Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[OH-].[Na+].C(OCC)C>C1COCC1.O>[CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1ccc(C(=O)O)cc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a well-stirred solution of methyl p-vinylbenzoate (36.0 g, 0.222 mole) in THF (200 mL) was added a solution of sodium hydroxide (17.78 g, 0.444 mole) in water (200 mL) at room temperature. After stirring overnight, water (100 mL), THF (150 mL), and ethyl ether (200 mL) was added and the phases separated. The aqueous phase was acidified with a solution of concentrated hydrochloric acid (41 mL) in water (90 mL) then extracted three times with THF (500-600 mL each). The latter combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to provide 32.7 g (99.5 percent) of white solids. Proton nmr (Gemini model 300 MHz) in deuterochloroform: delta 8.08 (2H), 7.50 (2H), 6.78 (1H), 5.90 (1H), 5.41 (1H).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:31])[C@@H:14]([CH3:30])[O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.[CH2:51]([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]([C:64](=[O:77])[C@@H:65]([NH2:76])[CH2:66][CH2:67][O:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH2:60][CH2:59]1)=[O:57])[CH2:52][CH2:53][CH3:54]>CN(C=O)C.C(Cl)CCl>[CH2:51]([O:55][C:56]([N:58]1[CH2:59][CH2:60][N:61]([C:64](=[O:77])[C@@H:65]([NH:76][C:27]([C:18]2[CH:17]=[C:16]([O:15][C@H:14]([CH3:30])[C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:31])[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=2)=[O:28])[CH2:66][CH2:67][O:68][CH2:69][C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH2:62][CH2:63]1)=[O:57])[CH2:52][CH2:53][CH3:54]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCOCc2ccccc2)CC1
Reactant: Cc1ccc2c(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)NC3CCC3)cc(C(=O)O)nc2c1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 1.0 g 4-[(R)-2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid in 30 ml DMF were added 1.2 g DIPEA, 319 mg HOAt and 450 mg EDC. After 5 minutes 1.1 g 4-((S)-2-Amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate were added and the mixture stirred for 16 h. The mixture was concentrated, diluted with DCM and washed with aqueous LiCl (4%), saturated aqueous NaHCO3 and brine. The crude product was used in the next reaction step. Yield: 2.8 g.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:34])[N:4]([C:19]2[CH:20]=[C:21]([C:26](=O)[CH2:27][C:28](OCC)=[O:29])[CH:22]=[CH:23][C:24]=2[CH3:25])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].O.[NH2:36][NH2:37].NN>CCO.C(O)(=O)C>[Br:1][C:2]1[C:3](=[O:34])[N:4]([C:19]2[CH:20]=[C:21]([C:26]3[CH:27]=[C:28]([OH:29])[NH:37][N:36]=3)[CH:22]=[CH:23][C:24]=2[CH3:25])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)CC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2cc(O)[nH]n2)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of ethyl 3-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylphenyl}-3-oxopropanoate (from Step 1) (0.20 g, 0.37 mmol) in EtOH (5.00 mL) was added hydrazine hydrate (0.01 mL, 0.41 mmol). The reaction mixture was heated at 60° C. with a condensere. After 1 h, additional hydrazine hydrate (0.01 mL) was added. After 2 h, acetic acid (2 drops) was added. At 4 h, additional hydrazine was added (0.1 mL). At 5 h, the reaction appeared to be complete. Left in fridge overnight. Precipitate filtered, washed with hexane, found to be product, a white solid (0.10 g, 54%). 1H NMR (CD3OD/400 MHz) δ 7.66 (m, 2H), 7.45 (m, 2H), 7.05 (t, 2H, J=9.6 Hz), 6.65 (s, 1H), 5.36 (s, 2H), 2.04 (s, 3H), 2.02 (s, 3H). ESHRMS m/z 502.0552 and 504.0569 (M+H calculated for C23H19BrF2N3O3 requires 502.0572 and 504.0555).
