Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[N:22]([CH2:26][CH:27]([O:30]C)[O:28]C)[N:21]=[CH:20]5)[C:11](=[O:32])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Cl>C1COCC1.O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][N:12]([C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[N:22]([CH2:26][CH:27]([OH:30])[OH:28])[N:21]=[CH:20]5)[C:11](=[O:32])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(Cn1ncc2cc(-n3ccc4oc(-c5ccc(Cl)cc5)cc4c3=O)ccc21)OC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1c2cc(-c3ccc(Cl)cc3)oc2ccn1-c1ccc2c(cnn2CC(O)O)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
To a solution of 2-(4-chlorophenyl)-5-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yl)furo[3,2-c]pyridine-4-one (1.66 g, 3.69 mmol) in THF (36 mL) at 40° C. was added HCl in H2O (36 mL, 2.0 M). The solution was heated to 70° C. for 3 h then to 80° C. for 2 h. The reaction mixture was diluted with H2O (75 mL) and CH2Cl2 (75 mL). The resulting solids were collected by filtration and dried to yield the title compound (1.00 g, 64%) as a light brown solid. ESI MS m/z 422 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:4]1([CH:10]([C:16]([F:19])([F:18])[F:17])[CH:11]([CH3:15])[C:12]([OH:14])=[O:13])SCCCS1)[CH3:3].Cl.C(#N)C.CI.[OH2:26]>>[NH2:1][C@H:2]([C:4]([CH:10]([C:16]([F:19])([F:18])[F:17])[CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:26])[CH3:3]
Reactant: O
Reactant: CC(C(=O)O)C(C(F)(F)F)C1(C(C)N)SCCCS1
Agent: Cl
Solvent: CI
Solvent: CC#N
Product: CC(C(=O)O)C(C(=O)[C@H](C)N)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The above named compound is prepared by treating 317 mg (1 mMole) of 3-[2-(1-aminoethyl)1,3-dithian-2-yl]-4,4,4-trifluoro-2-methylbutyric acid with 1.0 ml of 1 N HCl and 10 ml of acetonitrile followed by treatment with 2 ml of methyl iodide. The mixture is stirred at 25° C. for 48hours then diluted with water. The mixture is then thoroughly washed with ether and the aqueous phase is concentrated to afford 3-alanyl-4,4,4-trifluoro-2-methylbutyric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:34][CH2:33][C:32]1[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: COc1ccc(CN)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: COc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 85.1 %

Procedure:
Couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (15 g, 35.3 mmol), with 4-methoxybenzylamine (13.7 mL, 106 mmol) using tris(dibenzylideneacetone)-dipalladium(0) (1.62 g, 1.76 mmol), BINAP (4.40 g, 3.5 mmol) and cesium carbonate (16.1 g, 49.4 mmol) at 80° C. for 17 h. Filter the mixture through a pad of Celite® and evaporate the filtrate. Dissolve the residue in DCM and filter through a pad of silica gel. Evaporate the filtrate and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 2:3) to give the desired intermediate as a white solid (12.4 g, 86%). MS (ES+) m/z: 412 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16](/[N:18]=[C:19](/[NH:28][CH2:29][C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([NH:37][C:38](=[O:53])[CH2:39][N:40]([CH2:48][CH2:49][CH2:50][CH:51]=[CH2:52])[C:41](=[O:47])[O:42]C(C)(C)C)=[C:32]([Cl:54])[CH:31]=3)\[NH:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:17])=[C:14]([CH3:55])[S:13][N:12]=2)=[CH:7][CH:6]=1)C=C>ClCCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[C:8]([O:23][C:21]([NH:20][C:19]1[NH:28][CH2:29][C:30]2[CH:35]=[C:34]([Cl:36])[C:33](=[C:32]([Cl:54])[CH:31]=2)[NH:37][C:38](=[O:53])[CH2:39][N:40]([C:41]([O:42][C:30]([CH3:35])([CH3:31])[CH3:29])=[O:47])[CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH2:1][O:4][C:5]2[CH:10]=[CH:9][C:8](=[CH:7][CH:6]=2)[C:11]2[C:15](=[C:14]([CH3:55])[S:13][N:12]=2)[C:16](=[O:17])[N:18]=1)=[O:22])([CH3:11])([CH3:9])[CH3:7]
Reactant: C=CCCCN(CC(=O)Nc1c(Cl)cc(CN/C(=N/C(=O)c2c(-c3ccc(OCC=C)cc3)nsc2C)NC(=O)OC(C)(C)C)cc1Cl)C(=O)OC(C)(C)C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCCl
Product: Cc1snc2c1C(=O)N=C(NC(=O)OC(C)(C)C)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CN(C(=O)OC(C)(C)C)CCCC=CCOc1ccc-2cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
The intermediate (114 mg, 0.140 mmol) from Step 4(B) was dissolved in 45 mL of 1,2-dichloroethane, followed by the addition of Grubbs Catalyst 1st Generation (22 mg, 0.020 mmol) with 1 mL of 1,2-dichloroethane. The resulted reaction mixture was stirred at 70° C. for 6 hrs. (additional 14 mg of Grubbs Catalyst was added 2 hrs. after the initial addition) Solvent was evaporated in vacuo to give a crude product, which was purified by flash chromatography (10% EtOAc/DCM, Rf 0.19) to give 75 mg (68%, theoretical yield 110 mg) of the product, which is a mixture of cis and trans isomers. LCMS (method B) RT 3.78 min., MH+787.8.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[O:26]C2CCCCO2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:26][CH:22]1[CH2:23][CH2:24][CH2:25][CH:21]1[CH2:20][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[C:12]([NH:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1)=[O:13]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2OC2CCCCO2)C(=O)Nc2nccs2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2O)C(=O)Nc2nccs2)cc1
Temperature: 60 °C
Yield: 26.7 %

