Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:17][C:16]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=4[CH:24]=[CH:25][C:15]=3[CH2:14]2)(=O)=O)=CC=1.[N-:26]=[N+:27]=[N-:28].[Na+]>>[N:26]([CH2:12][CH:13]1[O:17][C:16]2[C:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=3[CH:24]=[CH:25][C:15]=2[CH2:14]1)=[N+:27]=[N-:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc4c(c3O2)CCCC4)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2ccc3c(c2O1)CCCC3

Procedure:
Treatment of (±)-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethyl 4-methylbenzenesulfonate (2.05 g, 5.72 mmol) with sodium azide (0.929 g, 14.30 mmol) generally according to the procedure described for Intermediate 24 gave (±)-2-(azidomethyl)-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan. Treatment of the azide with palladium on carbon (10 wt. %, 0.094 g) generally according to the procedure described for Example 2 afforded 0.917 g (67%) of (±)-1-(2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>220° C. (dec.); Anal. calcd. for C13H17NOHCl.0.1H2O: C, 64.15; H, 7.50; N, 5.75. Found: C, 64.41; H, 7.64; N, 5.67.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[CH:28]1([NH:33][CH3:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH:28]1([N:33]([CH3:34])[C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:27])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Reactant: CNC1CCCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1)C1CCCC1
Temperature: 70 °C
Reaction time: 22 h
Yield: 92.8 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.269 mmole), cyclopentyl-methylamine (107 mg, 1.08 mmole), N-ethyldiisopropylamine (376 ul, 2.15 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 404 ul, 0.673 mmole) in tetrahydrofurane (4 ml) was stirred for 22 hours at 70° C. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording N4-cyclopentyl-N4,1-dimethyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (113 mg, 92.7%) as an off-white solid. mp.: 222-4° C., MS: m/z=453.5 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[H-].[Na+].[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[C:32]#[N:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:25]2[C:24]3[C:29](=[CH:30][C:21]([O:20][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:22]([C:32]#[N:33])[CH:23]=3)[N:28]=[CH:27][CH:26]=2)=[C:4]([CH3:9])[C:3]=1[CH3:10]
Reactant: Cc1c(N)ccc(O)c1C
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(N)ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)c1C
Temperature: 100 °C
Yield: 42.7 %

Procedure:
4-Amino-2,3-xylenol (2.80 g) purchased from Tokyo Chemical Industries was dissolved in dimethylsulfoxide (15 ml), and after gradually adding sodium hydride (816 mg) at room temperature, the mixture was stirred for 20 minutes. 7-Benzyloxy-4-chloro-6-cyanoquinoline (3.0 g) was added, and the mixture was heated at 100° C. for 4 hours while stirring. After cooling to room temperature, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water, 1N aqueous sodium hydroxide and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained crude product was washed with ethyl acetate to obtain the title compound (1.72 g) as light brown crystals.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1.Cl.O.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[OH:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)[C:12]([S:18][C:19]2[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1
