Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:20][CH2:21][CH2:22][C@H:23]2[O:27][C:26](=[O:28])[N:25]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:24]2[C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>O1CCOCC1.C(Cl)Cl>[CH3:52][S:53]([O:20][CH2:21][CH2:22][C@H:23]1[O:27][C:26](=[O:28])[N:25]([CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:24]1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1)(=[O:55])=[O:54]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@H](CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(Cl)c(Cl)c2)N1CC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@H]1OC(=O)N(CC2CCCCC2)C1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
An alcohol derivative (930 mg, 91%) was prepared according to the procedures described in Example 12(d) using 2-[3-(cyclohexylmethyl)-(5R)-(3,4-dichlorophenyl)-2-oxooxazolidin-5-yl]ethanol triphenylmethylether (1.69 g, 2.75 mmol) and a solution of hydrogen chloride in dioxane (4N, 6.9 ml). The alcohol derivative (880 mg, 2.36 mmol) was dissolved in methylene chloride (18 ml), and triethylamine (0.50 ml, 3.55 mmol) and methanesulfonyl chloride (0.22 ml, 2.84 mmol) were added to the solution. The mixture was stirred at room temperature overnight. To the reaction mixture, methylene chloride was added, and this was washed with water and then with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by flash chromatography on a silica gel column using n-hexane/ethyl acetate=4/1−1/1 as an eluant to afford the title compound (1.03 g, 97%).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].C([O-])(O)=O.[Na+].[C:14](ON1C(=O)CCC1=O)([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15].CCOCC.O>O.CC(C)=O>[C:14]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5])([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCO)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: O=C(N[C@@H](CCO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 88 %

Procedure:
L-homoserine (15 g, MW119.12, 0.126 mol) and NaHCO3 (22 g, MW84, 0.26 mol) were dissolved in water (600 mL). The solution was chilled in an ice bath, followed by addition of Fmoc-OSu (42.5 g, MW337.3, 0.126 mol) in acetone (400 mL). The mixture was stirred overnight. A mixture of ether/water (200 mL/200 mL) was added, and the solid was filtered off. The filtrate was separated and the aqueous phase was washed with ethyl twice (100 mL×2), followed by acidifying with 3N HClaq (about 100 mL) to pH3-4. The suspension was extracted with ether (200 mL×2). The combined organic phases were washed with brine once (100 mL) and dried over Na2SO4. After evaporation, white solid was obtained (weight: 38 g, yield: 88%).
Reaction SMILES: ClN1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]=[N:17][OH:18])=[N:14][CH:15]=1.CN([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])C.C(N(CC)CC)C.Cl>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:27]([O:26][C:24]([C:23]1[C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][N:14]=2)=[N:17][O:18][CH:22]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)C=CN(C)C
Reactant: ON=Cc1ccc(F)cn1
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1conc1-c1ccc(F)cn1
Temperature: 60 °C
Reaction time: 64 h
Yield: 71.5 %

Procedure:
To a solution of N-chlorosuccinimide (17.34 g, 130 mmol) in DMF (128 mL) was added 5-fluoro-pyridine-2-carbaldehyde oxime (18.2 g, 130 mmol) portionwise over 2 h at room temperature and as the reaction warmed up to 60° C. the mixture was cooled back to room temperature with an ice-water bath and the resulting mixture was then stirred for 64 h at room temperature. To this solution was then added ethyl 3-(N,N-dimethylamino)acrylate (18.6 g, 130 mmol) and triethylamine (36.2 mL, 260 mmol) in chloroform (64 mL) and the resulting mixture was then stirred for 1 h at room temperature and poured onto a mixture of ice water and HCl (4 N, 1 L) and extracted with ethylacetate. The organic extract was then washed with water, saturated aqueous sodium hydrogen carbonate solution, brine, dried with sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethylacetate=100:0 to 1:1) afforded the title product (21.96 g, 72%) which was obtained as a yellow solid. MS: m/e=237.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(Cl)([Cl:17])=O>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1

