Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC[C:14](=[O:15])[CH2:13]CCCCCCC=CCCC1.[C:19](O)(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].S(=O)(=O)(O)O.[C:44]([O:63][CH2:64][CH3:65])(=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]/[CH:52]=[CH:53]\[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61].[Sn](C)(C)(C)C>>[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[C:61]([O:15][CH2:14][CH3:13])(=[O:37])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH:53]=[CH:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][C:44]([O:63][CH2:64][CH3:65])=[O:62]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=C1CCCCCCCC=CCCCCCCC1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC
Agent: C[Sn](C)(C)C
Agent: O=C1CCCCCCC/C=C\CCCCCCC1
Agent: O=S(=O)(O)O
Product: CCCCCCCCC=CCCCCCCCC
Product: CCOC(=O)CCCCCCCC=CCCCCCCCC(=O)OCC

Procedure:
In 1994 (Choo, Ooi, & Ooi, 1994), synthesis of Civetone was reported from Palm oil. In this process Oleic acid (C18:1) was obtained from Palm oil by hydrolytic splitting with 99% purity. See FIG. 2. The pure Oleic acid was esterified under acidic conditions using concentrated sulfuric acid at 110° C. Self-metathesis of ethyl oleate was performed using WCl6 and SnMe4 to give two products, 9-Octadecene and Diethyl 9-Octadecenedioate, with almost quantitative yields of 97 and 99% respectively. Silica-gel chromatography was used to separate the two products. The Diethyl 9-Octadecenedioate was cyclized using base catalyzed Dieckmann Condensation under inert conditions. Dieckmann Condensation was carried out under argon using potassium hydride (KH) in dry THF at 55° C. for 3 hours to give 2-ethoxycarbonyl-9-cycloheptadecenone with 63% yield which was purified by silica-gel chromatography. Civetone was synthesized by hydrolysis followed by decarboxylation of 2-ethoxycarbonyl-9-cycloheptadecenone using 5% NaOH/THF/Ethanol with 93% yield which was also purified by silica-gel chromatography.
Reaction SMILES: O.[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:17]([NH:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)C[C@H](NC(=O)c1ccccc1)C(=O)O
Reaction time: 2 h
Yield: 68.4 %

Procedure:
To a vigorously stirred solution of 2 g (0.013 mol) of L-asparagine monohydrate and 2.02 g (0.014 mol) of potassium carbonate in 15 ml of water, 1.51 ml (0.013 mol) of benzoyl chloride was added dropwise, over a period of 15 min., at room temperature. The stirring was continued for 2 hour, then the mixture was extracted with 10 ml of ether and the aqueous phase was acidified to pH 2 with concentrated hydrochloric acid. The white precipitate was filtered off, washed with water and purified by crystallization from isopropyl alcohol to give 2.1 g (68% yield) of the title compound at 190°-192° C.; NMR (DMSO-d6): 2.62 (m, 2H, CH2); 3.32 (broad s, 1H, OH); 4.72 (m, 1H, CH); 6.64-8.0(m. 7H, aromatic, NH2); 8.6 (d, 1H, NH).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)c1ccccc1
Yield: 39 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (20 mg) with benzoyl chloride (10 uL) provided 10 mg (39%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:39])[C:29]3[N:33]=[C:32]([CH2:34][CH2:35][O:36][CH3:37])[NH:31][C:30]=3[CH:38]=2)[CH:20]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[CH3:37][O:36][CH2:35][CH2:34][C:32]1[NH:31][C:30]2[CH:38]=[C:26]([O:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)[CH:27]=[C:28]([CH3:39])[C:29]=2[N:33]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: COCCc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCc1nc2c(C)cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc2[nH]1

Procedure:
29 mg (0.11 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 29 mg (0.09 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(2-methoxyethyl)-4-methyl-1H-benzo-[d]imidazole and 50 μL (0.39 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 50° C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](C)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][C:11]=1F.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][N:4]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:26][CH:27]=2)[C:3](=[O:19])[C:2]=1[Br:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(Cn2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 3.3 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(0.5 g, 1.78 mmol) was dissolved in N,N-dimethylformamide (5 mL). 4-(Bromomethyl)phenylacetic acid (0.5 g, 2.14 mmol) was added followed by K2CO3 (0.3 g, 2.14 mmol). The reaction was heated to 80° C. and shaken for 16 hours, then heated to 100° C. and shaken for 16 hours more. The reaction mixture was partitioned between water and ethyl acetate and extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified (pH 2) with 1N HCl and extracted with ethyl acetate (3×50 ml). The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) followed by reversed phase chromatography (C18, 0.1% aqueous trifluoroacetic acid /acetonitrile) to yield a white solid (25 mg, 3%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.38 (m, 3H), 7.25-7.20 (m, 7H), 6.05 (d, J=8.0 Hz, 1H), 5.21 (s, 2H); 5.13, (s, 2H); 3.62, (s, 2H). ES HRMS m/z 428.0510 (M+H C21H18BrNO4 requires 428.0492).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)Cl>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)=[N:13][C:14]([S:17]([CH3:18])=[O:38])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ccccc2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ccccc2)cc1Cl
Reaction time: 5 h

