Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([OH:13])[C:5]1[CH:6]=[CH:7][C:8]([OH:12])=[C:9]([OH:11])[CH:10]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[CH:45]=[C:44]([CH:49]([CH3:53])[C:50]([OH:52])=O)[CH:43]=[CH:42]2>C(#N)C>[OH:11][C:9]1[CH:10]=[C:5]([CH:4]([OH:13])[CH2:3][N:2]([CH3:1])[C:50](=[O:52])[CH:49]([C:44]2[CH:43]=[CH:42][C:41]3[C:46](=[CH:47][CH:48]=[C:39]([O:38][CH3:37])[CH:40]=3)[CH:45]=2)[CH3:53])[CH:6]=[CH:7][C:8]=1[OH:12]
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Reactant: CNC[C@H](O)c1ccc(O)c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: COc1ccc2cc(C(C)C(=O)N(C)CC(O)c3ccc(O)c(O)c3)ccc2c1
Reaction time: 0.17 h

Procedure:
Epinephrine (Aldrich, 3.18 grams [g], 17.3 millimoles [mmol]), 1-hydroxylbenzotriazole hydrate (Aldrich, 1.76 g, 12.9 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (Aldrich, 2.49 g, 12.9 mmol) were added to acetonitrile (200 milliliters [ml]). After stirring for 10 minutes, a solution of 6-methoxy-α-methyl-2-naphthaleneacetic acid (Aldrich, 2.0 g, 8.66 mmol), in 50 ml of acetonitrile, was added dropwise. After stirring for 16 hours, the reaction mixture was concentrated in vacuo (under reduced pressure), and the residue was partitioned between water (100 ml) and methylene chloride (100 ml). The layers were separated and the aqueous layer was extracted with methylene chloride (2×50 ml) and ethyl acetate (50 ml). The combined organic extracts were treated with methanol until a clear solution was formed. This solution was dried (magnesium sulfate) and concentrated in vacuo. Flash chromatography of the residue (silica gel, 95:5, volume:volume [v:v], methylene chloride:methanol), and concentration of the appropriate fractions resulted in the formation of a solid. The solid was recrystallized from a mixture of ethyl acetate and hexane to give N-(2(3,4-dihydroxyphenyl)-2-hydroxyethyl)-N-methyl-2-(6-methoxy-2-naphthyl)propionamide, a mixture of diastereomers, as a white solid (0.95 g, 27% yield).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[C:39](#[N:41])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([C:39]#[N:41])[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(C#N)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
A solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1 was treated with tetra-n-butyl ammonium cyanide in acetonitrile at 100° C. for 4 hours. Solvent was concentrated to dryness and purified by chromatography to give a protected intermediate that was de-protected similar to step 5, Example 76, to give 4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidine-2-carbonitrile. MS: ES+: 399
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[CH2:12]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+].C1C[O:31]CC1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:31])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCOC1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Product: OC1(c2ccccc2C(F)(F)F)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.25 g (0.135 mol) of Mg are mixed with a spatula tipfull of 12, and a solution of 30.4 g (0.135 mol) of 2-bromo-1-trifluoromethylbenzene in 125 ml of THF is added dropwise. The mixture is stirred for one hour at room temperature and 10.1 g (0.041 mol) of benzylpiperidone are added dropwise. The mixture is stirred for 1 hour at room temperature and a saturated ammonium chloride solution is added. After extraction with ethyl ether, the organic phase is dried and the solvent is evaporated off under reduced pressure. The product is purified by chromatography on a silica gel column using a cyclohexane/ethyl acetate mixture as the eluent to give 6.8 g of 1-benzyl-4-hydroxy-4-(2-tri-fluoromethylphenyl)piperidine, which is hydrogenated with 0.7 g of 10% Pd/C in 75 ml of 95% ethanol which has been brought to acid pH by the addition of hydrochloric acid, the mixture being heated at a temperature of 60° C. for 8 hours. The catalyst is filtered off to give 2.1 g of the title product M.p. 247-251° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[Br:12].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[Br:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[NH:1][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2Br)cc1
Temperature: 0 °C
Reaction time: 52 h

