Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][NH:22][CH:23]1[CH2:29][O:28][CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:21][N:22]([C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1)[CH:23]1[CH2:29][O:28][CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]1
Reactant: CNC1COCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4COCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1

Procedure:
A solution of 4-chloro-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (110 mg (0.36 mmol) 107.a, of tert-butyl 6-(methylamino)-1,4-oxazepane-4-carboxylate (84 mg (0.36 mmol) X.3, and DIEA (0.127 mL (0.730 mmol) in DMF (2.8 mL) was heated at 90° C. in a sealed tube for 18 hr. The mixture was diluted with H2O and extracted with EtOAc (2×). The combined organics were washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo, absorbing onto 4 g SiO2. Purification by flash column chromatography (ISCO 24 g SiO2, 10% EtOAc/hexanes then gradient to 80% EtOAc/hexanes) afforded tert-butyl 6-(methyl-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1,4-oxazepane-4-carboxylate (0.142 g) 107.4 as a yellow glassy solid. LCMS (ESI) m/z: 502.20 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][OH:23].Cl.N1C=CC=CC=1.C(OCCO)C>>[OH:23][CH2:22][C:21]1[C:20]([CH3:27])=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1c(N)cccc1CO
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(CO)c3C)c2cc1OC
Temperature: 139 °C
Yield: 91.6 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.151 g (1.1 mmol) of 3-amino-2-methylbenzyl alcohol, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 6 hours; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.32 g (91.5%) of the desired product as light tan crystals. MP 123-125° C.; : mass spectrum (electrospray, m/e,): 349.9(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:11]Br>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Nc1ncccc1C(=O)O
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
25.00 g (0.181 mol) of 2-aminonicotinic acid were dispersed in 100 ml of glacial acetic acid. To this suspension was added a solution of 12.0 ml (0.23 mol) of bromine in 50 ml of glacial acetic acid. The mixture was stirred at room temperature for 20 hours. The precipitate formed was filtered off and washed with 100 ml of glacial acetic acid in several portions until the filtrate remained colorless. The crude was dried by suction and crystallized from boiling methanol to afford 38.63 g (0.178 mol, 98% yield) of 2-amino-5-bromonicotinic acid as slightly greenish to off-white crystalline needles. 1H-NMR (d6-DMSO) δ: 8.45 [1H] d, 8.34 [1H] d.; MS: m/z 217 [MH+].
Reaction SMILES: [CH:1]([O:6][CH3:7])(OC)OC.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[CH2:12][C:11](=[O:22])[NH:10]1>C(OC(=O)C)(=O)C.CN(C)C=O>[CH3:7][O:6]/[CH:1]=[C:12]1/[C:11](=[O:22])[NH:10][C:9](=[O:8])[C:18]2[C:13]/1=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2
Reactant: O=C1Cc2cc(C(=O)O)ccc2C(=O)N1
Reactant: COC(OC)OC
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CO/C=C1/C(=O)NC(=O)c2ccc(C(=O)O)cc21
Temperature: 125 °C

Procedure:
Trimethyl orthoformate (0.114 mL, 1.04 mmol) is added to a solution of 1,3-Dioxo-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid (102.5 mg, 0.5 mmol) in acetic anhydride (0.8 mL) and N,N-dimethylformamide (0.2 mL). After it is heated at 125° C. for 30 min, it is cooled and filtered to collected 75 mg (60%) of the title compound as a yellow solid. MS (ESI) m/z 246.1 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10](I)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]12([C:23]3[CH:32]=[C:31]4[C:26]([CH:27]=[CH:28][C:29](B(O)O)=[CH:30]4)=[CH:25][C:24]=3[O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:11]=[C:10]([C:29]2[CH:28]=[CH:27][C:26]3[C:31](=[CH:32][C:23]([C:13]45[CH2:14][CH:15]6[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]6)[CH2:22]4)[CH2:20]5)=[C:24]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:25]=3)[CH:30]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Reactant: COC(=O)c1ccc(I)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1O
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
300 mg (8.8 mmol) of tetrakis (triphenyl-phosphine)palladium(0), 50 ml of toluene and 2.46 g (8.8 mmol) of methyl 2-hydroxy-4-iodobenzoate were introduced into a three-necked flask under a stream of nitrogen and stirring was carried out at room temperature for 20 minutes. 5.52 g (13.4 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid and 8.8 ml of an aqueous potassium carbonate solution (2N) were then added and the reaction mixture was heated at reflux for 8 hours. The reaction mixture was evaporated to dryness, the residue was taken up in water and ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (10/90). 1.65 g (36%) of methyl 2-hydroxy-4-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]benzoate were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][C:7]([CH:22]=[O:23])=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[Cl:9].[O-:25]Cl=O.[Na+]>CC(O)(C)C.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][C:7]([C:22]([OH:25])=[O:23])=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[Cl:9]
Reactant: [O-][Cl+][O-]
Reactant: COC(=O)CCCC(C=O)=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)CCCC(C(=O)O)=C(Cl)c1ccc(-c2ccccc2)cc1
Reaction time: 16 h