Procedure:
In DCM (20 mL) was dissolved N-benzyl-4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-formamide (201 mg, 0.47 mmol). Then was added m-CPBA (80 mg, 0.47 mmol). The reaction was conducted at ambient temperature for 5 h. After the reaction was completed, the reaction mixture was washed with water and extracted with DCM. The organic phase was dried, and the solvent was removed by rotary evaporation. The obtained solid was used in the subsequent procedure without further purification.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[Cl:12].[C:13]([O:17][C:18](=[O:41])[NH:19][C:20]([C:22]1[S:23][C:24]([S:39][CH3:40])=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][C:33](O)=[C:32](B)[C:31]=2O)(=[O:29])=[O:28])[CH:26]=1)=[NH:21])([CH3:16])([CH3:15])[CH3:14].C(O)C.C1(C)C=CC=CC=1>C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[C:13]([O:17][C:18](=[O:41])[NH:19][C:20]([C:22]1[S:23][C:24]([S:39][CH3:40])=[C:25]([S:27]([C:30]2[CH:31]=[C:32]([C:2]3[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=3[Cl:12])[CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:26]=1)=[NH:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1Br
Reactant: Bc1c(O)ccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2Cl)c1
Temperature: 80 °C
Yield: 29 %

Procedure:
2-Bromo-1-chloro-3-methyl-5-nitro-benzene (45 mg, 0.219 mmol), {[4-(3-Boranyl-dihydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (50 mg, 0.11 mmol, Example 140: step a) and Pd(PPh3)4 (25 mg, 0.02 mmol) were combined in aqueous Na2CO3 (2M, 500 μL), ethanol (500 μL) and toluene (1 mL). The reaction was heated to 80° C. overnight. The resulting residue was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and the solvent was removed in vacuo followed by preparative TLC purification (30% EtOAc/hexanes) that yielded the title compound (20 mg, 29%). ESI-MS (m/z): Calcd. for C24H24ClN3O6S3: 582.1 (M+1); found: 582.1.
Reaction SMILES: N[CH:2]([C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)CC(O)[CH2:6]1)[CH2:3]C.ClC1C=C2C(C=C[N:24]=C2OC)=CC=1F.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([CH:36]=[CH:37][N:38]=[C:39]2[O:42][CH3:43])=[CH:34][C:33]=1[O:44][CH:45]1[CH2:50]CC(C(N)(C2C=CC(OC)=CC=2)C)C[CH2:46]1>>[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([CH:36]=[CH:37][N:38]=[C:39]2[O:42][CH3:43])=[CH:34][C:33]=1[O:44][CH:45]1[CH2:50][CH:6]([C:5]([NH2:24])([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:2][CH3:3])[CH2:46]1
Reactant: COc1nccc2cc(F)c(Cl)cc12
Reactant: COc1ccc(C(C)(N)C2CCC(Oc3cc4ccnc(OC)c4cc3Cl)CC2)cc1
Reactant: CCC(N)C1(c2ccc(F)cc2)CC(O)C1
Product: CCC(N)(c1ccc(F)cc1)C1CC(Oc2cc3ccnc(OC)c3cc2Cl)C1

Procedure:
1-[3-(7-chloro-1-methoxyisoquinolin-6-yloxy)-cyclobutyl]-1-(4-fluorophenyl)-propylamine (2 isomeric mixtures) were prepared from 1-(1-aminopropyl)-1-(4-fluorophenyl)cyclobutan-3-ol (114) and 7-chloro-6-fluoro-1-methoxyisoquinoline (10) as described for (109). The two stereoisomers could be separated by silica gel chromatography, relative stereochemistry was not assigned.
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]1[S:10][CH:9]=[C:8]([CH:11]=O)[CH:7]=1.[C:13]([O:22]CC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[CH:11][C:8]1[CH:7]=[C:6]([CH3:5])[S:10][CH:9]=1)[CH2:14][C:13]([OH:22])=[O:21])=[O:17])[CH3:20]
Reactant: Cc1cc(C=O)cs1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1csc(C)c1)CC(=O)O
Yield: 60 %

