Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[OH:8].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[C:7]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:2]([Br:1])[CH:3]=1
Reactant: COC(=O)Cc1cc(Br)c(O)c(C=O)c1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cc1cc(Br)c(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C

Procedure:
To a 250 mL round-bottomed flask with a teflon stir bar and a reflux condensor were added methyl (3-bromo-5-formyl-4-hydroxyphenyl)acetate (23.3 g, 85.3 mmol, prepared as described in Reference A above), dichloromethane (100 mL), benzyl bromide (15.32 g, 10.64 mL, 89.59 mmol), and N-ethyldiisopropylamine (11.6 g, 15.6 mL, 89.5 mmol). The reaction mixture was heated to reflux for 14 h and then allowed to cool to room temperature. Dichloromethane (100 mL) was added and the organic layer was separated and washed with 200 mL of a 3% solution of NaOH in water. The organic layer was concentrated to give (4-benzyloxy-3-bromo-5-formyl-phenyl) acetic acid methyl ester (30.65 g) as oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>CCOCC>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][CH2:14][N:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)[CH3:18]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C1CNCCO1
Solvent: CCOCC
Product: CCOC(=O)CCN1CCOC(C(=O)OCC)C1
Temperature: 100 °C

Procedure:
A mixture of ethyl morpholine-2-carboxylate (3 g, 18.85 mmol) and ethyl acrylate (5 ml, 18.85 mmol) was heated at 100° C. for 14 h. The reaction was cooled to RT then diluted with Et2O and extracted with aqueous 3M HCl. The combined aqueous layers were basified by solid K2CO3 and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a pale-yellow oil, which was used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:24]N1C(=O)CCC1=O>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([I:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH2:3][CH2:2]1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)ccc1=O
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)cc(I)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
A 0.2 M solution of the title compound (264 mg, 0.8 mmol) from Example 98 in DMF stirred at 0° C. was treated with three equal portions of N-iodosuccinimide (187 mg, 84 mmol). After 15 min, the icebath was removed and the mixture was stirred at rt for 2 h. The reaction mixture was treated with 10% sodium thiosulfate (aq) (5 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to afford a crude solid. The resulting solid was purified by silica gel column chromatography using a gradient of EtOAc (0 to 100%) in DCM to afford the title compound (333 mg, 91%) as a white solid. LCMS (M+H)+=460.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[NH:13][C:14]([NH:16][C:17]([O:19][CH3:20])=[O:18])=[S:15].[C:21](Cl)(=[O:23])[CH3:22]>O1CCCC1>[C:21]([NH:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[NH:13][C:14]([NH:16][C:17]([O:19][CH3:20])=[O:18])=[S:15])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CCCCSc1ccc(NC(=S)NC(=O)OC)c(N)c1
Solvent: C1CCOC1
Product: CCCCSc1ccc(NC(=S)NC(=O)OC)c(NC(C)=O)c1
Reaction time: 2 h

Procedure:
0.7 G. of 2-amino-4-n-butylthio-1-(3-methoxycarbonyl-2-thioureido)benzene is dissolved in 20 ml. tetrahydrofuran and treated with 1.5 ml. of acetyl chloride. The mixture is stripped after two hours and the residue recrystallized from methanol, yielding pure 2-acetamido-4-n-butylthio-1-(3-methoxycarbonyl-2-thioureido)benzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([O:21]CC)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CCOC(=O)Cc1ccc2nc(Nc3ccccc3Br)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc2nc(Nc3ccccc3Br)oc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
Ethyl 2-(2-bromophenylamino)-6-benzoxazolylacetate (3.82 g, 10.6 mmol) was dissolved in THF-methanol (1:1, 40 ml). To the resulting solution, 1.0M-NaOH (52.0 ml, 52.0 mmol) was added, followed by stirring at room temperature for 1.5 hours. To the residue, which had been obtained by distilling off the solvent under reduced pressure, was acidified with 1.0N-HCl. The crystals thus obtained were collected by filtration under reduced pressure, washed with water and dried overnight under reduced pressure at 60° C., whereby 2-(2-bromophenylamino)-6-benzoxazolylacetic acid (3.40 g, 93%) was obtained as a white crystalline powder.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.CN(C=O)C>[CH3:9][C:10]1[N:11]=[CH:12][N:13]([C:2]2[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH:14]=1
Reactant: Cc1c[nH]cn1
Reactant: Nc1ccc(I)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(N)nc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a seal tube charged with 5-iodopyridin-2-amine 143-1 (1.1 g, 5 mmol), 4-methyl-1H-imidazole 143-2 (0.61 g, 7.4 mmol), CuI (0.31 g, 1.63 mmol) and Cs2CO3 (3.25 g, 10 mmol) was added DMF (10 mL). The reaction vessel was flushed with nitrogen and sealed. The reaction was stirred at room temperature for 30 minutes before being heated up to 110° C. for 24 hours. The reaction was diluted into ethyl acetate and the salt was removed by filtration. The filtrate was dried and the residue was purified by silica gel flash chromatography, eluted with 10% methanol in ethyl acetate to give 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine 143-3 as off-white solid. MS m/z 175.2 (M+1).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([C:24]#[N:25])=[C:12]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:11]=1.[ClH:33]>C(#N)C.[Cu](Cl)Cl>[Cl:33][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([C:24]#[N:25])=[C:12]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:11]=1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccccc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(Sc2ccccc2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under argon, 24.5 g (182 mmol) of anhydrous copper(II) chloride are suspended in 180 ml of acetonitrile, and 21.4 g (182 mmol) of isopentyl nitrite are then added dropwise. After 20 minutes of stirring at room temperature, 10 g (30.5 mmol) of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,5-pyridinedicarbonitrile [Kambe et al., Synthesis, 531-533 (1981)] are added. The mixture is stirred at room temperature over the weekend. For work-up, 150 ml of 1 N hydrochloric acid are added to the mixture, the mixture is extracted 4× with dichloromethane and the organic phase is washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is triturated with a little ethyl acetate and allowed to stand in a fridge for one hour. The crystals are filtered off with suction and washed with a little cold ethyl acetate and diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14](O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)=O)=[O:7].C(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl>O=[Pt]=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([NH:8][CH2:9][CH:10]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[CH2:14][CH2:13][NH:12]1)=[O:7]
Reactant: COc1ccc(C(O)CNC(=O)CNC(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Agent: O=[Pt]=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(cc1OC)C(CNC(=O)c1cc(OC)c(OC)c(OC)c1)NCC2
Temperature: 0 °C

