Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][CH:3]=1.[C:11]1([NH2:18])[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][CH:16]=1>>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[NH:18][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: Nc1ccccc1N
Product: Brc1cccc(-c2nc3ccccc3[nH]2)n1
Temperature: 220 °C
Yield: 65 %

Procedure:
The mixture of 6-Bromopyridine-2-carboxylic acid (2.01 g, 10 mmol) and benzene-1,2-diamine (1.08, 10 mmol) in polyphosphoric acid was heated at 220° C. for 4 h. The solution was poured into ice-water, and the formed precipitate was collected by filtration and further washed with NaHCO3 and water. After recrystallization in ethanol, the desired product was obtained in yield of 65% (1.76 g). 1H NMR (400 MHz, CDCl3, ppm): 8.31 (d, 2H, J=7.2 Hz), 8.03 (t, 1H, J=7.6 Hz), 7.63 (m, 2H), 7.24 (s, 2H). 13C NMR (100 MHz, CDCl3): 150.20, 148.63, 142.46, 139.46, 135.32, 129.87, 128.04, 124.30, 123.29, 122.92, 120.21, 110.09.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][CH3:5].[N+:8]([CH3:11])([O-:10])=[O:9]>>[CH3:5][NH:4][C:3]([S:2][CH3:1])=[CH:11][N+:8]([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: CN=C(SC)SC
Product: CNC(=C[N+](=O)[O-])SC

Procedure:
A mixture of nitromethane (3 ml), methyl carbonimidodithioic acid dimethyl ester (X, 675 mg), rare earth exchange Y-zeolite (RE 70 Na Y) (675 mg) was heated at 90°-110° C. for 72 hr. It was filtered and the solvent was removed by distillation leaving the required 1-methylamino-1-methylthio-2-nitroethene (II) as residue. m.p. 112°-114° C.
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[C:6](=[O:17])[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH:10]=1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CO>[CH2:18]([N:7]1[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH:10]=[C:5]([Br:4])[C:6]1=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=c1[nH]cc(-c2ccncn2)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1c(Br)cc(-c2ccncn2)cn1Cc1ccccc1
Temperature: 70 °C

Procedure:
A solution of sodium methoxide (1.85 g) in 100 ml DMF and 30 ml MeOH is added to a stirred, suspension of 3-bromo-5-(4-pyrimidinyl)-2(1H)-pyridone in 100 ml DMF. Benzyl chloride (3.9 ml) is added to the reaction mixture, and the mixture is heated to 70° C. for 2 hours and allowed to cool to RT overnight. The reaction mixture is filtered and the solvent evaporated in vacuo. The residue is suspended in H2O, filtered and dried. The resultant solid is dissolved in hot isopropanol, filtered through charcoal and recrystallized, yielding 1-benzyl-3-bromo-5-(4-pyrimidinyl)-2-pyridone, M.P. 189°-191.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3Cl)[CH:12]=2)[N:6]=1)=[O:4].[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH2:31])=[CH:26][CH:25]=2>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[NH:31][C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22]([CH3:21])=[CH:30]4)[CH:12]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cccc(-c2cc3nccc(Cl)c3s2)n1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: COC(=O)c1cccc(-c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)n1

