Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:7]=O.[C:14]([CH2:17][CH:18]=[PH2][PH3][PH4])([OH:16])=[O:15].[CH:22]1C=CC=C[CH:23]=1>>[CH2:22]([O:16][C:14](=[O:15])[C:17]([CH3:18])=[CH:7][C:6]1[C:9]([O:11][CH3:12])=[CH:10][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[OH:13])[CH3:23]
Reactant: c1ccccc1
Reactant: O=C(O)CC=[PH2][PH3][PH4]
Reactant: COc1cc(O)c(C=O)c(OC)c1
Product: CCOC(=O)C(C)=Cc1c(O)cc(OC)cc1OC
Yield: 81 %

Procedure:
4,6-Dimethoxysalicylaldehyde (30.0 g, 165 mmol; Aldrich Inc.) and carboxyethylidene-triphosphorane (60.0 g, 166 mmol; Aldrich Inc.) were stirred in 300 ml of anhydrous benzene at room temperature overnight under a nitrogen atmosphere and the reaction was allowed to complete, during which period the reaction was conducted in a dark room. Then, the benzene solvent was removed in vacuo to give a crudely purified product. The resulting crude product was crudely purified by silica gel column chromatography (hexane/ethyl acetate 1:1 as a developing solvent) to give a mixture of cis- and trans-isomers. The thus obtained mixture was purified by column chromatography using aminopropyl-modified silica gel (300 g of NHDM-1020 silica gel available from Fuji Silicia Chemicals Co. Ltd; n-hexane/ethyl acetate 2:1 which elutes only the cis-isomer and chloroform/methanol 4:1 which elutes only the trans-isomer) to give 35.4 g of the desired product in 81% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[CH2:12](C([Sn])=C(CCCC)CCCC)[CH2:13]CC>CN(C=O)C.C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[CH:3][C:2]([CH:12]=[CH2:13])=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 52.5 %

Procedure:
The title compound was prepared by following general procedure 2. 5-Bromo-2-trifluoromethylpyridine (2.0 g, 8.8 mmol) was dissolved in DMF:THF (3:1, 12 mL). Tributylvinyltin (3.0 g, 9.68 mmol) and Pd(PPh3)4 (0.135 g, 0.11 mmol) was added to this solution at RT under nitrogen and was heated at 100° C. for 2 h. After completion of the reaction (TLC), the reaction mixture was cooled to RT and diluted with water (120 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (2% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-(trifluoromethyl)-5-vinylpyridine as a light yellow oil (0.8 g, 52% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:3]=1[C:4]([NH:6][C:7](=[S:10])[SH-]C)=[S:5].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20]>C1(C)C=CC=CC=1>[Cl:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]([NH:20][C:19]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:17]([Cl:16])[CH:18]=1)=[S:10])=[S:5]
Reactant: C[SH-]C(=S)NC(=S)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: S=C(NC(=S)c1c(Cl)cccc1Cl)Nc1ccc(Cl)c(Cl)c1

Procedure:
3.0 g of N-(2,6-dichlorothiobenzoyl)-S-methyldithiocarbamate and 1.6 g of 3,4-dichloroaniline are dissolved in 25 ml of toluene and subsequently heated while refluxing for 5 hours. The resulting yellow precipitate is worked up in the usual manner. Yield 2.1 g. Melting point 168°-170° C.
Reaction SMILES: [CH:1]1([C:4](=O)[CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:3][CH2:2]1.[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19].[Na].C[OH:25]>>[CH:1]1([CH2:4][C:5](=[O:25])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:21]([N+:18]([O-:20])=[O:19])[CH3:22])[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(C=Cc1cccc(C(F)(F)F)c1)C1CC1
Reactant: CC[N+](=O)[O-]
Agent: [Na]
Product: CC(C(C(=O)CC1CC1)c1cccc(C(F)(F)F)c1)[N+](=O)[O-]

