Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-])=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>C1(C)C=CC=CC=1.[Pd]>[C:1]([O:5][C:6](=[O:20])[N:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH2:17])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COc1ccc(N)c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a suspension of N-(5-methoxy-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester (5.8 g) in toluene (55 ml) was added 7.5% palladium on carbon (1.2 g, which contain 50% water) and the air of the reaction vessel was replaced with nitrogen and the mixture was stirred under a hydrogen atmosphere at 40° C. for 3 hours. After the reaction the mixture was cooled to room temperature and the hydrogen in the reaction vessel was replaced with nitrogen. The palladium on carbon was removed by filtration and the filtrate was evaporated in vacuo to 22 ml. To this solution was slowly added methylcyclohexane (44 ml) and the precipitated crystals were filtered to give the title compound (4.4 g, yield 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[S:5][C:6]=1[CH3:7].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[S:5][C:6]=1[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1cc(Br)c(C)s1)OC
Solvent: O
Solvent: ClCCl
Product: COC(CN(Cc1cc(Br)c(C)s1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-((4-bromo-5-methylthiophen-2-yl)methyl)-2,2-dimethoxyethanamine (14.5 g, 49 mmol) was dissolved in DCM (100 ml) and TEA (14 ml, 99 mmol) was added. The reaction was cooled to 0° C. with an ice bath and 4-tosyl chloride (8.5 ml, 59 mmol) was added portionwise. The reaction was allowed to warm up to RT and stirred overnight. The reaction was then diluted with DCM and water. The layers were separated and the organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate purified by column chromatography on silica gel using a gradient of 30 to 70% EtOAc in hexanes to give N-((4-bromo-5-methylthiophen-2-yl)methyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide as light brown oil.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([C:7]#[C:8][CH2:9][O:10][S:12]([CH3:11])(=[O:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC#Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC#Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Phenyl-prop-2-yn-1-ol 37 (3.0 g, 22.7 mmol) is dissolved in DCM (50 mL). The solution is cooled to 0° C., then methanesulfonyl chloride (4.5 mL, 34.1 mmol) and triethyl amine (4.7 mL, 34.1 mmol) is added. The mixture is allowed to warm to room temperature and stirred overnight at room temperature. The mixture is washed with H2O (2×30 mL). The organic layer is dried (MgSO4), filtered, and concentrated to afford crude methanesulfonic acid 3-phenyl-prop-2-ynyl ester 38 as a clear oil: 1H-NMR (400 MHz, CDCl3) δ=7.47-7.32 (m, 5H), 4.38 (s, 2H), 3.67 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:18]([OH:20])=O)[C:10](=[O:14])[C:11]=1[CH2:12][CH3:13].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:45][C@H:46]([CH3:49])[CH2:47][OH:48]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:18]([NH:45][C@H:46]([CH3:49])[CH2:47][OH:48])=[O:20])[C:10](=[O:14])[C:11]=1[CH2:12][CH3:13]
Reactant: C[C@@H](N)CO
Reactant: CCc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)O)ccc2C)c1=O
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: CCc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)N[C@H](C)CO)ccc2C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
To a cooled solution (0° C.) of 3-[4-[(2,4-difluorobenzyl)oxy]-5-ethyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 4) (0.25 g, 0.62 mmol) and 4-methylmorpholine (0.10 mL, 0.94 mmol) in DMA (2 mL) was added isobutyl chloroformate (0.12 mL, 0.94 mmol). Stirred 5 min at 0° C., 30 min at ambient temperature. Added (R)-(−)-2-amino-1-propanol (0.07 mL, 0.94 mmol) and DMAP (0.02 g, 0.12 mmol) to the cooled (0° C.) reaction mixture. Stirred at ambient temperature for 3 h. Purified crude product by preparatory HPLC using a 10–90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=458) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as an off-white foam (0.20 g, 70%). 1H NMR (CD3OD/400 MHz) δ8.18 (s, 1H), 7.90 (m, 1H), 7.73 (m, 1H), 7.57 (q, 1H, J=8.4 Hz), 7.50 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.52 (q, 2H, J=12.4 Hz), 4.16 (m, 1H), 3.57 (m, 2H), 2.21 (q, 2H, J=7.6 Hz), 2.17 (s, 3H), 1.22 (m, 3H), 1.05 (t, 3H, J=7.2 Hz). ESHRMS m/z 458.1855 (M+H calculated for C24H26F2N3O4 requires 458.1886).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([OH:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](Cl)(=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[C:21]([O:14][C:12]1[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=[C:9]([S:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: Oc1nc(SCc2ccccc2)nn1-c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1nc(SCc2ccccc2)nn1-c1ccccc1