Procedure:
4.48 g. of α-(3,4,5-trimethoxybenzamido)-N-[2-hydroxy-2-(3,4-dimethoxyphenyl)-ethyl]-acetamide [producible from 2-(3,4-dimethoxyphenyl)-2-hydroxyethylamine and 3,4,5-trimethoxybenzamidoacetyl chloride] is allowed to stand in 100 ml. of chloroform with 6.2 g. of phosphorus pentachloride for 3 days at 20°. The mixture is decomposed with ice water and washed several times with NaHCO3 solution. The chloroform solution is evaporated. The thus-obtained crude 1-(3,4,5-trimethoxybenzamidomethyl)-6,7-dimethoxy-isoquinoline is taken up in 50 ml. of methanol, combined with 400 mg. of PtO2, and hydrogenated at 20° and under normal pressure. The product is filtered and evaporated. Chromatography on silica gel (with chloroform/methanol 19:1) yields 1-(3,4,5-trimethoxybenzamidomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; hydrochloride, m.p. 234°-236°.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])([O-])=O.[Zn+2:9].[N+]([O-])([O-])=O.[P:14](=[O:18])([OH:17])([OH:16])[OH:15]>O>[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Zn+2:9].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Zn+2:9].[Zn+2:9]
Reactant: O=P(O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [Zn+2]
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=P([O-])([O-])[O-]

