Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH:14]([O:23][Si](C(C)(C)C)(C)C)[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:10][CH:9]=1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([Cl:40])[CH:39]=1.F>C(#N)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.C(O)C.C1(C)C=CC=CC=1>[Cl:33][C:34]1[CH:35]=[C:36]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:31][CH:32]=2)[CH:37]=[C:38]([Cl:40])[CH:39]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCc1cccnc1)COc1ccc(Br)cc1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: F
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CC#N
Solvent: Cc1ccccc1
Product: OC(CCc1cccnc1)COc1ccc(-c2cc(Cl)cc(Cl)c2)cc1
Temperature: 120 °C
Yield: 78.9 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (3 ml), aqueous sodium carbonate (2 M, 1.4 ml), (±)-3-(4-(4-bromophenoxy)-3-(tert-butyldimethylsilyloxy)butyl)pyridine (0.67 g), ethanol (0.8 ml), 3,5-dichlorobenzeneboronic acid (0.30 g) and tetrakis(triphenylphosphine)palladium(0) (73 mg) with heating at 120° C. for 6 hours. The residue obtained after work up was deprotected as in Example 34e) using hydrofluoric acid (40%, 4 ml) in acetonitrile (30 ml). The residue obtained after work up was purified by column chromatography over silica eluting with dichloromethane then ether then ethyl acetate to give an oil (0.47 g). This was recrystallised from ether to give the title compound as a white solid (0.21 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])=[CH:12][CH:11]=2)[C:5]([C:22]#[N:23])=[C:4]([O:24][CH3:25])[N:3]=1.[S-2:26].[Na+].[Na+]>CN(C=O)C>[OH:21][C@@H:18]([CH2:19][OH:20])[CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:7]([C:8]#[N:9])=[C:2]([SH:26])[N:3]=[C:4]([O:24][CH3:25])[C:5]=2[C:22]#[N:23])=[CH:11][CH:12]=1
Reactant: COc1nc(Cl)c(C#N)c(-c2ccc(OC[C@@H](O)CO)cc2)c1C#N
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(S)c(C#N)c(-c2ccc(OC[C@@H](O)CO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.278 mmol) of 2-chloro-4-(4-{[(2S)-2,3-dihydroxypropyl]oxy}phenyl)-6-methoxypyridine-3,5-dicarbonitrile are initially charged in 5 ml of DMF, 26 mg (0.334 mmol) of sodium sulphide are added and the mixture is stirred at room temperature for 4 hours. The reaction mixture is reacted further without any further purification.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].CI.[C:10](O)(=[O:12])[CH3:11]>[Pd].C(OC=C)(=O)C>[C:1]([O:4][CH:5]([O:7][C:10](=[O:12])[CH3:11])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: C=COC(C)=O
Solvent: CI
Product: CC(=O)OC(C)OC(C)=O
Reaction time: 1.5 h

Procedure:
Into an autoclave were charged 135 g of acetic anhydride, 15 g of methyl iodide and 4.5 g of palladium (5%) supported on barium sulfate (Kawaken Finechemical Co.). The reaction was effected for 90 minutes in the same way as in Example 9. GC analysis showed that 0.415 g of vinyl acetate and 14.0 g of ethylidene diacetate were formed with considerable amount of acetic acid.
Reaction SMILES: Cl.[CH:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][CH:20]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:4][CH2:3]1.[CH3:27][O:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][C:36](Br)=[CH:37][CH:38]=2)[N:33]([CH3:41])[CH:32]=1)=[O:30].N1CCCC1C(O)=O.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CS(C)=O.[Cu]I>[CH3:27][O:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][C:36]([N:23]3[CH2:24][CH2:25][CH2:26][CH:20]([O:19][CH2:18][C:6]4[C:7]([C:10]5[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=5[Cl:16])=[N:8][O:9][C:5]=4[CH:2]4[CH2:3][CH2:4]4)[CH2:21][CH2:22]3)=[CH:37][CH:38]=2)[N:33]([CH3:41])[CH:32]=1)=[O:30]
Reactant: COC(=O)c1cn(C)c2cc(Br)ccc12
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1COC1CCCNCC1
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)C1CCCN1
Solvent: CS(C)=O
Product: COC(=O)c1cn(C)c2cc(N3CCCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)ccc12
Temperature: 100 °C
Yield: 11.6 %