Procedure:
To a solution of 4-amino-3-bromobenzotrifluoride (20.0 g, 83.3 mmol) in pyridine at room temperature is added p-toluenesulfonyl chloride (19.8 g, 104.1 mmol) in portions over 3 minutes, and the resulting mixture stirred for 52 hours. The suspension is poured into an ice-water mix (300 ml), filtered; and the filtered solid is washed with water (250 ml). The solid is dissolved in dichloromethane (200 ml) and the resulting solution is washed with 1N HCl (2×150 ml), water (2×200 ml), dried (Na2SO4), and concentrated to a solid. The solid is suspended in ethanol (700 ml) and heated at reflux for 10 minutes, filtered while hot to remove insolubles, and the filtered solids washed with ethanol (250 ml). After concentration of the filtrate, the resulting solid is suspended in methanol (500 ml), treated with K2CO3 (2.0 g, 14.4 mmol), and the mixture is stirred at room temperature for 46 hours. After filtration of the suspension, the filtered solid is washed with methanol (150 ml), and the filtrate is concentrated to give the title compound as a foam. Mass spectrum (ES+): 394 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[CH3:28][S-:29].[Na+]>O1CCOCC1.CN(C=O)C>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([S:29][CH3:28])[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(SC)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium methanethiolate in dioxane and DMF. ES-MS m/e (%): 417 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:13]1[N:14]=[CH:15][N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:13]1[N:14]=[C:15]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12
Reactant: c1ccn2cnnc2c1
Reactant: Fc1cccc2ccc(Cl)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Fc1cccc2ccc(-c3nnc4ccccn34)nc12

Procedure:
2-Chloro-8-fluoroquinoline (0.75 g, 4.13 mmol) was combined with [1,2,4]triazolo[4,3-a]pyridine (0.541 g, 4.54 mmol), micronized Cs2CO3 (2.69 g, 8.26 mmol), and PdCl2(PPh3)2 (0.290 g, 0.413 mmol) then the mixture was slurried in dioxane (20 mL). The reaction was deoxygenated with argon and heated to reflux for 20 hours, then cooled, diluted with CHCl3 and filtered through a pad of Celite®. The filtrate was concentrated onto Na2SO4 powder (15 g) and the mixture was chromatographed on SiO2 eluting with a stepped gradient of 0-2% MeOH/ethyl acetate. The desired product was isolated as a cream-colored solid (1.12 g). MS APCI (+) m/z 265.3 (M+1) detected.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[S-:9][C:10]#[N:11].N1C2C(=CC=CC=2)C=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:5]([O:4][C:2]([N:11]=[C:10]=[S:9])=[O:3])[CH:6]([CH3:8])[CH3:7]
Reactant: N#C[S-]
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: CC(C)COC(=O)N=C=S
Temperature: 27.5 °C

Procedure:
136.58 grams (1 mole) of 99% isobutyl chloroform ate are added to a 50% thiocyanate solution containing 81 grams (1 mole) of NaSCN, 81 grams of water, 4.36 grams of quinoline (catalyst) and 1.8 grams of Na2CO3 (base) while maintaining a reaction temperature of 25-30° C. with agitation. The reaction is monitored for the consumption of the chloroformate during the formation of an upper layer of isobutoxycarbonyl isothiocyanate (approximately 4 hours). The contents of the reaction vessel are filtered to remove solid sodium chloride and the isobutoxycarbonyl isothiocyanate is isolated in the form of a layer that separates from the aqueous layer.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH2:11]([N:29]=[C:30]=[O:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:30]([NH:29][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 83.3 %

Procedure:
A mixture of 0.5 g (3.6 mmol) of 3-nitroaniline, 1.2 mL (3.9 mmol) of octadecyl isocyanate 0.7 mL (5 mmol) of triethylamine and 0.1 mL of 4-dimethylaminopyridine in 30 mL of anhydrous THF was stirred at reflux for 18 hours. The reaction mixture was concentrated at reduced pressure and the residue was recrystallized from THF methanol-water to give 1.3 g of N-(3-nitrophenyl)-N'-octadecylurea.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O)[CH3:36].[C:46](=O)([O-])[O-:47].[Na+].[Na+]>C(O)(C)C.C1(C)C=CC=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:38]4[CH:39]=[CH:40][C:41]([O:47][CH3:46])=[CH:42][C:37]=4[CH2:35][CH3:36])=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(Br)nc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C([O-])[O-]
Reactant: CCc1ccccc1B(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCc1cc(OC)ccc1-c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)cn1
Temperature: 80 °C
Reaction time: 9 h
Yield: 59 %

