Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.Br[C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1>C1COCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:47]=[CH:48][C:39]=1[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Brc1ccc2ccccc2n1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2ccc3ccccc3n2)C1
Temperature: 65 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of Zn dust (1.70 g, 26.0 mmol) in THF (5 mL) under an Argon atmosphere, 1,2-dibromoethane (250 μl) was added at rt. The resulting mixture was heated at 65° C. for 3 min and allowed to cool to rt. TMSCl (350 μl) was then added and the mixture was stirred at rt for 30 min. tert-Butyl 3-iodoazetidine-1-carboxylate (5.70 g, 20.0 mmol) in THF (15 mL) was then added slowly and the resulting mixture was allowed to stir at rt for 45 min. A solution of Pd2(dba)3 (183 mg, 0.200 mmol) and trifurylphosphine (186 mg, 0.801 mmol) in THF (5 mL) were stirred at rt for 10 min under an Argon atmosphere and the resulting mixture was added to the organozinc reagent prepared, followed by addition of 2-bromoquinoline (5.00 g, 24.0 mmol). The mixture was then heated at 65° C. for 48 h under Argon. The reaction mixture was allowed to cool to rt and filtered through a pad of diatomaceous earth. The filtrate was concentrated and the residue obtained was purified by flash column chromatography on silica gel (0:1-1:0% EtOA/heptanes) to obtain tert-butyl 3-(quinolin-2-yl)azetidine-1-carboxylate.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([NH:16][C@@H:17]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[C:18]3[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:15])[CH:10]=2)[C:5]1=[O:38])[CH:2]=[CH2:3]>[Pd].CCOC(C)=O>[O:38]=[C:5]1[C:6]2[C:11](=[CH:10][C:9]([C:14]([NH:16][C@@H:17]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=3)[C:18]3[C:23]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:15])=[CH:8][CH:7]=2)[C:12](=[O:13])[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCN1C(=O)c2ccc(C(=O)N[C@@H](c3ccc(C(F)(F)F)cc3)c3ncccc3C(F)(F)F)cc2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN1C(=O)c2ccc(C(=O)N[C@@H](c3ccc(C(F)(F)F)cc3)c3ncccc3C(F)(F)F)cc2C1=O
Temperature: 23 °C
Reaction time: 0.03 h

Procedure:
To a 50 mL round bottom flask containing (S)-2-allyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide (Example 276) (160 mg, 0.300 mmol) was added EtOAc (15 mL). The resulting mixture was stirred at 23° C. for 2 min. At this time, Pd/C (10%, 50 mg) was added and hydrogen was bubbled through the mixture for 10 min. The reaction mixture was then left under 1 atm of hydrogen for 1 h. The solid was filtered off on a pad of Celite™ and eluted with EtOAc (75 mL). The solvent was evaporated to give (S)-1,3-dioxo-2-propyl-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.93 (d, J=4.1 Hz, 1H), 8.42 (d, J=7.6 Hz, 1H), 8.30-8.19 (m, 2H), 8.11-8.01 (m, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.64-7.45 (m, 5H), 6.88 (d, J=7.6 Hz, 1H), 3.68 (t, J=1.0 Hz, 2H), 1.72 (sxt, J=7.4 Hz, 2H), 0.95 (t, J=7.5 Hz, 3H). MS (ESI pos. ion) m/z: 536.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][C:11](=[O:13])[CH3:12].C(N(CC)C(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: CC(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)CSc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3-Bromothiophenol (2.89 g, 15.29 mmol) and chloroacetone (1.278 mL, 16.06 mmol) were mixed in THF (80 mL) and cooled to 0° C. N,N-Diisopropylethylamine (6.65 mL, 38.23 mmol) was added and the reaction was stirred at 0° C. for five minutes then allowed to warm to room temperature and stirred overnight. The reaction was then extracted with EtOAc and H2O and the organic portion was concentrated to afford the title compound.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH:8]([C:20]1[O:24][N:23]=[C:22]([CH3:25])[N:21]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[CH3:6][NH:7][CH:8]([C:20]1[O:24][N:23]=[C:22]([CH3:25])[N:21]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: Cc1noc(C(Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC(Cc1ccc2ccccc2c1)c1nc(C)no1