Reactant: CC(C)c1nc(COCc2ccccc2)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To the compound (6) was added concentrated aqueous hydrochloric acid (50 ml). The mixture was heated at 90° C. for 2 hours and then cooled down. To the mixture were added water (50 ml) and toluene (20 ml). The aqueous layer was separated and neutralized by 30% aqueous sodium hydroxide. The compound (12) was extracted with ethyl acetate (50 ml), and the ethyl acetate layer was washed with water (30 ml). Each aqueous layer was extracted with ethyl acetate (20 ml). The ethyl acetate layer was collected and concentrated under reduced pressure to yield oily residue. To the oily residue was slowly added diisopropyl ether (50 ml) for crystallization. The obtained slurry was stirred at room temperature for 30 minutes, filtered, washed with diisopropyl ether (30 ml) and dried to yield the compound (12) (10.4 g) as a white crystal. Yield from the compound (22):82%
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[C:11]([C:12](=[CH:17][O:18][CH3:19])[C:13]([O:15][CH3:16])=[O:14])=[C:10]([O:20][CH3:21])[N:9]=[CH:8][N:7]=1.[Br:25]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[C:11]([C:12](=[CH:17][O:18][CH3:19])[C:13]([O:15][CH3:16])=[O:14])=[C:10]([O:20][CH3:21])[N:9]=[CH:8][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC=C(C(=O)OC)c1c(OC)ncnc1Oc1cccc(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(C(=O)OC)c1c(OC)ncnc1Oc1cccc(CBr)c1

Procedure:
Methyl α-[4-(3-methylphenoxy)-6-methoxy-pyrimidin-5-yl]-β-methoxyacrylate (2.7, 8.4 mmol), N-bromosuccinimide (1.6 g, 6 mmol) and a catalytic amount of AIBN are refluxed in CCl4 for 90 minutes. Filtration of the succinimide and evaporation of the solvent gives the methyl α-[4-(3-bromomethylphenoxy)-6-methoxy-pyrimidin-5-yl]-β-methoxyacrylate as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]([O:27][C@@H:28]([C:30]1[N:35]=[C:34](OS(C)(=O)=O)[CH:33]=[CH:32][N:31]=1)[CH3:29])(=[O:26])[CH2:23]CC>ClCCl>[C:22]([O:27][C@@H:28]([C:30]1[N:31]=[C:32]([N:11]2[CH2:12][CH2:13][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([OH:14])[CH2:9][CH2:10]2)[CH:33]=[CH:34][N:35]=1)[CH3:29])(=[O:26])[CH3:23]
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: CCCC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@H](C)c1nccc(N2CCC(O)(Cc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-benzyl-4-hydroxypiperidine (0.95 g, 5.0 mmol) and triethylamine (0.51 g, 5.0 mmol) in dichloromethane (10 mL) was added (R)-1-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Eight, 1.23 g, 4.0 mmol) and stirred at ambient temperature for 18 h. The mixture was washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound of Example 174, Step A as a viscous oil, 0.99 g (52%). 1H NMR (CDCl3, 300 MHz) δ 0.95 (t, 3H), 1.53 (d, 3H), 1.65-1.78 (m, 4H), 1.88 (m, 2H), 2.08 (m, 2H), 2.48 (t, 2H), 3.45 (m, 2H), 4.42 (br s, 1H), 5.68 (q, 1H), 6.41 (d, 1H), 7.30-7.48 (m, 5H), 8.18 (d, 1H); MS (Cl) 384 (MH+).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]3)[CH2:9]2)C=CC=CC=1.[ClH:24]>C(O)C.[Pd].[OH-].[OH-].[Pd+2]>[ClH:24].[ClH:24].[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]2)[CH2:9]1
Reactant: OC1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C1
Agent: [Pd+2]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OC1CCN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
1-[1-(Diphenylmethyl)azetidin-3-yl]pyrrolidin-3-ol (310 mg, 0.98 mmol) was dissolved in ethanol (20 mL). A mixture of palladium hydroxide on carbon and palladium on activated carbon was added and to the resultant mixture was then added concentrated HCl (0.1 mL) dropwise. The mixture was stirred under hydrogen (5 atm) at room temperature overnight and then the catalyst was filtered off by means of Celite®. The solvent was removed by evaporation and the residue triturated with CH2Cl2. There was obtained 154 mg (79%) of 1-azetidin-3-ylpyrrolidin-3-ol dihydrochloride as a solid. 13C NMR (75 MHz, D2O): 48.8 (s), 65.1 (s), 67.7 (s), 70.9 (s), 76.2 (s), 85.7 (s); LCMS: m/z 143 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([CH2:37][NH2:38])([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>ClCCl.[Cl-].[Na+].O>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([CH2:37][NH:38][C:8](=[O:10])[CH3:9])([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[CH2:29][CH2:30]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC1(N2CCN(c3ccncc3)CC2)CCN(Cc2ccccc2)CC1