Procedure:
To a stirred slurry of 613 mg (1.17 mmol) of (S)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-bromo-pyridin-3-yl)propanoate and 422 mg (2.34 mmol, 2 eq.) of 2-ethylphenylboronic acid in 20 mL of 1:1 isopropanol/toluene was added 10.0 mL of 2 M aqueous sodium carbonate solution. The reaction mixture was purged twice with argon and evacuated and then 43.2 mg (0.059 mmol, 0.05 equivalents) of bis(tricyclohexylphosphine)palladium (II) chloride was added and the mixture was again purged with argon and evacuated. The rapidly stirred mixture was heated at 80° C. under argon. After 9 h, the reaction mixture was cooled to room temperature and partially concentrated to remove isopropanol. The residue was partitioned between ethyl acetate and water and the aqueous phase was extracted once more with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated to give a brown oil. Purification by chromatography on silica gel using ethyl acetate/dichloromethane (3:17) as eluant (5×15 cm column), gave the expected compound as a colorless oil, 401 mg, 59% yield.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:34]2([CH3:35])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[CH3:22])[CH2:12][C@@H:11]([O:37][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:34]2([CH3:35])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:27])[CH3:28])[CH3:22])[CH2:12][C@@H:11]([OH:37])[CH2:10]1
Reactant: C[C@H](OCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](OCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.1 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(3-hydroxy-3-methylbutyloxy)pregna-5,7,16-triene (27 mg, 0.0419 mmol) in tetrahydrofuran (1 ml) was combined with 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (0.25 ml, 0.25 mmol), and stirred at room temperature for 20 hours, then with heating under reflux for 2 hours. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine successively, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by preparative thin layer chromatography (0.5 mm×1 and 0.25 mm×1, dichloromethane:ethanol=20:1, developed twice) to give the title compound as a colorless oil (17.3 mg, 99%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH3:9][C:10]1[CH:18]=[C:17]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:17]([C:19]([F:28])([C:20]([F:21])([F:22])[F:23])[C:24]([F:25])([F:26])[F:27])=[CH:18][C:10]=2[CH3:9])[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1C(=O)Cl
Reactant: Nc1cccc(N)c1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1C(=O)Nc1cccc(N)c1

Procedure:
N-(3-Amino-phenyl)-2-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzamide was prepared from benzene-1,3-diamine and 2-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzoyl chloride (Example I4) using the same procedure. 1H-NMR (CDCl3, 400 MHz): 7.6 (m, 1H), 7.52 (s, 2H), 7.40 (s, 1H), 7.30 (s, 1H), 7.13 (t, 1H), 6.72 (d, 1H), 6.50 (d, 1H), 3.76 (s, 2H), 2.24 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=1.BrCCC=C>O1CCCC1>[CH2:13]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)[CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: [Li]CCCC
Agent: C=CCCBr
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCCCc1ccc(C(=O)O)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (100 ml of 2.5M solution in hexane, 0.25 mol) was added to a stirred solution of diisopropylamine (35 ml, 0.25 mol) in dry tetrahydrofuran (250 ml) at -78° C. under a nitrogen atmosphere. The solution was allowed to warm up to -5° C., stirred for 30 minutes, cooled back to -78° C., and treated with p-toluic acid (17.0 g, 0.125 mol) in portions over 2 hours. The resulting mixture was allowed to warm up to -5° C. and stirred for 30 minutes. The resulting black solution was again cooled to -78° C. and treated dropwise with a solution of 4-bromobutene (17 ml, 0.166 mol) in dry tetrahydrofuran (100 ml) over 1 hour. The resulting yellow solution was allowed to warm up to room temperature and stirred for an additional 12 hours. The solvent was evaporated off under reduced pressure and the residue was treated with hydrochloric acid (500 ml of 5M) and extracted with dichloromethane (3×300 ml). The combined extracts were washed with water (2×250 ml), brine (250 ml) and dried over sodium sulfate. The solvent was evaporated off under reduced pressure to give crude 4-(4-pentenyl)benzoic acid as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:12][CH3:13])[C:9]([OH:11])=O.[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:12][CH3:13])[C:9]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([C:15]#[N:14])=[CH:17][CH:18]=1)=[O:11]
Reactant: COC(C(=O)O)c1ccccc1Cl
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1Cl

Procedure:
(RS)-(2-Chloro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-2-(2-chloro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Light yellow oil. MS 315.1 ([M+H]+)
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:8][CH2:7][CH2:6][CH2:5][CH:4]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[K+]>C1(C)C=CC=CC=1>[CH2:24]([O:1][CH2:2][C:3]1[O:8][CH2:7][CH2:6][CH2:5][CH:4]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: OCC1=CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOCC1=CCCCO1
Yield: 84.9 %