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:14]([N:16]1[C@H:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([NH2:45])[N:40]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>C(#N)C.C(OCC)(=O)C>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:14]([N:16]1[C@H:20]([C:21]([NH:45][C:41]2[N:40]=[N:39][CH:44]=[CH:43][CH:42]=2)=[O:22])[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:15])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:2]
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1
Reactant: Nc1cccnn1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2cccnn2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
To a solution of (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (590 mg, 0.95 mmol), 3-pyridazinamine (100 mg, 1.05 mmol) and 2-chloro-4,6-bis(methyloxy)-1,3,5-triazine (183 mg, 1.05 mmol) in acetonitrile (30 mL) under N2 was added 4-methylmorpholine (212 mg, 2.1 mmol) dropwise. The mixture was stirred at rt overnight. TLC showed that the reaction was complete. The mixture was diluted with ethyl acetate and washed with 5% citric acid, followed by brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (2:1) to provide the titled compound (460 mg, 79%)
Reaction SMILES: [NH:1]([C:5]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][C:6]=1[CH2:7]Br)[C:2]([CH3:4])=[O:3].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>C(Cl)(Cl)Cl.C(O)C>[NH:1]([C:5]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][C:6]=1[CH2:7][N:20]([CH2:21][CH3:22])[CH2:18][CH3:19])[C:2]([CH3:4])=[O:3]
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(CBr)c1
Reactant: CCNCC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(NC(C)=O)c(CN(CC)CC)c1

Procedure:
30 gm of 2-acetamino-5-carbethoxy-benzyl bromide were dissolved in a mixture of 400 ml of chloroform and 100 ml of ethanol, and the solution was refluxed with 22 gm of diethylamine for 1 hour. Thereafter, the reaction solution was cooled, then evaporated in vacuo, the residue was distributed between a mixture of dilute ammonia and chloroform, and the chloroform phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silicagel (elution agent: ethyl acetate) and recrystallized from ethanol, yielding 2-acetamino-5-carbethoxy-N,N-diethyl-benzylamine, m.p. 57-59° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH3:13][N:14](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.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>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[N:3]=[C:2]([C:13]#[N:14])[CH:11]=[CH:10][C:9]1=2
Reactant: CC(=O)N(C)C
Reactant: O=C1CCCc2nc(Cl)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(n1)CCCC2=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Under nitrogen, 42.25 g (0.23 mol) of 2-chloro-7,8-dihydroquinolin-5(6H)-one, 54.64 g (0.47 mol) of zinc cyanide and 13.44 g (0.01 mol) of tetrakis(triphenylphosphine)palladium were suspended in 200 ml of anhydrous N,N-dimethylacetamide (water content <0.01%, degassed with nitrogen beforhand), heated to 100° C. and stirred at this temperature for 2 hours. After complete conversion (monitored by TLC, mobile phase petroleum ether/ethyl acetate 2:1), the reaction mixture (grey suspension) was cooled to room temperature and filtered through Celite, and the filter cake was washed with 500 ml of ethyl acetate. 