Procedure:
The title compound was prepared from 6-(7-chloro-thieno[3,2-b]pyridin-2-yl)-pyridine-2-carboxylic acid methyl ester and 2-methyl-5-aminoindole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.43 (d, 1H), 8.22 (s, 1H), 8.18 (d, 1H), 8.11 (t, 1H), 8.02 (d, 1H), 7.26 (m, 2H), 6.92 (d, 1H), 6.59 (d, 1H), 6.10 (s, 1H), 3.89 (s, 3H), 2.36 (s, 3H); RP18-HPLC RT: 5.34 minutes; API MS: 415 (M+1).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]=O)[CH2:8][CH2:7]1.[OH:25][C:26]([CH3:36])([CH3:35])[CH2:27][NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C.C(OCC)(=O)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9](/[CH:13]=[C:33]2/[C:29]([NH:28][CH2:27][C:26]([OH:25])([CH3:36])[CH3:35])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: CC(C)(O)CNC1=NC(=O)SC1
Reactant: O=CC1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]azepane-4-carbaldehyde (133.2 mg) in 2-propanol (1.89 mL) were added 4-[(2-hydroxy-2-methylpropyl)amino]-1,3-thiazol-2(5H)-one (142 mg) and piperidinium acetate (54.7 mg). The reaction mixture was stirred at 60° C. overnight, cooled to room temperature, and diluted with ethyl acetate. The mixed solution was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (86.3 mg).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:11][CH:10]2[CH2:12][CH:7]([CH:8]=[CH:9]2)[C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].C(O)(C)C>[CH2:1]([CH:5]1[CH2:11][CH:10]2[CH2:12][CH:7]([CH2:8][CH2:9]2)[C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCC1CC2C=CC(C2)C1=O
Agent: [Pd]
Solvent: CC(C)O
Product: CCCCC1CC2CCC(C2)C1=O
Temperature: 100 °C
Yield: 54.4 %

Procedure:
3-Butylbicyclo[3.2.1]oct-6-en-2-one (100 g, synthesized as above) was placed in a stainless steel autoclave with isopropanol (50 g) and palladium on carbon (Pd/C, 1 g). The mixture was placed under 300 psi of hydrogen gas (H2) and heated at 100° C. until gas uptake ceased. The resulting material was removed from the autoclave, filtered, and distilled to yield 3-butylbicyclo[3.2.1]octan-2-one (55 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[Cl:25][C:26]([Cl:31])([Cl:30])[C:27](Cl)=[O:28].CCOCC.O>CCOCC>[Cl:25][C:26]([Cl:31])([Cl:30])[C:27]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:28]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)c1ccccn1
Solvent: CCOCC
Solvent: O
Product: CC(C)[C@@H](C(=O)O)N(C(=O)C(Cl)(Cl)Cl)c1ccc(Cl)cc1

Procedure:
To the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine (1.19 mmole) in ether (4.5 ml), under nitrogen, is added dimethylaminopyridine (4.25 mmole) which is cooled in an ice-bath and then trichloroacetyl chloride (3.58 mmole) in ether added slowly. The reaction mixture is heated at 40° for 3 days. The reaction is worked up with ether/water. The aqueous phase is extracted with ether and then the combined ether phases are washed with water and brine and dried over sodium sulfate. The residue is subjected to prep. TLC eluting with 10% ether/hexane to yield the m-phenoxybenzyl ester of N-trichloroacetyl,N-(4-chlorophenyl)valine. MS m/e 553 (M+, 1.8), 183 (100).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:28].[Na+].OO>C1COCC1>[OH:28][CH2:3][CH2:2][CH2:1][O:4][C:5]1([CH3:18])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: [OH-]
Reactant: C=CCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(OCCCO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
To a solution of tert-butyl 4-(allyloxy)-4-methylpiperidine-1-carboxylate (8.4 g, 32.9 mmol) in THF (200 mL) at room temp was added 0.5 M solution of 9-BBN (132 mL, 65.8 mmol) and the resulting mixture was stirred at room temp for 16 h. Mixture was then cooled in an ice bath and 1N NaOH (164 mL, 164 mmol) followed by 30% H2O2 (30.2 mL, 296 mmol) were added and the mixture was stirred for 1 h. Mixture was then extracted with ethyl acetate (250 mL), washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-80% EtOAc/Hexane) to afford tert-butyl 4-(3-hydroxypropoxy)-4-methylpiperidine-1-carboxylate (6.4 g, 23.41 mmol, 71.2% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 3.84-3.79 (m, 2H), 3.74 (dt, J=13.4, 3.7 Hz, 2H), 3.57 (t, J=5.6 Hz, 2H), 3.19-3.06 (m, 2H), 1.85 (quin, J=5.6 Hz, 2H), 1.75 (d, J=13.1 Hz, 2H), 1.48 (s, 9H), 1.47-1.41 (m, 2H), 1.21 (s, 3H). LCMS (M+Na)=296.7.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Reactant: Brc1ncccn1
Product: O=C(c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1)c1ncccn1