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCC1(N2CCN(c3ccncc3)CC2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
Triethylamine (2.5 equiv.) followed by acetyl chloride (1.2 equiv.) were added under cooled conditions to a solution of (1-benzyl-4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-4-yl)methanamine (4.67 mmol, 1 equiv.) in dichloromethane. The resulting solution was warmed to room temperature and stirred for 3 h. The mixture was diluted with dichloromethane and given water and brine washes respectively. The organic layer was dried over sodium sulfate, filtered and the solvent removed. The crude product was purified by column chromatography (silica). Yield: 52%
Reaction SMILES: [I:1][C:2]1[CH:47]=[CH:46][C:5]([CH2:6][N:7]([CH2:20][C:21]2[N:22]([CH2:26][C:27]([N:29]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[O:28])[CH:23]=[CH:24][N:25]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[I:1][C:2]1[CH:47]=[CH:46][C:5]([CH2:6][N:7]([CH2:20][C:21]2[N:22]([CH2:26][C:27]([N:29]([CH2:30][C:31]([OH:33])=[O:32])[CH2:38][C:39]([OH:41])=[O:40])=[O:28])[CH:23]=[CH:24][N:25]=2)[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1ccc(I)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(CCN(Cc2ccc(I)cc2)Cc2nccn2CC(=O)N(CC(=O)O)CC(=O)O)cc1
Yield: 104.8 %

Procedure:
A solution of di-tert-butyl 2,2′-((2-(2-(((4-iodobenzyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetyl)azanediyl)diacetate (28.8 mg, 0.0369 mmol) in DCM (0.50 mL) and TFA (0.5 mL) was stirred at room temperature for 5 hrs. Solvent was removed under a stream of nitrogen to give a residue, which was purified by HPLC to give compound (19) as a white solid (25.9 mg, 78.2%). 1H NMR (400 MHz, DMSO-d6) 7.70-7.66 (m, 4H), 7.57 (s, 1H), 7.55 (s, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.28 (s, 2H), 7.17 (d, J=8.0 Hz, 2H), 5.26 (s, 2H), 4.34 (s, 2H), 4.06 (s, 2H), 3.91 (s, 2H), 3.69 (s, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H); MS (ESI), 670.1 (M+H)−.
Reaction SMILES: [C:1]([C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[C:1]([C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(c1ccccc1)C1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=C(c1ccccc1)C1(c2ccccc2)CCN(CCCc2ccccc2)CC1

Procedure:
3 g 4-benzoyl-4-phenylpiperidine was taken up in 200 ml n-butanol with 1.5 ml 1-bromo-3-phenylpropane and 10 g sodium carbonate, and refluxed for 4 hours. The resulting mixture was filtered and the filtrate concentrated in vacuo, taken up in ethyl acetate and washed with water. The ethyl acetate layer was dried over potassium carbonate and eluted through a short silica plug with 1:1 hexane/ethyl acetate. The eluted product was concentrated to dryness overnight, giving 3.14 g of product, melting point: 185°-186° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]=[C:5]([C:7]1[CH:31]=[CH:30][C:10]2[S:11][CH:12]=[C:13]([C:14]3[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16]([CH:23]([CH3:25])[CH3:24])[C:15]=3[O:26]COC)[C:9]=2[CH:8]=1)[CH3:6].Cl>CO.[OH-].[Na+]>[OH:26][C:15]1[C:16]([CH:23]([CH3:24])[CH3:25])=[CH:17][C:18]([CH:20]([CH3:22])[CH3:21])=[CH:19][C:14]=1[C:13]1[C:9]2[CH:8]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:32])=[O:2])[CH:31]=[CH:30][C:10]=2[S:11][CH:12]=1
Reactant: COCOc1c(-c2csc3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=CC(=O)O)c1ccc2scc(-c3cc(C(C)C)cc(C(C)C)c3O)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
