Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH:19]([CH3:20])[CH2:18][O:17][CH2:16][CH:15]3[CH3:21])[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)=[CH:35][CH:34]=1>>[CH3:21][CH:15]1[CH2:16][O:17][CH2:18][CH:19]([CH3:20])[N:14]1[C:12]1[N:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:31][CH3:32])=[CH:24][CH:23]=2)[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)=[O:41])=[CH:7][CH:6]=2)[N:13]=1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3C(C)COCC3C)n2)cc1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3C(C)COCC3C)n2)cc1
Yield: 0.8 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-4-ylcarbamate. Yield 15 mg, 0.8% yield.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[NH:18][CH3:19])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:21]([O:25][C:26](=[O:29])[CH2:27]Br)([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]([CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:29])[C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:20])[NH:18][CH3:19])=[CH:15][CH:16]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CNC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 41.9 mg) was added to a solution of N-(tert-butoxycarbonyl)-4-methylcarbamoylaniline (250 mg) in dimethylformamide (2.5 ml) in ice water bath under nitrogen and stirred for 30 minutes under same condition. To the mixture was added tert-butylbromoacetate (234 mg) and stirred at ambient temperature for 20 hours. The reaction mixture was poured into water and extracted with chloroform. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate--n-hexane to give N-(tert-butoxycarbonyl)-N-(tert-butoxycarbonylmethyl)-4-methylcarbamoylaniline (280 mg).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:39][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][CH:36]=1
Reactant: CN(C[C@@H](N)c1cccc(F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cccc(F)c1

Procedure:
Compound 66 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound. LC/MS [341 (M+H)].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cccc2c(Cl)nccc12
Temperature: 70 °C

Procedure:
A solution (40 ml) of 1-chloro-5-nitroisoquinoline (2.23 g, synthesized according to the method described in J. Med. Chem. 45, 3, 740 (2002)) in ethyl acetate was added with tin(II) chloride dihydrate (12.39 g, Wako Pure Chemical Industries) at room temperature and stirred with heating at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, then added with ice (200 g) and stirred for 0.5 hour. The reaction mixture was filtered through Celite and extracted three times with ethyl acetate (200 ml for each time), and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (749 mg).
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[CH2:32][O:33]C(/N=N/C(OCC)=O)=O.O>C1COCC1>[CH3:32][O:33][C:3]1[CH:2]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: Oc1cccc2ncccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an oven dry three neck flask was added 5-hydroxy-quinoline (5 g, 34.5 mmol), and triphenylphosphine. The solids were dissolved in THF (100 mL) and DEAD (8.19 mL, 51.7 mmol) was added slowly. The maroon reaction mixture was stirred at room temperature overnight and then poured into H2O (100 mL) and extracted into EtOAc (3×150 mL). The combined organic fractions were dried over Na2SO4, filtered, concentrated, and purified by column chromatography using 20% EtOAc/hexanes as the eluent. The title compound was isolated as 3.5 g (64%) of a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][CH2:25][CH:24]4[C:28]4[O:32][N:31]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[CH:29]=4)[N:20]=[C:19]([NH:39][C:40]4[CH:44]=[C:43]([CH3:45])[NH:42][N:41]=4)[CH:18]=3)[CH2:13][CH2:12]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:9]1[C:10]2([CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][CH2:25][CH:24]4[C:28]4[O:32][N:31]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[CH:29]=4)[N:20]=[C:19]([NH:39][C:40]4[CH:44]=[C:43]([CH3:45])[NH:42][N:41]=4)[CH:18]=3)[CH2:13][CH2:12]2)[CH2:11][NH:8]1
Reactant: Cc1cc(Nc2cc(N3CCC4(CC3)CN(C(=O)OC(C)(C)C)C4)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2cc(N3CCC4(CC3)CNC4)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-[2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-7-yl]-4-(5-methyl-1H-pyrazol-3-ylamino)-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Example 147) (110 mg, 0.19 mmol) and TFA (2 ml) were stirred at ambient temperature for 60 minutes. The volatiles were removed by evaporation, the residue dissolved in DCM poured onto an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation to afford the desired product as a yellow solid. (66 mg, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13]O.S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH:12]([CH3:13])[CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CC[C@H](C)CO
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)COC(=O)c1ccc(O)cc1
Yield: 82.9 %