Procedure:
This compound is prepared by method C using compound 12l and 2-bromopyrimidine
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1>Cl.O1CCOCC1.CO>[NH2:32][CH2:31][CH2:30][C:24]1([CH2:23][CH2:22][N:19]2[CH2:18][CH2:17][CH:16]([N:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[O:10])[CH2:21][CH2:20]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCNC(=O)OC(C)(C)C)CCCCC3)CC2)nc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.9 %

Procedure:
tert-Butyl [2-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethyl]carbamate (0.4760 g) was dissolved in a 4N hydrochloric acid/1,4-dioxane solution (10.0 mL) and methanol (5 mL). The solution was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to give the title compound (0.5036 g).
Reaction SMILES: [CH3:1][N:2]([CH3:52])[CH2:3][CH2:4][N:5]([CH2:49][CH2:50][OH:51])[C:6]([C@:8]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:42])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:41]=[CH:40][C:33]([C:34]([O:36]CCO)=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7].[OH-].[Na+]>O1CCOCC1.O>[CH3:52][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH2:49][CH2:50][OH:51])[C:6]([C@:8]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:42])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:41]=[CH:40][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N(CCO)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OCCO)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N(CCO)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C
Yield: 88.8 %

Procedure:
A mixture of 2-hydroxyethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)ethyl)(2-hydroxyethyl)carbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (6 mg, 8.37 μmol) and sodium hydroxide (0.042 mL, 0.042 mmol) in dioxane (1 mL) was heated up at 78° C. for 3 hours. The solution was diluted with water and filtered. The clear solution was purified by prep HPLC to provide the title compound as a white solid (5 mg, 84%). LCMS: m/e 673.58 (M+H)+, 2.08 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.55 Hz, 2H), 5.43-5.31 (m, 1H), 4.78 (d, J=1.53 Hz, 1H), 4.66 (s, 1H), 4.26-4.13 (m, 2H), 3.90-3.78 (m, 2H), 3.75-3.63 (m, 4H), 3.30 (s, 6H), 3.20-3.07 (m, 1H), 2.60-2.45 (m, 1H), 1.74 (s, 3H), 2.26-1.22 (m, 21H), 1.08 (s, 3H), 1.07 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7](O)=[O:8])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.CN(C)C1C=CN=CC=1.O>[C:1]1(=[O:21])[N:5]([CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([NH2:24])=[O:8])[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12
Reactant: O=C(O)C(c1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C(c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a stirred mixture of α-phthalimidophenylacetic acid (2.50 g, 8.89 mmoL) in tetrahydrofuran (50 mL) is added carbonyldiimidazole (1.50 g, 9.25 mmoL) and a few crystals of 4-dimethylaminopyridine. The reaction is then heated to 50° C. for 45 minutes. After the reaction mixture cools to room temperature, 1 mL of concentrated ammonium hydroxide is added via syringe. The reaction is stirred for 1 hour, then diluted with 50 mL of water and partially concentrated to remove the majority of the tetrahydrofuran. The resulting slurry is filtered and the solid washed with copious amounts of water. The solid is dried in vacuo (60° C.,<1 mm) to afford 1.9 g (76%) of α-phthalimidophenylacetamide, which may be alternatively named as N-phthaloylphenylglycinamide, as an off-white powder: mp 218-220° C.; 1H NMR (DMSO-d6)δ 9.00-7.75 (m, 4 H, Ar), 7.61 (br s, 1H, CONH2), 7.55-7.20 (m, 6H, Ar, CONH2), 5.82 (s, 1H, CHCO2); 13(1NMR (DMSO-d6)δ 168.2, 167.1, 135.6, 134.5, 131.4, 129.4, 127.9, 127.7, 123.1, 56.3. Anal (C16H12N2O3), C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:23][CH:22]2[CH2:31][C:32]([O:34]CC)=[O:33]>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[C:12]([F:15])([F:14])[F:13])[CH2:28][CH2:29]1)[CH2:23][CH:22]2[CH2:31][C:32]([OH:34])=[O:33]
Reactant: O=C(O)Cc1ccc(Cl)cc1C(F)(F)F
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Product: O=C(O)CC1CC2(CCN(C(=O)Cc3ccc(Cl)cc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 2-(4-chloro-2-(trifluoromethyl)phenyl)acetic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MS Method 1 tR=2.00, min, m/z=500.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1.[NH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C=O)C>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@@H:2]([NH:1][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11](=[O:13])[N:53]2[CH2:54][CH2:55][N:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=3)[CH2:51][CH2:52]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: C1CCC(N2CCNCC2)NC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccn2)CC1