200 ml of saturated aqueous sodium chloride solution were then added to the resulting organic solution. A white precipitate was formed, which was filtered off and discarded. The organic phase was separated off, washed three times with in each case 200 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness. The residue obtained was applied to 20 g of silica gel and purified by column chromatography on silica gel (80 g cartridge; flow rate: 60 ml/min; mobile phase: petroleum ether/ethyl acetate 95:5→60:40 over 40 min, then isocratic petroleum ether/ethyl acetate 60:40 for 30 min). This gave 26.35 g (0.15 mmol, 66% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C([Li])CCC.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([S:23](F)(=[O:25])=[O:24])[N:17]=1>C(COC)OC>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][S:23]([C:18]1[N:17]=[C:16]([CH3:15])[CH:21]=[C:20]([CH3:22])[N:19]=1)(=[O:24])=[O:25]
Reactant: Cc1cc(C)nc(S(=O)(=O)F)n1
Reactant: Cc1cccc(Cl)c1N
Agent: [Li]CCCC
Solvent: COCCOC
Product: Cc1cc(C)nc(S(=O)(=O)Nc2c(C)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloro-6-methylaniline (0.5 g, 3.5 mmol) in dimethoxyethane (15 mL) cooled to 0° C. was added butyl lithium (2.2 mL, 3.5 mmol) and the mixture was allowed to stir for 15 minutes. Then 4,6-dimethyl-2-pyrimidinesulfonyl fluoride (0.66 g, 3.5 mmol), prepared according to Brown and Hoskins, J. Chem. Soc. Perkin 1, 522-527 (1972) was added. The mixture stirred with warming to 25° C. for 1 hour. The mixture was concentrated and the residue triturated with butyl chloride. The resultant solid was acidified with 1N HCl and the solid was filtered. The product was a yellow-brown solid, m.p. 215°-219° C. NMR (200 MHZ) D6 -Acetone: δ 8.2 (bs, 1H), 7.4 (s, 1H), 7.2 (bs, 3H), 2.5 (s, 6H) and 2.35 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[N:13]([CH2:22][CH3:23])[C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)=[O:3].O.[O-:25][Mn](=O)(=O)=O.[K+]>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][S:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[N:13]([CH2:22][CH3:23])[C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)(=[O:25])=[O:3]
Reactant: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1S(C)=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)C)cc1S(C)(=O)=O
Yield: 81.5 %

Procedure:
The sulfoxide of Example 37, (100 mg, 0.3 mmoles) was stirred in 4 mL of CH2Cl2 and 8 mL water with 20 mg (0.09 mmole) of benzyltriethylammonium chloride and 94.5 mg (0.6 mmole) KMnO4 at 25° C. for 16 h. The mixture was partitioned between 60 mL EtOAc and 40 mL water and the EtOAc was washed with water, brine, dried and stripped in vacuo. The residue was purified by silica gel chromatography using 25% EtOAc/hexanes to give 85 mg product (81% yield); mp 174-175.3° C. Elemental analysis for C18H25N3O2S: Theory C, 62.22; H, 7.25; N, 12.09; S, 9.23. Found: C, 62.13; H, 7.28; N, 11.93; S, 9.12.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)([O-])=[O:2].O.O.O.C([O-])(=O)C.[Na+].N>O1CCCC1.CO>[OH:2][NH:1][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CN=C(c2ccccc2)c2cc(NO)ccc2N1
Reaction time: 0.33 h

Procedure:
A mixture of 16.8 g. of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one, 500 ml. of tetrahydrofuran, 250 ml. of methanol, 56 g. of stannous chloride dihydrate and 68 g. of sodium acetate trihydrate was stirred at room temperature under an atmosphere of nitrogen for 24 hours. 1 l. of tetrahydrofuran and 15 ml. of concentrated ammonia were then added. The inorganic salts were removed by filtration through celite. The filtrate was evaporated. The solid residue was stirred with 100 ml. of methylene chloride and 250 ml. of water for 20 minutes under nitrogen. The insoluble crystals were collected to leave light yellow material. For analysis it was recrystallized from ethanol/methylene chloride, m.p. 186°-187°.