Procedure:
6-(4'-Biphenylyl)-6-chloro-5-formyl-hex-5-enoic acid methyl ester (1 g) was dissolved in t-BuOH (75 mL). A solution of NaClO2 (2.42 g) and NaH2PO4 (2.42 g) in 25 mL H2O was added dropwise. The solution was stirred for 16 hours. The methanol was removed in vacuo. The solution was acidified (3N HCl) and the product ester 12 extracted with EtOAc. 1 g, 95%. NMR and IR spectra of 12 were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:29])[CH2:18][N:19]4[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.I[CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:29])[CH:18]([N:19]4[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:27])([F:26])[F:28])=[N:20]4)[CH2:31][CH:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Reactant: ICC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1C(CC1CCOCC1)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 5.5 %

Procedure:
A mixture of 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]ethanone (0.100 g, 0.25 mmol), 4-(iodomethyl)tetrahydro-2H-pyran (0.165 g, 0.75 mmol) and NaH (0.030 g, 0.75 mmol, 60% in mineral oil) in DMF (0.8 mL) was stirred at rt for 1.5 hrs. It was then quenched with sat. NH4Cl. The mixture was partitioned between EtOAc (50 mL) and brine (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.007 g, 6%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.43 (dd, J=8.8, 4.8 Hz, 2H), 7.16 (dd, J=8.8, 8.4 Hz, 2H), 6.31 (s, 1H), 5.54 (m, 1H), 3.95 (m, 2H), 3.78 (m, 1H), 3.47 (m, 1H), 3.34 (m, 2H), 2.75 (m, 2H), 2.30 (s, 3H), 2.20 (m, 3H), 1.88 (m, 3H), 1.40 (m, 3H); MS: (ES) m/z calculated for C25H27F4N5O2 [M+H]+ 506.2, found 506.2.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:17])[O:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=2)([OH:3])=O.[CH:18]1[C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=[N:20][CH:19]=1>>[C:24]([NH:26][NH:27][C:1]([C:4]1[C:5](=[O:17])[O:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=2)=[O:3])(=[O:25])[C:23]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: NNC(=O)c1ccncc1
Reactant: COc1cc(C)c2cc(C(=O)O)c(=O)oc2c1
Product: COc1cc(C)c2cc(C(=O)NNC(=O)c3ccncc3)c(=O)oc2c1

Procedure:
Compound 213 was prepared following the preparation of compound 26 except that 3-carboxy-5-methyl-7-methoxy-coumarin reacted with isoniazid to give the title compound 213.
Reaction SMILES: Cl.N[C@H]1CCCC[C@H]1CNC.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH:21][C:22]([C:24]1[C:25](=[O:52])[C:26]([O:44]CC2C=CC=CC=2)=[C:27]2[C:41](=[O:42])[N:31]3[CH:32]4[CH:37]([CH2:38][N:39]([CH3:40])[CH:30]3[CH2:29][N:28]2[CH:43]=1)[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:23]>[Pd]>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH:21][C:22]([C:24]1[C:25](=[O:52])[C:26]([OH:44])=[C:27]2[C:41](=[O:42])[N:31]3[CH:32]4[CH:37]([CH2:38][N:39]([CH3:40])[CH:30]3[CH2:29][N:28]2[CH:43]=1)[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:23]
Reactant: CN1CC2CCCCC2N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3CC12
Agent: [Pd]
Agent: CNC[C@@H]1CCCC[C@@H]1N
Agent: Cl
Product: CN1CC2CCCCC2N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3CC12
Yield: 63 %

