Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](OC)=[CH:16][CH:15]=3)[C:11](=[O:22])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[CH3:29]C([O-])(C)C.[K+].[C:35](OC)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1(C)C=CC=CC=1>[C:35]([C@@H:10]1[CH2:9][CH:8]([CH2:7][C:4]2[CH:5]=[CH:6][C:1]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:2][CH:3]=2)[N:12](/[CH:13]=[CH:14]/[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:29]=2)[C:11]1=[O:22])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(CN2C(=O)CC[C@H]2Cc2ccc(-c3ccccc3)cc2)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-5-Biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (3a, R1=styryl) (1.00 g, 2.8 mmol) is heated to dissolve in 3 mL of anhydrous toluene under N2, add t-BuOK (0.43 g, 3.7 mmol) in one portion, stir at this temperature for 10 min, then add methyl benzoate dropwise, the reaction mixture reflux overnight, cool to room temperature, quench with saturated NH4Cl aqueous solution, separate the organic phase, extract with toluene (30 mL*3), the combined organic extracts are washed with saturated Na2CO3 aqueous solution and brine, dry over anhydrous Na2SO4 and concentrate under vacuum. The residue is purified by silica gel column chromatography, eluting with 5:1 heptane/ethyl acetate to obtain (S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl), the ratio of (3S,5S) to (3R,5S) is 70:30 as determine by HPLC. Spectroscopic data as Example 8, Method 1.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:8]3[C:9](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(-c3ccc(Cl)cc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(4-chlorobenzoyl)-5-methoxybenzoic acid unpurified with hydrazine hydrate.
Reaction SMILES: [CH2:1]([C:3]1[S:21][C:6]2[NH:7][C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:40]=[C:39](C(Cl)(Cl)Cl)[O:38][N:37]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-:46].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:21][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:46])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:20])[N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCc1cc2c(=O)n(CCc3ccccc3)c(=O)[nH]c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A mixture of 6-ethyl-3-(2-phenylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.25 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.43 g), potassium carbonate (0.14 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from acetone-diethyl ether to give the title compound as colorless crystals (0.17 g, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].O.[CH:13](O)=[O:14]>>[CH:13]([NH:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[Br:1])=[O:14]
Reactant: O=CO
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Solvent: O
Product: O=CNc1cc([N+](=O)[O-])ccc1Br
Yield: 98 %

Procedure:
A solution of 2-bromo-5-nitroaniline (5.27 g, 24.3 mmol) in 98% formic acid (30 ml) was heated to reflux for 90 min under nitrogen. The cooled reaction mixture was then poured into cold water (600 ml) which afforded a yellow precipitate. The solid was isolated by filtration and the cake washed with cold water (2×200 ml). Subsequent drying overnight under vacuum overnight afforded N-formyl-2-bromo-5-nitroaniline (5.84 g, 98%) as a yellow solid: 1H NMR (DMSO-d6) δ 10.14 (br s, 1H), 9.01 (d, J=2.4 Hz, 1H), 8.46 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.91 (dd, J=8.8, 2.5 Hz, 1H); 13C NMR (DMSO-d6) δ 161.2, 146.9, 136.6, 134.0, 120.6, 119.8, 116.7.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][C:16](C(O)=O)([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(OP(OC2C=CC=CC=2)([N:32]=[N+]=[N-])=O)=CC=1.C(N(CC)CC)C.[Si](O[K])(C)(C)C>C1(C)C=CC=CC=1.C1COCC1>[NH2:32][C:16]12[CH2:19][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([CH2:18][CH2:17]1)[CH2:13][CH2:14][CH2:15]2
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(NC12CCCC(C(=O)O)(CC1)C2)OCc1ccccc1
Agent: C[Si](C)(C)O[K]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC12CCCC(NC(=O)OCc3ccccc3)(CC1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A mixture of 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylic acid (8.5 g, 28.0 mmol), diphenylphosphonic azide (9.3 g, 33.8 mmol) and triethylamine (5 mL, 68 mmol) in toluene (150 mL) was stirred at room temperature for one hour, and then refluxed for three hours. After cooled to 0° C., a solution of TMSOK (10.7 g, 83.6 mmol) in THF (85 mL) was added. The reaction mixture was warmed to room temperature and stirred for 1 h, and then quenched with 5% citric acid (20 mL) and concentrated under reduced pressure. The residue was treated with aq. HCl (2 N, 200 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×100 mL). The aqueous phase was adjusted to pH 9˜10 with Na2CO3 and extracted with dichloromethane/methanol (10/1, 3×150 mL). The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to afford 5.13 g (42%) of benzyl 5-aminobicyclo[3.2.1]octan-1-ylcarbamate as a yellow solid. ESI-MS m/z: 275 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([O:33][C:34]4[CH:42]=[CH:41][CH:40]=[C:39]5[C:35]=4[CH:36]=[N:37][N:38]5[C:43]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([O:33][C:34]4[CH:42]=[CH:41][CH:40]=[C:39]5[C:35]=4[CH:36]=[N:37][N:38]5[C:43]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[CH:24]=3)[CH2:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of EXAMPLE 521G (2.51 g) in tetrahydrofuran (30 mL) and methanol (10 mL) was added lithium hydroxide (1.0M, 10 mL) and the solution heated to 60° C. After 4 hours the reaction was cooled, diluted with dichloromethane (150 mL) and quenched with 1N aqueous HCl (10 mL) and water (30 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 120 g) eluting with a gradient of 0.25% to 2.5% methanol/dichloromethane over 40 minutes gave the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH2:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]#[CH:13].C(NC(C)C)(C)C.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.O1CCOCC1>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[N+:8]([C:4]1[CH:3]=[C:2]([C:13]#[C:12][CH2:11][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC#Cc1cccc([N+](=O)[O-])c1
Temperature: 45 °C

