Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.C(N(CC)CC)C.ClC(OCC)=O.[NH2:26][CH2:27][CH2:28][C:29]1[CH:43]=[CH:42][C:32]([O:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1>O1CCCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:33][C:34]([CH3:40])([CH3:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:42][CH:43]=1)=[O:8]
Reactant: O=C(O)C=Cc1ccccc1Cl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)C=Cc2ccccc2Cl)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a mixture of 11.50 g. (63 mMol) o-chlorocinnamic acid, 200 ml. anhydrous tetrahydrofuran and 6.38 g. (63 mMol) anhydrous triethylamine, there are added dropwise at -15° C., 7.50 g. (69 mMol) ethyl chloroformate. The reaction mixture is then stirred for 15 minutes at -15° C. Subsequently, a solution of 15.80 g. (63 mMol) ethyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionate in 50 ml. anhydrous tetrahydrofuran is added dropwise thereto and the reaction mixture is stirred for a further 2 hours at -10° C. and then left to stand for a day at ambient temperature. Thereafter, the tetrahydrofuran is distilled off in a vacuum and the residue is taken up in methylene chloride. The methylene chloride phase is extracted with 0.5 N aqueous sodium hydroxide solution, filtered, dried over anhydrous sodium sulphate and evaporated. After recrystallization of the residue from a mixture of ligroin and acetone (30:5 v/v), there is obtained, in a yield of 65% of theory, ethyl 2-{4-[2-(2-chlorocinnamoylamino)-ethyl]-phenoxy}-2-methylpropionate, which melts at 76° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][C:9](OCC)=[O:10])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:3]=1[C:20]#[N:21].[Li]CCCC.O>C1COCC1>[O:10]=[C:9]1[CH2:8][CH2:7][N:6]2[N:5]=[C:4]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:3]([C:20]#[N:21])=[C:2]2[NH:1]1
Reactant: CCOC(=O)CCn1nc(-c2cccnc2)c(C#N)c1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(-c2cccnc2)nn2c1NC(=O)CC2
Temperature: -60 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 3-(5-amino-4-cyano-3-(pyridine-3-yl)-1H-pyrazol-1-yl)propanoate (213 mg, 0.75 mmol) in THF (5 mL) was added n-BuLi (0.6 mL, 1.49 mmol) at −60° C. The resulting mixture was stirred at −60° C. for 3 hours. 2 mL of water was added to quench the reaction and the THF was removed in vacuo. The residue was purified by HPLC to afford the desired product: MS (m/z): 240.1 [M+H]+, 1H NMR (DMSO, 400 MHz): δ11.79 (s, 1 H), 8.99 (s, 1 H), 8.65 (d, 1 H, J=5.2 Hz), 8.17 (d, 1 H, J=8.4 Hz), 7.57 (dd, 1 H, J=8.4 Hz, J=5.2 Hz), 4.38 (t, 2 H, J=7.6 Hz), 2.89 (t, 2 H, J=7.6 Hz).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:5]=1[CH2:6][O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C@H:11]1[CH2:23][CH3:24])=[O:9].[CH3:30]I.[ClH:32]>CN(C=O)C>[ClH:32].[F:3][C:4]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:5]=1[CH2:6][O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]1[CH2:23][CH3:24])=[O:9]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(O)ccc1F
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H]1CNCCN1C(=O)OCc1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A mixture of 6.27 mg (0.157 mmol) NaH (60% suspension in mineral oil) and 40 mg (0.105 mmol) (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2-fluoro-5-hydroxy-benzyl) ester in 1 ml DMF was stirred for 30 min at room temperature under argon. 16.4 mg (0.115 mmol) methyliodide was added and the mixture was stirred 30 min at room temperature. After addition of 60 ul HCl (37%) the mixture was purified with preparative HPLC eluting with an acetonitrile/water gradient. The fractions containing the desired intermediate were combined and 0.05 ml HCl (37%) was added before evaporation to dryness. The residue was taken up in 1 ml dioxane and 0.15 ml HCl (37%) and stirred for 30 min at 60° C. Evaporation of the mixture yielded 20 mg (57%) of the title compound. MS (ISP): 297 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(O)C.Cl.[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]Br)=[CH:30][CH:29]=1>O1CCCC1>[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])=[CH:30][CH:29]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cccc(-c2ccc(OCCCCCCCCCCCBr)cc2)c1F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(=O)OCC
Yield: 84.7 %