Procedure:
In a manner similar to that described in example Z-35, from racemic-{[(1S,2S)-2-aminocyclohexyl]methyl}methylamine hydrochloride (46 mg, 0.215 mmol) and 16a (35 mg, 0.0744 mmol) was prepared racemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-methyl-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (17 mg, 41%) as a white solid. This material was deprotected in a second step similar to the procedure described in example Z-37. Thus, from racemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-methyl-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (17 mg, 0.0302 mmol) and 10% Pd/C (1 mg) was prepared the title compound as a white solid (9 mg, 64%). 1H NMR (CDCl3) 10.44 (m, 1H), 8.29 (s, 1H), 7.34 (m, 1H), 6.79 (m, 2H), 4.78 (m, 1H), 4.62 (br s, 2H), 4.29 (br s, 2H), 3.41 (s, 1H), 2.92 (m, 1H), 2.66 (m, 1H), 2.35-2.25 (m, 4H), 1.90-1.74 (m, 2H), 1.67-1.24 (m, 6H); ES+ MS: 473 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:25][C:26]1[C:32]([OH:33])=[CH:31][C:29]([NH2:30])=[C:28]([F:34])[CH:27]=1>CC(O)CCC>[OH2:13].[ClH:2].[Cl:25][C:26]1[C:32]([OH:33])=[CH:31][C:29]([NH:30][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[C:28]([F:34])[CH:27]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ccnc2cc1OCCCN1CCOCC1
Product: O
Yield: 150.1 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline hydrochloride (300 mg, 0.73 mmol), and 4-chloro-2-fluoro-5-hydroxyaniline (130 mg, 0.8 mmol), (as described in EP 61741 A2), in 2-pentanol (15 ml) was heated at reflux for 5 hours. The resulting solid was collected by filtration, washed with acetone and dried under vacuum to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-morpholinopropoxy)quinoline hydrochloride hydrate (283 mg, 73%) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[F:10].[C-]#N.[K+].[OH-:14].[K+].CN([CH:19]=[O:20])C>O>[Cl:9][C:5]1[C:4]([F:10])=[C:3]([CH2:2][C:19]([OH:20])=[O:14])[CH:8]=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: Fc1c(Cl)cccc1CBr
Reactant: [OH-]
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1cccc(Cl)c1F
Temperature: 75 °C
Reaction time: 48 h

Procedure:
1-Bromomethyl-3-chloro-2-fluoro-benzene (10.00 g, 44.80 mmol) and KCN (5.80 g, 89.07 mmol) were mixed in DMF and the resulting reaction mixture was stirred at 75° C. for 2 days. The reaction mixture was cooled to room temperature, and water was added. The mixture was extracted with Et2O (3×300 mL). The combined organic phases were washed with H2O (2×200 mL) and brine (1×200 mL), then dried over MgSO4 and concentrated. The crude nitrile was taken up in water and KOH (5.00 g, 89.11 mmol) was added. The resulting mixture was refluxed for 14 hours. After cooling to room temperature, the reaction mixture was diluted with water and washed with Et2O (2×150 mL). The aqueous layer was acidified with concentrated HCl and was extracted with Et2O (3×300 mL). The combined organic phases were washed with H2O (2×200 mL) and brine (1×200 mL), then dried over MgSO4 and concentrated to afford the title acid.
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][O:11][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=2[O-])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:14][C@@H:13]1[NH:8][CH2:9][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[O:11][CH2:12]1
Reactant: C[C@H]1COC(c2cccc[n+]2[O-])CN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1COC(c2ccccn2)CN1
Yield: 30.1 %

Procedure:
To a suspension of 10% palladium-on-carbon (2 g) in ethanol (30 mL) was added a solution of 2-((5S)-4-benzyl-5-methylmorpholin-2-yl)pyridine 1-oxide (3.5 g, 13.06 mmol) in ethanol (10 mL). The mixture was subjected to a hydrogen atmosphere using a balloon filled with hydrogen gas for 2 h. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford (5S)-5-methyl-2-(pyridin-2-yl)morpholine (0.7 g). MS (ES+) (M+H) 179.0.
Reaction SMILES: [OH-:1].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1>C1(C)C=CC=CC=1>[C:4]([C:15]1[CH:16]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:3](=[O:2])[N:7]2[C:6]=1[C:11]1[S:12][CH:13]=[CH:14][C:10]=1[CH2:9][CH2:8]2)(=[O:1])[CH3:3]
Reactant: [OH-]
Reactant: Oc1c(-c2cccc(F)c2)sc2[n+]1CCc1ccsc1-2
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(-c2cccc(F)c2)c(=O)n2c1-c1sccc1CC2