Procedure:
4.0 g of p-hydroxybenzoic acid and 12.5 g of (S)-(-)-2-methylbutanol were refluxed for 6 hours in toluene in the presence of sulfuric acid, while the generated water was removed out. Subsequently, the reaction solution was washed with water to remove sulfuric acid out. After the resulting solution was dried and concentrated, the concentrate was purified by column chromatography to obtain 5.0 g of the objective ester compound (liquid state at room temperature, [α]D23 =+4.9° (CHCl3)). (Yield: 83%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][CH:68]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:67][CH2:66]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10][C@H:9]2[C:28]([N:65]2[CH2:70][CH2:69][CH:68]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:67][CH2:66]2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CC1CCNCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCC(CC(N)=O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.138 mmol) in methylene chloride (10 mL), HATU (Aldrich, 79 mg, 0.21 mmol) was added followed by the addition of DIPEA (0.145 mL, 0.83 mmol) and piperidin-4-yl-acetamide (Chembridge, 41 mg, 0.21 mmol). The mixture was stirred at rt for 3 hrs then overnight after the addition of 3 mL of DMF. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (12 g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 21 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:64]([NH2:68])([CH2:66][CH3:67])[CH3:65]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:68][C@H:64]([CH2:66][CH3:67])[CH3:65])[CH:5]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CC[C@H](C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC[C@H](C)Nc1cc(C(=O)OC)ccn1
Temperature: 90 °C

Procedure:
Degas with nitrogen a suspension containing 2-chloro-isonicotinic acid methyl ester (2.15 g, 12.5 mmol), palladium acetate (281 mg, 1.25 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl (780 mg, 1.25 mmol), cesium carbonate (4.95 g, 15 mmol), and (S)-sec-butylamine (1.5 mL, 15 mmol) in toluene (30 mL) and heat in a sealed tube at 90° C. overnight. Cool to room temperature and filter the solids through a filtering agent. Wash with ethyl acetate (30 mL), concentrate and purify (silica gel chromatography, eluting with 15:85 to 30:70 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=24)[N:17]=[CH:16][N:15]([C@H:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[OH:31])[C:14]3=[O:32])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:33][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:3][C:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=24)[N:17]=[CH:16][N:15]([C@H:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[OH:31])[C:14]3=[O:32])=[CH:6][CH:5]=1)([CH3:33])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 6-[(6-acetylpyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 10, 0.018 g, 0.042 mmol) in 1 mL of THF at 0° C. was added methylmagnesium bromide (0.035 mL, 3.0 M diethyl ether solution, 0.10 mmol). After 30 min, the mixture was treated with saturated aqueous ammonium chloride and extracted 2× with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 446.2067 for [M+H]+ [Calc'd for C26H28N3O4, [M+H]+=446.2074]: 1H NMR (400 MHz, CDCl3) δ 8.95-8.93 (m, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 7.85-7.81 (m, 2H), 7.67-7.60 (m, 2H), 7.39 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 4.89-4.80 (m, 2H), 4.33 (s, 2H), 4.25-4.04 (m, 3H), 3.60-3.57 (m, 1H), 3.36-3.28 (m, 1H), 2.30-2.15 (m, 1H), 2.02-1.98 (m, 1H), 1.47 (s, 6H).
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[O:26][C:25]([CH3:31])([CH3:30])[CH:24]=[CH:23]3)=[O:19])=[CH:11][C:10]=1[O:32][CH3:33])C1C=CC=CC=1>CO.[Pd]>[CH3:30][C:25]1([CH3:31])[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([C:18](=[O:19])[CH2:17][C:12]3[CH:13]=[C:14]([O:15][CH3:16])[C:9]([OH:8])=[C:10]([O:32][CH3:33])[CH:11]=3)[CH:21]=2)[O:26]1
Reactant: COc1cc(CC(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CC(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1O
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-benzyloxy-3,5-dimethoxy-phenyl)-1-(2,2-dimethyl-2H-chromen-6-yl)-ethanone (62.8 mg) dissolved in methanol (5.0 mL) and hexanes (3.3 mL) was added palladium on carbon (19.13 mg, 10% on carbon). The reaction mixture was purged with nitrogen numerous times before being exposed to a hydrogen atmosphere. Hydrogenation proceeded at room temperature and at atmospheric pressure. After 15 minutes, the reaction was purged again with nitrogen and the reaction mixture was filtered to remove the catalyst. The filtrate was concentrated to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]2[N:12]3[N:18]=[C:17]([CH3:19])[CH:16]=[C:13]3[NH:14][N:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:20](Cl)([CH:22]=[CH2:23])=[O:21].O.C(OCC)(=O)C>C(#N)C.CC(N(C)C)=O.N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O>[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]2[N:12]3[N:18]=[C:17]([CH3:19])[CH:16]=[C:13]3[NH:14][N:15]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:21])[CH:22]=[CH2:23]
Reactant: C=CC(=O)Cl
Reactant: Cc1cc2[nH]nc(CCCc3cccc(N)c3)n2n1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC(=O)Nc1cccc(CCCc2n[nH]c3cc(C)nn23)c1