Procedure:
1.5 g of 4-fluoro-3-trifluoromethylbenzoic acid, 0.65 ml of thionyl chloride and two drops of DMF are heated under reflux for 12 h in 17 ml of toluene and the mixture is subsequently concentrated and used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[C:14]([O:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][N:20]=1)([CH3:17])([CH3:16])[CH3:15].Cl.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[C:14]([O:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[C:7](=[O:12])[C:6]=3[CH:13]=2)[CH:22]=[CH:21][N:20]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)Oc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: O=C1NCCOc2ccc(Br)cc21
Agent: Cl
Product: CC(C)(C)Oc1cc(-c2ccc3c(c2)C(=O)N(Cc2ccccn2)CCO3)ccn1

Procedure:
Compound VI-4 was prepared according to Example 36 using 7-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one, 2-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and 2-(chloromethyl)pyridine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26](OC)=O.[H-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]1[O:1][C:2]2[C:3]([C:20](=[O:22])[CH:21]=1)=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=2[C@@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]1[CH2:14][OH:15]
Reactant: COC(=O)c1ccccc1Cl
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO

Procedure:
Compound(5) was converted into (−)-trans-1-[2-Hydroxy-3-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4,6-dimethoxyphenyl]-1-ethanone(compound(10) using the procedures described in examples 6 & 7. Compound(10) (0.75 g, 2.4 mmol), was reacted with methyl 2-chlorobenzoate (1.36 g, 7.9 mmol) in dry DMF (15 mL) in the presence of NaH (50%, 0.582 g, 12.9 mmol), using the procedure described in example 8 to get the title compound(11).
Reaction SMILES: [CH2:1]([CH:4]1[C:8]([OH:10])([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].N1C=CC=CC=1.ClCCl.[C:21](Cl)(=[O:23])[CH3:22]>O>[C:21]([O:10][C:8]1([CH3:9])[CH:7]=[CH:6][C:5](=[O:11])[CH:4]1[CH2:1][CH:2]=[CH2:3])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: C=CCC1C(=O)C=CC1(C)O
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: C=CCC1C(=O)C=CC1(C)OC(C)=O
Reaction time: 2 h
Yield: 94.1 %

Procedure:
Into a flask equipped with a stirrer and a thermometer, dl-2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (30.4 g), pyridine (30 g) and dichloromethane (300 g) were charged, and acetyl chloride (30 g) was dropwise added thereto at a temperature from 10° to 20° C. in 2 hours. Then, stirring was continued at a room temperature for 24 hours. To the reaction mixture kept below 10° C., water (100 ml) was added to decompose excess of acetyl chloride. From the resultant mixture, the organic layer was separated and washed with 1% hydrochloric acid, 1% sodium bicarbonate solution and water in order. Removal of the solvent by distillation gave dl-3-acetoxy-2-allyl-3-methyl-4-cyclopentenone (36.5 g). Yield, 94%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(N(C(C)C)CC)(C)C.C1(P([N:37]=[N+:38]=[N-:39])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOCC>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([N:37]=[N+:38]=[N-:39])=[O:13]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cnc2ccccc2n1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NC(=O)c1cnc2ccccc2n1
Reaction time: 8 h

Procedure:
A stirred solution quinoxaline-2-carboxylic acid (348 mg, 2 mmol) in THF (6 mL) at rt under nitrogen was treated with diisopropylethylamine (365 μL, 2.1 mmol) followed by diphenylphosphoryl azide (410 μL, 1.9 mmol). After stirring overnight the reaction was diluted to 60 mL with Et2O and washed 2×60 mL with sat. NaCl. There was an insoluble brown oil, which was drained off with the aqueous layer and assumed to be a diphenyl phosphate impurity. The organics were dried (MgSO4), filtered and concentrated to a tan solid, which corresponds to the acyl azide (350 mg, 92%). 1H-NMR (400 MHz, CDCl3) δ9.58 (s, 1H), 8.32 (d, 1H), 8.21 (d, 1H), 7.94 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]2)=[CH:4][N:3]=1.[F:13][C@H:14]1[CH2:16][C@H:15]1[C:17](O)=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:17]([C@@H:15]3[CH2:16][C@@H:14]3[F:13])=[O:18])[N:8]=[CH:9]2)=[CH:4][N:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Reactant: Nc1cc2cnc(Cl)cc2cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc2cnc(Cl)cc2cn1)[C@@H]1C[C@@H]1F
Temperature: 70 °C
Yield: 43.4 %