Procedure:
Phosphating solution based on zinc diacid phosphate, nitric acid, zinc nitrate and phosphoric acid in a percentage amount, diluted in water, of between 5 and 20%, at a temperature of 60-85° C. for a variable between 5 and 15 minutes, so as to produce a compact and homogeneous zinc phosphate coating with a very fine crystalline structure so as to facilitate mechanical deformation of the cold material;
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH2:10][NH+:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2].[I-].[C:29]([Mg]Br)#[C:30][CH3:31].O1CCCC1>C(OCC)C>[CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH:10]([C:29]#[C:30][CH3:31])[N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2]
Reactant: CC#C[Mg]Br
Reactant: CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC#CC1c2c(ccc(OC)c2OC)C(CC)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of 13-ethyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (200 mg, 0.4 mmol) in anhydrous diethyl ether (5 mL) at 0° C. was added a solution of 1-propynylmagnesium bromide solution in tetrahydrofuran (0.5 M, 8 mL, 4 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 13-ethyl-9,10-dimethoxy-8-prop-1-ynyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (130 mg, 80%). LC/MS m/e calcd for C25H25NO4 (M+H)+: 404.48, observed: 404.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.33 Hz, 3 H) 1.65 (d, J=2.02 Hz, 3 H) 2.60-2.81 (m, 4 H) 3.07 (m, 1 H) 3.18-3.25 (m, 1 H) 3.81 (d, J=8.84 Hz, 6 H) 5.32 (d, J=2.02 Hz, 1 H) 6.05 (d, J=6.32 Hz, 2 H) 6.86 (s, 1 H) 6.95 (s, 1 H) 6.96-7.02 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[NH:25])=[CH:23][C:17]=4[N:16]=3)[C:9]=2[OH:27])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C1COCC1.O>[Cl:14][C:12]1[CH:11]=[C:10]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=[NH:25])=[CH:23][C:17]=3[N:16]=2)[C:9]([OH:27])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH:3]=2)[CH:13]=1
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(Cl)cc(-c4cccc(N)c4)c3O)nc2c1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1cccc(-c2cc(Cl)cc(-c3nc4cc(C(=N)N)ccc4[nH]3)c2O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(3′-Amino-5-chloro-2-hydroxy-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine 73 (0.070 g, 0.15 mmol) and THF/water (1:1, 0.5 mL) is chilled (0° C.) and treated with 2 N NaOH (0.16 mL, 0.32 mmol) and methane sulfonyl chloride (0.013 mL, 0.16 mmol) in alternating portions. The mixture is kept at 0° C. for 1 h and then treated with another portion of 2 N NaOH (0.016 mL, 0.032 mmol) and methane sulfonyl chloride (0.001 mL, 0.013 mmol). After another 1 h, the solvents were reduced in volume under reduced pressure, and the crude material is purified by C18 reversed-phase HPLC (2-65% MeCN/H2O containing 20 mM HCl, over 50 min.). The appropriate fractions were pooled and the solvent is removed under reduced pressure. 2-(5-chloro-2-hydroxy-3′-methanesulfonylamino-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine 74 is obtained as a tan powder (0.012 g, 16% yield) (Example 288, Table 2a):
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:14][CH2:13]1.[CH3:29]N(C)C=O.[H-].[Na+].IC>O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([CH3:29])[C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:14][CH2:13]1
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)OCC(CN1CCC(CNc3nc4ccccc4s3)CC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN(CC1CCN(CC2COc3ccccc3O2)CC1)c1nc2ccccc2s1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 11.85 parts of N-[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinylmethyl]-2-benzothiazolamine in 72 parts of N,N-dimethylformamide were added portionwise 1.5 parts of a sodium hydride dispersion 50%. Upon completion, stirring was continued for 30 minutes. A solution of 4.6 parts of iodomethane in 18 parts of N,N-dimethylformamide was added dropwise. The whole was stirred overnight at room temperature. The reaction mixture was poured into water and the product was extracted twice with 4-methyl-2-pentanone. The combined organic layers were dried, filtered and evaporated. The residue was separated by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 1,1'-oxybisethane, yielding 1 part of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-N-methyl-2-benzothiazolamine; mp. 125.4° C. (compound 62).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][C:9]([OH:12])([CH3:11])[CH3:10])[CH:7]=1.[OH:14][C:15]([CH3:48])([CH3:47])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH3:25])[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:14][C:15]([CH3:47])([CH3:48])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:27]=[CH:28][C:29]([C:2]3[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH2:8][C:9]([OH:12])([CH3:11])[CH3:10])[CH:7]=3)=[CH:30][CH:31]=2)[CH3:25])[CH2:19][CH2:18]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(O)Cn1cc(Br)ccc1=O
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CC(C)(C)O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
To a solution of 5-bromo-1-(2-hydroxy-2-methylpropyl)pyridin-2(1H)-one (20 mg, 81.3 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg) under nitrogen. The mixture was stirred for 1 h at rt, and a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (38.95 mg, 81.3 mmol) in EtOH (2 mL) and satd aq NaHCO3 (2 mL) were added. The resulting mixture was stirred at 100° C. for 2 h, quenched with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC and preparative HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxy-2-methylpropyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (6.5 mg, 15.5%). LC-MS Method 2 tR=0.99 min, m/z=519; 1H NMR (CDCl3): δ 7.60-7.57 (d, 1H), 7.43 (s, 1H), 7.36-7.26 (m, 5H), 7.15 (d, 2H), 7.01 (d, 2H), 6.70 (d, 1H), 2.85 (m, 1H), 5.69-5.66 (m, 1H), 4.13-4.09 (s, 2H), 4.05-3.98 (s, 1H), 2.89-2.86 (m, 1H), 2.44-2.36 (m, 1H), 2.28-2.16 (m, 5H), 1.58-1.53 (d, 3H), 1.33-1.30 (s, 6H), 1.19 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.B.CO>C1COCC1>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Cl)c1F
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of (3-chloro-2-fluoro-phenyl)-acetonitrile (1.48 g, 8.8 mmol) in anhydrous THF (20 mL) was added a solution of borane (20 mL, 1M in THF) dropwise. The resulting reaction mixture was heated at reflux temperature for 2 hours. After cooling to room temperature, MeOH was added and the mixture was stirred at room temperature for additional 30 min. After removal of volatiles under reduced pressure, desired title product (1.30 g, 90%) was obtained as oil. MS: 174.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([OH:22])[CH2:7]1)=[O:5])[CH3:2].[OH:23]O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N+:10]([O-:23])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([OH:22])[CH2:7]1)=[O:5])[CH3:2]
Reactant: OO
Reactant: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(O)C1
Product: CCOC(=O)N1CCc2c(C)c3ccccc3[n+]([O-])c2C(O)C1
Yield: 17 %