Procedure:
Sodium ethylate (17 g, 0.24 mol) was added under vigorous stirring to a solution of 5-methylthiophene-3-carbaldehyde (26 g 90% purity, 0.20 mol) and diethyl succinate (54 g, 0.31 mol) in ethanol (400 mL). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 300 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 700 mL of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. The residue was chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture (1:1). Fractions with the target product were collected and evaporated in vacuum to give the desired product 30 g (0.12 mol, 57%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.S(Cl)([Cl:14])(=O)=O.[N:16]1C=CC=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH2:18][CH2:17][NH2:16])=[CH:5][C:4]=1[Cl:14]
Reactant: COc1ccc(C=O)cc1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccncc1
Product: COc1ccc(CCCN)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
4-Methoxy-benzaldehyde (Aldrich) (42 g, 0.31 mole) and pyridine (0.6 ml, catalytic) were stirred together under nitrogen and sulfuryl chloride (51 g, 0.37 mole) added over 30 min, maintaining the internal temperature of the reaction at between 25 and 30° C. There was a vigorous evolution of gas. The mixture was stirred at room temperature for a further 30 min, and then warmed to 70° C. for 4 h. Excess reagents were removed by evaporation in vacuo and the residue taken up in 50 ml diisopropyl ether and poured onto 500 ml hexane with vigorous stirring, from which the product precipitates. The solid was filtered off and washed with hexane and then dried in vacuo to give the title product (40.3 g, 77%), m.p. 55-56° C.; 1HNMR (400 MHz, CDCl3) δ: 3.99 (s, 3H), 7.05 (dd, 1H), 7.91 (d, 1H), 9.86 (s, 1H); Anal. Found: C, 56.13; H, 4.14%. C8H7ClO2 requires C, 56.33; H, 4.14%.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:25]=[CH:24][C:18]2[NH:19][C:20]([CH2:22]Cl)=[N:21][C:17]=2[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:25]=[CH:24][C:18]2[NH:19][C:20]([CH2:22][O:34][C:31]3[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:33][CH:32]=3)=[N:21][C:17]=2[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2[nH]c(CCl)nc2c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Yield: 30.6 %

Procedure:
A mixture of N-tert-butyl-2-(2-chloromethyl-1H-benzoimidazol-5-yl)benzenesulfonamide (100 mg, 0.26 mmol), α,α,α-trifluoro-p-cresol (43.0 mg, 0.26 mmol), Na2CO3 (28.1 mg, 0.26 mmol), Cs2CO3 (86.5 mg, 0.26 mmol), and catalytic KI (1.5 mg, 0.009 mmol) in acetone (2 mL) was refluxed for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, EtOAc: hexanes, 1:1) to afford the title compound as an off-white solid (40.1 mg, 30% yield). Calcd. For C25H24F3N3O3S: 504.54 (M+H), Found 504.2.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:22]#[N:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:29][CH2:28]1)[C:22]#[N:23]
Reactant: N#Cc1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 90 °C
Yield: 70.2 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-4-(piperazin-1-yl)benzonitrile hydrochloride (118 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propionitrile (2 ml) and heated in a closed vial at 90° C. for 2 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo and purified using flash column chromatography on silica gel (80 g SiO2, dichloromethane-methanol 100:0-95:5). The resulting solid was suspended in ether (7 mL), stirred until a fine suspension resulted, filtered and the solid was dried in vacuum to afford (S)-3-chloro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile (135.4 mg, 0.320 mmol, 70.2% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.80-2.03 (m, 3 H) 2.10-2.25 (m, 1 H) 2.39-2.61 (m, 4 H) 2.94-3.19 (m, 4 H) 3.35-3.46 (m, 3 H) 3.51-3.65 (m, 1 H) 3.91-4.05 (m, 1 H) 6.97 (d, J=1.77 Hz, 1 H) 7.22 (d, J=8.59 Hz, 1 H) 7.62 (d, J=1.52 Hz, 1 H) 7.74 (dd, J=8.46, 1.89 Hz, 1 H) 7.93 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C22H23ClN6O, 423; found, 423. melting point 213-215° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:7](O)/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[C:1]([O:6][CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCCC/C=C/CO
Reactant: CC(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CCCCCC/C=C/COC(=O)C(C)C
Yield: 64.2 %