Procedure:
N-{(1R)-1-[(4-Chlorophenyl)methyl]-2-oxo-2-(4-(2-pyridyl)piperazinyl)ethyl}(tert-butoxy)carboxamide was prepared according to the procedure for Preparation XIX using Boc-p-Cl-D-Phe-OH (550 mg, 1.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (1.1 g, 3.80 mmol), HOAT (260 mg, 1.9 mmol), DMF (15 mL), and 1-(2-piperidyl)piperazine (280 μl, 1.8 mmol) (Aldrich). The crude material was concentrated in vacuo to yield 810 mg. MS (ESI, pos. ion) m/z: 445 (M+H), (ESI, neg. ion) m/z: 443 (M−H). Calc'd for C23H29ClN4O3: 444.95.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14]O>S(=O)(=O)(O)O>[C:1]1([CH:7]2[CH2:8][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)C1CC(c2ccccc2)C1
Agent: O=S(=O)(O)O
Product: COC(=O)C1CC(c2ccccc2)C1

Procedure:
A mixture of the cis and trans isomers of 3-phenylcyclobutane carboxylic acid (6.8g.) in methanol (100ml.) and concentrated sulphuric acid (0.5ml.) was refluxed overnight. The solution was concentrated to about 15ml., water was added and the mixture was extracted with ethyl acetate. The ethyl acetate extracts were combined and dried over anhydrous magnesium sulphate, the solvent was evaporated and the residue was distilled, to give methyl 3-phenylcyclobutanecarboxylate as a mixture of cis- and trans-isomers, b.p. 100°-120° C./0.2 mm. Hg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]1)=[O:4].[CH3:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1>ClCCCl.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:8][C:9]=1[N:10]([C:32]([CH:29]1[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]1)=[O:33])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NCC1CCCN(C)C1
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCCN(C)C1)C(=O)C1CCC(C)CC1
Yield: 95 %

Procedure:
3-[(1-Methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (162 mg, 0.348 mmol) was dissolved in 1,2-dichloroethane (3.0 mL) and treated with trans-4-Methyl-cyclohexanecarbonyl chloride in 1,2-dichloroethane (1.0 mL, 0.43 mol). The solution was heated at reflux for 1 day. The solvent was then evaporated and the residue purified by silica gel column chromatography using hexanes:EtOAc as eluent to provide 3-[(4-Methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester as an oil (0.194 g, 95% yield). 1H NMR (CDCl3, 400 MHz) Rotamer 65/35: 7.90 (s, 0.35H), 7.70 (d, 0.65 H), 7.62-7.10 (m, 10H), 5.20-5.00 (m, 2H), 4.70(m, 0.35H), 4.60-4.40 (m, 0.65H), 4.12 (m, 1H), 3.82 (s, 3H), 3.52 (t, 0.65H), 3.20 (t, 0.35H), 2.70 (d, 0.65H), 2.52 (t, 0.35H), 1.90 (m, 1H), 1.80-1.20 (m, 13H), 1.00-0.85 (m, 1H), 0.76 (d, 3H), 0.64 (m, 2H).
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH2:19][OH:20])[CH2:16][C:15]1=[O:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(Cl)Cl>[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]=[O:20])[CH2:16][C:15]1=[O:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.9 %