Procedure:
A mixture of the product of stage (c) (20 g), toluene (150 ml) and acetyl chloride (12.2 ml) was heated under reflux for 5 hours. The volatile materials were removed in vacuo, and the residue was triturated with ether and filtered off. Recrystallisation from ethanol gave 19.8 g of desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:21]([CH2:24][OH:25])[CH2:22][NH2:23].CCN(C(C)C)C(C)C>CCCCO>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:23][CH2:22][CH2:21][CH2:24][OH:25])[CH:3]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: NCCCO
Reactant: Clc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCCNc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 200 °C
Yield: 40 %

Procedure:
165 mg of 6-chloro-N-(4-morpholinophenyl)pyrimidin-4-amine, 86 mg of propanolamine and 147 mg of DIPEA were dissolved in 2 mL of n-BuOH, The mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. n-BuOH was evaporated off and the evaporation residue was subjected to crystallization from n-BuOH-EtOH solvent mixture. 3-(6-(4-Morpholinophenylamino)pyrimidin-4-ylamino)propan-1-ol was obtained in the form of a colorless solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl.[NH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[C:25]([CH3:34])[CH:24]=1)[CH3:22].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.CN(C)C=O>[CH3:34][C:25]1[CH:24]=[C:23]([C@H:21]([NH:20][C:12](=[O:14])[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([C:3]([CH3:4])([CH3:5])[C:2]([F:1])([F:18])[F:17])=[CH:16][CH:15]=2)[CH3:22])[CH:28]=[CH:27][C:26]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: Cc1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Reactant: CC(C)(c1ccc(OCC(=O)O)cc1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc([C@@H](C)NC(=O)COc2ccc(C(C)(C)C(F)(F)F)cc2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
To a N,N-dimethylformamide (DMF) (3 ml) solution of [4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetic acid (131 mg, 0.5 mmol) and N-{4-[(1R)-1-aminoethyl]-2-methylphenyl}methanesulfonamide hydrochloride (132 mg, 0.5 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (144 mg, 0.75 mmol), 1-hydroxybenzotriazole (HOBt) monohydrate (85 mg, 0.55 mmol) and triethylamine (0.21 ml) were added and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with ethyl acetate. The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=1/1 to furnish 92 mg (39% yield) of the title compound as a white solid.
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([O:8][NH:9][C:10](=[O:29])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][C:21]=2[F:28])[CH2:4][O:3]1.Cl>C(O)C>[CH2:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:12]2[C:13]([F:18])=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[C:10]([NH:9][O:8][CH:5]([CH2:6][OH:7])[CH2:4][OH:3])=[O:29])=[C:21]([F:28])[CH:22]=1)[CH3:27]
Reactant: CCc1ccc(Nc2c(C(=O)NOC3COC(C)(C)OC3)ccc(F)c2F)c(F)c1
Agent: Cl
Solvent: CCO
Product: CCc1ccc(Nc2c(C(=O)NOC(CO)CO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a stirring solution of the product of Example 33, Step C, N-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzamide (0.416 g, 0.980 mmol) in ethanol (5 mL) was added 1 molar aqueous hydrochloric acid solution (1 mL). After stirring for 1 hour at ambient temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water and twice with brine. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. The affording foam was crystallized in ethyl acetate and heptane to afford 2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-1-hydroxymethyl-ethoxy)-benzamide (0.318 g, 84.6%) as a white crystalline solid: m.p. 91-93° C.; 1 NMR (400 MHz; CD3OD) δ 7.38 (1 H, t, J=6.8 Hz), 6.85-6.96 (3 H, m), 6.73-6.78 (1 H, m), 3.86-3.82 (1 H), 3.64 (4 H, d, J=4.9 Hz), 2.58 (2 H, q, J=15.1, 7.6 Hz), 1.19 (3 H, t, J=7.6 Hz); 19F-NMR (376 MHz; CD3OD) δ −132.4, −134.6, −147.2; MS(APCI+)=385; Anal.calcd/found for C18H19F3N2O4: C, 56.25/56.38; H, 4.98/4.81; N, 7.29/7.25.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH3:11].Cl.CS([O-])(=O)=O.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]=1[S:28](=[O:31])(=[O:30])[NH2:29]>>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][N:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH:3]2[CH3:11])=[O:24])=[CH:21][C:20]=1[S:28]([NH2:29])(=[O:31])=[O:30]