Procedure:
To an oven dried, argon filed, flask was added 1-bromo-3-nitrobenzene (14) (3.09 g, 15.3 mmol), tert-butyl prop-2-ynylcarbamate (15) (2.8 g, 18.0 mmol), diisopropylamine (92.5 ml, 17.8 mmol), CuI (0.054 g, 0.18 mmol), PdCl2(PPh3)2 (0.42 g, 0.6 mmol) and dioxane (17 ml). The resulting mixture was purged with argon three times and then a solution of t-Bu3P-dioxane solution (0.9 ml, 0.9 mmol) was added. The mixture was heated at 45° C. for 15 h, cooled to room temperature, diluted with ethyl acetate, filtered through celite and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave tert-butyl 3-(3-nitrophenyl)prop-2-ynylcarbamate (16) as colorless oil. Yield (4.98 g, 100%); 1H NMR (400 MHz, CDCl3) δ 8.25 (t, J=1.6 Hz, 1H), 8.15 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 7.69 (dt, J=7.6, 0.8 Hz, 1H), 4.78 (br s, 1H), 4.16 (d, J=5.6 Hz, 2H), 1.47 (s, 9H).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:22]=[CH:21][C:9]([CH2:10][C:11]2[S:12][C:13](/[CH:16]=[CH:17]/[N+:18]([O-:20])=[O:19])=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.C(O)(=O)C.[BH4-].[Na+]>O>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][C:11]2[S:12][C:13]([CH2:16][CH2:17][N+:18]([O-:20])=[O:19])=[CH:14][CH:15]=2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(Cc2ccc(/C=C/[N+](=O)[O-])s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(Cc2ccc(CC[N+](=O)[O-])s2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.4 %

Procedure:
To a dimethyl sulfoxide (20.0 mL) solution of 2-(4-methyl-benzyl)-5-((E)-2-nitro-vinyl)-thiophene (1.20 g, 4.63 mmol) described in Manufacturing Example 92-1-3 and acetic acid (1.20 mL) was added sodium borohydride (280 mg, 7.41 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 20 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was crystallized with a tetrahydrofuran-ethyl acetate-heptane system and filtered to obtain the title compound (525 mg, 43.4%).
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[C:8]=2[Cl:11])[C:3]1=O.BrC1CC2C(=CC=CC=2F)C1=[O:25].ClC1C(Cl)=CC=C2C=1CCC2=O>[Cu](Br)Br.O1CCOCC1>[Br:1][CH:2]1[CH2:3][C:4]2[C:9](=[C:8]([Cl:11])[C:7]([Cl:12])=[CH:6][CH:5]=2)[C:10]1=[O:25]
Reactant: O=C1c2cccc(F)c2CC1Br
Reactant: O=C1c2ccc(Cl)c(Cl)c2CC1Br
Agent: Br[Cu]Br
Agent: O=C1CCc2c1ccc(Cl)c2Cl
Solvent: C1COCCO1
Product: O=C1c2c(ccc(Cl)c2Cl)CC1Br