Procedure:
25.2 g (0.1 mol) of 3-[3-(3-aminophen yl)-propyl]-6-methyl-1H-pyrazolo[5,1-c]-1,2,4-triazole synthesized according to Preparation Example 9 described in Japanese Patent Application (OPI) No. 42045/83 corresponding to European Patent Application No. 0073636A1 was dissolved in a mixture of 200 ml of acetonitrile, 100 ml of dimethylacetamide, 16 ml of pyridine, and 1 ml of nitrobenzene. 9.5 g (0.105 mol) of acryl chloride was gradually added dropwise thereto, and, after reaction for one-hour at a temperature not higher than 10° C. with stirring, water and ethyl acetate were added thereto, followed by extracting procedure. The ethyl acetate phase was well washed with saturated sodium chloride aqueous solution, then the solvent was removed. The product was crystallized from acetonitrile. Recrystallization of the crude product from acetonitrile yielded 20.6 g of C-5 having m.p. of 195° to 197° C.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH:5]1[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.[Li]CCCC.[CH2:24]=[O:25].[Cl-].[NH4+]>C1COCC1>[OH:25][CH2:24][C:2]#[C:3][CH2:4][CH:5]1[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
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCC(CC=C(Br)Br)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC#CCO)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(3,3-dibromoprop-2-en-1-yl)piperidine-1-carboxylate from step 1 of this Example (19.5 g, 50.9 mmol) was dissolved in THF (170 mL) and cooled to −78° C. n-BuLi (2.5 Min hexanes, 46.8 mL, 117 mmol) was added slowly, maintaining internal temperature below −65° C. The mixture was stirred for additional 30 min, before paraformaldehyde (4.59 g, 152.7 mmol) was added in one portion. The reaction was stirred at −78° C. for 30 min and warmed to room temperature and allowed to stir at RT for 1 hour. Saturated aqueous ammonium chloride was added, and the aqueous layer was extracted 3 times with ethyl acetate. Column chromatography eluting with 30% acetone/hexanes afforded the product as colorless oil.
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:8])[N:7]=1)[NH2:2].C([O:15][C:16](=O)[CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:18]([CH3:20])=O)C>C(O)C.O.C(O)(=O)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:17]2[C:16](=[O:15])[N:1]([C:3]3[S:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:8])[N:7]=3)[NH:2][C:18]=2[CH3:20])=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Reactant: COC(=O)c1sc(NN)nc1C
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1sc(-n2[nH]c(C)c(Cc3ccc(Cl)cc3)c2=O)nc1C
Temperature: 25 °C
Yield: 42 %

Procedure:
To a solution of methyl 2-hydrazinyl-4-methylthiazole-5-carboxylate (0.25 g, 1.33 mmol) and 2-(4-chlorobenzyl)acetoacetic ethyl ester (0.24 g, 0.93 mmol) in ethanol (10 mL) and water (1 mL) was added 1 drop of acetic acid at ambient temperature. The reaction mixture was heated to reflux for 17 hours, cooled to ambient temperature. The precipitate was collected by filtration and titrated with ethyl ether to afford the title compound in 42% yield (0.22 g): 1H NMR (300 MHz, DMSO-d6) δ 7.27 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 3.78 (s, 3H), 3.52 (s, 2H), 2.58 (s, 3H), 2.14 (s, 3H); MS (ES+) m/z 378.1 (M+1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][C:21]#[N:22]>O1CCCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCCBr
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCCCOc1cccc(CN2CCCCC2)c1
Yield: 69.9 %