Reactant: CC1Cc2ccccc2N1N
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Product: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
Process according to claim 1, characterised in that the 1-amino-2,3-dihydro-2-methyl-1H-indole is reacted in the form of a hydrochloride or a methanesulphonate with the 4-chloro-3-sulphamoylbenzoyl chloride.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]=1[F:18])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:27][CH:26]=[CH2:25])[CH2:16][CH2:17]2)[C:7]=1[F:18])(=[O:3])=[O:4]
Reactant: C=CCBr
Reactant: CS(=O)(=O)Oc1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(c2cccc(OS(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 2-fluoro-3-piperidin-4-ylphenyl methanesulfonate (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and allylbromide (0.01 g). MS m/z (rel. intensity, 70 eV) 313 (M+, 28), 312 (25), 286 (42), 234 (bp), 207 (19).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.S(Cl)(Cl)=O>C(OCC)(=O)C>[OH:12][C:9]1[CH:8]=[CH:7][C:6]([C:5]2[O:13][CH2:2][CH2:3][N:4]=2)=[CH:11][CH:10]=1
Reactant: O=C(NCCO)c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Oc1ccc(C2=NCCO2)cc1
Yield: 87 %

Procedure:
To a slurry of 18.0g (0.1 moles) of N-(2-hydroxyethyl)-p-hydroxybenzamide in 100 ml of ethyl acetate was added a solution of 23.80g (0.2 moles) of thionyl chloride in 25 ml of ethyl acetate. Thionyl chloride addition was slow enough to maintain the reaction temperature below 50° C. After 2 hours at room temperature the precipitate was collected by vacuum filtration and then dissolved in 200 ml of water. The solution was neutralized with 5% sodium hydroxide solution. The white precipitate which formed was collected by vacuum filtration and then dried in a vacuum oven at ≈70° C. overnight. This material was identified by NMR and IR spectroscopy as the desired 2-(p-hydroxyphenyl)-oxazoline. An 87% yield was obtained.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].[C:6]([N:14]=[C:15]=[S:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:1]([NH:5][C:15]([NH:14][C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[S:16])[CH2:2][CH2:3][NH:4][C:15]([NH:14][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:16]
Reactant: NCCCN
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)NCCCNC(=S)NC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To an ice cold solution of propane-1,3-diamine (2.77 g, 37.4 mmol) in CH2Cl2 (60 mL) is added dropwise benzoyl isothiocyanate (12.50 g, 77 mmol). The reaction mixture is stirred at room temp for 3 h and the solvent is removed in vacuo. The residue is suspended in MeOH (80 ml) and filtered to give 13.2 g (88%) of the title compound as a white solid. LC/MS (Condition A): ret. T=3.81 min, (M+H)+ 401.14.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([Sn](C)(C)C)=[CH:3][CH:2]=1.N#N.Br[C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[C:17]#[N:18]>C1(C)C=CC=CC=1.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:17]([C:16]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:15]=1[C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)#[N:18]
Reactant: N#Cc1cc(F)ccc1Br
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(F)cc2C#N)cc1
Temperature: 25 °C

Procedure:
A solution of p-tolyltrimethyltin (1.26 g; 4.96 mmol) in dry toluene (8 mL) was degassed with a stream of N2 for ca. 5 min. To this solution under N2 was added 2-bromo-5-fluorobenzonitrile (0.901 g; 4.51 mmol) and Pd(PPh3)4 (260 mg; 5 mol%). The reaction was stirred at reflux under N2 for 12 hr and then cooled to room temperature. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The product was purified by flash chromatography on a silica gel column, eluting with Hex/CH2Cl2 to afford the title compound as a slightly yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:12][OH:13])=[CH:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([C:7]2[C:8]([CH:12]=[O:13])=[CH:9][O:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cocc1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1cocc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-phenyl-3-furanmethanol (Compound 53, 458 mg, 2.63 mmol), powdered 4A molecular sieves (500 mg), 4-methyl-morpholine-N-oxide (462 mg, 3.95 mmol) and tetrapropylammonium perruthenate (46 mg, 0.13 mmol) in anhydrous dichloromethane (40 ml) were stirred at room temperature for 3 hours. Residue was filtered through silica and concentrated to a brown oil which was purified by flash chromatography on silica using 10% ethyl ether/hexanes to give the titled aldehyde.
