Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[N:14][CH:15]=1
Reactant: NC(N)=S
Reactant: COc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)nc1
Solvent: CCO
Product: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)nc1
Yield: 5.7 %

Procedure:
A mixture of 2-bromo-1-{4-((5-methoxypyridin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (18-3, 1.89 g, 5.40 mmol) and thiourea (0.47 g, 6.18 mmol) in 95% EtOH (20.0 mL) was heated at reflux for 2.0 h. The solution was concentrated and added with water (10 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-{4-((5-methoxypyridin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (18-4, 0.10 g) as yellow solids in 5.7% yield: 1H NMR (500 MHz, CDCl3) δ 7.60 (m, 1 H), 7.30 (m, 1 H), 6.89 (m, 1 H), 6.77 (s, 2 H), 6.25 (s, 1 H), 3.83 (s, 3 H), 2.17 (s, 6 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH2:18])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH:18][C:36](=[O:37])[CH2:35][NH:34][C:32](=[O:33])[C:31]1[CH:39]=[CH:40][CH:41]=[C:29]([C:28]([F:27])([F:43])[F:42])[CH:30]=1)[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#C[C@H](O)[C@@H](N)CNC(=O)OCc1ccccc1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
(2S,3S)-(2-Amino-3-hydroxy-hex-4-ynyl)-carbamic acid benzyl ester (2.53 g, prepared as in WO PCT 0250019) was dissolved in CH2Cl2 (50 ml) and 4-methylmorpholine (2.53 ml) and cooled to 0° C. prior to the addition of (3-trifluoromethyl-benzoylamino)-acetic acid (1.49 g) and HATU (2.23 g). After the reaction was stirred overnight at room temperature, the CH2Cl2 was removed and EtOAc was added. The organic layer was washed with saturated NH4Cl solution (aq) brine, dried, filtered, and concentrated. Flashed chromatography of the resulting residue gave (2S,3S)-{3-hydroxy-2-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-hex-4-ynyl}-carbamic acid benzyl ester (1.3 g). MS found: (M+H)+=492.3.
Reaction SMILES: P(O)(O)(O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[C:19]1([C:25]([CH3:30])([OH:29])[C:26]([OH:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C@:25]([CH3:30])([OH:29])[C:26]([OH:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(O)(C(=O)O)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P(O)(O)O
Product: C[C@@](O)(C(=O)O)c1ccccc1

Procedure:
We next examined the preparation of aryllactic acid derivatives 6 through hydrolysis of the corresponding cyanohydrins 5. Phenyllactic acid and derivatives serve as versatile building blocks for the preparation of numerous biologically active compounds. (Coppola, G. M.; Schuster, H. F. Chiral α-Hydroxy Acids in Enantioselective Synthesis; Wiley-VCH: Weinheim, Germany 1997.) Upon screening our nitrilase library against the parent cyanohydrin 5a (Ar=phenyl), we found several enzymes that provided 6a with high enantiomeric excess. One enzyme, SEQ ID NOS: 103, 104, was further characterized. After optimization, SEQ ID NOS:103, 104, was shown to provide (S)-phenyllactic acid (6a) with complete conversion (50 mM) and very high enantioselectivity (98% ee) over 6 h. The highest enantioselectivity previously reported for biocatalytic conversion of 5 to 6 was 75% ee achieved through a whole cell transformation using a Pseudomonas strain. (Hashimoto, Y.; Kobayashi, E.; Endo, T.; Nishiyama, M.; Horinouchi, S. Biosci. Biotech. Biochem. 1996, 60, 1279.)
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[C:10]([NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:10]([NH:14][C:15](=[O:23])[C:16]1[C:21]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Reactant: Cc1ccccc1[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(Cl)ncc1C(=O)NC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
92 ml (92 mMol) o-Tolylmagnesium chloride solution (1M in THF) were added over 15 minutes to a solution of 5.0 g (23 mMol) N-tert.-butyl-6-chloro-nicotinamide in 25 ml THF cooled to 0° C. The reaction mixture was stirred 18 hours at 30° C. and cooled again to 0° C. 5.6 ml (138 mMol) Methanol were added over 30 minutes, stirring was pursued for 10 minutes and 6.3 g (27 mMol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were added. After 1 hour at room temperature, the reaction mixture was concentrated to 50 g under reduced pressure, heated to 50° C. and 100 ml tert.-butyl-methylether were added. The resulting suspension was refluxed for 30 minutes, cooled to room temperature and, after 1 hour, filtered off. The filtrate was concentrated and dried under high vacuum to yield 6.3 g (90%) of N-tert.-butyl-6-chloro-4-o-tolyl-nicotinamide as an orange foam.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:2]/[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Product: COC(=O)c1ccc(C(=O)/C=C/N(C)C)cc1
Temperature: 105 °C