Procedure:
A solution of 2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-N-thiazol-2-yl-propionamide (350.8 mg, 0.73 mmol) in ethanol (7.3 mL) was treated with pyridinium p-toluenesulfonate (18.4 mg, 0.073 mmol). The resulting reaction mixture was heated at 60° C. for 4 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The resulting yellow residue was diluted with ethyl acetate (100 mL) and then washed with a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 1/3 hexanes/ethyl acetate) afforded the 3-(2-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (77.0 mg, 27%) as a white solid: mp 205-206° C.; EI-HRMS m/e calcd for C18H22N2O4S2 (M+) 394.1021. found 394.1018.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[CH3:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:20])[CH2:18]Br)=[CH:15][CH:14]=1.Br>CC#N>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:18][C:17]([C:16]3[CH:21]=[CH:22][C:13]([CH3:12])=[CH:14][CH:15]=3)=[O:20])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Cc1[nH]c2ncccc2c1C
Agent: Br
Solvent: CC#N
Product: Cc1ccc(C(=O)Cn2cccc3c(C)c(C)nc2-3)cc1

Procedure:
A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (0.16 g, 1.1 mmol) and p-methylphenacyl bromide (0.26 g, 1.2 mmol) in 4.5 ml CH3CN was warmed to reflux which was enough to initiate crystallisation of the product as a light yellow solid. The precipitate was isolated as described in example 27 furnishing 0.29 g (74%) pure hydrobromide.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([C:14]3[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:15]=3[O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:11][N:10]=2)=[N:6][CH:7]=1.[CH3:34][N:35](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:34]([C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([C:14]3[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:15]=3[O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:11][N:10]=2)=[N:6][CH:7]=1)#[N:35]
Reactant: CN(C)C=O
Reactant: COc1cccc(OCCCNC(=O)OC(C)(C)C)c1-c1cc(Nc2cnc(Br)cn2)n[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cccc(OCCCNC(=O)OC(C)(C)C)c1-c1cc(Nc2cnc(C#N)cn2)n[nH]1
Temperature: 80 °C
Yield: 73 %

Procedure:
A solution of tert-butyl 3-(2-(3-(5-bromopyrazin-2-ylamino)-1H-pyrazol-5-yl)-3-methoxyphenoxy)propylcarbamate (0.378 g, 0.730 mmol) and zinc cyanide (0.10 g, 0.870 mmol) in DMF (10 mL) is degassed with a stream of nitrogen for one hour and then heated to 80° C. To the reaction is added Pd(Ph3P)4 (0.080 g, 0.070 mmol), and the mixture is heated overnight. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is purified by silica gel chromatography (CH2Cl2/MeOH) to give 0.251 g (73%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:35])[C:33]=1[F:34])[C:28](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:17]([C:7]1[N:8]([CH2:12][C:13]2[N:16]=[C:28]([C:27]3[CH:26]=[C:25]([F:24])[C:33]([F:34])=[C:32]([F:35])[CH:31]=3)[O:15][N:14]=2)[C:9]2[C:5]([CH:6]=1)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH2:18][CH3:19]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(F)c(F)c(F)c2)n1
Temperature: 150 °C
Yield: 45.4 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 3,4,5-trifluorobenzoyl chloride (0.241 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.065 g (45% yield) of pure product: MS (ES) m/z 464 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=O)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:38])([F:37])[C:27]1[N:28]=[C:29]2[C:34](=S)[NH:33][CH2:32][CH2:31][N:30]2[CH:36]=1>COCCO>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]1[N:33]2[C:34]([C:29]3[N:30]([CH:36]=[C:27]([C:26]([F:38])([F:25])[F:37])[N:28]=3)[CH2:31][CH2:32]2)=[N:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cn2c(n1)C(=S)NCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Solvent: COCCO
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCn1cc(C(F)(F)F)nc1-2