Procedure:
A mixture of 7-chloro-2,6-naphthyridin-3-amine (230 mg, 1.3 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (266 mg, 2.6 mmol), HATU (1.1 g, 2.8 mmol), and N,N-diisopropylethylamine (0.45 mL, 2.6 mmol) in N,N-dimethylformamide (3 mL) was heated at 70° C. for 16 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-60% ethyl acetate in heptane) to afford the title compound as a white solid (150 mg, 44%). 1H NMR (400 MHz, DMSO) δ 11.22 (s, 1H), 9.29 (s, 1H), 9.28 (s, 1H), 8.66 (s, 1H), 8.16 (s, 1H), 5.08-4.85 (m, 1H), 2.29 (m, 1H), 1.71 (m, 1H), 1.22 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([CH:31]=[CH:32][C:33]([O:35][CH3:36])=[O:34])[CH:28]=[CH:27][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:26])[C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[C:16]([N+:23]([O-])=O)[CH:15]=1.[Cl-].[NH4+].CO.O>[Zn].CO>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([CH:31]=[CH:32][C:33]([O:35][CH3:36])=[O:34])[CH:28]=[CH:27][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:26])[C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([NH2:23])[CH:15]=1
Reactant: COC(=O)C=Cc1ccc(OCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)C=Cc1ccc(OCCCCCCOC(=O)c2cc(N)cc(N)c2)c(OC)c1
Yield: 95.4 %

Procedure:
1.0 g (1.99 mmol) of 3,5-dinitrobenzoic acid 6-[2-methoxy-4-(2-methoxycarbonylvinyl)phenoxy]hexyl ester and 0.42 g (7.96 mmol) of ammonium chloride were suspended in 20 ml of a mixture consisting of methanol : water 9:1. 2.6 g (39.8 mmol) of zinc were then added in portions in the course of 30 minutes. After 2 hours at room temperature 20 ml of methanol were added. After a further 17 hours the reaction suspension was partitioned between methylene chloride and water and the organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water. The organic phase was then dried over magnesium sulphate, filtered and concentrated by evaporation. Chromatography of the residue on 150 g of silica gel using ethyl acetate yielded 0.84 g of 3,5-diaminobenzoic acid 6-[2-methoxy-4-(2-methoxycarbonylvinyl)phenoxy]hexyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)[CH:2]=1.[ClH:20]>ClCCl.O1CCOCC1>[ClH:20].[NH:10]1[CH2:11][CH2:12][CH:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cncc(OC2CCNC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a cooled solution of tert-butyl 3-(pyridin-3-yloxy)pyrrolidine-1-carboxylate (600 mg, 2.27 mmol; which may be prepared as described in Step 1) in dichloromethane (15 mL) was added dropwise HCl 4N in dioxane (11.1 mL). The solution was warmed to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure to give the title compound (263 mg, 58%) as a yellow wax.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:11])[C:4]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(C(C)C)C(C)C)C.O>CS(C)=O>[CH3:11][N:3]1[C:4]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]=[C:2]1[N:22]1[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1c(Cl)nc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cccnc21

Procedure:
A solution of 3.83 g (0.011 mol)-2-chloro-3-methyl-3H-imidazo[4,5]pyridine, 2.2 g (0.012 mol) of 1-Boc-piperazine and 5 ml (0.029 mol) of ethyl-diisopropylamine in 15 ml of DMSO is stirred for 12 hours at 130° C. Water is added and the mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: dichloromethane/acetone=20:1).
Reaction SMILES: C[O:2][C:3]1[C:20]([O:21]C)=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([O:25]C)=[C:15]([O:23]C)[CH:16]=3)[C:11]3[C:6](=[CH:7][C:8]([O:29]C)=[C:9]([O:27]C)[CH:10]=3)[C:5]=2[CH:4]=1.I>C(O)(=O)C>[OH2:2].[OH:2][C:3]1[C:20]([OH:21])=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([OH:25])=[C:15]([OH:23])[CH:16]=3)[C:11]3[C:6](=[CH:7][C:8]([OH:29])=[C:9]([OH:27])[CH:10]=3)[C:5]=2[CH:4]=1
Reactant: COc1cc2c3cc(OC)c(OC)cc3c3cc(OC)c(OC)cc3c2cc1OC
Agent: I
Solvent: CC(=O)O
Product: O
Product: Oc1cc2c3cc(O)c(O)cc3c3cc(O)c(O)cc3c2cc1O
Temperature: 25 °C
Yield: 171.1 %