Procedure:
N-Methyl-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphtyl)ethyl]carbamic acid tertbutyl ester (3.3 g, 9.0 mmol) was dissolved in a saturated solution of hydrogen chloride in ethyl acetate (75 mL). After 3 hours at 20° C. the reaction mixture was filtered to give 1.52 g of (R) N-methyl-N-{1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl}amine hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>O1CCOCC1>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:4][CH2:3][CH2:2][NH2:1]
Reactant: NCCO
Reactant: Clc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NCCOc1ccccn1
Temperature: 25 °C

Procedure:
A mixture of 500 mg of 2-aminoethanol and 328 mg of 60% sodium hydride-mineral oil dispersion in dioxane (27 mL) was heated to reflux for 30 min. After cooling to room temperature, 930 mg of 2-chloropyridine was added and the mixture was warmed to reflux and maintained at this temperature for 18 hrs. The reaction mixture was concentrated, diluted with water, and extracted with chloroform (3×). The organic extracts were washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and the residue was purified by silica gel chromatography to give the title product as a yellow oily material. MS (M+H)+=138.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:19][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN1CCCC1=O.O>[C:20]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:2]2[N:7]=[C:6]([N:8]3[CH2:12][CH2:11][C:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]3=[O:17])[CH:5]=[CH:4][N:3]=2)=[CH:23][CH:22]=1)#[N:19]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCC1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCC1(C#N)CCN(c2ccnc(NCc3ccc(C#N)cc3)n2)C1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (20 mg) obtained in Step A of Example 2 and 4-(aminomethyl)benzonitrile hydrochloride (27 mg) in N-methylpyrrolidone (2 mL) was added diisopropylethylamine (0.028 mL), and the mixture was stirred at 60° C. for 3 hr. To the reaction mixture were added ethyl acetate (3 mL) and water (1 mL), and the mixture was stirred for 5 min. The organic layer was filtered through Top-Phase Separation Filter Tube, and the solvent was evaporated at 60° C. The residue was purified by HPLC (C18, mobile phase: acetonitrile/10 mM aqueous ammonium hydrogen carbonate solution), and dried at 60° C. to give the title compound.
Reaction SMILES: Br[C:2]1[CH2:3][CH:4]2[C:9]([CH3:11])([CH3:10])[O:8][C:7](=[O:12])[NH:6][C:5]2=[C:13]([F:15])[CH:14]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[Cl:26].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:26][C:18]1[CH:19]=[C:20]([C:2]2[CH:14]=[C:13]([F:15])[C:5]3[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=3[CH:3]=2)[CH:21]=[CH:22][C:17]=1[F:16]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC1(C)OC(=O)NC2=C(F)C=C(Br)CC21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC1(C)OC(=O)Nc2c(F)cc(-c3ccc(F)c(Cl)c3)cc21
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
A mixture of 6-bromo-8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one (0.176 g, 0.64 mmol), 4-fluoro-3-chlorophenyl boronic acid (0.15 g, 0.84 mmol), tetrakis(triphenylphosphine)-palladium (0) (0.04 g, 0.032 mmol), and sodium carbonate (0.20 g, 1.92 mmol) in DME (10 mL) and water (5 mL) was subject to a blanket of nitrogen for 15 minutes at 50° C. and then was heated at 85° C. for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate (100 mL) was added. The organic layer was washed twice with aqueous ammonium chloride (100 mL) and once with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 6-(3-chloro-4-fluoro-phenyl)-8-fluoro-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one as a white solid (0.13 g, 66%): mp 246-248° C.; 1H-NMR (DMSO-d6) δ10.5 (s, 1H), 8.00 (dd, 1H, J=7.09, 2.32 Hz), 7.78-7.73 (m, 1H), 7.62 (dd, 1H, J=11.86, 1.77 Hz), 7.7 (t, 2H, J=9 Hz), 1.7 (s, 6H); MS (APCI) m/z 324 ([M+H]+, 100%); Anal. Calc. For C16H12F2NO2 0.5 H2O C, 57.76, H, 3.94, N, 4.21. Found: C, 57.49, H, 3.69, N, 4.03.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@H:17]3[O:21]C(C)(C)[N:19]([C:24](=[O:28])[CH:25]([F:27])[F:26])[C@@H:18]3[CH2:29][F:30])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-]>[CH2:1]([NH:3][CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]([OH:21])[C@@H:18]([NH:19][C:24](=[O:28])[CH:25]([F:26])[F:27])[CH2:29][F:30])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCNCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNCc1ccc(-c2ccc([C@@H](O)[C@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.4 %