Procedure:
A mixture of 4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-azepane hydrochloride (298 mg, 0.713 mmol), 6-bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester (195 mg, 0.727 mmol), copper (I) iodide (40 mg, 0.208 mmol), DL-proline (60 mg, 0.516 mmol), and potassium carbonate (385 mg, 2.79 mmol) in dimethyl sulfoxide (3 mL) is heated to 100° C. for 18 h under nitrogen atmosphere. Saturated aqueous ammonium chloride is added and the mixture is extracted with ethyl acetate (3×). The combined ethyl acetate layers are washed with water (2×), brine (3×), dried (MgSO4), and concentrated under reduced pressure. The residue is purified via flash chromatography (40 g silica) using a gradient of ethyl acetate in heptane (0 to 70%) to provided the title compound (47 mg, 12%). LC-ES/MS m/z 569.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([NH2:26])([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl>[CH3:17][C:18]([NH:26][C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CC(C)(N)c1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)CCNC(=O)OCc1ccccc1)c1ccccc1
Yield: 55.6 %

Procedure:
6.6 g of N-benzyloxycarbonyl-β-alanine, 4.0 g of α,α-dimethylbenzylamine and 7.4 g of triethylamine were dissolved in 400 ml of anhydrous methylene chloride. To this solution were then added 8.8 g of 2-chloro-1-methylpyridinium iodide slowly at room temperature, and the mixture was heated under reflux for 2 hours. The reaction mixture was then washed, in turn, with a 10% w/v aqueous solution of sodium hydroxide, with a 1N aqueous solution of hydrochloric acid and with a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. The solution was concentrated by evaporation under reduced pressure, to give 10.7 g of crude crystals. Recrystallization of these from a mixture of hexane and benzene afforded 5.6 g (yield 56%) of the title compound melting at 96°-97° C.
Reaction SMILES: CC1C=CC([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=C(C=1)C(O)=O.[F:16][C:17]1[C:25]([F:26])=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19](I)[CH:18]=1.N1C=CN=N1>>[F:16][C:17]1[C:25]([F:26])=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[CH:18]=1
Reactant: O=C(O)c1cc(F)c(F)cc1I
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: c1c[nH]nn1
Product: O=C(O)c1cc(F)c(F)cc1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 4,5-difluoro-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 226 [M+1]+.
Reaction SMILES: C[O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][C:8]2[C:12]3[C:13](=[O:27])[N:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[N:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]=3[NH:10][N:9]=2)=[CH:5][CH:4]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][C:8]2[C:12]3[C:13](=[O:27])[N:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[N:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]=3[NH:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2c(Cc3ccc(O)cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 96.2 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (100 mg, 0.26 mmol, prepared in Example 21) in acetic acid (1 ml) was added 47% hydrogen bromide (44 μl), and the mixture was heated under reflux. After additional 47% hydrogen bromide (144 μl) was added, the mixture was heated under reflux overnight. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-(4-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (92.1 mg, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][N:24]([CH3:26])[CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:44]1([CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.CCCCCC.C(OCC)C.C(OCC)(=O)C.O1CCCC1>[C:44]1([CH2:50][C:51]([NH:53][C:54](=[S:55])[NH:1][C:2]2[CH:28]=[CH:27][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:21][CH2:20][N:19]([CH:22]5[CH2:23][N:24]([CH3:26])[CH2:25]5)[CH2:18][CH2:17]4)=[O:15])[CH:8]=3)=[CH:4][CH:3]=2)=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)C1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.3 %