Procedure:
First, 0.62 g of sodium ethoxide, 1.5 g of diethyl malonate, and 50 ml of dry ethanol were placed in a 100 ml flask whose content was replaced with argon. Then, 20 ml of tetrahydrofuran solution in which 4 g of 2,3-difluoro-4'-(11-bromoundecyl)oxybiphenyl was dissolved was added dropwise to the reaction mixture, and the resultant reaction mixture was stirred under reflux for 8 hours. The reaction mixture was poured into diluted hydrochloric acid, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 4 g of 2,3-difluoro-4'-[12,12-bis(ethoxycarbonyl)dodecyl]oxybiphenyl (Y: 84.7%). The compound thus obtained had a purity of 99.8% by GC.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[Cu](C#N)[C:17]#[N:18]>CN(C)C=O>[C:17]([C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[CH:4][N:3]=1)#[N:18]
Reactant: N#C[Cu]C#N
Reactant: N#Cc1cccc(-c2cc(Cl)ncn2)c1
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2cc(C#N)ncn2)c1

Procedure:
4-chloro-6-(3-cyanophenyl)-pyrimidine is reacted with copper cyanide in boiling N,N-dimethylformamide to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=O)=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]2[NH:15][C:11]3=[N:10][C:9]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[F:1])[CH:13]=[C:12]3[N:14]=2)=[CH:25][CH:24]=1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Fc1ccc(-c2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Temperature: 140 °C
Reaction time: 48 h
Yield: 65.3 %

Procedure:
3″-Fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1,158 mg, 0.56 mmol), 4-fluorobenzoyl chloride (73.0 μL, 0.62 mmol) and pyridine (ca. 4 mL) were placed in a sealed tube. The solution was initially heated at 140° C. for 48 h and afterwards, at 160° C. for another 48 h. Then, the reaction mixture was cooled to room temperature, the pyridine was removed in vacuo, and the crude oil was purified by flash column chromatography (CH2Cl2/EtOH, 95:5) affording the title compound as a white solid (141 mg, 65%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(#N)C>[CH2:12]([O:11][P:7]([CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(CCNCCO)OCC
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(CCO)CCP(=O)(OCC)OCC
Temperature: -10 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
The mixture of diethyl 2-(2-hydroxyethylamino)ethylphosphonate (6 g, 26.7 mmol) and K2CO3 (3.7 g, 26.7 mmol) in dry acetonitrile (80 ml) was cooled to −10° C. and ethyl bromoacetate (6.7 g, 40 mmol) was added. The reaction mixture was stirred at −10° C. for 1 h and then at room temperature for 2 days. The solvent was then removed by evaporation. Water and CHCl3 were added, the organic layer separated, washed with brine and dried over anhydrous MgSO4. After filtration, solvent was evaporated and the residue was purified by column chromatography on silica gel (CHCl3-MeOH), the ethyl 2-((2-(diethoxyphosphoryl)ethyl)(2-hydroxyethyl)amino)acetate was obtained in 64% yield (5.32g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:27][C:28]([OH:30])=[O:29]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][C:28]([OH:30])=[O:29])=[CH:4][CH:3]=1
Reactant: O=C(O)CBr
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2F)CC1
Product: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:36][NH:37][C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])[C:10](=O)[CH2:11][C@H:12]1[N:15]([C:16](=O)[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[C:14](=[O:24])[C@@H:13]1[C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH3:26])=[O:6])[CH:2]=[CH2:3].P(OCC)(OCC)OCC.C1(C=CC(O)=CC=1)O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([C:10]1[CH2:11][C@H:12]2[N:15]([C:14](=[O:24])[C@@H:13]2[C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:30])[CH3:29])[CH3:26])[C:16]=1[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:36][NH:37][C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(=O)C(=O)OCC=C
Agent: CCOP(OCC)OCC
Agent: Oc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)NCC(CNC(=O)OCC=C)C1=C(C(=O)OCC=C)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2C1
Temperature: 130 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
A solution of 0.48 g of allyl 2-[(3S,4R)-4-(4-allyloxycarbonylamino-3-(N-allyloxycarbonylaminomethyl)-2-oxobutyl]-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-oxoazetidin-1-yl]-2-oxoacetate and 0.39 ml of triethyl phosphite in 2.4 ml of toluene was stirred at 90° C. for 10 hours. After ylid was identified by thin layer chromatography the temperature was raised to 130° C. and 42 mg of hydroquinone was added. After stirring for 4 hours at 130° C., the reaction mixture was cooled to room temperature and then ethyl acetate was added. The organic layer was washed in turn with 5% aqueous potassium carbonate and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel to give 0.28 g of allyl (5R,6S)-3-[2-allyloxycarbonylamino-1-(N-allyloxycarbonylaminomethyl)ethyl]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[CH2:7][C:6]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1Cl>[O:11]=[C:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[CH:7]=[C:6]2[S:1][CH2:2][CH2:3][CH2:4][N:5]12
Reactant: O=C1Cc2ccccc2C(=O)N1CCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Product: O=c1c2ccccc2cc2n1CCCS2

