Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]([NH:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][C:36]=3[NH:37][CH3:38])=S)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[S].C([OH:42])C>[Hg]=O>[OH2:42].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[N:37]([CH3:38])[C:36]4[CH:35]=[CH:34][N:33]=[CH:32][C:31]=4[N:30]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CNc1ccncc1NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CCO
Agent: O=[Hg]
Agent: [S]
Product: Cn1c(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)nc2cnccc21
Product: O
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of 8 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N'-[4-(methylamino)-3-pyridinyl]thiourea, 15 parts of mercury(II)oxide, 0.1 parts of sulfur and 120 parts of ethanol was stirred and refluxed for 3 hours. After the addition of another 15 parts of mercury(II)oxide, stirring at reflux was continued for 2 hours. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 4.4 parts (59%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-1-methyl-1H-imidazo[4,5-c]pyridin-2-amine monohydrate; mp. 144.6° C. (compound 108).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH3:24])[CH:5]([N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:8]1[CH3:23])[CH3:6].Br[CH2:26][CH2:27][O:28][CH3:29]>[Cl-].[Na+].O>[C:19]([O:18][C:16]([C:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]([CH:5]([CH:4]([O:3][CH2:26][CH2:27][O:28][CH3:29])[CH3:24])[CH3:6])[C:8]=1[CH3:23])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COCCBr
Reactant: Cc1c(C(=O)OC(C)(C)C)c2cccnc2n1C(C)C(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCOC(C)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Temperature: 40 °C

Procedure:
Sodium hydride (0.026 g, 0.657 mmol) and (±)-tert-butyl 1-(3-hydroxybutan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (0.1 g, 0.329 mmol) were added to a 25 mL rbf and the atmosphere was purged with N2. DMF (5 mL) was added and the reaction was heated at 40° C. for 1 h. The reaction was cooled to ambient temperature and 1-bromo-2-methoxyethane (0.062 ml, 0.657 mmol) was added. The reaction was heated at 90° C. for 3 d. LCMS showed ˜60% conversion. The reaction was poured into half-saturated brine, extracted with EtOAc, the org layer was washed with half-saturated brine, brine, filtered, concentrated and loaded onto a column with aid of DCM. 2×12 g column, the column was then treated with 2 CV of Hex then 20% EtAOc in Hex to elute (±)-tert-butyl 1-(3-(2-methoxyethoxy)butan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (44.4 mg, 37.3%). LRMS (M+H+) m/z: calcd 363.46. found 363.1.
Reaction SMILES: C([Cl:4])(=O)C.C(O[C:10](=O)[N:11]([C@H:13]([C:15](=[O:47])[NH:16][C@@H:17]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:18]([N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:21]1[C:30](=[O:40])[NH:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=1[F:39])=[O:19])[CH3:14])C)(C)(C)C>CO>[ClH:4].[F:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[NH:31][C:30]([C@@H:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][CH2:29][N:20]1[C:18](=[O:19])[C@H:17]([CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1)[NH:16][C:15](=[O:47])[C@@H:13]([NH:11][CH3:10])[CH3:14])=[O:40]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: CO
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of acetyl chloride (552 mg, 500 μL, 7.03 mmol, Eq: 74.3) in MeOH (2 mL) was added to a vial containing ((S)-1-{(S)-1-cyclohexyl-2-[(S)-1-(2,6-di fluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (58 mg, 94.7 μmol, Eq: 1.00). The mixture was stirred at RT for 1 h. The solvent was evaporated and the resulting solid was dissolved in MeCN (3 mL) and water (1 mL) and the solution lyophilized to give (S)-2-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2,6-difluoro-phenyl)-amide hydrochloride (50 mg) as a white powder (50 mg), m/z=513 (M+H).
Reaction SMILES: S(Cl)(Cl)=O.Cl.[NH2:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH2:16](O)[CH3:17]>>[CH2:16]([O:14][C:13](=[O:15])[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[NH2:6])[CH3:17]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H](N)CCCCN