Procedure:
To a solution of 1-{(4S,5R)-5-[4-(6-Ethylaminomethyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidin-3-yl}-2,2-difluoro-ethanone (0.062 g, 0.147 mmol) in CH2Cl2 (5 mL) is added trifluroacetic acid (1.0 mL) at room temperature. The resulting reaction mixture is stirred at room temperature for 5 hours. Solvent is evaporated in vacuo to get the crude residue and diluted with aqueous bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by combi-flash chromatography using 15% methanol in CH2Cl2 as an eluent. Obtained solid is washed with n-pentane and diethyl ether to afford the title compound (0.035 g) after drying in lypholizer. 1H NMR (400 MHz, DMSO-d6) δ: 1.16 (t, J=7.2 Hz, 3H), 2.83-2.88 (q, 2H), 4.14 (s, 2H), 4.30-4.33 (m, 1.5H), 4.41-4.45 (m, 0.5H), 4.55-4.56 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.89 (t, J=4.08 Hz, 1H), 5.93 (d, J=4.55 Hz, 1H), 6.20 (t, J=53.76 Hz, 1H), 7.47 (d, J=8.24 Hz, 2H), 7.54 (d, J=8.2 Hz, 1H), 7.72 (d, J=8.24 Hz, 2H), 8.12-8.15 (dd, J1=2.32 Hz, J2=8.16 Hz, 1H), 8.85 (d, J=8.8 Hz, 1H), 8.90 (d, J=2.12 Hz, 1H). LC-MS (m/z): [M+H]=382.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH3:16])[O:8][C:6]=2[CH:7]=1.C(OC(=O)[NH:23][CH:24]([CH2:27][C:28]([F:31])([CH3:30])[CH3:29])[CH2:25][OH:26])(C)(C)C>>[F:31][C:28]([CH3:30])([CH3:29])[CH2:27][CH:24]([NH2:23])[CH2:25][O:26][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH:9]([CH3:16])[O:8][C:6]=2[CH:7]=1
Reactant: CC(C)(F)CC(CO)NC(=O)OC(C)(C)C
Reactant: CC1Oc2cc(Cl)ccc2-c2ccncc21
Product: CC1Oc2cc(OCC(N)CC(C)(C)F)ccc2-c2ccncc21
Yield: 53.2 %

Procedure:
Prepared as described in Example 8, Part D using 8-chloro-5-methyl-5H-chromeno[3,4-c]pyridine (0.100 g, 0.432 mmol) and tert-butyl(4-fluoro-1-hydroxy-4-methylpentan-2-yl)carbamate (0.168 g, 0.712 mmol) to afford 4-fluoro-4-methyl-1-(5-methyl-5H-chromeno[3,4-c]pyridin-8-yloxy)pentan-2-amine (80 mg, 0.23 mmol, 99% yield) as a yellow oil. 1H NMR (400 MHz, MeOD) δ 8.66 (d, J=6.4 Hz, 1 H), 8.64 (s, 1 H), 8.24 (d, J=6.4 Hz, 1 H), 8.08 (d, J=8.8 Hz, 1 H), 6.94 (dd, J=2.4 Hz, 8.8 Hz, 1 H), 6.78 (d, J=2.8 Hz, 1 H), 5.57 (q, J=6.4 Hz, 1 H), 4.38 (dd, J=6.4 Hz, J=10.8 Hz,1 H), 4.22 (dd, J=6.4 Hz, 10.8 Hz, 1 H), 3.99 (m, 1 H), 2.16 (m, 2 H), 1.75 (d, J=6.8 Hz, 3 H), 1.55 (s, 3 H), 1.50 (s, 3 H); LCMS (ESI) m/e 331.2 [(M+H)+, calcd for C19H24FN2O2331.2] LC/MS retention time (method D): tR=0.97 min; HPLC retention time (method B): tR=8.04 min.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[N:9][CH:8]=[N:7][C:6]=2[CH:5]=[N:4]1)[CH3:2].C1C(=O)N([Br:19])C(=O)C1.O>CN(C=O)C>[Br:19][C:5]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:11]=2[N:3]([CH2:1][CH3:2])[N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1ncc2ncncc21
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(Br)c2ncncc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a solution of 1-ethyl-1H-pyrazolo[4,3-d]pyrimidine (300 mg) in DMF (6 mL) was added NBS (721 mg) at room temperature, and the mixture was stirred at 80° C. overnight. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (310 mg). 1H NMR (300 MHz, CDCl3) δ 1.62 (3H, t, J=7.3 Hz), 4.54 (2H, q, J=7.3 Hz), 9.14 (1H, s), 9.17 (1H, s).
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([Cl:15])=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([O:9][CH3:10])=[O:8])=[O:3].Cl.[CH2:17]([O:20][NH2:21])[CH2:18][CH3:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:15][C:5]1[C:4]([C:2]([NH:21][O:20][CH2:17][CH2:18][CH3:19])=[O:3])=[C:13]([Cl:14])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCON
Reactant: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCONC(=O)c1c(Cl)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 30° C., 10.7 g (0.04 mol) of methyl 3-chlorocarbonyl-2,4-dichlorobenzoate in 100 ml of methylene chloride were slowly added dropwise to a solution of 4.50 g (0.04 mol) of O-propylhydroxylamine hydrochloride and 4.05 g (0.04 mol) of triethylamine in 200 ml of methylene chloride. After stirring for 2 hours at room temperature, the reaction mixture was washed with dilute phosphoric acid, dried and concentrated. The resulting residue was chromatographed over silica gel (eluent:toluene/ethyl acetate=9/1). 11.50 g.of methyl 2,4-dichloro-3-propoxyaminocarbonylbenzoate were obtained.
Reaction SMILES: [CH:1]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>C(O)C.[Pd]>[CH2:1]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC=Cc1c[nH]c2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCc1c[nH]c2ccccc12