Procedure:
A mixture of methyl 4-acetylbenzoate (5.00 g, 28.1 mmol) in DMF-DMA (38 mL, 284 mmol) was heated at 105° C. for 20 hours. The reaction was cooled, concentrated, and used crude in the next reaction.
Reaction SMILES: [OH:1][NH:2][CH:3]([C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)=[CH:10][CH:9]=1)[CH3:7])[C:4]#[N:5].Cl.[NH2:25]O.C([O-])(=O)C.[Na+]>CCO>[F:22][C:20]([F:23])([F:21])[C:18]1[N:19]=[C:15]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([C@H:6]([C:3]3[C:4]([NH2:25])=[N:5][O:1][N:2]=3)[CH3:7])=[CH:13][CH:12]=2)[S:16][CH:17]=1
Reactant: NO
Reactant: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)C(C#N)NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1nonc1N
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of intermediate 13a (0.738 gr, 2.16 mmol), hydroxylamine hydrochloride (83 mg, 2.50 mmol) and sodium acetate (410 mg, 5 mmol) in EtOH (15 ml) was refluxed for 4 h. After cooling, the precipitate was collected by filtration and dried. The precipitated α-oximido-acetamidoxime sodium acetate derivative was refluxed with excess PCl5 in dry Et2O (15 ml) for 6 h. After cooling at room temperature the reaction was quenched with a buffered solution at pH 8.2 (10 ml) and the two phases separated. The aqueous layer was extracted with Et2O (2×10 ml) and the collected organic phases were dried over anhydrous Na2SO4 and evaporated under vacuum to give 4-[(1R)-1-{4-[(4-(trifluoromethyl)-1,3-thiazol-2-yl)amino]phenyl}ethyl]-1,2,5-oxadiazol-3-amine (0.57 g, 1.62 mmol) as a white solid (75%). 1H-NMR (DMSO-d6): δ 8.25 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 7.05 (s, 1H), 5.15 (bs, 2H, NH2), 3.90 (q, 1H, J=7 Hz), 1.75 (d, 3H, J=7 Hz).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][N:16]=[CH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH2:28])=[N:20]1>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:28][C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][N:20]=2)[C:3]2[CH:18]=[CH:17][N:16]=[CH:15][C:4]=2[N:5]=1
Reactant: Clc1ccccc1-c1nc(Cl)c2ccncc2n1
Reactant: Nc1n[nH]c2ccccc12
Product: Clc1ccccc1-c1nc(Nc2n[nH]c3ccccc23)c2ccncc2n1

Procedure:
Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[3,4-d]pyrimidine (100 mg, 0.36 mmol) and 1H-indazol-3-ylamine (88 mg, 0.66 mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (72 mg, 33% yield). HPLC-Method A, Rt 3.21 min; 1H NMR (DMSO, 500 MHz): δ12.95 (1H, s), 10.90 (1H, bs), 9.25 (1H, s), 8.75 (1H, m), 8.55 (1H, m), 7.65 (1H, m), 7.55 (1H, m), 7.50-7.30 (5H, m), 7.00(1H, m); MS (m/z), MH+373.1.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1>C(O)C>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=2)=[CH:20][CH:19]=1)#[N:28]
Reactant: CCc1cc(Cl)n2nccc2n1
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Solvent: CCO
Product: CCc1cc(NCc2ccc(-c3ccccc3C#N)cc2)n2nccc2n1