Procedure:
A mixture of 129 mg (0.475 mmol) of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 129 mg (0.583 mmol) of 2-(trifluoromethyl)-6,7-dihydroimidazo[1,2-a]pyrazine-8(5H)-thione (Intermediate 11), and 8.5 mL of 2-methoxyethanol was stirred at reflux for 3 days. The cooled solution was concentrated, and the residue was purified by preparative HPLC (C18 reverse phase column, 20-90% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the title compound as an oil. LC-MS 517 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:63])/[C:16](/[C:38]3[N:39]=[C:40]([NH:43]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:41][CH:42]=3)=[N:17]\[O:18]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:12](=[O:64])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10].[Na+].[C:66]([CH2:69][S:70][C:71]1[N:75]=[C:74]([SH:76])[S:73][N:72]=1)(=[NH:68])[NH2:67].C(O)=O>CN(C=O)C>[C:66]([CH2:69][S:70][C:71]1[N:75]=[C:74]([S:76][CH2:2][C:3]2[CH2:4][S:5][C@@H:6]3[C@H:13]([NH:14][C:15](=[O:63])/[C:16](/[C:38]4[N:39]=[C:40]([NH2:43])[S:41][CH:42]=4)=[N:17]\[OH:18])[C:12](=[O:64])[N:7]3[C:8]=2[C:9]([OH:11])=[O:10])[S:73][N:72]=1)(=[NH:67])[NH2:68]
Reactant: O=C([O-])C1=C(CO)CS[C@@H]2[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reactant: N=C(N)CSc1nsc(S)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: N=C(N)CSc1nsc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)n1
Yield: 26.3 %

Procedure:
To a solution of 909 mg of sodium 3-hydroxymethyl-7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-trityloxyiminoacetamido]-3-cephem-4-carboxylate and 619 mg of 3-amidino methylthio-5-mercapto-1,2,4-thiadiazole in 8 ml of DMF was added 1.4 g of ethyl o-phenylenephosphate under ice-cooling and stirring. The reaction mixture was stirred at room temperature for 4 hours and then subjected to a column chromatography on silica gel (150 g), being eluted with aceton/water (95:5). The eluate was concentrated to dryness under reduced pressure to obtain a powder to which was added 20 ml of formic acid. After stirring at room temperature for 14 hours, the mixture was distilled under reduced pressure to remove formic acid. The residue was added with water and THF, adjusted to pH 7 under ice-cooling, washed with ethyl acetate, concentrated under reduced pressure and then subjected to a column chromatography on XAD-II (140 mg), being washed with water and eluted with 20% aqueous ethanol. The eluate was concentrated under reduced pressure and then lyophilized to give 155 mg of the title compound as a pale yellow powder.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([OH:12])=[O:11])[CH2:5][CH2:4]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[CH3:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:10]([O:12][C@@H:46]2[CH:47]3[CH2:50][CH2:51][N:44]([CH2:49][CH2:48]3)[CH2:45]2)=[O:11])[CH2:5][CH2:4]1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC1CCN(C(C(=O)O)c2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC1CCN(C(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.4 %

Procedure:
2-(4-Methylpiperidin-1-yl)-2-phenylacetic acid hydrochloride (105 mg, 0.39 mmol), HOBT (119 mg, 0.78 mmol), and DCC (161 mg, 0.78 mmol) were dissolved in dry THF (5 ml). (R)-quinuclidin-3-ol (149 mg, 1.17 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. THF was evaporated, the residue was dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(4-methylpiperidin-1-yl)-2-phenylacetate (58 mg, 43.5% yield).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=2[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:9][CH:8]=1.C(=O)=O.C(O)(C)C>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]2[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=2[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][CH:12]=1
Reactant: COc1ccc(Nc2ccccc2C(=O)N2CCCCC2)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(c1ccccc1Nc1ccc(O)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Boron tribromide (10 ml in 25 ml of methylene dichloride) was added dropwise over a 30 minute period to a solution of 15.5 g of 1-[2-(4-methoxyphenylamino)benzoyl]piperidine in 80 ml of dry methylene dichloride cooled in a bath of Dry Ice and isopropyl alcohol. The reaction mixture was allowed to warm to room temperature and to stand overnight. The solvent was then removed in vacuo, and the residue was treated with 100 ml of distilled water and made basic with about 250 ml of saturated sodium bicarbonate solution. The solid which formed was collected by filtration and recrystallized from ethanol to give 10.2 g of 1-[2-(4-hydroxyphenylamino)benzoyl]piperidine, colorless powder, m.p. 199°-201° C.(decompn.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:16]([F:19])([F:18])[F:17])([C:13](O)=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:16]([F:18])([F:19])[F:17])([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1(C(F)(F)F)CCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(C(F)(F)F)CCN(Cc2ccccc2)C1
Reaction time: 3 h
Yield: 99.9 %