Procedure:
Isobutyric acid (22.0 g, 0.25 mole), trans-2-nonen-1-ol (44.3 g, 0.25 mole), xylene (100 ml) and p-toluenesulfonic acid are heated to 145°C. The solution is refluxed for 5 minutes and 4.5 ml water is collected by distillation. The reaction mixture is cooled and first washed with water followed by 5% sodium carbonate. The washed solution is dried over sodium sulfate and distilled to yield 34.1 g of trans-2-nonenyl isobutyrate, b.p. 87° - 88°C/0.5 mm. An analytical sample is obtained for taste evaluation using gas chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.C(O)CCC.C(N(CC)CC)C.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:1][C:2]1[C:7]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:6][CH:5]=[N:4][C:3]=1[Cl:9]
Reactant: NCc1ccccc1
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1c(Cl)ncnc1NCc1ccccc1
Temperature: 100 °C
Yield: 96.1 %

Procedure:
To a solution of 5-amino-4,6-dichloropyrimidine (8.4 g, 0.051 mol) in 1-butanol (50.0 mL, 0.547 mol) was added triethylamine (12 mL, 0.084 mol) and benzylamine (17 mL, 0.15 mol), and the mixture was heated at 100° C. for 3 hours. The reaction was cooled at 0 C, filtered and washed with ethanol. The residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3, and concentrated. The residue was triturated in diethyl ether to obtain 11.5 g (96%) of a light brown solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[Cl:11].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C=O)C.O>[Cl:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH2:2][N:16]1[C:12](=[O:22])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]1=[O:17])[CH:7]=[O:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=Cc1ccc(CBr)c(Cl)c1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Temperature: 60 °C
Yield: 66.7 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (3.8 g, 14 mmol) in DMF (40 mL) was added potassium pthalimide (3.54 g, 19.14 mmol), and the mixture was heated at 60° C. for 6 h. The reaction mixture was cooled to ambient temperature and diluted with H2O (100 mL). The solid obtained was separated by filtration and dried under vacuum to afford the title compound as a white solid (2.8 g, 60%): mp 123-126° C.; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s, 2H); ESIMS m/z 298.03 ([M−H]−).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:4][C@H:3]1[NH:33]C(=O)OC(C)(C)C.CCN([CH:47]([CH3:49])C)C(C)C.[C:50]([O-])([OH:52])=[O:51].[Na+]>C(Cl)Cl>[NH2:33][C@@H:3]1[CH2:4][C@H:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[N:18]=2)[CH2:6][C@H:7]([CH3:8])[C@@H:2]1[NH:1][C:50](=[O:51])[O:52][CH2:47][CH3:49]
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N[C@@H]1[C@H](N)C[C@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H]1C
Yield: 14 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-2-amino-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexylcarbamate (1.0 equiv.) in CH2Cl2 (0.03 M) at 0° C. was added DIEA (3.0 equiv.) and then ETHYL CHLOFORMATE (1.0 equiv.). The homogeneous solution was left standing at 0° C. at for 4 hrs. Neutralize the reaction with sat. NaHCO3 solution. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography. The Boc protected product was treated with 25% TFA/CH2Cl2 for 20 minutes at which time the volatiles were removed in vacuo and the residue was dissolved in DMSO and purified by RP-HPLC. The product fractions were lyophilized directly to yield ethyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamate in 14% yield. LC/MS (m/z)=528.2 (MH+), Rt=0.65 min.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[CH3:21][C:22]1([CH3:27])[CH2:26][CH2:25][NH:24][CH2:23]1>O.C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:16]([O:20][C:2]1[C:7]([F:8])=[C:6]([N:24]2[CH2:25][CH2:26][C:22]([CH3:27])([CH3:21])[CH2:23]2)[N:5]=[CH:4][N:3]=1)[C:17]#[C:18][CH3:19]
Reactant: Fc1ncnc(F)c1F
Reactant: CC1(C)CCNC1
Reactant: CC#CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC#CCOc1ncnc(N2CCC(C)(C)C2)c1F
Temperature: 30 °C

Procedure:
To a mixture obtained by adding 110.0 g of 4,5,6-trifluoropyrimidine, 114.6 g of potassium carbonate and 16.6 g of triethylamine to 220.0 g of toluene, 60.4 g of 2-butyn-1-ol is added dropwise at 25 to 30° C. over one hour, followed by stirring at 30° C. Then, 220.0 g of water is added dropwise into the reaction mixture, followed by stirring. Then, 85.4 g of 3,3-dimethylpyrrolidine is added dropwise and, after the mixture is stirred at 30° C., the reaction mixture is allowed to stand. After separating into the organic layer and the aqueous layer, the aqueous layer is removed and the organic layer is washed once with 220.0 g of 5% hydrochloric acid and then washed once with 220.0 g of water. The organic layer is concentrated to obtain 4-(2-butynyloxy)-5-fluoro-6-(3,3-dimethylpyrrolidin-1-yl)pyrimidine (hereinafter referred to as the present compound (1)).