3-[3-(3,5-Di-iso-propyl-2-methoxymethoxyphenyl)-benzo[b]thien-5-yl]-but-2-enoic acid methyl ester (15 mg, 0.033 mmol) (see Example 55, step F) was dissolved in MeOH (2 ml) and 1N NaOH (2 ml). The mixture was then stirred at 60° C. for 2 h, then cooled to ambient temperature and brought to pH 2 with 1N HCl . The reaction mixture was allowed to stir for 1 h, it was extracted with ethyl acetate (3×5 mL) and the organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (10% ethyl acetate in hexanes) to give 3-[3-(2-hydroxy-3,5-diisopropyl-phenyl)-benzo[b]thien-5-yl]-but-2-enoic acid as a white solid (11.7 mg, 89%). 1H NMR (250 MHz, CDCl3): δ 7.89 (d, 1H, J=8.75), 7.70 (d, 1H, J=0.62), 7.50 (m, 2H), 7.08 (d, 1H, J=1.2), 6.95 (d, 1H, J=1.2), 6.14 (bs, 1H), 3.29 (m, 1H), 2.85 (m, 1H), 2.55 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H), 1.20 (s, 3H). MS [EI+] 395 (M+H−H2O)+, [EI−] 393 (M−1)−. HPLC [MetaSil AQ C18 (0.46×25 cm) 95% CH3CN(0.1% TFA) in H2O(0.1% TFA)] 4.388 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([C:11]#[N:12])[N:4]=1.Cl>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([CH2:11][NH2:12])[N:4]=1
Reactant: COc1ccc(C#N)nc1OC
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN)nc1OC
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-dimethoxy-6-cyanopyridine (7-5, 5.1 g, 31.1 mmol) in MeOH (260 mL) was added Pearlman's Catalyst (2.18 g, 3.11 mmol) and concentrated HCl (20.0 mL, 249 mmol). The system was then stirred under an atmosphere of hydrogen via a balloon for 1.5 h. The reaction contents were filtered through a pad of celite and methanol was removed in vacuo. The crude mixture was then basified using saturated Na2CO3 and then extracted using 4:1 Chloroform:Ethanol. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to yield the desired product (7-6) as a bone semi-solid. ESI+ MS [M+H]+ C8H12N2O2: M-16 (—NH2), 152.06 found, 152.2 required.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=[O:35])=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][OH:35])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2csc3c(/C=C/CO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
A mixture of Example 176C (30 mg, 0.062 mmol) and sodium borohydride (10 mg, 0.186 mmol) in methanol was stirred at ambient temperature for one hour then concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC then lyophilized to provide the desired product as the acetate salt. 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 7.99 (d, 1H), 7.97 (s, 1H), 7.69 (d, 1H), 7.62 (s, 1H), 7.58 (m, 1H), 7.35 (s, 1H), 7.33 (t, 1H), 7.21 (t, 1H), 7.15 (t, 1H), 7.08 (d, 1H), 6.70 (d, 1H), 6.36 (m, 1H), 5.62 (br s, 2H), 4.20 (d, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 1.87 (s, 3H); MS m/e 485.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]1[CH3:18].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[N:12]([CH3:18])[CH2:13][CH2:14][C:15]([CH3:17])=[CH:16]1
Reactant: COc1ccc(C2C=C(C)C=CN2C)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C2C=C(C)CCN2C)c(OC)c1
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a stirred solution of 2-(2,4-dimethoxyphenyl)-1,4-dimethyl-1,2-dihydropyridine (4) (0.48 g, 2.06 mmol) in methanol (5 ml) at room temperature was added sodium borohydride (98 mg, 2.51 mmol), gas evolution commenced immediately, the resulting mixture was stirred for 3 hours. At this time the solvent was evaporated and the residue suspended in water (5 ml) and extracted with ethyl acetate (2×10 ml). The organic extract was then extracted with 2M hydrochloric acid (2×15 ml). The aqueous layer was basified with 2M sodium hydroxide and extracted with ethyl acetate (2×20 ml), the organic extract was dried over anhydrous magnesium sulphate, filtered and evaporated to yield 6-(2,4-dimethoxyphenyl)-1,4-dimethyl-1,2,3,6-tetrahydropyridine (6) (350 mg, 73%) as a yellow oil, 1H NMR CDCl3 δ?1.55 (s, 3H), 1.9 (m, 1H), 2.2 (s, 3H), 2.5 (m, 2H), 2.95 (m, 1H), 3.8 (s, 6H), 4.1 (m, 1H), 5.2 (m, 1H), 6.5 (m, 2H), 7.3 (d, 1H J=4).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[Li+].[CH3:10][CH:11]([N-]C(C)C)C.ICC>C1COCC1>[CH2:10]([C:5]1[S:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1)[CH3:11]