Procedure:
The compound from step 456a (2.32 g) was dissolved in 60 mL of dry THF, 1.12 eq of LAH (1N in dry THF) was added, and the reaction was stirred under N2 for 3 hours. The reaction was quenched by the sequential dropwise addition of 0.35 mL water, 0.35 mL of 15% NaOH and 1.3 mL of water, then the mixture was stirred for 1 hour and filtered. The filtrate was dried and concentrated to give 2.2 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:29][CH:30]([O:36][CH2:37][CH3:38])[C:31]([O:33]CC)=[O:32])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:29][CH:30]([O:36][CH2:37][CH3:38])[C:31]([OH:33])=[O:32])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(NC(=O)OC(C)(C)C)c1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(NC(=O)OC(C)(C)C)c1)C(=O)O
Yield: 22.9 %

Procedure:
Ethyl 3-[3-[(tert-butoxycarbonyl)amino]-4-(2-{4-[(methylsulfonyl)oxy]phenyl}ethoxy)phenyl]-2-ethoxypropanoate (0.036 g; 0.100 mmole) was dissolved in THF and water (2:1), 0.1 M lithium hydroxide (1 ml) was added and the reaction mixture was stirred over night. Water was added and the THF evaporated. The remaining water was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate. Evaporation gave 0.012 g (52% yield) of the product.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][C:6]1[C:12]([CH3:13])=[CH:11][C:9](N)=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1.[Cu][C:18]#[N:19].[C-]#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.Cl.C1(C)C=CC=CC=1>[CH3:5][C:6]1[C:12]([CH3:13])=[CH:11][C:9]([C:18]#[N:19])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C
Reactant: N#C[Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)c([N+](=O)[O-])cc1C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
0.41 g Sodium nitrite in water is added to 1 g 4,5-dimethyl-2-nitroaniline in 3 mL conc. HCl and stirred for 1 hour at +4° C. This solution is added to a mixture of 0.67 g copper (I) cyanide, 0.98 g sodium cyanide, 0.32 g sodium carbonate, 25 mL of water and 3 mL toluene. The mixture is stirred for 12 hours at room temperature and worked up to give 0.45 g 4,5-dimethyl-2-nitrobenzonitrile. 4,5-Dimethyl-2-nitrobenzonitrile is reduced with iron powder in acetic acid to yield 4,5-dimethyl-2-aminobenzonitrile. 4,5-Dimethyl-2-aminobenzonitrile is heated at reflux for 12 hours in conc. HCl to give 4,5-dimethyl-2-aminobenzoic acid. 4,5-Dimethyl-2-aminobenzoic acid is reacted with trimethylsilyl diazomethane to yield methyl 4,5-dimethyl-2-aminobenzoate (Chem. Pharm. Bull. Vol. 29, 1475 (1981)).
Reaction SMILES: FC(F)(F)C([N:5]([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][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:45][C:46](=[O:50])[C@H:47]([CH3:49])[NH2:48])C>CCOCC>[C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:48][C@H:47]([C:46]([OH:50])=[O:45])[CH3:49])=[O:11])=[CH:13][CH:14]=1)([O:32][CH3:33])=[O:31]
Reactant: COC(=O)CCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-4-(15-carbomethoxypentadecylamino)benzoyl chloride and 1.2 g. of triethylamine in 20 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]Cl.[H-].[Na+]>CN(C)C=O>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][N:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][S:1][C:5]=2[C:6]1=[O:10]
Reactant: O=c1[nH]ccc2ccsc12
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCn1ccc2ccsc2c1=O
Temperature: 80 °C
Yield: 95.2 %

Procedure:
To a solution of thieno[2,3-c]pyridin-7(6H)-one (1.82g, 12 mmol) in dry dimethylformamide (18 ml), under a nitrogen atmosphere, was added 3-(dimethylamino)propyl chloride hydrochloride (2.25 g, 14.4 mmol). Sodium hydride in mineral oil (60%, 1.35 g, 33 mmol) was carefully added to this solution and the mixture was warmed at 80° C. for 3 hours. The cooled reaction mixture was diluted with ice-water and the crude product was extracted into methylene chloride. This organic layer was extracted with dilute hydrochloric acid and the acid layer was made basic with sodium hydroxide solution. After extraction of the product into methylene chloride, this solution was dried over anhydrous sodium sulfate, filtered and evaporated to give an oily product (2.7 g, 95% yield) which contained less than 12% of the by-product resulting from O-alkylation. Some of this material was further purified by formation of the hydrochloride salt upon treatment with ethanolic HCl. Recrystallization from hot ethanol gave pure salt, m.p. 185°-190° C.