Procedure:
Thionyl chloride (5.0 ml, 8.06 g, 68 mmoles) was dropped into 500 ml of icecooled dry ethanol. The stirred mixture was kept for 20 min at this temperature and L-lysine hydrochloride (20 g, 109 mmoles) was added.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[C:9]1([C:19]2[CH:20]=[C:21]([CH:37]=[CH:38][CH:39]=2)[C:22](OCC(C)(NS(C(F)(F)F)(=O)=O)C)=[O:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]=1.C(OCC)(=O)C>CN(C)C=O.O>[ClH:1].[C:9]1([C:19]2[CH:20]=[C:21]([CH:37]=[CH:38][CH:39]=2)[C:22]([NH:4][C:3]([NH2:5])=[NH:2])=[O:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]=1
Reactant: CC(C)(COC(=O)c1cccc(C2=CCCc3ccccc32)c1)NS(=O)(=O)C(F)(F)F
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N=C(N)NC(=O)c1cccc(C2=CCCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a solution of guanidine hydrochloride (0.87 g) in N,N-dimethylformamide (5 ml) was added sodium methoxide (1.6 ml, 28% in methanol) under nitrogen atmosphere. After being stirred for 30 minutes at room temperature, to the reaction mixture was added a solution of 2-methyl-2-trifluoromethylsulfonylaminopropyl 3-(3,4-dihydro-1-naphthyl)benzoate (0.59 g) in N,N-dimethylformamide (5 ml). After being stirred for 21 hours at room temperature, the reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was dissolved in ethyl acetate and crystallized from slight excess 4N-hydrogen chloride-ethyl acetate. The crystalline was triturated with diethyl ether to give [3-(3,4-dihydro-1-naphthyl)benzoyl]guanidine hydrochloride (0.25 g).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:50])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:50])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 62.7 %

Procedure:
Starting with 0.153 g (0.74 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.41 g (0.74 mmol) of 2-[(7-bromoheptyl)oxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.286 g; 77.8% overall yield) was obtained as a white solid, mp 152°-153° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]([N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:11])=[CH:4][CH:3]=1.CO.NN>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH:10]([NH2:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(C#Cc1ccc(Cl)cc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: ClCCl
Solvent: CO
Product: CC(N)C#Cc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a solution of 2-[3-(4-chloro-phenyl)-1-methyl-prop-2-ynyl]-isoindole-1,3-dione (4.1 g, 13.2 mmol) in 20 mL of dichloromethane was added 30 mL of methanol followed by hydrazine (4.2 mL, 133 mmol, 10 eq.). The mixture was stirred for 1 hr, filtered, concentrated and chromatographed with 3% methanol-dichloromethane to provide 1.5 g of 3-(4-chloro-phenyl)-1-methyl-prop-2-ynylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[Cl:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](=[O:15])[CH2:8][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[CH:12][CH:11]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: COC(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cc(Cl)ccn1)c1ccc(Cl)cc1

Procedure:
To a solution of 4-chloro-2-methylpyridine (23.07 g, 181 mmol) and methyl 4-chlorobenzoate (30.8 g, 181 mmol) in dry THF (500 mL) at 0° C. was added 1 M LiHMDS in THF (63.5 g, 380 mmol) slowly via a dropping funnel. When complete, the reaction was quenched with NaHCO3 solution, concentrated under reduced pressure, and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[O:11]([CH2:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>[OH-].[Na+]>[O:11]([CH2:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)COc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(COc1ccccc1)Nc1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of anthranilic acid (5 g, 0.036 mol) in NaOH (3 g, 30 mL) was added phenoxyacetyl chloride (6.2 g, 5.2 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min, acidified with dilute hydrochloric acid and filtered. The filtered solid was dissolved in EtOAc and filtered. The filtrate was dried, filtered, concentrated and dried for 4 h under vacuum, affording 8 g (81%) of the title compound, mp 201°-203° C. A small amount (100 mg) of the title compound was recrystallized from EtOH, affording 75 mg of the title compound, mp 202°-203° C.; 1H NMR (DMSO-d6) δ 13.70 (s, 1H, COOH), 12.20 (s, 1H, NH), 8.71 (d, 1H, J=8.4), 8.02 (dd, 1H, J=7.6), 7.65-7.60 (m, 1H), 7.35-6.89 (m, 6H), 4.73 (s, 2H) ; 13C NMR (DMSO-d6) δ 169.44, 167.23, 157.11, 140.22, 134.34, 131.32, 129.65, 129.45, 123.06, 121.65, 120.96, 119.45, 116.14, 114.81, 114.38, 67.22; MS (EI, m/z) 271 (M+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:21]([O:23][CH3:24])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:25].[CH3:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[CH2:33](OCC)C>>[N:27]1([CH3:26])[CH2:32][CH2:31][CH2:33][C@H:28]1[C:29]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:21]([O:23][CH3:24])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:30].[ClH:25]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)CC(C)C
Reactant: CN1CCOCC1
Reactant: CCOCC
Agent: Cl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C
Reaction time: 24 h