Procedure:
To a solution of 4-(1-methylazetidin-3-yl)piperazine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (130 mg) in ethanol (6.0 ml)-tetrahydrofuran (6.0 ml) was added (1S)-(+)-10-camphorsulfonic acid (150 mg), followed by stirring at room temperature for 15 min. A solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 4.08 ml) was added to the reaction mixture, followed by stirring at room temperature for 2 hrs. Ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml) were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the titled compound were concentrated to give a residue, to which diethyl ether (5 ml) and hexane (10 ml) were added to give a precipitate. The precipitate was suspended in the solvent. Then the precipitate was filtered off, washed with hexane, and dried under aeration to provide the titled compound (44.3 mg, 23.3%) as pale yellow powder.
Reaction SMILES: CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][CH:36]=[O:37])=[C:31]([O:38][CH:39]([CH3:41])[CH3:40])[CH:30]=2)[CH2:25][CH2:24]1.[F:42][C:43]1[CH:44]=[CH:45][C:46]([O:66][CH3:67])=[C:47]([C:49]2[C:53]3[N:54]=[C:55](S(C)(=O)=O)[N:56]=[CH:57][C:52]=3[S:51][C:50]=2[C:62]([O:64][CH3:65])=[O:63])[CH:48]=1>CN(C=O)C>[CH:36]([N:35]([C:32]1[CH:33]=[CH:34][C:29]([N:26]2[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]2)=[CH:30][C:31]=1[O:38][CH:39]([CH3:41])[CH3:40])[C:55]1[N:56]=[CH:57][C:52]2[S:51][C:50]([C:62]([O:64][CH3:65])=[O:63])=[C:49]([C:47]3[CH:48]=[C:43]([F:42])[CH:44]=[CH:45][C:46]=3[O:66][CH3:67])[C:53]=2[N:54]=1)=[O:37]
Reactant: CC(C)Oc1cc(N2CCN(C)CC2)ccc1NC=O
Reactant: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1-c1cc(F)ccc1OC
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc2cnc(N(C=O)c3ccc(N4CCN(C)CC4)cc3OC(C)C)nc2c1-c1cc(F)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
0.7 ml of 1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]pyrrolidine (BTPP) is added to a solution of 245 mg of N-[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide in 5 ml of anhydrous DMF. After 10 min, a solution of 350 mg of methyl 7-(5-fluoro-2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate in 6.5 ml of anhydrous DMF is added and the mixture is stirred at ambient temperature for 42 h. The mixture is then evaporated under vacuum at a temperature of 60° C., and the residue is purified on 120 g of silica, elution being carried out with 5% of methanol in dichloromethane, so as to obtain 503 mg of methyl 2-{formyl[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylate in the form of an orangey-coloured solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].C(OCC)(=O)C>ClCCl.O>[CH3:17][Si:18]([CH3:20])([CH3:19])[C:3]1([OH:9])[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][CH:2]1[CH3:1]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccc(O)c(C)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1=CC(C)C(O)([Si](C)(C)C)C=C1
Yield: 92.4 %

Procedure:
To a stirred solution of 2,4-dimethyl phenol (5.47 g, 44.8 mmol) in dry dichloromethane (120 ml) at 0° C. under nitrogen was added triethylamine (1.1 eq., 4.99 g, 6.9 ml) followed by the slow addition of trimethyl silyl chloride (1.05 eq., 5.11 g, 6.00 ml). The reaction was monitored by thin layer chromatography (10% ethyl acetate in 60-80 light petroleum) and upon completion (˜2 hr) water (50 ml) was added. The organic layer was washed with water (2×50 ml), dried (Na2SO4), filtered and the solvent removed to give the title compound (8.13 g, 93%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]([Cl:11])=[N:4][N:3]=1.[Br-].[CH2:13]([Zn+])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>C1COCC1.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>[CH2:13]([C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]([Cl:11])=[N:4][N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1nnc(Cl)c2c1CCC2
Reactant: [Zn+]Cc1ccccc1
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: [Br-]
Solvent: C1CCOC1
Product: Clc1nnc(Cc2ccccc2)c2c1CCC2
Temperature: 60 °C
Yield: 75.8 %

