Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(Cl)C=1C(C1C2C(=NC=C([C:41]3[CH:42]=[N:43][N:44]([CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:45]=3)C=2)NC=1)C>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[CH:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:41]3[CH:42]=[N:43][N:44]([CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:45]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CC(c1c(Cl)cccc1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12

Procedure:
Prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]-pyridine according to typical Suzuki coupling procedure described for synthesis of 3-[1-(2,6-Dichlorophenyl)ethyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine in example 1. MS (ES+): m/z 458.01, 460.03 [MH+]. HPLC: tR=2.34 min (ZQ3, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH2:16]([NH2:18])[CH3:17]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:18][CH2:16][CH3:17])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: CCN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Solvent: ClCCl
Product: CCNS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Yield: 97.8 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and ethylamine (2.0 mL, 2.0 M in THF, 4.00 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N-ethyl-2-(trifluoromethyl)benzenesulfonamide (0.50 g, 98%) was provided after purification. MS (ESI) m/z 332. HPLC purity 100.0% at 210-370 nm, 9.1 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: C1C2N(C(=O)CC2)C(=O)C1.O[N:12]=[C:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:14][CH2:15][C:16](O)=[O:17].[H][H]>[Rh]>[O:17]=[C:16]1[NH:12][CH:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:14][CH2:15]1
Reactant: O=C(O)CCC(CCC(=O)O)=NO
Reactant: [H][H]
Agent: [Rh]
Agent: O=C1CCC2CCC(=O)N12
Product: O=C(O)CCC1CCC(=O)N1

Procedure:
In a process for preparing dihydro-1H-pyrrolizine-3,5(2H, 6H)-dione comprising the steps of catalytically hydrogenating an ester of 4-(hydroxyimino)heptanedioic acid and subsequently cyclizing the resulting product to dihydro-1H-pyrrolizine-3,5(2H,6H)-dione, the improvement comprises reacting an alcoholic solution of a mono(lower alkyl) ester of 4-(hydroxyimino)heptanedioic acid, wherein lower alkyl comprises from one to three carbon atoms, with hydrogen gas at a temperature of about 60° C. in the presence of rhodium/alumina catalyst and a tertiary lower alkyl amine, wherein said lower alkyl amine comprises from three to nine carbon atoms, to produce 5-oxo-2-pyrrolidinepropanoic acid; and thereafter heating said 5-oxo-2-pyrrolidinepropanoic acid in the presence of a cyclizing agent selected from acetic anhydride, 2,2,6-trimethyl-1,3-dioxen-4-one, and diketene at a temperature of about 90° C. to produce dihydro-1H-pyrrolizine-3,5(2H,6H)-dione.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:18].[C:19]([Cu])#[N:20]>CN1C(=O)CCC1>[Cl:18][C:3]1[C:4]2[N:8]=[C:7]([CH2:9][CH3:10])[N:6]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:5]=2[CH:16]=[CH:17][C:2]=1[C:19]#[N:20]
Reactant: CCc1nc2c(Cl)c(Br)ccc2n1CC(F)(F)F
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCc1nc2c(Cl)c(C#N)ccc2n1CC(F)(F)F
Temperature: 220 °C
Yield: 49.2 %

Procedure:
5-Bromo-4-chloro-2-ethyl-1-(2,2,2-trifluoroethyl)-1H-benzimidazole (0.036 g, 0.106 mmol) and CuCN (0.020 g, 0.222 mmol) were combined in NMP (3 mL) and heated to 220° C. for 20 min in a microwave. The cooled mixture was partitioned between Et2O and water, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.015 g): 1NMR (400 MHz, CDCl3) δ 7.56 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.68 (q, J=8.2 Hz, 2H), 2.96 (q, J=7.4 Hz, 2H), 1.45 (t, J=7.4 Hz, 3H); MS (ESI) m/z 288 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27]CS([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][CH2:44][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][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(OC)cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: Cl
Product: COc1cc(OC)cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(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-phenyl-piperidine-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]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13]C)=O)C1C=CC=CC=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[N:35]([CH2:39][CH2:40][C:41]([NH2:44])([CH3:43])[CH3:42])[N:34]=2)=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[N:35]([CH2:39][CH2:40][C:41]([NH:44][CH2:20][CH:19]([C:16]3[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH2:11][OH:13])[CH:15]=3)[OH:25])([CH3:42])[CH3:43])[N:34]=2)=[CH:31][CH:32]=1
Reactant: Cc1nc(-c2ccc(F)cc2)nn1CCC(C)(C)N
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Product: Cc1nc(-c2ccc(F)cc2)nn1CCC(C)(C)NCC(O)c1ccc(O)c(CO)c1