Procedure:
A suspension of 1.0 g (7.74 mmoles) of N-Me-(L)-Pro,OH (Sigma) in 60 ml of dry methylene chloride (CH2Cl2) was brought, in an argon atmosphere, to the temperature of an ice and salt bath. The following were then added in succession: 1.250 g (7.74 mmoles) of commercial 1-hydroxybenzotriazole (HOBt) and 1.600 g (7.75 mmoles) of N,N'-dicyclohexylcarbodiimmide (DCC), leaving the system under stirring and maintaining control of the temperature for a further 30 minutes. To the reaction mixture was then added with 2.800 g (7.61 mmoles) of (L)-Leu-(L)-TrpOMe.HCl (Novabiochem) and 0.840 ml (7.62 mmoles) of 4-methylmorpholine (NMM), leaving the system under stirring for 12 hours with the temperature free to rise to room temperature. The fine white precipitate was then filtered away and washed with a little CH2Cl2. The latter was put back into the filtered reaction solution, which was concentrated under vacuum to approximately half its original volume, filtering away the new white precipitate. It was then extracted in succession using 5% NaHCO3 (3×30 ml) and saturated aqueous NaCl (2×30 ml), discarding the aqueous phases. The organic phase was then extracted with acetate buffer at pH 4 (3×30 ml), discarding the organic phase. The aqueous phase was brought to pH 6 and extracted using CH2Cl2 (3×30 ml). The organic phase, extracted with saturated aqueous NaCl (2×30 ml), was left in a cold chamber, under argon atmosphere and anhydrous Na2SO4 for 24 hours. The desiccant was then filtered away, the organic solution concentrated to a small volume and the residual yellowish liquid added dropwise under energetic stirring to an excess of dry petroleum ether (30/50), obtaining an abundant white precipitate. After several hours in a cold chamber the white solid was filtered and, taken up at the limit of solubility with anhydrous dioxane, was precipitated again in an excess of a solution of 1.0 M of gaseous HCl in anhydrous ethyl ether. After leaving the suspension to rest in a cold chamber for approximately 1 hour, the excess of acid was eliminated under a flow of dry nitrogen, then adding a large excess of anhydrous ethyl ether. The abundant fine milk-white precipitation, filtered under vacuum and washed in a little anhydrous ethyl ether, was left for 24 hours under vacuum on P2O5 . 2.550 g (70.0%) of an analytically pure semi-crystalline white solid were recovered.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.C(N(CC)CC)C.C1COCC1.[Br:35][CH:36]([CH3:40])[C:37](Br)=[O:38]>O>[Br:35][CH:36]([CH3:40])[C:37]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1)=[O:38]
Reactant: CC(Br)C(=O)Br
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CN)no1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Br)C(=O)NCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a mixture of 4.13 g of 3-aminomethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole, 1.56 g of triethylamine and 60 ml of THF was added dropwise with stirring 3.3 g of α-bromopropionyl bromide at 0°-5° C. After stirring for 1 hour at room temperature, the reaction mixture was diluted with water and extracted with benzene. The organic phase was successively washed with sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene-ethyl acetate (5:1, v/v). Crystallization of the clean fractions from diisopropyl ether yielded 4.88 g of 3-(2-bromopropionylaminomethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole as colorless needles, m.p. 98°-99° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:12])[CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[ClH:13].[C:14](OCC)(=O)[CH3:15]>C(O)C>[ClH:13].[NH2:12][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH2:8][C:9]([O:11][CH2:14][CH3:15])=[O:10]
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(N)c1ccccc1
Yield: 98.6 %

Procedure:
DL-3-amino-3-phenylpropionic acid (5.4 g, 0.032 moles) was added to saturated HCl (100 ml) in ethanol. The reaction mixture was stirred for 4 hours at room temperature under nitrogen. HCl in ethanol was removed under vacuum to afford a residue. The concentrated residue was trituated with ethyl acetate. The ethyl acetate was then removed in vacuum and the procedure was repeated twice. The resulting residue was dried under high vacuum to give a yellow solid (7.4 g, 98.6% yield). 1H NMR (400 MHz, CD3OD) δ 7.46-7.41 (m, 5H), 4.70 (m, 1H), 4.16-4.11 (m, 2H), 3.11-2.96 (m, 2H), 1.19 (t, 3H, 7.18 Hz). HRMS (M+H) calculated for C11H15N1O2 194.1176, found 194.1210.
Reaction SMILES: [CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20](=O)[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=O)OC.O.[NH2:28][NH2:29]>>[CH3:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20]1[N:28]=[N:29][C:3]2[C@@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@@H:5]([C:4]=2[CH:19]=1)[CH2:6][CH2:7]3
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)CC(C)(C)C)OC
Reactant: NN
Solvent: O
Product: CC(C)(C)Cc1cc2c(nn1)[C@]1(C)CC[C@H]2C1(C)C