Procedure:
A mixture of 112 mg. of N-(3-mercaptopropyl)homophthalimide, 172 mg. of p-toluenesulfonic acid, and 4 ml. of o-dichlorobenzene was heated to 120° C. for 30 minutes. After cooling the reaction mixture, the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was extracted with 50 ml. of benzene. The extract was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. By recrystallizing the residue thus obtained from isopropyl alcohol, 70 mg. of 6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16].C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16])=[O:25]
Reactant: [O-][n+]1ccccc1SCc1ccccc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(Cc1ccccc1F)c1cccc[n+]1[O-]

Procedure:
The procedure employed is identical to that of Example 68 using 5.7 gm (0.024 mol) 2-(2-fluorophenylmethylthio)pyridine N-oxide in 50 ml of chloroform with 4.8 gm (0.024 mol) MCPBA in 75 ml chloroform.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C@@:12]1([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30](=[O:33])[N:29]([CH3:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH3:20])[CH2:14][CH2:13]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC#N>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C@:12]2([CH2:11][CH2:10][CH2:9][OH:8])[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30](=[O:33])[N:29]([CH3:34])[CH:28]=4)=[CH:23][CH:22]=3)[CH3:20])[CH2:14][CH2:13]2)=[CH:36][CH:37]=1
Reactant: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Yield: 3.1 %

Procedure:
A mixture of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (200 mg, 0.35 mmol) and TBAF (182 mg, 0.7 mmol) in CH3CN was stirred and heated to reflux for 15 min. When the reaction was over, the mixture was washed with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude product, which was purified by preparative HPLC to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (5.01 mg, 4%). LC-MS Method 2 tR=1.065 min, m/z=464.21; 1H NMR (CDCl3): δ=1.38 (m, 1H), 1.47 (d, 3H), 1.63 (m, 2H), 1.91 (m, 2H), 2.10-2.30 (m, 3H), 2.87 (m, 1H), 2.84 (m, 1H), 3.51 (m, 2H), 3.56 (s, 3H), 5.63 (m, 1H), 6.67 (m, 1H), 6.87-6.98 (m, 4H), 7.15 (m, 2H), 7.27 (m, 1H), 7.29 (m, 1H), 7.32 (m, 1H), 7.55 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH:6]=[C:7]([C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=1)[CH2:8]2.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([OH:34])[CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2.[H-].[Na+].CS(C)=O>CCO.O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([O:34][CH2:2][CH2:3][N:4]3[CH:9]4[CH2:10][CH2:11][CH:5]3[CH:6]=[C:7]([C:12]3[CH:21]=[CH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[CH:13]=3)[CH2:8]4)[CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2
Reactant: ClCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Reactant: COc1cc(O)c2ncccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCO
Product: COc1cc(OCCN2C3C=C(c4ccc5ccccc5c4)CC2CC3)c2ncccc2c1
Yield: 38 %