Procedure:
The procedure of Example IX using 36 g of 1-cyclopropyl-3-(m-trifluoromethylphenyl)prop-2-en-1-one, 14 ml of nitroethane and 1.85 g of sodium in 150 ml of methanol gives 36 g of 1-cyclopropyl-3-(m-trifluoromethylphenyl)-4-nitropentanone as an oily residue which is used in the crude state for the remainder of the operations.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13](CI)[O:12][C:11](=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17]([O-:20])([O-])=[O:18].[Cs+].[Cs+].[CH3:23]COCC.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:10]2[CH2:11][O:12]2)[CH2:13][C:17]([O:20][CH3:23])=[O:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)C(CI)O1
Reactant: CCOCC
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COC(=O)CC(c1ccc(Cl)c(Cl)c1)C1CO1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Treat a solution of the product of step 1 (1.5 g, 4.02 mmol) in dry CH3OH (15 mL) under N2 with Cs2CO3 (1.57 g, 4.8 mmol, 1.2 eq). Stir for 30 min, then pour the suspension into Et2O (200 mL)/water (100 mL). Extract the aqueous layer with Et2O (100 mL), wash the combined ether layers with 40 mL of saturated NaCl, dry (MgSO4), and concentrate to give 1.11 g (4.02 mmol,>99%) of methyl β-(3,4-dichlorophenyl)-oxiranepropanoate as a colorless oil.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:28].[H-].[Na+].Br[CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1.O>CN(C)C=O.CCOC(C)=O>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=[C:11]2[N:10]([CH2:32][C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)[C:9]1=[O:28]
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3c(ccn3COCC[Si](C)(C)C)c21
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)n(Cc2ccc(C#N)cc2)c2cnc3c(ccn3COCC[Si](C)(C)C)c21
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a solution of 1-[(1S,2R)-2-methylcyclohexyl]-6-{[2-(trimethylsilyl)ethoxy]methyl}-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (100 mg) in N,N-dimethylformamide (1 mL) was added 60% sodium hydride (13 mg) at 4° C. The mixture was stirred at the same temperature for 0.5 hour. To the mixture was added 4-(bromomethyl)benzonitrile (73 mg) and the solution was stirred at ambient temperature for 1 hour. To the solution was added water and EtOAc. The mixture was extracted with EtOAc and washed with brine. The extract was dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with EtOAc and n-hexane (1:3 to 1:1) to give 4-({1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-6-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}methyl)benzonitrile (117 mg) as a white amorphous.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH:20]=O.C(O)(=O)C.[CH:35]([O:38][C:39]([N:41]1[C:50]2[C:45](=[N:46][C:47]([O:51][CH3:52])=[CH:48][CH:49]=2)[C@H:44]([NH2:53])[CH2:43][C@@H:42]1[CH3:54])=[O:40])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH:35]([O:38][C:39]([N:41]1[C:50]2[C:45](=[N:46][C:47]([O:51][CH3:52])=[CH:48][CH:49]=2)[C@H:44]([NH:53][CH2:20][C:19]2[CH:18]=[C:17]([C:16]([F:30])([F:29])[F:15])[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=2)[CH2:43][C@@H:42]1[CH3:54])=[O:40])([CH3:37])[CH3:36]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc2c(n1)[C@H](N)C[C@H](C)N2C(=O)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1ccc2c(n1)[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.6 %

Procedure:
Add sodium triacetoxyborohydride (1.160 g, 5.50 mmol) to a mixture of 3,5-bis(trifluoromethyl)benzaldehyde (0.217 mL, 1.32 mmol), acetic acid (0.010 mL, 1.65 mmol), and (+/−)-cis-4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.318 mg, 1.12 mmol) in dichloroethane (10 mL). Stir thie mixture at room temperature under an atmosphere of nitrogen for 14 h. Add a saturated solution of sodium bicarbonate, separate the layers, and extract the aqueous layer with dichioromethane. Dry the combined organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate (gradient eluent, 0-60% ethyl acetate in hexane), to afford the title compound (0.462 g, 83%). MS (ES+): 506 (M+H).
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:30][C:31](O)=[O:32]>>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:30][C:31]([N:18]1[CH2:19][CH2:20][CH:15]([C:12]2[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:11]=2)[CH2:16][CH2:17]1)=[O:32]
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Reactant: O=C(O)Cc1nc2ccccc2s1
Agent: Cl
Product: O=C(Cc1nc2ccccc2s1)N1CCC(c2nc(CCc3ccccc3)cs2)CC1