Procedure:
5.5 g (30.3 mmol) of the chloride from Example 1, Step B and 6.3 g (30.3 mmol) of 4-aminomethyl-2'-cyanobiphenyl (prepared according to EP 459 136) were heated in 150 ml dry ethanol for 10 h. After removal of the solvent in vacuo yellow crystals formed. These were purified by suspension in acetone and dissolved in ethyl acetate. The solution was washed with 10% sodium carbonate solution, the organic layer dried over sodium sulfate, and evaporated to dryness to give colorless crystals of the title compound, m.p. 230°-233° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH3:35])[CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:34]([N:27]([C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH3:33])[CH3:35]
Reactant: CCCOCCN(CC)c1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25 g), 4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl borate (0.3 g), 1M potassium carbonate solution (2.5 ml), ethanol (2.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-[N-ethyl-N-(2-propoxyethyl)amino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g) as green oil.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[C:14]1(=[O:19])[O:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][OH:19])=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: O=C1CCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To 60 mL of benzene was added NaOMe (5.4 g, 99.612 mmol) under nitrogen atmosphere and stirred. The above mixture was added then with 30 mL of 4-chloroacetophenone (5.9 mL, 45.278 mmol) after mixing it with 30 mL of benzene and stirred for 30 min at 40° C. Then, γ-butyrolactone (7.0 mL, 90.556 mmol), after mixing it with 30 mL of benzene, was slowly added thereto and stirred for 16 hrs at 40° C. The progress and completion of the reaction were confirmed by means of TLC. Upon completion of the reaction, the reaction mixture was cooled down to room temperature and the solvent was removed from the reaction mixture under reduced pressure. The reaction mixture was diluted with EtOAc, and added with water. The aqueous layer was extracted with EtOAc and the organic layer was dried with anhydrous MgSO4 and filtered. The resulting filtrate was concentrated under reduced pressure and the resulting concentrate was passed through column chromatography (EtOAc:Hexane=1:1, v/v) to obtain 5.9 g (54%) of target compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)=[O:28])[CH:23]=[CH:22][C:20]=2[N:21]=1.O1CCOCC1>CN(C)C=O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([NH:26][C:24]2[CH:23]=[CH:22][C:20]3[N:21]=[C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=5)[N:5]=[CH:4][N:3]=4)[S:18][C:19]=3[CH:25]=2)=[O:28])=[CH:31][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1nc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2s1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)cc4s3)c2cc1OC

Procedure:
1-(4-Chloro-3-trifluoromethylphenyl)-3-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]urea was prepared from 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 29 mg, 0.13 mmol) and 1-(2-aminobenzothiazol-6-yl)-3-(4-chloro-3-trifluoromethylphenyl)urea (Intermediate 3, 50 mg, 0.13 mmol) according to GP 1. Dimethylformamide was used as a solvent instead of dioxane. After removal of the solvent in vacuo, the residue was subjected to silica gel chromatography applying a dichloromethane-methanol gradient. The crude product was dissolved in dimethylformamide (2 mL) and water was added (2 mL). After storage at 4° C. overnight, the resulting precipitate was filtered off, washed with water and dried to obtain a yellow solid (27 mg, 48 μmol, 37%). LC/ESI-MS: m/z=575 [M(35Cl)+H]+; m/z=573 [M(35Cl)−H]=; Rt=4.14 min.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][CH2:29]O>OS(O)(=O)=O>[CH2:28]([O:18][C:17](=[O:19])[CH2:16][CH:15]([C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1)[C:20]#[C:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:29]
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)O)cc1OC1CCCC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC(C#Cc1ccccc1)c1ccc(OC)c(OC2CCCC2)c1

