methanol-water. 3-Chloro-4-hydroxy-cinnamic acid of melting point 180°-182° C is obtained.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])=[O:7])(C)(C)C.Cl.[C:32]([O:36][C:37]([NH:39][C@H:40](C(O)=O)[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:32]([O:36][C:37]([NH:39][C@H:40]([C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])=[O:7])[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A mixture of 412 mg (0.96 mmole) of (2R, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-N-hexyl-4-hydroxy-2-methylhexanamide (prepared as described in Preparation 7) and 8.0 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was mixed with benzene. The solvent was then removed by distillaticn under reduced pressure. This operation was repeated three times in total, and the final residue was dried in vacuo for 8 hours. The dried material was then suspended in 50 ml of anhydrous tetrahydrofuran, and 289 mg (1.06 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to the resulting suspension. 0.17 ml (1.06 mmole) of 95% diethyl cyanophosphonate and 0.6 ml (4.3 mmole) of triethylamine were then added, in that order, whilst ice-cooling and under an atmosphere of nitrogen, to the resulting mixture, and the mixture was stirred for 15 hours. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure, after which the residue was mixed with water and the crystals which deposited were collected by filtration. The crystals were then dissolved in methylene chloride and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was triturated with diisopropyl ether to afford 465 mg of the title compound as a white powder, melting at 156°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Br[CH2:23][CH2:24][NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(NCCBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCNC(=O)c2ccccc2)CC1
Yield: 59.8 %

Procedure:
To 1.92 g (0.01 mol) of 1-(2-methoxyphenyl)piperazine, 1.01 g (0.01 mol) of triethylamine, 150 ml of toluene and 2.28 g (0.01 mol) of N-(2-bromoethyl)benzamide were added, and the mixture was refluxed for 3-4 hours under stirring. After the reaction, the solvent was concentrated under vacuum to half of its original volume, and a mixture of the residue with water was extracted with ethyl acetate. After separating the solvent layer, the aqueous layer was further extracted with ethyl acetate, and a mixture of the extract with the previously separated solvent layer was washed with water. To the organic layer, 1N HCl was added until the pH became 3.0, and the aqueous layer was separated. The separated aqueous layer was neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried with Glauber's salt, and distilled under vacuum to remove the solvent. The resulting residue was mixed with benzene-ether to provide 2.03 g (yield: 60%) of crystalline 1-(2-methoxyphenyl)-4-(2-benzoylaminoethyl)piperazine. Recrystallization from a mixture of isopropyl alcohol and ether gave a colorless needles having a melting point of 139°-140° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Yield: 98.1 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and diethylamine (0.26 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N,N-diethyl-2-(trifluoromethoxy)benzenesulfonamide (0.38 g, 98%) was provided after purification. MS (ESI) m/z 376. HPLC purity 100.0% at 210-370 nm, 10.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl.CN([CH2:5][CH:6]1[C:18](=[O:19])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)C.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.O>CN(C)C=O>[CH3:21][C:22]1[N:26]([CH2:5][CH:6]2[C:18](=[O:19])[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]([CH3:20])[C:9]=3[CH2:8][CH2:7]2)[CH:25]=[CH:24][N:23]=1
Reactant: CN(C)CC1CCc2c(c3ccccc3n2C)C1=O
Reactant: Cc1ncc[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Reaction time: 6 h
Yield: 97 %

Procedure:
3-[(Dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (10 g, 34 mmol) and 2-methylimidazole (16.8 g, 205 mmol, 6.0 eq.) were suspended in mixture of water (75 ml) and dimethyl formamide (37.5 ml). The reaction mixture was heated to reflux (102–103° C.) and stirred for a further 6 hours at this temperature. The reaction mixture was cooled to 5–10° C. and stirred for half an hour at this temperature. The precipitated crude ondansetron base was filtered and washed with cold water (3×90 ml) and dried under vacuum at 60° C. to give ondansetron base (9.68 g, 96.4% yield) in 98.9% HPLC purity.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:19]=[C:18]([O:20][C@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15]([C:16]#[N:17])=[CH:14][N:13]=1.N1C=CC=CC=1>C1COCC1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:19]=[C:18]([O:20][C@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC[C@@H](C)Oc1cc(N)ncc1C#N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC[C@@H](C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Phenyl chloroformate (1.53 ml, 12.2 mmol) was added drop wise to a mixture of (R)-6-amino-4-((1-methoxypropan-2-yl)oxy)nicotinonitrile (intermediate 146, 1.37 g, 5.55 mmol) and pyridine (0.99 ml, 12.2 mmol) in THF (60 ml) at 0° C. The reaction mixture was stirred for 12 h at room temperature and additional pyridine (0.98 ml, 12.2 mmol) and phenyl chloroformate (1.53 ml, 12.2 mmol) were added. After stirring for a further 36 h at room temperature the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution, the organic layer washed with saturated brine, dried over MgSO4 and evaporated. The residue was triturated with Et2O and the product obtained by filtration as a white solid. (UPLC-MS 6) tR 1.04; ESI-MS 328.4 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:13]2[S:14]C=C(C(OCC)=O)[N:17]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1(C)C=CC=CC=1.C1COCC1>[NH2:17][C:13]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[S:14]
Reactant: CCOC(=O)c1csc(N2CCOCC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: NC(=S)N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A solution of 7.0 ml (7.0 mmol) of lithium aluminum hydride in toluene was diluted with 10 ml of THF, cooled to 0° C., and treated with a solution of 1.7 g (7.0 mmol) of ethyl 2-(4-morpholinyl)thiazole-4-carboxylate in 25 ml of THF. The resulting solution was stirred for 1 h, quenched cautiously with aqueous Rochelle's salts, diluted with chloroform, filtered, dired over Na2SO4, and concentrated in vacuo. Silica gel chromatography using 2-4% methanol in chloroform provided 856 mg (61%) of the desired compound, Rf 0.16 (4% methanol in chloroform). 1H NMR (CDCl3) δ2.44 (br, 1H), 3.46 (t, J=5 Hz, 4H), 3.81 (t, J=5 Hz, 1H), 4.55 (br s, 2H), 6.45 (s, 1H). Mass spectrum: (M+H)+ =200.