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 308 mg) is reacted analogously to Example I-63 with 1,3-benzothiazol-2-ylacetic acid (252 mg). After chromatographic purification, this gives 2-(1,3-benzothiazol-2-yl)-1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (109 mg).
Reaction SMILES: CCCCCC.[H-].[Na+].[CH2:9]([C:11]1[CH:20]=[C:19]([CH3:21])[C:18]2[C:17](=[O:22])[NH:16][C@@H:15]3[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C@H:14]3[C:13]=2[CH:12]=1)[CH3:10].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[CH2:33]([N:16]1[C@@H:15]2[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:25][C@H:14]2[C:13]2[CH:12]=[C:11]([CH2:9][CH3:10])[CH:20]=[C:19]([CH3:21])[C:18]=2[C:17]1=[O:22])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a suspension of hexane-washed sodium hydride (6 mg of 60% dispersion in mineral oil, 0.15 mmol) in 1 mL THF was added (±)-trans-tert-butyl 8-ethyl-6-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 74, Part A (25 mg, 0.076 mmol) in 2 mL of THF. The mixture was stirred at ambient temperature for 30 min, at which time gas evolution had ceased. Then there was added benzyl bromide (0.027 mL, 0.23 mmol) and the resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was quenched with 1N HCl and diluted with ethyl acetate. The organics were washed sequentially with sat'd aq. NaHCO3, and brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (elution with 4:1 hexane/EtOAc) to afford 28 mg (88%) of the title compound as an oil. LRMS (ESI): 421.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:32])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=1[F:31])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:31][C:16]1[CH:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:28])=[O:29])[CH:19]=[CH:20][C:15]=1[NH:14][C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2)c(F)c1

Procedure:
2-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.45 g, 0.93 mmol) was dissolved in 15 mL DCM and 15 mL trifluoroacetic acid and the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated, and the residue was redissolved in 100 mL EtOAc, washed with sat. NaCl, dried with MgSO4, filtered and concentrated to yield title compound as an oil. (0.27 g, 80%) APCI (AP−): 361.1 (M−H)−.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:19]=2)[CH:14]=1)=O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.O1CCCC1.[OH-].[Na+]>O>[CH2:2]([C:1]1[S:43][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:19]=3)[CH:14]=2)=[N:10][N:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)NNC(=O)CCCCCC)ccc2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCOc1ccc2cc(-c3nnc(CCCCCC)s3)ccc2c1
Yield: 45.2 %

Procedure:
In a 50 ml-round-bottomed flask, 1.20 g (2.64 mM) of N-heptanoyl-N'-(6-decyloxy-2-naphthoyl)-hydrazine, 1.20 g (2.97 mM) of Lawesson's reagent and 15 ml of tetrahydrofuran were placed, followed by refluxing for 45 minutes under stirring. After the reaction, the reaction mixture was poured into a solution of 0.95 g of sodium hydroxide in 100 ml of iced water to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and purified by silica gel column chromatography (eluent: toluene). The resultant crystal was recrystallized from a mixture solvent (toluene-methanol) two times and further recrystallized from ethyl acetate and from toluene each once to obtain 0.54 g of 2-hexyl-5-(6-decyloxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 45.2%). ##STR29##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.C(N(CC)CC)C.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CS(C)=O>[OH:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[NH:3][C:2](=[O:1])[C:7]=1[C:25]([NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: O=C=Nc1ccccc1
Reactant: COc1nc(O)cc(O)n1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1nc(O)c(C(=O)Nc2ccccc2)c(=O)[nH]1

Procedure:
To a solution of 4,6-dihydroxy-2-methoxypyrimidine (6 g) in dry dimethyl sulfoxide was added triethylamine (5.9 ml). The solution was brought to 60° and phenyl isocyanate (5 g) was added; the solution was maintained at 80°-90° for two hours, cooled and water added slowly to cause precipitation.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nc(C)cs2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1csc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)n1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(4-methylthiazol-2-yl)-2-naphthalenyl]ethynylbenzoate (Compound 16) (145.0 mg, 0.34 mmol) and 4 ml of EtOH at room temperature was added aqueous NaOH (1 ml, 1 M, 1 mmol). The resulting solution was warmed to 50° C. for 1 hour and concentrated in vacuo. The residue was suspended in a solution of CH2Cl2 and ether (5:1) and acidified to pH 5 with 1M aqueous HCl. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and the solvents removed under reduced pressure to give the title compound as a white solid. 1H NMR (d6-DMSO): δ 7.94 (2H, d, J=8.1 Hz), 7.87 (1H, d J=1.6 Hz), 7.63 (2H, d, J=8.3 Hz), 7.50 (1H, dd, J=1.6, 8.1 Hz), 7.45 (1H, d, J=8.1 Hz), 7.27 (1H, s), 6.58 (1H, t, J=4.8 Hz), 2.43 (3H, s), 2.37 (2H, d, J=4.8 Hz), 1.26 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6].[H][H]>C(O)C.[Pd]>[NH2:14][C:3]1[C:2]([CH3:1])=[CH:13][CH:12]=[CH:11][C:4]=1[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6]
Reactant: [H][H]
Reactant: Cc1cccc(C(=O)NC(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C(=O)NC(C)C)c1N
Yield: 96.5 %