Procedure:
white solid. MS (ESI): 259.1 (MH+). Prepared from (1R,4S)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, (4,4-dimethyl-2-oxo-pentyl)-phosphonic acid dimethyl ester, hydrazine monohydrate. Minor product, regioisomer of compound of example 22, isolated and purified by silica gel chromatography.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH:5]([NH:8][CH:9]([CH3:11])[CH3:10])([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH:5]([N:8]([CH:9]([CH3:11])[CH3:10])[CH2:3][C:2]#[CH:1])([CH3:7])[CH3:6]
Reactant: C#CCBr
Reactant: CC(C)NC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
Propargyl bromide (23.5 g, 197 mmol) was added dropwise to a mixture of diisopropyl amine (20 g, 197 mmol) and cesium carbonate (64 g, 197 mmol) in 350 mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The inorganic salts were then filtered off, and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were then evaporated to give 12 g of diisopropyl-prop-2-ynyl-amine: mass spectrum (m/e): M+H 139.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].[CH3:19]I.O>CN(C)C=O>[CH3:19][N:6]([C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)[C:3](=[O:5])[CH3:4]
Reactant: COC(=O)/C=C/c1ccc(NC(C)=O)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(N(C)C(C)=O)nc1
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 20.6 mg) in N,N-dimethylformamide (1 ml) was added dropwise a solution of methyl (E)-3-(6-acetylaminopyridin-3-yl)acrylate (180 mg) in N,N-dimethylformamide (2 ml) at 0° C. under nitrogen and the mixture was stirred for 1 hour. Methyl iodide (116 mg) was added to the mixture under the same condition and the mixture was stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was collected by vacuum filtration and washed with diisopropyl ether to give methyl (E)-3-[6-(N-methyl-N-acetylamino)pyridin-3-yl]acrylate (115 mg) as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:14][C:12]1[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[CH2:9][C:10](=[O:15])[CH:11]=1)[CH3:18]
Reactant: CCO
Reactant: O=C1CC(=O)CC(c2ccccc2O)C1
Solvent: O
Product: CCOC1=CC(=O)CC(c2ccccc2O)C1

Procedure:
5-(2-Hydroxyphenyl)-1,3-cyclohexanedione (5.0 g) was dissolved in ethanol (225 ml). The solution was heated under reflux for 3h and diluted to 2 l. by the addition of water. The solid which separated out was collected by filtration, washed with water and dried. Recrystallisation from ethanol afforded the title compound (1.5 g) as pale yellow prisms m.p. 194°-197°.
Reaction SMILES: ClC1C=C([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[O:10])C=CC=1.[CH3:28][NH2:29]>C(O)C>[Cl:27][C:23]1[CH:22]=[C:21]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[CH2:8][NH:29][CH3:28])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: CN
Reactant: O=C(Cc1cccc(Cl)c1)Nc1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Solvent: CCO
Product: CNCC(=O)Nc1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1

Procedure:
A mixture of 6.0 g of 3-chlorophenyl-4'-(m-chlorophenylsulfonyl)acetanilide, 1100 ml of methylamine and 20 ml of ethanol was refluxed for 3.5 hours. The solvent was evaporated and the residue partitioned between dichloromethane and water. The dichloromethane portion was evaporated and the residue crystallized from ethanol giving 2.48 g of the desired product, mp 110°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:9][C:8]([CH:26]=C)=[CH:7][N:6]=1)=[O:4].C(=O)(O)[O-:29].[Na+].CSC>C(Cl)Cl.CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[N:9][C:8]([CH:26]=[O:29])=[CH:7][N:6]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: C=Cc1cnc(C(=O)OC)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: [Na+]
Solvent: CSC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ncc(C=O)nc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
A mixture of 3-(di-tert-butoxycarbonyl-amino)-5-vinyl-pyrazine-2-carboxylic acid methyl ester (1 g, 2.64 mmol) and sodium bicarbonate (0.332 g, 3.95 mmol) in DCM (45 ml) and MeOH (15 ml) was cooled to −78° C. and purged with oxygen for 5 min. The reaction mixture was treated with ozone for 40 min until the mixture turned blue. The reaction mixture was purged with oxygen for 10 min and with nitrogen for 10 min, then dimethyl sulfide (0.487 ml, 6.59 mmol) was added at −78° C. and the mixture was allowed to warm to room temperature. The mixture was diluted with DCM and washed with 10% aq. sodium thiosulfate. The aq. layer was extracted with DCM and the combined organic layers were dried with Na2SO4 and evaporated to provide the title compound as yellow oil. The compound was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].CN[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:25]([N:27](CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([NH:27][CH2:25][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(CC)CC
Reactant: CNc1ccccc1
Reactant: O=C1CC(c2ccc(F)c(F)c2)CC(=O)O1
Solvent: ClCCl
Product: O=C(O)CC(CC(=O)NCc1ccccc1)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Difluorophenyl)glutaric anhydride (3.61 g) in CH2Cl2 (75 mL) at 0° C. was treated sequentially with N-methylaniline (2.16 mL), triethylamine (2.78 mL) and N,N-dimethylaminopyridine (195 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 (300 mL) and washed with 1N HCl (1×100 mL) and water (1×100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (4.3 g).