Procedure:
A solution of 3-(1-piperidinylmethyl)phenol (12.05 g) in dry tetrahydrofuran (50 ml) was added dropwise to a suspension of sodium hydride [from 6.0 g of 50% suspension in oil washed with petroleum ether] in dry tetrahydrofuran (70 ml). The mixture was stirred under reflux for 30 minutes and allowed to cool. 4-Bromobutyronitrile (14.89 g, 10.0 ml) was added to the cool mixture and the mixture so obtained was stirred under reflux for 22 hours. Tetrahydrofuran was evaporated under reduced pressure and the residue was dissolved in water (100 ml). The solution was extracted with ether (3×50 ml), and the aqueous layer was adjusted to pH 9 with K2CO3. The aqueous solution was extracted with chloroform (3×100 ml), the chloroform extracts were dried (K2CO3 and chloroform was removed under reduced pressure to give a pale brown oil, (16.22 g). This oil was purified by column chromatography (Kieselgel 60 70-230 mesh silica) using chloroform as eluant. The fractions containing the desired product were collected and the solvent was evaporated in vacuo to give 4-[3-(1-piperidinylmethyl)phenoxy]butyronitrile as an oil (11.37 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]([CH2:14][C:15]([CH3:17])=[CH2:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[S:21]>CN(C)C=O>[CH3:18][N:19]([C:20](=[S:21])[O:3][C:4]1[C:13]([CH2:14][C:15]([CH3:17])=[CH2:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:23]
Reactant: C=C(C)Cc1cccc(C(=O)OC)c1O
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)Cc1cccc(C(=O)OC)c1OC(=S)N(C)C
Yield: 60.1 %

Procedure:
To 1 liter of dry dimethylformamide were added 16 g of 60% sodium hydride in oil. After stirring under a nitrogen atmosphere, 81.7 g of 2-hydroxy-3-(2-methyl-2-propenyl) benzoic acid, methyl ester, as a solution in dimethylformamide, were added in dropwise fashion. After stirring at room temperature, a solution 49.6 g of dimethylthiocarbamoyl chloride in dimethylformamide was added over a one hour period. The reaction mixture was stirred at room temperature overnight, then poured onto ice and extracted with diethyl ether and ethyl acetate. The combined organic extracts were washed successively with a 10% sodium hydroxide solution and water, dried over sodium sulfate, and concentrated in vacuo. The residue was vacuum distilled, and the fraction distilling at 162°-168° C. and 0.6 torr provided 69.9 g of the desired subtitle intermediate. NMR, MS.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[Cl:19].[CH3:20][C:21]1[CH:25]=[C:24]([CH:26]=[O:27])[O:23][N:22]=1.[Li]CCCC>C1COCC1>[Cl:12][C:7]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([Cl:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:26]([C:24]3[O:23][N:22]=[C:21]([CH3:20])[CH:25]=3)[OH:27])[CH:3]=2)[N:8]=1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1-c1ccccc1
Reactant: Cc1cc(C=O)on1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)on1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-bromo-2,4-dichloro-3-phenylquinoline (363 mg, 1.03 mmol, Intermediate 1: step c) and 3-methylisoxazole-5-carbaldehyde (149 mg, 1.34 mmol) in THF (5 mL) at −78° C. was added n-BuLi (1.6 M in hexane, 0.707 mL, 1.13 mmol) dropwise. The mixture was stirred at −78° C. for 30 minutes, then moved to an ice bath and stirred for 30 minutes. The reaction was quenched by addition of saturated aqueous NH4Cl and then diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated to afford the crude title compound which was used without further purification in the next reaction.
Reaction SMILES: [N:1]([N:3]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:4]1[C:5]([OH:7])=[O:6])=O.FC(F)(F)C(O)=O>ClCCl>[NH:1]1[N:3]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:4]2[C:5](=[O:7])[O:6]1
Reactant: O=NN1CCCCC1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1ONN2CCCCC12
Yield: 76 %

Procedure:
N-Nitrosopipecolinic acid (prepared by the method of W. Lijinsky, L. Keefer and J. Loo Tetrahedron 1970, 26, 5137) (1.82 g, 11.5 mM) ) in dichloromethane (15 ml) was cooled in ice and treated dropwise with trifluoroacetic acid (1.62 ml, 11.5 mM). The mixture was stirred with cooling for 6 h then diluted with further dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate solution until the washings were neutral. The organic phase was dried (MgSO4) and evaporated to give the title compound as a yellow oil (1.12 g, 76%); νmax (CH2Cl2) 1732 cm−1; δH (CDCl3) 1.90-2.02 (2H, m), 2.04-2.19 (2H, m), 2.63 (2H, t, J 6 Hz) and 4.25 (2H, t, J 6 Hz); EI m/e 140 (93%).