Procedure:
The 2-nitrobenzamide of Step A (1.70 g, 7.6 mmol) was hydrogenated over 5% Pd/C in 40 mL of ethanol at 50 psi. When the uptake of hydrogen ceased the reaction was filtered through Celite® diatomaceous filter aid and the Celite® was washed with ether. The filtrate was evaporated under reduced pressure to afford 1.41 g of the title compound as a solid melting at 149-151° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][OH:11])[NH2:9])[CH:5]=[N:6][CH:7]=1.[C:12](Cl)(=O)[CH3:13]>N1C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[N:9]=[C:12]([CH3:13])[O:11][N:10]=2)[CH:3]=1
Reactant: CC(=O)Cl
Reactant: NC(=NO)c1cncc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1nc(-c2cncc(Br)c2)no1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-N′-hydroxypyridine-3-carboximidamide (1.0 eq.) in pyridine was added acetyl chloride (2 eq). The reaction stirred at 100° C. for 1 h and 2 eq of acetyl chloride was added. After 1 h, the mixture was cooled, diluted with EtOAc and aqueous NaHCO3. The organic extracts were washed with aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 70:30) afforded the title compound as a white solid.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH3:17])=O.[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23]CCCC.C(O)CCCCCCCC=C>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH2:4]([OH:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC=CCCCC
Reactant: CCCCC=CCCCCCCCCOC=O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: C=CCCCCCCCCO
Product: C=CCCCC
Product: CCCCC=CCCCCCCCCO

Procedure:
FIG. 9 shows a synthesis of 9-tetradecenyl formate, in which 5-decene is cross-metathesized with 9-decenol in the presence of Grubbs' catalyst to produce 9-tetradecenol while 1-hexene is removed from the reaction under vacuum, and in which the metathesis product, 9-tetradecenol, is reacted with formyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=O)[CH2:25][C:26](=[O:28])[CH3:27])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=[S:39])[CH2:25][C:26](=[O:28])[CH3:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)CC(C)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=S)CC(C)=O

Procedure:
In analogy to the procedure described in example 192 g, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent to give the title compound as brown solid.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)C(=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1)[CH3:2].[NH:29]1[CH2:36][CH2:35][CH2:34][CH:30]1[C:31]([OH:33])=O>C(O)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[C:31](=[O:33])[CH:30]3[CH2:34][CH2:35][CH2:36][N:29]3[C:10](=[O:9])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C(O)C1CCCN1
Reactant: CCc1cc2c(=O)oc(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Solvent: CC(=O)O
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)C1CCCN1C2=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 65.1 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-2H-thieno[2,3-d][1,3]oxazine-1(4H)-yl)methyl]biphenyl-2-carbonitrile (1 g), D,L-proline (0.44 g) and acetic acid (50 mL) was stirred at 100° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.74 g, 65%).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([NH2:16])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([NH:16][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])[CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NC1CC2CCC(C1)N2Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1NC1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.1 %

Procedure:
5.62 g (27.82 mmol) 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine (u17094-94) and 9.7 ml (55.46 mmoml) of Hunig's base were dissolved in 200 ml NMP. 4.32 g (30.60 mmol) 1-fluoro-2-nitrobenzene was then added and the mixture was stirred at RT for 3 hrs. The reaction mixture was diluted with EtOAc and washed with water and dried over sodium sulfate. The solvent was removed partially under reduced pressure and was left in refrigerator overnight. The solid was filtered off to afford 2.92 g of product as a yellow powder. The solvent was removed from filtration to give additional 5.7 g of product as an orange-yellow residue.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccccc1Cl
Temperature: 65 °C

Procedure:
Sodium hydride (1.00 g) was added in portions to a solution of 2-chlorophenol (5.00 g) in N,N-dimethylformamide (100 mL) under nitrogen. To the resulting solution was added 2-fluoro-1-nitrobenzene (5.00 g). The mixture was heated at 65° C. overnight, and then was evaporated under vacuum. The residue was partitioned between chloroform and 1 N NaOH, and the layers were separated. The aqueous layer was extracted once more with chloroform, and the combined chloroform layers were washed with water and brine, dried over magnesium sulfate, and evaporated under vacuum to a yellow oil. The oil was crystallized from ethyl ether/hexane at -78° C. to yield the title compound as a light yellow solid. Mp: 48°-49° C.