Procedure:
8-(2-Chloroethyl)-3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-2-ene (0.50 g, 1.70 mmol), 0.39 g (2.20 mmol) 6-methoxyquinolin-8-ol, 0.08 g (2.00 mmol) NaH (60% dispersion in mineral oil) and 3 mL DMSO are stirred at 50 C for 16 h. The reaction mixture is poured into 100 mL of H2O and extracted with 3×50 mL EtOAc. The combined organics are washed with 3×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered, and the volatiles are evaporated. The crude product is subjected to flash chromatography on SiO2 gel, eluting with EtOAc and then 40/1 EtOAc/2M NH3 in MeOH, to produce an off-white solid. This solid is treated with 0.06 g (0.67 mmol) (CO2H)2 in 4 mL of absolute EtOH to give 0.33 g (0.13 mmol, a 38% yield) of the oxalate salt of the title compound as a white solid. mp: 100-103° C.; MS (ES) m/z 437 (MH)+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]=[C:12]2[CH3:15])=[CH:7][CH:6]=1.Cl>CO>[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH:12]2[CH3:15])=[CH:7][CH:6]=1
Reactant: COc1ccc2c(c1)C(C)=NCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)C(C)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Sodium borohydride (3.81 g, 100.8 mmol) was slowly added at 0° C. to a solution of 7-methoxy-1-methyl-3,4-dihydroisoquinoline (14.72 g, 84 mmol) prepared in Step 2 in anhydrous methanol (100 ml). The reaction mixture was stirred overnight at room temperature. 1N hydrochloric acid was added to the reaction mixture, which was concentrated under reduced pressure, basified with potassium hydroxide, and then extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 11.01 g of the titled compound as brown oil. (Yield: 74%) The product was used in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]I)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:21])[CH:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:16])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:15]([CH3:16])([S:17]([CH3:20])(=[O:18])=[O:19])[C:14]([O:13][CH2:11][CH3:12])=[O:21])=[CH:4][CH:3]=1
Reactant: Brc1ccc(CCI)cc1
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(CCc1ccc(Br)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A suspension of 1-bromo-4-(2-iodo-ethyl)-benzene (25.0 g, 80 mmol) and (+/−)-2-methanesulfonyl-propionic acid ethyl ester (15.9 g, 88.4 mmol) in DMF (100 mL) with solid Cs2CO3 (52.4 g, 161 mmol) was stirred overnight at room temperature. After 16 hours the reaction was poured into water (500 mL). The resulting suspension was stirred for 2 h. The mixture was extracted with diethylether (2×). The organic layers were combined and washed with water then brine, dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate 9:1-8:2) afforded the title compound as a white solid (21.0 g, 72%). 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.22 Hz, 3H) 1.70 (s, 3H) 2.14-2.24 (m, 1H) 2.42-2.55 (m, 2H) 2.68-2.78 (m, 1H) 3.04 (s, 3H) 4.25-4.31 (m, 2H) 7.07 (d, J=8.20 Hz, 2H) 7.43 (d, J=8.20 Hz, 2H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:20]([N:19]([CH3:18])[C:15]([C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:14][CH2:13]1)=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture comprising 500 mg of trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid, 250 mg of N-methyl-benzylamine, 434 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 306 mg of 1-hydroxybenzotriazol and 5 ml of N,N-dimethylformamide was stirred at room temperature for 15 hours. The reaction mixture was made basic by adding an aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and then, the solvent was removed under reduced pressure to obtain 691 mg of N-benzyl-trans-4-tert-butoxycarbonylamino-N-methylcyclohexanecarboxamide. A mixture comprising 670 mg of this compound, 5 mL of 4N-hydrochloric acid-dioxane and 5 ml of dioxane was stirred at room temperature for 12 hours. The reaction mixture was concentrated to obtain 585 mg of trans-4-amino-N-benzyl-N-methylcyclohexanecarboxamide hydrochloride (Reference Example 11-1 in Table 7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](OC)=[CH:5][C:4]=1[C:11](=[O:29])[CH2:12][N:13]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:14]1.N1C=CC=C(C2C=C([C:41](OCC)=[O:42])NN=2)C=1.BrCC(C1C=CC(OC)=CC=1OC)=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:42][CH3:41])[CH:6]=[CH:5][C:4]=1[C:11](=[O:29])[CH2:12][N:13]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:14]1
Reactant: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Reactant: CCOC(=O)c1cc(-c2cccnc2)n[nH]1
Agent: COc1ccc(C(=O)CBr)c(OC)c1
Product: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1ccc(OC)cc1OC

Procedure:
This compound was made in an analogous fashion to ethyl 1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate using ethyl 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate and 2-bromo-1-(2,4-dimethoxyphenyl)ethanone (purchased from Aldrich). 1H-NMR δ 9.08 (s, 1H), 8.58 (d, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.33 (m, 11-1), 7.27 (s, 1H), 6.58 (dd, 1H), 6.49 (d, 1H), 5.98 (s, 2H), 4.31 (q, 2H), 4.00, (s, 3H), 3.88 (s, 3H), 1.34 (t, 3H). Calculated mass for C21H21N3O5, 395.15, observed, 396.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:6]([S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[NH:4][C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].ClC1C=C(C=CC=1)C(OO)=[O:31].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[C:6]([S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[C:5]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[NH:4][C:3]=1[S:21]([C:22]([F:25])([F:24])[F:23])=[O:31]
Reactant: O=S(=O)(c1c(-c2ccc(Cl)cc2)[nH]c(SC(F)(F)F)c1Br)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=S(c1[nH]c(-c2ccc(Cl)cc2)c(S(=O)(=O)C(F)(F)F)c1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A solution of 3-bromo-5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]-2-[(trifluoromethyl)thio]pyrrole (0.4 g, 0.00082 mol) in chloroform (5 mL) is cooled with an ice bath, treated with a solution of 3-chloroperoxybenzoic acid (0.24 g, 60%, 0.00082 mol) in chloroform (10 mL), stirred for two hours, warmed to room temperature and stirred overnight. The reaction mixture is treated with saturated sodium metabisulfite solution, diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. The residue is placed on a prep plate and eluted with a 1:2 ethyl acetate/hexanes solution to give the title product as a white solid (0.25 g, mp 120°-170° C.) which is identified by 1HNMR spectral analysis.