Reaction SMILES: [CH:1]([Li])=[CH2:2].[C:4]1([CH:14]=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.CO.CCOCC>C1COCC1>[C:4]1([CH:14]([OH:15])[CH:1]=[CH2:2])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: [Li]C=C
Reactant: O=Cc1cccc2ccccc12
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: C=CC(O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of vinyl lithium (2.04 g, 0.06 mole, 2.5 ml) in dry THF (30 ml) under N2 with stirring, at -60° was added dropwise a solution of naphthaldehyde (4.68 g, 0.03 mole) in 10 ml THF. The reaction was kept at -60° for 30 min, the flask was then warmed to room temperature and 5 ml MeOH added cautiously with rigorous stirring, followed by 100 ml of ether. The ethereal solution was washed with brine and dried over MgSO4. After evaporation of the solvent, the residue was chromatographed through Florisil (250 g), eluted first with hexane and then a mixture 20% ether in hexane, giving the expected product. 4.77 g (86% yield). b.p. 92-105°/10μ.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[NH2:25][C:26]([NH2:28])=[S:27].C[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:28]=[C:26]([SH:27])[N:25]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: NC(N)=S
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Sc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2.8 g (7.8 mmole) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one, 2.8 g (37 mmole) of thiourea, and 8.0 ml (32 mmole) of a 4.0M methanol solution of sodium methoxide in 80 ml of methanol was stirred at room temperature for 18 hr. The mixture was diluted with water and extracted with ether. The aqueous layer was neutralized with acetic acid and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow solid, mp 238°-239° C. Recrystallization from tetrahydrofuran gave yellow crystals, mp 232°-234° C.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC([O-])(C)C.[K+].O=[C:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1>C1COCC1>[C:1]([CH:3]=[C:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#N)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.47 %

Procedure:
Diethyl cyanomethylphosphonate (4.247 mL, 26.99 mmol) was suspended in THF (135.0 mL) and cooled to 0° C. Potassium 2-methylpropan-2-olate (32.39 mL, 32.39 mmol) was added portion-wise and stirred at 0° C. for 10 minutes. tert-Butyl 3-oxopyrrolidine-1-carboxylate (5 g, 26.99 mmol) was added dropwise as a solution in THF (25 mL). The resulting mixture was allowed to warm to ambient temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue partitioned between saturated aqueous NH4Cl and EtOAc. The organics were washed with brine, dried, MgSO4 and concentrated under reduced pressure to afford the crude material, which was passed through a pad of Celite® and silica, eluting with DCM to furnish tert-butyl 3-(cyanomethylene)pyrrolidine-1-carboxylate (2.5 g, 12.00 mmol, 44.47% yield. 1H NMR (CDCl3) δ 5.8 (s, 1H), 4.26 (t, 2H), 3.85 (s, 2H), 2.28 (t, 2H), 2.06-1.96 (m, 1H), 1.54 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>ClCCl>[Br:38][CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17]
Reactant: CC(C)(C)OC(=O)COc1cccc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CBr)c1

Procedure:
t-Butyl-3-(hydroxymethyl)-phenoxyacetate is dissolved in dichloromethane (1.3 L) at room temperature. Triphenylphosphine (127 g, 0.48 mol) is added with stirring, followed by dropwise addition of CBr4 (146 g, 0.44 mol). The resultant mixture is stirred for 1 hour at room temperature and then evaporated in vacuo. The residue (553 g) is adsorbed onto silica-gel (100 g) and then placed on a sintered glass funnel containing 700 g of silica gel. The column is eluted with hexane (2×4000 L) followed by 4:1 hexane/EtOAc (2×4000L). The hexane/EtOAc solutions are combined and evaporated in vacuo to provide t-butyl 3-(bromomethyl)-phenoxyacetate as a colorless oil. MS Found: M+18+:318, 320.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH3:21])[C:17]=3[CH:22]=2)[C:3]1=[O:23].S(Cl)([Cl:27])(=O)=O.ClCCCl>C(Cl)Cl>[Cl:27][C:6]1[C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH3:21])[C:17]=3[CH:22]=2)[C:3](=[O:23])[N:2]([CH3:1])[C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nsc2ccc(-n3c(=O)c(Cl)c(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.8 %