Procedure:
Subsequently, to the obtained 2,3,6,7,10,11-hexamethoxytriphenylene (28.2 g, 0.069 moles), 57% hydroiodic acid (235.3 g, 1.05 moles) and acetic acid (145 mL) were added, and the solution was refluxed for 2 hours. After completion of the reaction, the solution was cooled down to room temperature, and the precipitated crystal was collected by filtration. The crystal collected by filtration was dried under reduced pressure to give gray type B crystal of 2,3,6,7,10,11-hexahydroxytriphenylene monohydrate (20.2 g, yield: 85.5%) (the method of JP-A-8-119894). Also, the resultant gray compound was confirmed to be 2,3,6,7,10,11-hexahydroxytriphenylene monohydrate by 1H-NMR analysis and measurement of water content by Karl-Fischer measuring instrument. In addition, the measurement results of X-ray powder diffraction spectrum of the type B crystal are shown in FIG. 5 and also, main peak values of the type B crystal are shown in Table 3. Also, the measurement of X-ray powder diffraction spectrum was carried out in the same way as in Example 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:13]=2[CH3:14])=[O:17])[CH:20]=[CH:21][C:22]=1[N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH2:29][CH2:28]1)#[N:25]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: COc1ccc(-n2ncc(C(=O)O)c2C)cc1
Product: COc1ccc(-n2ncc(C(=O)Nc3ccc(N4CCC(N5CCOCC5)CC4)c(C#N)c3)c2C)cc1
Yield: 62 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-methoxyphenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl) benzonitrile (1.2 g), the title compound (1.3 g) was obtained, melting point: 238° C.
Reaction SMILES: CC1C=CC(S([CH:11]([C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH3:22])[C:13]=2[CH3:23])(=O)=O)=CC=1.[OH-].[Na+].[CH3:32][N:33](C)[CH:34]=O>>[CH3:32][N:33]([CH:11]([C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][CH:28]=1)[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH3:22])[C:13]=1[CH3:23])[CH3:34]
Reactant: CN(C)C=O
Reactant: CCn1c(C)c(C(c2cccn2C)S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(C)c(C(c2cccn2C)N(C)C)c2ccccc21