Procedure:
5-Hydroxy-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester-6-oxide was prepared from 5-hydroxy-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester and hydrogen peroxide analogous to Example 163.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])=[CH:4][CH:3]=1.BrC1SC([CH2:35][N:36]2C3C(=CC=CC=3)C3(C4=CC5OCOC=5C=C4OC3)C2=O)=CC=1>>[O:28]=[C:9]1[C:10]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]1[CH2:7][C:5]1[O:6][C:2]([C:35]#[N:36])=[CH:3][CH:4]=1
Reactant: O=C1N(Cc2ccc(Br)o2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: O=C1N(Cc2ccc(Br)s2)c2ccccc2C12COc1cc3c(cc12)OCO3
Product: N#Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)o1

Procedure:
Following the procedure described in EXAMPLE 10.79, and making non-critical variations using 1′-[(5-bromo-2-furyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 1′-[(5-bromo-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, the title compound was obtained (44%) as a colorless solid: mp 167-169° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-7.27 (m, 1H), 7.21-7.17 (m, 1H), 7.12-7.08 (m, 1H), 7.07-7.03 (m, 1H), 6.95 (d, 1H), 6.51 (s, 1H), 6.44 (d, 1H), 6.08 (s, 1H), 5.86 (q, 2H), 4.96 (ABq, 2H), 4.78 (ABq, 2H); MS (ES+) m/z 387.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[N:6]=[CH:5][CH2:4][CH2:3]1.[CH2:8]([Mg]Br)[CH:9]=[CH2:10].C(OCC)C>C1COCC1>[CH2:10]([CH:5]1[NH:6][C:2]([CH3:7])([CH3:1])[CH2:3][CH2:4]1)[CH:9]=[CH2:8]
Reactant: C=CC[Mg]Br
Reactant: CC1(C)CCC=N1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC1CCC(C)(C)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of 5,5-dimethyl-1-pyrroline (2.3 g, 23.7 mmol) in anhydrous THF (50 ml) 1.0 M solution of allylmagnesium bromide in diethyl ether (43.3 ml, 47.3 mmol) was added dropwise at 0° C. The reaction mixture was allowed to stir at 0° C. for 1 hour and brought to room temperature and stirred for 3 hours. Analysis of the reaction mixture by LC-MS indicated the completion of the reaction. The reaction mixture was cooled to 0° C. and quenched with 5 ml of 1N aqueous HCl and partitioned with 50 ml of EtOAc. Organic layer was separated and the aqueous layer was worked up with 2×50 ml of EtOAc. Combined organic layers were dried over MgSO4 and concentrated under vacuum gave the product as light yellow oil in 44% yield (1.5 g). The crude product was taken to the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:52][CH2:53][C:54]1[C:55]([OH:62])=[N:56][C:57]([CH3:61])=[CH:58][C:59]=1[CH3:60]>ClCCl>[OH:62][C:55]1[C:54]([CH2:53][NH:52][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([CH:3]([O:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:2]([CH3:1])[CH3:20])=[CH:19][CH:18]=2)=[C:59]([CH3:60])[CH:58]=[C:57]([CH3:61])[N:56]=1
Reactant: CC(C)C(Oc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(Oc3ccccc3)C(C)C)cc2)c(O)n1
Temperature: 25 °C
Yield: 32.1 %

Procedure:
A mixture of 4-(2-methyl-1-phenoxypropyl)benzoic acid (208 mg, 0.77 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-te-tramethyluroniumhexafluorophosphate (439 mg, 1.2 mmol), triethylamine (0.32 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1.0 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was washed with water (30 mL). The organic phase was separated, dried over sodium, filtered, concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(2-methyl-1-phenoxypropyl)benzamide (Compound I-43) as a white solid (100 mg, 32%). LRMS (M+H+) m/z: calcd 404.21. found 404. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.33 (t, J=5.1 Hz, 1H), 7.47 (s, 1H), 7.34 (m, 3H), 7.20 (m, 3H), 6.88 (m, 2H), 5.84 (s, 1H), 5.54 (d, J=6.6 Hz, 1H), 4.25 (d, J=4.5 Hz, 2H), 2.35-2.30 (m, 1H), 2.17 (s, 3H), 2.13 (s, 3H), 1.01 (d, J=6.6 Hz, 6H).