Reaction SMILES: [OH:1][C@H:2]([CH3:22])[C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])[CH2:8][CH2:7]1)=[O:4].Cl.O1CCOCC1>ClCCl>[NH2:14][C@@H:12]([C@H:9]1[CH2:8][CH2:7][C@H:6]([NH:5][C:3](=[O:4])[C@H:2]([OH:1])[CH3:22])[CH2:11][CH2:10]1)[CH3:13]
Reactant: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trans-tert-butyl (R)-1-(4-((R)-2-hydroxypropanamido)cyclohexyl)ethylcarbamate (66 mg, 0.21 mmol) was dissolved in dichloromethane (10 mL). A solution of HCl in dioxane (209.9 μL of 4 M, 0.84 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours. The crude mixture was concentrated in vacuo and coevaporated three times with diethylether. The residue was dissolved in methanol (10 mL), passed through a sodium bicarbonate cartridge and concentrated in vacuo to give the desired compound as a white solid (45 mg, quantitative yield).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH:22]([CH3:29])[CH:23]2O>C1(C)C=CC=CC=1>[C:13]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][C:22]([CH3:29])=[CH:23]2
Reactant: CC1Cc2c(-c3ccccc3-c3ccccc3)cccc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=Cc2cccc(-c3ccccc3-c3ccccc3)c2C1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of p-toluenesulfonic acid monohydrate (1.57 g, 8.26 mmol, 0.2 equiv), compound 18 (13.0 g crude, 41.17 mmol, 1.0 equiv) and toluene (300 mL) was refluxed for 1 hour. After cooling to room temperature, the mixture was washed sequentially with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an AnaLogix (65-200 g) column, eluting with a gradient of 0 to 10% ethyl acetate in heptanes to give compound 19 (10.25 g, 88% overall yield for 2 steps) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[N:7]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([N+:26]([O-])=O)=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:29])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:41])[N:7]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:29])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cc([N+](=O)[O-])ccc32)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cc(N)ccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To 4 mL of a methanol solution containing 200 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-nitro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 20 mg of 10% palladium on carbon was added under nitrogen atmosphere, then stirred under hydrogen atmosphere at room temperature for 2 hours. The insoluble material was filtered off, and the solvent was removed under reduced pressure to afford 180 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:36]([N:39]1[CH2:43][CH2:42][CH:41](O)[CH2:40]1)([CH3:38])[CH3:37]>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH:41]3[CH2:42][CH2:43][N:39]([CH:36]([CH3:38])[CH3:37])[CH2:40]3)[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2cc(O)ccc2n1
Reactant: CC(C)N1CCC(O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc(OC3CCN(C(C)C)C3)ccc2n1
Temperature: 35 °C

Procedure:
A mixture of 0.960 g (0.0044 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl ester, 2.32 g (0.0088 mmol) of triphenylphospine (Fluka), 0.739 g (0.0057 mmol) of 1-isopropyl-3-pyrrolidinol and 1.61 ml (0.0088 mmol) of di-tert.-butyl azadicarboxylate 40% in toluene in 100 ml THF was stirred for a prolonged period of time at 35° C. The mixture was filtered through a pad of silica and washed with 30 ml of THF. The mixture was evaporated to dryness and purified on silica eluting with a gradient of DCM/MeOH 98/2. The product fractions were evaporated and the residue was triturated with diethyl ether to yield after drying under vacuum 1.35 g (94%) of the title compound as white solid. MS (m/e): 329.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:15]([O:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=2[CH:11]=1)[CH:14]=[CH2:13]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2nc(C#N)sc2c1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
2-cyano-6-hydroxybenzothiazole 32 (336.2 mg, 1.91 mmol) and allyl bromide (331 μl, 3.82 mmol) were dissolved in N,N-dimethylformamide (1.5 ml), potassium carbonate (404.6 mg, 1.53 mmol) was added in an argon atmosphere, and the reaction mixture was stirred for an hour at room temperature. Water (20 ml) was added to the reaction mixture, and after extraction with ethyl acetate (3×50 ml) and drying of the organic layer with anhydrous sodium sulfate, the result was concentrated in vacuo. The resulting residue was purified by preparative thin-layer silica gel column chromatography {one 20 cm×20 cm×1.75 mm plate; hexane-ethyl acetate (1:1)}, yielding 6-allyloxy-benzothiazole-2-carbonitrile 33 (418.1 mg, 90%) as a pale yellow solid.