Procedure:
The 2-bromo-4,5-dichloro-1-indanone can be prepared as in Example 14 for the preparation of 2-bromo-4-fluoro-1-indanone but starting with 12.67 g of 4,5-dichloro-1-indanone, 37.3 g of copper bromide and 400 ml of dioxane. 16.79 g of 2-bromo-6,7-dichloro-1-indanone are thus obtained which melt at 131° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[C:16]([F:23])[CH:15]=1.Cl.CN(C)CCCN=C=NCC>C(O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[O:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[N:1]=2)=[C:16]([F:23])[CH:15]=1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: Fc1cc(Br)ccc1N=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCO
Product: Fc1cc(Br)ccc1Nc1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
2-Amino-4-(trifluoromethyl)phenol (580 mg, 3.25 mmol) and 4-bromo-2-fluoro-1-isothiocyanatobenzene (750 mg, 3.25 mmol) were stirred in ethyl alcohol at ambient temperature for 18 h. The flask was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h before being heated at reflux overnight The reaction was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 N aqueous hydrochloric acid solution and water, dried (Na2SO4), and concentrated in vacuo. The crude material was suspended in ether, sonicated, and the resulting solid was collected by filtration to provide the title compound (214 mg, 18%). LC-MS m/z 375.1 (MH+), retention time 3.70 minutes.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][C:12]=1[Cl:26]>>[Cl:26][C:12]1[CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:15]([N+:1]([O-:4])=[O:2])=[CH:16][C:11]=1[Cl:10]
Reactant: CCCCCCCCCc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred and cooled (0°-5° C.) mixture of 110 parts of concentrated nitric acid solution and 314 parts of concentrated sulfuric acid solution are added dropwise 60 parts of 1,2-dichloro-4-nonylbenzene. Upon completion, stirring is continued for 30 minutes at 0° C. The reaction mixture is poured onto crushed ice and the product is extracted with 2,2'-oxybispropane. The extract is washed successively with water and a sodium hydrogen carbonate solution, dried, filtered and evaporated, yielding 70 parts (100%) of 1,2-dichloro-4-nitro-5-nonylbenzene as an oily residue.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C(O[C:25]([N:27](C)[C@@H:28]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:29](O)=[O:30])=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl.O1CCOCC1>ClCCl>[CH3:25][NH:27][C@H:28]([C:29]([NH:17][C@@H:14]1[C@@H:12]2[C@@H:11]([CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=3)[CH2:13]2)[CH2:16][CH2:15]1)=[O:30])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CN[C@@H](CC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3aR,4S,6aS)-2-(6-(Trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (95.7 mg, 0.353 mmol) was combined with (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid (101 mg, 0.388 mmol) and 1-hydroxybenzotriazole hydrate (59.4 mg, 0.388 mmol) in dichloromethane (1 mL). After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.068 mL, 0.388 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with 2×2 mL of dichloromethane. The combined extracts were applied directly to a 12 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane. The resulting oil was treated with 4 N hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) for 3 hours at room temperature. The solvent was removed under a stream of nitrogen and the residue basified with aqueous sodium bicarbonate and extracted with 2×2 mL of dichloromethane. The combined extracts were applied directly to a 12 g silica gel cartridge and purified with a gradient of 1-10% methanol in (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.36 (d, J=7.3, 1H), 7.51 (t, J=7.9, 1H), 6.98 (d, J=7.2, 1H), 6.52 (d, J=8.6, 1H), 4.45-4.35 (m, 1H), 3.74 (dd, J=10.9, 2.8, 1H), 3.62 (dd, J=10.8, 7.5, 1H), 3.52 (dd, J=10.7, 7.8, 1H), 3.29 (dd, J=10.8, 3.4, 1H), 3.24-3.18 (m, 1H), 2.79-2.64 (m, 2H), 2.42 (s, 3H), 2.14 (td, J=12.5, 7.0, 1H), 2.01-1.79 (m, 3H), 1.69 (dq, J=12.8, 8.0, 1H), 1.51 (dd, J=14.1, 6.6, 1H), 1.44-1.33 (m, 1H), 1.00 (s, 9H); MS (ESI+) m/z 413 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH3:7].Cl.[O:10]=[C:11]1[NH:15][CH2:14][CH2:13][N:12]1[CH2:16][CH2:17][NH:18][C:19]([NH2:21])=[NH:20].[C:22](=O)([O-])[O-].[Cs+].[Cs+]>CN(C(OC)OC)C.CN1C(=O)CCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:22][N:21]=[C:19]([NH:18][CH2:17][CH2:16][N:12]2[CH2:13][CH2:14][NH:15][C:11]2=[O:10])[N:20]=1
Reactant: CC(=O)c1cccs1
Reactant: N=C(N)NCCN1CCNC1=O
Reactant: O=C([O-])[O-]
Agent: COC(OC)N(C)C
Agent: Cl
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C1NCCN1CCNc1nccc(-c2cccs2)n1
Temperature: 100 °C
Yield: 69.1 %