Reactant: O=C(O)c1cccs1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1ccc(C(=O)O)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of thiophencarboxylic acid (4.00 g, 30.9 mmol) in THF (24 mL) is added dropwise via a syringe to a stirred solution of LDA (32.5 mL, 2 M in toluene) in THF (40 mL) cooled to −78° C. The temperature of the reaction is maintained at −78° C. for 10 min before iodoethane (4.87 g, 30.9 mmol) is added. The mixture is stirred at −78° C. for 1 h and is then allowed to warm to rt overnight. The reaction is quenched by the addition of water. The mixture is acidified and extracted three times with diethyl ether. The org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on reversed phase silica gel to give the title compound (1.10 g) as a brownish solid; LC-MS: tR=0.80 min, 1H NMR (CDCl3): δ 1.34 (t, J=7.3 Hz, 3H), 2.90 (q, J=7.6 Hz, 2H), 6.84 (d, J=3.5 Hz, 1H), 7.73 (d, J=3.8 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([F:11])[CH:4]=1.[CH2:12]([N:18](CCCCCC)CCCCCC)CCCCC.[C-]#N.[Na+]>O>[F:11][C:5]1[CH:4]=[C:3]([CH2:2][C:12]#[N:18])[CH:8]=[CH:7][C:6]=1[O:9][CH3:10]
Reactant: COc1ccc(CBr)cc1F
Reactant: CCCCCCN(CCCCCC)CCCCCC
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1ccc(CC#N)cc1F

Procedure:
A mixture of 4-(bromomethyl)-2-fluoroanisole (45.8 g, 0.21 mol), trihexylamine (1.4 g) and sodium cyanide (20.5 g, 0.42 mol) in water (50 ml) is heated at 60°-65° C. for 18 hours. The mixture is cooled and extracted in its ether, washed with water, saturated sodium chloride solution and dried (CNa2SO4). Evaporation of the solvent gives a solid, (33.2 g): m.p. 42°-46° C.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:7]3[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=1[C:6]=23.C[Sn](C)(C)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C(#N)C>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:28]1[CH:29]=[CH:30][C:25]([C:2]2[C:3]([F:22])=[CH:4][C:5]3[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:7]4[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=2[C:6]=34)=[CH:26][CH:27]=1
Reactant: C[Sn](C)(C)c1ccncc1
Reactant: CCOC(=O)c1cn2c3c(c(Br)c(F)cc3c1=O)OC[C@@H]2C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)c1cn2c3c(c(-c4ccncc4)c(F)cc3c1=O)OC[C@@H]2C
Temperature: 150 °C

Procedure:
Ethyl (S)-10-bromo-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate (U.S. Pat. No. 4,839,355, Example 5f) (3.50 g), 2.97 g of 4-(trimethylstannyl)pyridine and 0.155 g of dichlorobis(triphenylphosphine)palladium were combined in a Parr apparatus in 200 ml of absolute ethyl alcohol and the mixture under nitrogen was heated at 150° C. for 41/2 hours, allowed to cool slowly and concentrated in vacuo. The concentrate was taken up in chloroform and residues were removed by filtration. The filtrate was extracted with sufficient 1M hydrochloric acid to extract all the product and the aqueous extract was poured onto ice and saturated sodium acetate was added. The resulting mixture was extracted with chloroform and the chloroform extract was washed with brine followed by sodium bicarbonate, dried over magnesium sulfate and concentrated to give, after recrystallization from acetonitrile, 2.56 g of a mixture of the title compound with its corresponding 6-carboxylic acid (73.5% yield); m.p. 249°-252° C. This was combined with 100 mg of the same product obtained previously by an analogous procedure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1.C(Cl)Cl>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:21][CH:22]=1)[CH3:28]
Reactant: CCOc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOc1ccc(-c2nccnc2N2CCNCC2)cc1

Procedure:
Deprotect 3′-(4-ethoxyphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (1.80 g, 4.7 mmol) using 4 M HCl in 1,4-dioxane (38 mL) in DCM (100 mL). Concentrate and dissolve the residue in DCM and 10% aqueous sodium carbonate. Separate the layers and extract the aqueous layer with DCM (2×150 mL). Combine the organic layers, wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title preparation (1.12 g, 84%). MS (ES): m/z=285 [M+H]+.