Procedure:
Prepared according to general working method A from 344 mg (1 mmol) of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 262 mg (1 mmol) of 3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:9][CH:10]=3)[N:5]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4]=2[CH:3]=1.[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:9][CH:10]=3)[N:5]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: COc1ccc(-c2ccc3c4ccc(Br)cc4n(-c4ccccc4)c3c2)c(-c2ccccc2)c1
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: CCO
Product: COc1ccc(-c2ccc3c4ccc(-c5ccccc5-c5ccccc5)cc4n(-c4ccccc4)c3c2)c(-c2ccccc2)c1
Temperature: 110 °C
Yield: 57.6 %

Procedure:
A mixture of 3 g (5.9 mmol) of 2-bromo-7-(5-methoxybiphenyl-2-yl)-9-phenyl-9H-carbazole, 1.5 g (7.7 mmol) of biphenyl-2-ylboronic acid, 0.12 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium, 15 ml of 2M Na2CO3, 20 ml of EtOH and 60 ml toluene was degassed and placed under nitrogen, and then heated at 110° C. for 8 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica(hexane-dichloromethane) afforded a white solid (2 g, 3.4 mmol, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[C:5]#[N:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:9]=[C:8]([CH3:10])[CH:7]=1)#[N:6]
Reactant: Cc1cc(N)cc(C#N)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: Cc1cc(C#N)cc(NC(C)c2cc(C(=O)N(C)C)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 48.9 %

Procedure:
3-amino-5-methylbenzonitrile (108 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure similar to the one described in Example 3.03 to give 8-(1-(3-cyano-5-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (45 mg, 48%) as a white solid. Mass Spectrum: M+H+ 461.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br:13]Br>C(O)(=O)C.Br>[Br:13][CH:10]([CH3:11])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:12]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(OC)cc1
Agent: Br
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(C)Br)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
0.30 mol of 4'-methoxypropiophenone is dissolved in 230 ml of glacial acetic acid and mixed with 3 drops of 48% HBr solution. In the stirred mixture, 0.30 mol of bromine is now slowly added in drops while being cooled in an ice bath such that the temperature in the flask does not exceed 15° C. The ice bath is removed, and it is stirred for about another 45 minutes in a continuous nitrogen stream to remove the HBR that is produced in the reaction. Then, it is carefully poured onto 300 ml of ice water. The settled precipitate is suctioned off, washed with several portions of water to remove all bromine and dried in a desiccator overnight. The crude product is recrystallized from 96% ethanol.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:33]=[CH:32][C:12]([O:13][CH2:14][C:15]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:16]=3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)O1.Br[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:37]=1>>[CH3:46][O:45][C:43]([CH2:42][C:39]1[CH:40]=[CH:41][C:36]([C:9]2[CH:33]=[CH:32][C:12]([O:13][CH2:14][C:15]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:16]=3[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[CH:11][CH:10]=2)=[CH:37][CH:38]=1)=[O:44]
Reactant: CC(C)(C)OC(=O)c1cc(C(F)(F)F)ccc1COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COC(=O)Cc1ccc(Br)cc1
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)cc3C(=O)OC(C)(C)C)cc2)cc1
Yield: 52 %