Procedure:
3-Hex-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred until the hydrogen gas consumption was completely stopped. The reaction mixture was filtered through celite. The solvent was evaporated to afford the product.
Reaction SMILES: NC1SC(C(OCC)=O)=C(C)N=1.[NH2:13][C:14]1[S:15][C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=1.Cl[CH2:29][CH2:30][N:31]=[C:32]=[O:33]>>[O:33]=[C:32]1[NH:31][CH2:30][CH2:29][N:13]1[C:14]1[S:15][C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([C:19]([F:22])([F:20])[F:21])[N:18]=1
Reactant: CCOC(=O)c1sc(N)nc1C(F)(F)F
Reactant: O=C=NCCCl
Agent: CCOC(=O)c1sc(N)nc1C
Product: CCOC(=O)c1sc(N2CCNC2=O)nc1C(F)(F)F
Yield: 30 %

Procedure:
Following the procedure as described in Example 3, making variations as required to replace ethyl 2-amino-4-methylthiazole-5-carboxylate with ethyl 2-amino-4-(trifluoromethyl)thiazole-5-carboxylate to react with 2-chloroethyl isocyanate, the title compound was obtained as a colorless solid in 30% yield: mp 185-187° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 5.54 (s, 1H), 4.36-4.21 (m, 4H), 3.74-3.68 (m, 2H), 1.36-1.31 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 159.8, 157.0, 125.4, 122.6, 121.8, 118.2, 62.0, 44.2, 43.8, 14.0; MS (ES+) m/z 310.2 (M+1).
Reaction SMILES: O[C:2]1([C:12]2[C:21]([OH:22])=[CH:20][C:15]3[O:16][CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:22][C:21]1[C:12]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:11])=[CH:13][C:14]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[CH:20]=1
Reactant: O=C1Nc2ccccc2C1(O)c1cc2c(cc1O)OCCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccccc2C1c1cc2c(cc1O)OCCO2
Temperature: -5 °C
Reaction time: 2.5 h
Yield: 78.2 %

Procedure:
A 2000 L reactor was charged with dichloromethane (489.4 kg), followed by 3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (92.0 kg, 307 mol) in four 23 kg portions over 1 h. The resultant solution was stirred at ambient temperature for 1 h and triethylsilane (107.2 kg, 921 mol) was added. The mixture was cooled to −5° C. and trifluoroacetic acid (105.1 kg, 921 mol) was added at a rate of 25-30 kg/h such that the temperature of the reaction mixture remained below 0° C. The mixture was stirred at −5-0° C. for 2.5 h, warmed to 18-20° C., stirred for a further 6.5 h and concentrated to dryness under reduced pressure at a temperature<30° C. Methyl tert-butyl ether (139.8 kg) was added to the residue at 15-20° C. and the mixture concentrated to near-dryness under reduced pressure at a temperature<35° C. The mixture was filtered in a centrifugal filter and a 2000 L reactor was charged with the filter cake, followed by methanol (72.7 kg). The mixture was stirred at 10-15° C. for 0.5 h and filtered in a centrifugal filter. The filter cake was dried under reduced pressure at 40-50° C. to afford 3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (68.0 kg, 78%) as a colorless solid: purity (HPLC-UV at 254 nm) 99.3%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CSC.CO>C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[OH:11]
Reactant: Cc1cccc2c1CCC2=O
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: Cc1cccc2c1CC[C@H]2O
Temperature: -30 °C
Reaction time: 0.83 h