Procedure:
A mixture containing 1.4 g. of 3-[(4-methylphenylsulfonyl)(1-methyl-2-pyrrolyl)methyl]-1-ethyl-2-methyl-1H-indole, 5 ml. of N,N-dimethylformamide and 30 ml. of 20% aqueous sodium hydroxide was heated 3 hours at 50° C. The reaction mixture was then cooled and diluted with 100 ml. of water and the product extracted with toluene. The toluene extracts were washed with water and evaporated to dryness affording 3-[(dimethylamino)(1-methyl-2-pyrrolyl)methyl]-1-ethyl-2-methyl-1H-indole as a brown gummy material, the infrared and nuclear magnetic resonance spectra of which were consistent with the assigned structure. A toluene solution of this product when contacted with acidic clay or phenolic resin developed an orange image.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.Br[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[CH3:24])=[C:14]([CH2:25][O:26][CH3:27])[CH:13]=1.[C:28](=[O:30])=[O:29]>CCOCC.CCOCC.CCOC(C)=O>[CH3:27][O:26][CH2:25][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH3:24])[C:28]([OH:30])=[O:29]
Reactant: O=C=O
Reactant: COCc1cc(Br)ccc1N1CCCCC1C
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: CCOCC
Product: COCc1cc(C(=O)O)ccc1N1CCCCC1C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
A 1.5M solution of tert-butyllithium in pentane (64 mL, 95 mmol) was added into anhydrous Et2O (130 mL) cooled at −78° C. A solution of 1-[4-bromo-2-(methoxymethyl)phenyl]-2-methylpiperidine (13.0 g, 43.5 mmol) in anhydrous Et2O (20 mL) was added slowly. After 40 minutes, the reaction mixture was poured on an excess of freshly crushed dry ice and stirred for 30 min. The mixture was diluted with Et2O/EtOAc (1:1, 800 mL) and washed with water (200 mL, pH=4-5 adjusted with a 5N aqueous solution of HCl). The aqueous layer was extracted with EtOAc (400 mL). The organic layers were combined, dried (MgSO4) and the solvents were removed under reduced pressure to give a yellow oil, which was triturated in iPr2O (˜20 mL) and pentane (˜20 mL). The precipitate was filtered off, washed with pentane and dried under reduced pressure to give the title compound as a beige powder. HPLC (Method A), Rt: 1.6 min (purity: 93.5%). HPLC/MS, M+(ESI): 264.2, M−(ESI): 262.2. 1H NMR (CDCl3, 300 MHz) δ 8.22 (d, J=2.1 Hz, 1H), 8.00 (dd, J=8.3, 2.1 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.60 (d, J=12.3 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 3.46 (s, 3H), 3.17 (m, 1H), 3.02 (m, 1H), 2.63 (m, 1H), 1.88-1.65 (m, 4H), 1.55-1.40 (m, 2H), 0.88 (d, J=6.2 Hz, 3H).
Reaction SMILES: CN(C)CCN[C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7].[NH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47]>>[OH:47][CH2:46][C:45]([NH:44][C:6]([C@@H:8]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]2[N:27]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:28]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[N:29][C:25]=2[CH:24]=1)=[O:22])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7])([CH3:49])[CH3:48]
Reactant: CC(C)(N)CO
Reactant: CN(C)CCNC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Product: CC(C)(CO)NC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
The carboxylic acid of example 133 was coupled to 2-amino-2-methyl-1-propanol under standard TBTU conditions to yield the title compound of example 139.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH:31]1[CH:38]2[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:40][CH:32]1[CH2:33]3)[CH2:37]2)=[O:29]>C(Cl)Cl.CCOCC>[C:2]1([C:8]2([C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:10][N:11]([C:28]([O:30][CH:31]3[CH:32]4[CH2:40][CH:36]5[CH2:35][CH:34]([CH2:39][CH:38]3[CH2:37]5)[CH2:33]4)=[O:29])[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(c2ccccc2)CCN(C(=O)OC2C3CC4CC(C3)CC2C4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.3 %

Procedure:
To a stirred, ice-cold solution of methyl 4-phenylpiperidine-4-carboxylate hydrochloride (983 mg, 3.8 mmol) and i-Pr2NEt (1.88 mL, 10.5 mmol) in CH2Cl2 (25 mL) was added 2-adamantyl chloroformate (750 mg, 3.5 mmol). The ice bath was allowed to melt and the mixture was stirred overnight at rt. The mixture was diluted with ether (150 mL), washed with 5% aq HCl (2×30 mL) and satd aq NaHCO3 (30 mL) and dried over MgSO4. Removal of the solvent left the crude product (1.37 g, 99%) as a white solid. A 40-mg portion was purified by prep HPLC to afford the title compound (32 mg). LC-MS Method 1 tR=2.4 min, m/z=398, 1H NMR (CDCl3) 1.58 (m, 2H), 1.70-2.10 (14H), 2.56 (d, 2H), 3.10 (br d, 2H), 3.68 (s, 3H), 4.08 (d, 2H), 4.83 (s, 1H), 7.27 (m, 1H), 7.36 (m, 4H).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][N:9]=1)=[O:7])(C)(C)C.COC1C=CC=C(OC)C=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[C:15]([C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=1)#[N:16]
Reactant: Cc1cc(C#N)cnc1C(=O)OC(C)(C)C
Agent: COc1cccc(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)cnc1C(=O)O
Reaction time: 6.5 h

Procedure:
To a solution of 5-cyano-3-methyl-pyridine-2-carboxylic acid tert-butyl ester (8.50 g, 38.9 mmol) in 1,3-dimethoxybenzene (51 ml, 389 mmol) was added TFA (85 ml) and stirred for 6.5 h. The reaction mixture was diluted with toluene and evaporated. The residue was taken up in toluene and evaporated (2×). The product was crystallized from TBME/hexanes to give the title compound as a white powder. HPLC: RtH1=2.314 min; ESIMS [M+Na]+=163; 1H-NMR (360 MHz, CDCl3): b 8.77 (s, 1H), 8.07 (s, 1H), 2.87 (s, 3H).