Procedure:
To a solution of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (compound 39, 500 mg, 2.64 mmol) in THF (5 mL) is added Pd(PPh3)4 (383 mg, 0.33 mmol). The mixture is degassed and benzyl zinc bromide (11 mL, 0.5 M in THF, 5.6 mmol) is added. The mixture is heated at 60° C. for 5 h. The reaction mixture is cooled down to RT and saturated aq. NaHCO3 solution is added and the mixture is extracted with EtOAc. The combined orgaqnic layers are washed with water, brine, dried over NaSO4, filtered and concentrated. The crude product is purified by flash chromatography (EtOAc/heptane 10%-30%) to give compound 44 (490 mg, 76%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9].[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1>[C:38]([O:1][CH2:2][CH2:3][CH2:4][C:5]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][CH:8]([CH3:9])[CH3:10])(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CCCO)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: CC(=O)OCCCC(C(=O)OCc1ccccc1)(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
A solution of 1.069 g of 1,2-dibenzyl 1-tert.butyl 1-(3-hydroxypropyl)-4-methyl-1,1,2(R)-pentanetricarboxylate in 10 ml of pyridine at 0° was treated with 0.643 g of acetic anhydride. The mixture was stirred at room temperature for 20 hours and evaporated. The residue was dissolved in ethyl acetate and the solution was washed with 1M hydrochloric acid and with saturated aqueous sodium hydroxide and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and there were obtained 1.155 g of 1,2-dibenzyl 1-tert.butyl 1-(3-acetoxypropyl)-4-methyl-1,1,2(R)-pentanetricarboxylate in the form of an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.N.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16]Cl>C1COCC1>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16][N:6]1[CH:7]=[N:8][C:4]([CH2:3][C@@H:2]([C:9]([OH:11])=[O:10])[NH2:1])=[CH:5]1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: ClCc1c(Cl)cccc1Cl
Agent: N
Solvent: C1CCOC1
Product: N[C@@H](Cc1cn(Cc2c(Cl)cccc2Cl)cn1)C(=O)O
Reaction time: 3 h
Yield: 56.5 %

Procedure:
L-histidine (3.13 g) was added to a solution of NaNH2 in liquid ammonia prepared from Na (0.93 g) and FeCl3 (catalytic amount) in liquid ammonia (50 ml) After 15 min., a solution of 2,6-dichlorobenzylchloride (3.96 g) in THF (5 ml) was added and the mixture was stirred for 3 hr. The reaction mixture was quenched with H2O and ether. The pH of the aqueous layer was adjusted to pH 8 with 5% HCl followed by cooling. The resulting precipitate was collected by filtration, washed with H2O, and dried to give 1-[(2,6-dichlorophenyl)methyl]-L-histidine (3.58 g). The obtained compound (0.80 g) was dissolved in MeOH (30 ml) and HCl gas was bubbled for 10 min. at 0° C. The reaction mixture was stirred for 15 hr. at room temperature and the solvent was removed in vacuo to give 1-[(2,6-Dichlorophenyl)methyl]-L-histidine methyl ester, dihydrochloride salt.
Reaction SMILES: [C:1]([N:3]1[CH2:8][C:7]2[C:9]3[C:18]([OH:19])=[CH:17][C:16]([CH:20]([CH3:28])[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][C:10]=3[O:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:30][OH:31].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:13][C:12]1([CH3:14])[C:6]2[CH2:5][CH2:4][N:3]([C:1](=[N:30][OH:31])[NH2:2])[CH2:8][C:7]=2[C:9]2[C:18]([OH:19])=[CH:17][C:16]([CH:20]([CH3:28])[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][C:10]=2[O:11]1
Reactant: NO
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C#N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C(N)=NO)CC1
Yield: 51.4 %