Procedure:
Anhydrous CrO3 (1.94 g, 19.38 mmol) is added to a solution of anhydrous pyridine (3.07 g, 38.76 mmol; in anhydrous CH2Cl2 (50 ml). The resulting mixture is stirred at r.t. for 15 min. A solution of 1-(t-butyldimethylsilyl)-4-(2-hydroxyethyl)-2-azetidinone (0.74 g, b 3.23 mmol) in anhydrous CH2Cl2 5 ml is added all at once. After stirring for 5 min, the CH2Cl2 solution is separated from a dark gummy precipitate which is washed with more CH2Cl2. The combined CH2Cl2 solution is evaporated under vacuum. The residue is taken up in ether filtered and washed with 5% NaHCO3, 5% HCl, 5% NaHCO3 and brine then dried and evaporated to give the aldehyde (0.543 g 74%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[CH:20]=[C:19]([C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=[CH:17][C:15]=3[NH2:16])=[O:13])=[CH:8][CH:7]=2)[N:5]=[N:4]1.[Cl:29][CH:30]([Cl:34])[C:31](Cl)=[O:32]>C(Cl)Cl>[Cl:29][CH:30]([Cl:34])[C:31]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([C:21]#[C:22][Si:23]([CH3:24])([CH3:26])[CH3:25])=[CH:20][C:14]=1[C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:3]2([C:2]([F:1])([F:27])[F:28])[N:5]=[N:4]2)=[CH:7][CH:8]=1)=[O:13])=[O:32]
Reactant: C[Si](C)(C)C#Cc1ccc(N)c(C(=O)c2ccc(C3(C(F)(F)F)N=N3)cc2)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1ccc(NC(=O)C(Cl)Cl)c(C(=O)c2ccc(C3(C(F)(F)F)N=N3)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.7 %

Procedure:
2-({4-[3-(trifluoromethyl)diazirin-3-yl]phenyl}carbonyl)-4-[2-(trimethylsilyl)ethynyl]aniline (47 mg, 0.12 mmol, 1 eq.) was dissolved in DCM (10 mL) and cooled to 0° C. Dichloroacetyl chloride (0.013 mL, 0.14 mmol, 1.15 eq.) was then added, and the reaction was stirred at 0° C. for 10 minutes. The reaction was then warmed to room temperature and stirred for 30 minutes. The solvent was evaporated, and the residue was purified by silica column (hexanes/ethyl acetate, 3:1), resulting in 57 mg (94%) of the title compound as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 11.83 (s, 1H, CHCl2), 8.56 (d, J=8.7, 1H, Ar—H), 7.76 (d, J=9.1, 2H, Ar—H), 7.69 (dd, J=1.5, 8.8, 1H, Ar—H), 7.61 (d, J=1.8, 1H, Ar—H), 7.32 (d, J=8.2, 2H, Ar—H), 6.03 (s, 1H, NH), 0.19 (s, 9H, Si(CH3)3). 13C NMR (126 MHz, CDCl3) δ 197.81 (Ar2—CO), 163.13 (NCOC), 139.23 (C—Ar), 138.79 (C—Ar), 138.33 (C—Ar), 136.61 (C—Ar), 134.08 (C—Ar), 130.47 (C—Ar), 126.71 (q, J=1.23, C—Ar), 123.41 (C—Ar), 122.03 (q, J=274.68, CF3), 121.60 (C—Ar), 120.94 (C—Ar), 103.04 (CSi(CH3)3), 96.22 (CCSi(CH3)3), 67.16 (CCl2), 28.64 (q, J=40.83, CN2), 0.03 (Si(CH3)3). Exact Mass, 511.05. 509.4841 [M−H]−, 511.487 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[CH3:28][C:29]1([CH3:42])[CH2:34][CH:33]([NH:35][C:36]2[NH:40][C:39]([CH3:41])=[N:38][N:37]=2)[CH2:32][CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:42])[CH2:34][CH:33]([N:35]2[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][C:11]=3[F:27])=[C:22]([CH2:23][CH2:24][CH3:25])[N:37]3[N:38]=[C:39]([CH3:41])[N:40]=[C:36]23)[CH2:32][CH2:31][O:30]1
Reactant: Cc1nnc(NC2CCOC(C)(C)C2)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCOC(C)(C)C2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (0.87 g) and N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5-methyl-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.34 g, 56%).