Procedure:
5.71 g of 6-hydroxymethyl-3,4-dihydro-2H-pyran, 16.79 g of hexadecyl bromide and 8.22 g of pulverized 85% potassium hydroxide were mixed in 160 ml of toluene and heated under reflux for 2 hours. The mixtured was then cooled, washed with water, dried and condensed by evaporation under reduced pressure. The resulting oily residue, 17 g, was subjected to column chromatography through 400 g of silica gel. The fraction eluted with a 1:5 by volume mixture of diethyl ether and hexane gave 14.38 g of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]([OH:5])#[C:2][CH2:3][CH3:4].I[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C.[Cu]I>[OH:5][CH2:1][CH2:2][C:3]#[C:4][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: CCC#CO
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#CCCO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a solution of butyn-1-ol (0.76 g, 0.11 mol) and methyl 4-iodophenylacetate (1.5 g, 0.0054 mol) in acetonitrile (10 mL) at 0° C., triethylamine (1.5 mL, 0.01 mol) was added, followed by the addition of bistriphenylphosphine palladium chloride (0.25 g, 0.36 mmol) and CuI (0.025 g). The reaction mixture was stirred at 0° C. under an argon atmosphere for 30 minutes and at room temperature for 3 hours. The dark colored reaction mixture was concentrated under reduced pressure, and the residue was partitioned between 5% citric acid (50 mL) and EtOAc (50 ML). The organic phase was washed with 5% citric acid (3×15 mL), water, dried (Na2SO4), filtered, and concentrated. The resulting material was purified by silica gel flash column chromatography eluting with 35% EtOAc in hexane to afford methyl 4-(4-hydroxy-1-butynyl)phenylacetate (1 g, 85%) as a dark colored liquid. FAB-MS m/z=219 (M+H), HRMS calcd. for C13H15O3 (M+H), 219.1021, found 219.1008. Calcd for C13H14O3 : C, 71.54, H 6.46; found: C, 71.04, H, 6.41.
Reaction SMILES: [NH3:1].[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=[O:10]>[Pd].[H][H]>[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=[O:10].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:1]
Reactant: N
Reactant: [H][H]
Agent: [Pd]
Agent: CC1CCCC(C)C1=O
Product: Cc1cccc(C)c1N
Temperature: 220 °C

Procedure:
A catalyst which is in the form of extrudate of 3 mm diameter and 10 mm length and which contains 1.8% by weight of palladium on a zinc-aluminum spinel as the carrier is introduced into a reactor consisting of a pressure-resistant cylindrical tube of 1.2 liters volume, and is heated to 220° C. Per hour, a gaseous mixture of 200 liters (S.T.P.) of ammonia and 200 liters (S.T.P.) of hydrogen and 100 g of vaporized 2,6-dimethylcyclohexan-1-one are passed over this catalyst bed under atmospheric pressure. The reaction product is cooled as soon as it leaves the reactor, and is distilled. 100 g of 2,6-dimethylcyclohexan-1-one give 93 g of 2,6-dimethylaniline of boiling point 216° C. at atmospheric pressure, corresponding to a yield of 97% of theory.
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([N:12]([CH:21]([C:25]2[CH:34]=[CH:33][C:28]3OC[CH2:31][O:32][C:27]=3[CH:26]=2)[C:22]([NH2:24])=[O:23])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:35]C1C(C(O)=S)=NC(C)=NC=1.COC1C=C(C=CC=1)C=O>>[CH3:35][C:2]1[C:3]([C:10]([N:12]([CH:21]([C:25]2[CH:34]=[CH:33][CH:28]=[C:27]([O:32][CH3:31])[CH:26]=2)[C:22]([NH2:24])=[O:23])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Cl)c(C(=O)N(Cc2ccc(C)cc2)C(C(N)=O)c2ccc3c(c2)OCCO3)n1
Reactant: Cc1ncc(C)c(C(O)=S)n1
Agent: COc1cccc(C=O)c1
Product: COc1cccc(C(C(N)=O)N(Cc2ccc(C)cc2)C(=O)c2nc(SC)ncc2C)c1

Procedure:
This was prepared in the same manner as the product from example 242 using 5-methyl-2-methylthiopyrimidine-4-carboxylic acid (preparation 17) and 3-methoxybenzaldehyde as the acid and aldehyde components to give the title compound as a solid, 0.97 g, (72%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[C:1]([CH:3]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: COC(=O)CC#N
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of Na3PO4 (9.84 g, 60.0 mmol), methyl cyanoacetate (2.38 g, 24.0 mmol), and tert-butyl 4-bromobenzoate (5.14 g, 20.0 mmol) were added Pd(dba)2 (575 mg, 1.00 mmol), toluene (60 mL), and P(t-Bu)3 (10% wt in hexanes, 11.56 mL, 3.89 mmol). After degassing for 20 minutes, the reaction was stirred at 80° C. for 16 h. The resulting mixture was diluted with EtOAc, washed with H2O and brine, dried (MgSO4), and concentrated. Flash chromatography on silica gel (0-15% EtOAc/hexanes) gave tert-butyl 4-(1-cyano-2-methoxy-2-oxoethyl)benzoate as a white solid. 1H NMR (CDCl3) δ8.02 (d, J=7.9 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 4.79 (s, 1H), 3.79 (s, 3H), 1.58 (s, 9H). MS (ESI) calcd [M+H]+ 276.1, found 276.1.