Procedure:
A mixture of 1-methyl-3-(3-methyl-1,2-benzisothiazol-5-yl)-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.00 g, 0.00293 mol), sulfuryl chloride (2.00 g 0.0148 mol) and 1,2-dichloroethane is stirred for five hours at reflux, cooled to room temperature, and diluted with methylene chloride. The resultant mixture is washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a residue. The residue is chromatographed on silica gel with ethyl acetate/hexanes to afford the title product as a white solid (0.350 g, 31.8%, mp 252-254° C.) which is identified by NMR spectral analysis.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:12]=1[C@H:11]([CH2:13][NH2:14])[CH2:10][CH2:9][CH2:8]2.C(#N)C.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>CN(C1C=CN=CC=1)C.O>[F:2][C:3]1[CH:4]=[C:5]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:12]=1[C@H:11]([CH2:13][NH:14][C:32](=[O:34])[CH3:33])[CH2:10][CH2:9][CH2:8]2
Reactant: NC[C@@H]1CCCc2cc(Sc3ccccc3)cc(F)c21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(=O)NC[C@@H]1CCCc2cc(Sc3ccccc3)cc(F)c21
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A mixture of C—((R)-8-fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine hydrochloride (1.36 kg), DMAP (10 g), acetonitrile (8.6 L), triethylamine (1.27 L), and acetic anhydride (0.41 L) was stirred at 25° C. After thirty minutes water (17.5 L) was added. The resulting slurry was stirred for 30 minutes at 25° C. The product was isolated by filtration and washed with 7.5 L of water. Drying overnight at 50° C. provided 1.34 kg of N—((R)-8-fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-acetamide (97.4% yield, 99.66% pure by HPLC, 98.08% ee): MP=94.6-95.9° C.; MS (M+1)=330; H1 NMR (300 MHz): δ (DMSO): 1.44-1.91 (4H, m), 1.83 (3H, s), 2.54-2.79 (2H, m), 3.06 (1H, m), 3.16 (2H, m), 6.83 (1H, dd, =1.51, 10.17 Hz), 6.90 (1H, bs), 7.30-7.45 (5H, m, phenyl), 8.01 (1H, bt, J=5.65 Hz, NH); [α]D=7.4° (MeOH). Chiral Assay (Area Norm): Column: Chiralpak AD-H (150×4.6 mm), mobile phase 88/12 hexane/ethanol(isocratic) Flow rate 0.7 ml/min, 25° C., uv @230 nm.: (R)-isomer 99.04/(S)-isomer 0.96
Reaction SMILES: [N:1]1([CH2:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.C1(=O)N(OC(N(C)C)=[N+](C)C)C(=O)CC1.C(N(CC)C(C)C)(C)C.[NH2:45][CH:46]([CH2:48][CH2:49][CH2:50][N:51]([CH2:54][CH3:55])[CH2:52][CH3:53])[CH3:47]>CN(C=O)C>[CH2:54]([N:51]([CH2:52][CH3:53])[CH2:50][CH2:49][CH2:48][CH:46]([NH:45][C:13](=[O:15])[CH2:12][CH2:11][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH3:47])[CH3:55]
Reactant: CCN(CC)CCCC(C)N
Reactant: O=C(O)CCN1CCCc2ccccc21
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCCC(C)NC(=O)CCN1CCCc2ccccc21

Procedure:
The procedure was carried out as described previously in step (b) of Example 8 with Compound 7 (1.9 g, 9.3 mmol), 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate (3.4 g, 11.2 mmol), N,N-diisopropyl ethylamine (3.4 mL, 19.5 mmol), 2-amino-5-diethylaminopentane (2.2 g, 13.9 mmol) and DMF (40 mL). Compound 10 was obtained (2.64 g) as a viscous liquid and used without any further purification. The structure of Compound 10 is given below:
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C([Mg]Br)C.C([Cu])#N.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O1CCCC1>[C:17]1([CH2:16][C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#CCCCC(=O)O
Reactant: BrCc1ccccc1
Agent: N#C[Cu]
Agent: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCCC#CCc1ccccc1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Hex-5-ynoic acid (0.1 mole) is added to a tetrahydrofuran solution of ethylmagnesium bromide (0.2 mole) maintained at 5° C. When the addition is complete, the solution is warmed to room temperature and CuCN (0.5 g) is added with stirring. After 20 minutes, a solution of benzylbromide (0.05 mole) in tetrahydrofuran is added dropwise over a one-half hour period. The reaction is maintained at room temperature until thin layer chromatography shows completion and then poured onto 1 N hydrochloric acid. This mixture is then extracted with ethyl ether and the ether layer separated. Removal of the ether gives a residue which is distilled under reduced pressure to afford the title product, 7-phenylhept-5-ynoic acid.