Procedure:
According to a method similar to Example (8-1), from tert-butyl 2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-5-(trifluoromethyl)benzoate (100 mg, 0.21 mmol) obtained in Example (2-4) and methyl (4-bromophenyl)acetate (62 mg, 0.27 mmol) obtained in Example (3-1), tert-butyl 2-[({4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-5-(trifluoromethyl)benzoate was obtained (54 mg, yield: 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CO.ClCCl>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: NC(=O)N1CCCCC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid piperidine-amide hydrochloride to give, after chromatography on silica gel eluting sequentially with 1% methanol/dichloromethane, 1.5% methanol/dichloromethane, 2% methanol/dichloromethane, and then 2.5% methanol/dichloromethane, the title compound: Rf =0.27 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:23])[NH:8][C@H:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12]C(C)(C)C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH:1]1([NH:6][C:7](=[O:23])[NH:8][C@H:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]([OH:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)[C@H](NC(=O)NC1CCCC1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCCC1)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.2 %

Procedure:
To a stirred solution of (R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate (1.31 g, 4.10 mmol) in CH2Cl2 (25 mL) was added TFA (4 mL) and triethylsilane (1.64 mL; 10.3 mmol) dropwise, and the resulting solution was stirred at room temperature for 6 hours. The volatile components were removed under reduced pressure and the crude product was recrystallized in ethyl acetate/pentanes to yield (R)-2-(3-cyclopentylureido)-2-phenylacetic acid as a white solid (0.69 g, 64%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17-1.35 (m, 2H) 1.42-1.52 (m, 2H) 1.53-1.64 (m, 2H) 1.67-1.80 (m, 2H) 3.75-3.89 (m, 1H) 5.17 (d, J=7.93 Hz, 1H) 6.12 (d, J=7.32 Hz, 1H) 6.48 (d, J=7.93 Hz, 1H) 7.24-7.40 (m, 5H) 12.73 (s, 1H). LC-MS: Anal. Calcd. for C14H18N2O3: 262.31; found: 263.15 (M+H)+. HPLC XTERRA® C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H3PO4, B=10% water, 90% methanol, 0.2% H3PO4, RT=1.24 min, 100% homogeneity index.
Reaction SMILES: Cl.Cl.[OH:3][CH2:4][C@@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][C@@H:8]2[CH2:7][CH2:6]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:3][CH2:4][C@@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][N:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)[CH2:13][C@@H:8]2[CH2:7][CH2:6]1
Reactant: OC[C@H]1CC[C@H]2CNCCN2C1
Reactant: Clc1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OC[C@H]1CC[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Yield: 59.3 %

Procedure:
A mixture of 2.5 g (10.3 mmol) of (7S,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine dihydrochloride, 7.62 g (51.5 mmol) of 2,5-dichloropyridine, 5.45 g (51.5 mmol) of sodium carbonate and 100 mL of isoamyl alcohol was heated at reflux or 72 h. The mixture was cooled, the mixture filtered to remove solids and the solvent evaporated in vacuo. Purification by flash silica gel chromatography using 95:5 chloroform:methanol gave 1.72 g (59%) of the title compound. mp (base) 61–62° C. 13C NMR (base, CDCl3): δ 26.6, 27.2, 34.3, 45.4, 50.9, 54.6, 58.4, 60.5, 68.0, 107.7, 120.1, 137.1, 146.2, 157.5. HRMS calcd for C14H20ClN3O: 281.1295, found: 281.1298.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:19]([F:25])([F:24])C(OC)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH:19]([F:25])[F:24]
Reactant: COC(=O)C(F)(F)Cl
Reactant: O=C(CCc1ccc(O)c(Cl)c1)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(OC(F)F)c(Cl)c1)C1CCCC1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A mixture of 3-(3-chloro-4-hydroxyphenyl)-1-cyclopentylpropan-1-one (15 g, 59.35 mmol, Example B(58), Step 2)), methyl 2-chloro-2,2-difluoroacetate (17.15 g, 118.7 mmol, 2 equiv) and K2CO3 (12.4 g, 124.6 mmol, 2.1 equiv) in dry DMF (150 mL) was stirred at 75–80° C. for 2 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with aqueous 1 M NaOH and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to fractional distillation affording 15.3 g (72%) of material that was about 80% pure by 1H NMR (bp 70° C./2 Torr).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4](Cl)=[N:5][OH:6].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]=[CH2:14].C(=O)(O)[O-].[K+]>ClC1C=CC=CC=1.O>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]1[O:6][N:5]=[C:4]([C:3]([N:2]([CH3:9])[CH3:1])=[O:8])[CH2:14]1
Reactant: CN(C)C(=O)C(Cl)=NO
Reactant: C=Cc1c(F)cccc1F
Agent: O=C([O-])O
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: O
Product: CN(C)C(=O)C1=NOC(c2c(F)cccc2F)C1
Temperature: 10 °C