Procedure:
A mixture of 0.5 g (1.31 mmole) of 2-cyano-5,5-dimethyl-8-(1,2-dimethylheptyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, 0.139 g (2.0 mmole) of hydroxylamine hydrochloride and 0.212 g (2.0 mmole) of sodium carbonate in 17 ml of dimethylformamide was heated on a steam bath for 1.5 hours. After cooling, the reaction mixture was partitioned between 50 ml each of chloroform and water. The organic layer was separated, washed with water, dried over Na2SO4 and filtered. After removal of the solvents on a rotary evaporator, the last traces of dimethylformamide were removed in vacuo. Crystallization from chloroform gave 280 mg (56%) of 5,5-dimethyl-8-(1,2-dimethylheptyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine-2-carboxamidoxime as colorless crystals. Recrystallization of the compound from chloroform gave poor recovery (17.5%) of the crystalline material, m.p. 142°-45° C. The assigned structure was confirmed by the ir, nmr and mass spectra (M+ at 415). Thin-layer chromatography (20% methanol/chloroform on silica gel) revealed two spots corresponding to the two stereoisomers.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[BH4-].[Na+]>CO>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=Cc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc(CO)c2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
To the solution of (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-formylphenyl)thiophene-2-carboxamide) (875 mg) in methanol (15 mL), sodium borohydride (97.2 mg) was added. The mixture was then stirred at room temperature for 4 h. The residue was partitioned between water and chloroform. The extracts were dried over magnesium sulfate, filtered, and evaporated, and the residue was then purified by flash chromatography using 5–20% 3.5M methanolic ammonia/chloroform mixtures as the eluent to give the title compound (547 mg); MS (ES+) 343 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14]([OH:16])=[O:15])[CH2:4][CH2:3]1.OS(O)(=O)=O.[OH-].[Na+].[C:24](=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CO>[CH3:24][O:15][C:14]([C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:16]
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1

Procedure:
The crude (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid (160 g, 0.73 mol) was dissolved in 300 mL of toluene and 550 mL of methanol. To the solution was added 9 mL of conc H2SO4 and the solution was heated to reflux overnight. The solution was cooled in an ice bath and neutralized to pH 5 with 25% NaOH, followed by adding 50 mL of saturated sodium bicarbonate to bring the solution to pH 7. The methanol was removed on a rotary evaporator and the residue was diluted with 500 mL of water and extracted with methylene chloride. The combined extracts were washed with brine and dried over MgSO4. Evaporation of the solvent afforded 132 g of (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid methyl ester as an oil which was >95% pure by NMR. 1H NMR (CDCl3) δ 2.0-2.6 (m,4H,CH2 's), 3.68 (s,3 H,CH3), 3.95 (dd, 1 H,J=4,9 Hz, H-4), 4.02 and 5.03 (AB, 2 H,Jgem =16 Hz, CH2Ph), 7.2-7.4 (m, 5 H, arom).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([N:11]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:10][C:3]=1[C:2]([F:18])([F:19])[F:1])#[N:6]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc(NCCC(F)(F)F)cc1C(F)(F)F
Product: CC(C)(C)OC(=O)CN(CCC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 1B using 2-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]benzonitrile and tert-butyl bromoacetate: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.8 Hz, 1H), 6.84 (d, J=2.6 Hz, 1H), 6.73 (dd, J=8.8, 2.6 Hz, 1H), 4.03 (s, 2H), 3.74 (t, J=7.5 Hz, 2H), 2.57-2.45 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:6]([CH3:7])=[C:5]([I:8])[S:4][C:3]=1[CH:9]=[O:10].[CH2:11](O)[CH2:12][OH:13]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:6]([CH3:7])=[C:5]([I:8])[S:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1
Reactant: Cc1c(I)sc(C=O)c1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Cc1c(I)sc(C2OCCO2)c1Br
Yield: 94.3 %

Procedure:
3-Bromo-5-iodo-4-methylthiophene-2-carbaldehyde (27 g, 82 mmol), ethylene glycol (5.9 mL, 110 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.6 mmol) were combined in benzene (200 mL) and the mixture was heated at reflux under Dean-Stark conditions for 8 h. At this time, the cooled solution was washed with 2.5 N aqueous NaOH (200 mL), water (4×200 mL) and brine (200 mL), dried (K2CO3) and concentrated in vacuo to give the title compound (29 g, 94%) as an orange oil.