Procedure:
To a solution of 4-methyl-indan-1-one (5.00 g, 34.20 mmole) and (S)-2-methyl-CBS-oxazaborolidine (5.00 mL, 1.0 M in THF, 5.00 mmol) in THF at −20° C. was added borane-methylsulfide (12.00 mL, 1.0 M in THF, 12.00 mmol) over 20 minutes. The resulting mixture was then stirred for 50 minutes and cooled to −30° C. Methanol (40.00 mL) was added and the resulting mixture was gradually warmed to room temperature and concentrated to give the crude alcohol.
Reaction SMILES: [C:1](O)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([CH:19]=[CH:18][C:16]([OH:17])=[CH:15][CH:14]=1)[OH:13]>CCOCC>[OH:13][C:12]1[CH:19]=[C:18]2[C:16](=[CH:15][CH:14]=1)[O:17][C:1](=[O:10])[CH2:2][CH:3]2[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: Oc1ccc(O)cc1
Solvent: CCOCC
Product: O=C1CC(c2ccccc2)c2cc(O)ccc2O1
Yield: 97 %

Procedure:
6-Hydroxy-4-phenyl-3,4-dihydrocoumarin (II) was prepared in a similar way in 97% yield from cinnamic acid and hydroquinone. M.p. 138° (IPE-Ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:9][CH2:10][CH2:11][CH2:12][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: BrCCCBr
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(SCCCBr)cc1

Procedure:
4-Fluorothiophenol (5.3 ml), 1,3-dibromo-propane (15.3 ml), K2CO3 (14 g) were dissolved in CH3CN (100 ml) and refluxed for 3 h. The insoluble salts were removed, the solvent was evaporated and the residue dissolved in ethyl acetate (70 ml). The solution was extracted with diluted NaOH and water, dried and the solvent evaporated in vacuo. The residue was purified by distillation to yield 8 g of the title compound as a colourless oil. Bp. 150-155° C. @ 20 mmHg.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:37])[CH2:31][CH2:30]3)=[CH:26][CH:27]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c(OC2CCN(c3ccc(CN4CCNCC4)cc3)CC2)nc(-c2ccncn2)cc1=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(N3CCC(Oc4nc(-c5ccncn5)cc(=O)n4C)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a mixture of 1-methyl-2-[1-(4-piperazin-1-ylmethyl-phenyl)piperidin-4-yloxy]-1H-[4,4′]bipyrimidinyl-6-one (80 mg, 0.17 mmol), formaldehyde solution (37% in water, 55 mg, 0.68 mmol) and acetic acid (one drop) in 1,2-dichloroethane (0.85 ml) was added sodium triacetoxyborohydride (130 mg, 0.61 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between water and chloroform. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; chloroform/methanol=95/5) to afford 1-methyl-2-{1-[4-(4-methyl-piperazin-1-ylmethyl)phenyl]piperidin-4-yloxy}-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (49 mg, 0.10 mmol, 59%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH2:41]([NH:48][C:14](=[O:16])[C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:17])=[CH:9][CH:10]=[N:11][CH:12]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(O)c1cnccc1-c1ccc(Cl)cc1F
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1cnccc1-c1ccc(Cl)cc1F
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinic acid (600 mg, 2.38 mmol) (as prepared in Ex. 2, Part A) in DMF (6 mL) cooled to 0° C. was added EDC (457 mg, 2.38 mmol) and HOBT (365 mg, 2.38 mmol) and the mixture was stirred for 5 min. To the resultant solution was added DIPEA (0.416 mL, 2.384 mmol) followed by benzyl amine (307 mg, 2.86 mmol) and the mixture was stirred at room temperature for 12 h. The reaction mixture was treated with ice and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (1×10 mL), dried (Na2SO4) and concentrated under reduced pressure to afford N-benzyl-4-(4-chloro-2-fluorophenyl)nicotinamide (680 mg, 2.00 mmol, 84% yield). LC/MS (ESI) m/e 341.0 [(M+H)+, calcd for C19H15ClFN2O 341.1]; LC/MS retention time (method A): tR=1.73 min.