Procedure:
To a 1000-mL round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel were added 2-(dimethylamino)-N-hydroxy-2-oxoethanimidoyl chloride (94.0 g, 0.62 mol) and a solution of 2,6-difluorostyrene (84.0 g, 0.60 mol) in chlorobenzene (275 g). The reaction mixture was cooled to 10° C., and then a solution of potassium bicarbonate (70 g, 0.70 mol) in water (350 mL) was added dropwise over 1 h while maintaining the temperature between 10 to 15° C. When gas chromatography analysis of the reaction mixture showed about 3% of 2-(dimethylamino)-N-hydroxy-2-oxo-ethanimidoyl chloride remaining, water (200 mL) was added to the reaction mixture, and the layers were separated. The organic layer was washed with water (300 mL) and concentrated under reduced pressure. Toluene was added to the resulting residue, and the mixture was concentrated under reduced pressure to provide the title compound as an oil (144g).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.O>CCCCCCC>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)=[O:10])[CH3:12]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: COc1cc(CO)ccc1O
Solvent: CCCCCCC
Solvent: O
Product: COc1cc(COC(=O)CCCCCCC(C)C)ccc1O
Temperature: 45 °C
Reaction time: 37.5 h
Yield: 93.2 %

Procedure:
8-Methylnonanoic acid (1.65 g, 9.59 mmol), vanillyl alcohol (1.34 g, 8.70 mmol), and lipase PS-C “Amano” I (enzyme immobilized on ceramic: 335 mg) were measured and placed in a flask (25 ml). The mixture in the flask free of a plug was heated with stirring in an oil bath at 45° C. for 37.5 hours. After 2 to 3 hours of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The flask was returned to room temperature, heptane (10 ml) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The immobilized enzyme and a small amount of precipitated vanillyl alcohol were removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained oil was analyzed by HPLC to find that dihydrocapsiate was contained in 95.7 area %. The mixture was partitioned with heptane (20 ml) and 10% aqueous citric acid solution (20 ml), and the aqueous layer was further extracted with heptane (20 ml). The combined heptane layer was washed with saturated brine (15 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a mixture (2.50 g) of dihydrocapsiate and 8-methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 73.1%, and the purity was 99.3 area % by HPLC. The mixture contained 27.4 wt % of 8-methylnonanoic acid relative to dihydrocapsiate.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1.C=O.[BH3-][C:32]#N.[Na+]>CO.O>[CH3:2][N:3]([CH3:32])[CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][O:24][CH2:25][C:26]([NH2:28])=[O:27])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCC(N)=O)CC4)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCC(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-[(carbamoylmethoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (115 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (4 mL) cooled down to 0° C. was added hydrochloric acid (12 M, 0.5 mL). The resulting solution was stirred for 1 h at 0° C. and concentrated in vacuo to give 2-[[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide hydrochloride (100 mg, crude) as a light yellow solid. The crude hydrochloride (100 mg) dissolved in methanol (3 mL) was added HCHO (37%, 0.5 mL) and stirred for 1 h at 0° C. Then NaBH3CN (44.35 mg, 0.71 mmol) was added and the resulting solution was stirred for 2 h at room temperature. The reaction mixture was diluted with water, extracted with 3×20 mL of chloroform/i-PrOH. The combined organic layers were concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 53.0% in 13 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide (35 mg) as a white solid. MS (ES): m/z 405 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.44 (1H, s), 5.28-5.21 (1H, m), 3.94-3.88 (3H, m), 3.61-3.56 (2H, m), 3.14-2.97 (2H, m), 2.67-2.54 (2H, m), 2.42-2.31 (10H, m), 2.02 (2H, d), 1.62-1.43 (4H, m).