Procedure:
A solution of (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylpropionic acid (250 mg, 0.69 mmol) in EtOH (20 ml) and H2SO4 (1 drop) was refluxed for 6 hr. The solvent was evaporated, the residue taken up in Et2O, washed with aqueous Na2CO3, dried, and the solvent evaporated. The residue was crystallized from hexane, and gave the titled compound, 180 mg (67%). 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 2 H), 7.28 (m, 3 H), 6.98 (m, 2 H), 6.82 (d, 1 H), 4.80 (m, 1 H), 4.32 (t, 1 H), 4.14 (q, 2 H), 3.80 (s, 3 H), 2.86 (d of d, 1 H), 2.76 (d of d, 1 H), 1.76-1.98 (m, 6 H), 1.62 (m, 2 H), 1.22 (t, 3 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@H:10]([C:15]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CN(Cc2ccccc2)C[C@@H]1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R,4S)-1-Benzyl-3-hydroxy-4-methylpyrrolidine (4.00 g) was dissolved in dichloromethane (40 mL). While the solution was chilled in a dry ice/acetone bath, triethylamine (3.06 mL) was added, followed by dropwise addition of methanesulfonyl chloride (1.70 mL) and stirring for 1 hour. Subsequently, water (40 mL) was added and the mixture was allowed to warm to room temperature. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (40 mL). The dichloromethane layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (120 mL), followed by the addition of tetrabutylammonium cyanide (5.53 g) and sodium cyanide (2.05 g) and stirring at 80° C. for 13 hours. Subsequently, the reaction mixture was concentrated under reduced pressure. Water (50 mL) was then added to the resulting residue and the mixture was extracted with diethyl ether (2×200 mL). The diethyl ether layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=4:1) to give (3R,4S)-1-benzyl-4-methyl-3-pyrrolidinecarbonitrile as a brown oil (3.32 g).
Reaction SMILES: [N:1]([C:4]([C:6]1[N:10]=[CH:9][O:8][N:7]=1)=[O:5])=[N+]=[N-].N[C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>C(Cl)(Cl)Cl>[C:12]12([NH:1][C:4]([C:6]3[N:10]=[CH:9][O:8][N:7]=3)=[O:5])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: [N-]=[N+]=NC(=O)c1ncon1
Solvent: ClC(Cl)Cl
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1ncon1
Reaction time: 24 h
Yield: 27 %

Procedure:
3-Azidocarbonyl-1,2,4-oxadiazole (350 mg.) was added to a solution of 1-aminoadamantane (378 mg.) in chloroform (15 ml.) and the mixture was stirred for 24 hr. The chloroform solution was evaporated to dryness under reduced pressure and the residue was recrystallised from aqueous methanol to give title compound (167 mg.), m.p. 141°-142°, νmax. (EtOH) 230 nm (ε 3,910), λmax. (Nujol) 3392 (--NH--) 1692 and 1515 cm.-1 (CONH). Further examples provided in Table II were prepared by the following general methods:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH3:13])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Br
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Cl)ccc1Br

Procedure:
A solution of 2-bromo-5-chlorobenzoic acid in ethanol (10 ml) and sulphuric acid (0.5 ml) was refluxed for 20 hours then cooled and evaporated. The residue was dissolved in diethyl ether/water and the organic layer dried (magnesium sulphate) and evaporated to give 516 mg of light brown oil.
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:10][S-:11].[Na+]>CN(C=O)C.O>[C:1]([C:3]1[C:8]([S:11][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncccc1F
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cccnc1C#N
Reaction time: 0.08 h

Procedure:
A stirred solution of 1.00 g (8.19 mmol) of 2-cyano-3-fluoropyridine and 0.631 g (9.01 mmol) of sodium thiomethoxide in 8 mL of DMF was stirred at room temperature for 1 h. The reaction mixture was diluted with water (80 mL) and stirred for 5 min. The resulting solid was filtered and dried on a high vacuum line to give the product as an off-white solid: 1H NMR (CDCl3) δ8.46 (d,1H, 4.6 Hz), 7.66 (d, 1H, 8.3 Hz), 7.44 (dd, 1H, 4.6, 8.3 Hz), 2.58 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC[C:28]1[N:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:28]3[N:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: Clc1ccc(CBr)nn1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)nn3)c2CC1

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 3-bromomethyl-6-chloropyridazine to give 3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. Use a method similar to the General Procedure 1-4 to give the title compound as an off-white powder. MS (APCI+) m/z: 340 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14]2)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: Cc1cnn(-c2nc(N)nc(S(C)=O)c2C#N)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cnn(-c2nc(N)nc(SCCc3ccccn3)c2C#N)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-(4-methyl-pyrazol-1-yl)-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 338 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][NH:27][CH3:28]>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([N:27]([CH3:28])[CH3:26])=[O:20]
Reactant: CNC
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)C(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), a 40% aqueous solution of dimethylamine (0.410 g, 3.64 mmol), and carbon tetrachloride (25 ml) were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting semi-solid product was recrystallized by adding hexane to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N',N'-dimethyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.410 g, 36.4% yield).