Procedure:
1-Thiophen-2-yl-ethanone (100 mg, 0.79 mmol) was dissolved in DMF-DMA (1 mL) and heated at 100° C. for 16 h. The solution was concentrated to give a gum. This was treated with a solution of N-[2-(2-oxo-imidazolidin-1-yl)-ethyl]-guanidine hydrochloride (233 mg, 1.12 mmol) in NMP (1.5 mL), cesium carbonate (228 mg, 0.7 mmol) was added and the mixture was heated at 100° C. for 16 h. The mixture was cooled and filtered, concentrated, and purified by preparative HPLC to give the product (140 mg, 61%) as an amorphous off-white solid. MS (M+H)+ 290.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[C:20](=[C:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30]CC)=O)[CH2:23][CH2:22]3)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH2:13][CH2:12][C:11]=2[CH:33]=1)#[N:6]>O>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[C:20](=[C:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28](=[O:30])[NH:3][CH2:2][CH2:1][NH2:4])[CH2:25][CH2:26]3)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH2:13][CH2:12][C:11]=2[CH:33]=1)#[N:6]
Reactant: NCCN
Reactant: CCOC(=O)CN1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Solvent: O
Product: N#Cc1ccc2c(c1)CCc1cccnc1C2=C1CCN(CC(=O)NCCN)CC1
Reaction time: 3 h
Yield: 62 %

Procedure:
Ethylenediamine (4 ml) was added to 0.5 g of 8-cyano-11-(1-ethoxycarbonylmethyl-4-piperidylidene)6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridine, followed by stirring at 70°-80° C. for 3 hours. After the reaction, water was added and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol (20:1 - 10:1), 0.32 g of 8-cyano-11-[1-(2-aminoethylcarbamoylmethyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine was obtained (yield: 62%).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[NH:3]1.[Cl:23]CC(Cl)=O>C1C=CC=CC=1>[Cl:23][CH2:8][C:2]([NH:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])=[O:7])=[O:1]
Reactant: O=C(Cl)CCl
Reactant: O=C1COC(c2ccccc2C(F)(F)F)c2ccccc2N1
Solvent: c1ccccc1
Product: O=C(CCl)Nc1ccccc1C(=O)c1ccccc1C(F)(F)F

Procedure:
To a solution of 2-amino-2'-trifluoromethyl-benzophenone 1 [L. H. Sternbach et al. Helv. Chim. Acta., 45, 2226 (1962)](8 g) in benzene (80 ml) is added chloroacetyl chloride (29 ml), and the mixture is refluxed under heating for 30 minutes. Benzene is evaporated under reduced pressure, and the residue is washed with n-hexane to give crystalline 2-(2-chloroacetyl)amino-2'-trifluoromethylbenzophenone (10.05 g), which is recrystallized from benzene-n-hexane to give the pure crystals, mp. 79°-81° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=1.[Mn]([O-])(=O)(=O)=[O:13].[K+].[Mn]([O-])(=O)(=O)=O.[OH2:23]>>[C:1]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=1)([OH:13])=[O:23]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(=O)Nc1cc(C)ccn1
Reactant: O
Agent: [K+]
Product: CC(=O)Nc1cc(C(=O)O)ccn1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
In a 500 mL beaker fitted with a large Teflon coated magnetic stirrer bar was added 200 mL of water and 20 g (133 mmol) of 4-methyl-2-acetylaminopyridine. The solution temperature was raised to 85° C. and 46 g (291 mmol, 2.2 eq) of potassium permanganate was added portionwise over 1 h at such a rate that the solution temperature remained between 85-90° C. After permanganate addition was completed, the mixture was stirred for 30 min at 90° C. The mixture was then filtered through a bed of celite while still hot and then the filtrate volume was reduced by two thirds in vacuo. After cooling to room temperature, the mixture was again filtered through celite. The pH of the filtrate was adjusted to 4.5 with concentrated HCl. The water was removed in vacuo and the product recrystallized from water/ethanol to give 3.4 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[CH3:1][CH:2]1[NH:7][CH:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cccc(CNC(=O)OC(C)(C)C)n1
Reactant: [H][H]
Solvent: CO
Product: CC1CCCC(CNC(=O)OC(C)(C)C)N1

Procedure:
Nishimura catalyst (0.53 g) was added to a solution of tert-butyl (6-methylpyridin-2-yl)methylcarbamate (4.4 g, 0.02 mmol) in MeOH (60 mL) in a Parr Shaker high pressure vessel which was installed on Parr Shaker. The vessel was shaken under constant 5 bar hydrogen pressure for 30 min. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo to give desired product rac-tert-butyl (6-methylpiperidin-2-yl)methylcarbamate which was used for next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 3.20-3.17 (m, 1H), 3.01-2.96 (m, 1H), 2.72-2.64 (m, 2H), 1.82-1.77 (m, 1H), 1.63-1.54 (m, 2H), 1.49 (s, 9H), 1.39-1.35 (m, 2H), 1.12-0.99 (m, 5H).