Procedure:
A solution of 0.303 g of 5,6-dihydro-3-hydroxy-2-(m-fluorophenyl )-thiazolo[3,2-a ]thieno[2,3-c ]pyridinium hydroxide (internal salt) and 0.145 ml of 3-butyl-2-one in 5 ml of toluene was heated under reflux for 1 hour. The solvent is evaporated in vacuo and the residue is chromatographed over silica gel with toluene/ethyl acetate (1:1). After recrystallization from ethanol, there was obtained 10-acetyl-4,5-dihydro-8-(m-fluorophenyl)7H-thieno[2,3-a]quinolizin-7-one of m.p. 109°110°.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][Br:9])[C:3](Br)=[O:4].C(N(CC)CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][Br:9])[C:3]([NH:30][CH:27]1[CH2:26][CH2:25][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:29][CH2:28]1)=[O:4]
Reactant: O=C(Br)C(Br)CCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)C(Br)CCCBr)CC1
Reaction time: 4 h
Yield: 90.5 %

Procedure:
To a solution of crude 2,5-dibromopentanoyl bromide (6.50 g, 20 mmol) and triethylamine (3.06 g, 30.2 mmol) in CH2Cl2 (40 mL) cooled to 0° C. was added tert-butyl-4-aminopiperidine-1-carboxylate (4.23 g, 21.1 mmol) in one portion. The reaction was allowed to stir for 4 hours at which point the reaction was quenched by the addition of saturated aqueous NaHCO3 (5 mL) and CH2Cl2 (10 mL). The organic layer was separated and the aqueous layer washed with additional CH2Cl2 (3×15 mL). The combined organic layers were dried with MgSO4 and concentrated. The crude material was purified over silica gel (3:1 hexanes/EtOAc) to give tert-butyl 4-(2,5-dibromopentanamido)piperidine-1-carboxylate (8.00 g, 90%) as a white solid.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([O:35][C@H:36]([C:47]4[CH:56]=[CH:55]N=C5[C:48]=4[CH:49]=[C:50]([O:57]C)[CH:51]=C5)[C@@H:37]4N5C[C@H](CC)[C@@H](CC5)[CH2:38]4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[CH2:59]([O:66]C1C(OC)=CC=CC=1CCC=C)C1C=CC=CC=1.O.C([OH:84])(C)(C)C>>[CH2:28]([O:35][C:36]1[C:37]([O:66][CH3:59])=[CH:38][CH:55]=[CH:56][C:47]=1[CH2:48][CH2:49][C@H:50]([OH:57])[CH2:51][OH:84])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=CCCc1cccc(OC)c1OCc1ccccc1
Reactant: CC(C)(C)O
Solvent: O
Product: COc1cccc(CC[C@H](O)CO)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a suspension of AD-mix-α (63.28 g) in water:tert-butyl alcohol (1:1, 300 mL) cooled to 0° C. is slowly added via an addition funnel to a solution of 2-(benzyloxy)-1-(3-butenyl)-3-methoxybenzene (12.13 g, 45.2 mmol) in water:tert-butyl alcohol (1:1, 300 mL). The reaction mixture is allowed to stir at room temperature for 12 h. The reaction mixture is quenched by the addition of sodium sulfite. The reaction mixture is diluted with water (500 mL) and ethyl acetate (500 mL). The aqueous phase is separated and extracted with ethyl acetate (2×200 mL). The combined organic extracts are washed with aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent is removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) provides 12.57 g (92%, 40% ee) of (2S)-4-[2-(benzyloxy)-3-methoxyphenyl]-1,2-butanediol as a colorless oil. [α]D25=−3.04 (c 10.2 in methanol, 40% ee); Rf=0.72 (silica, ethyl acetate:hexanes 4:1); Anal. Calcd. for C18H22O4.0.1H2O: C, 71.08; H, 7.36. Found: C, 70.95; H, 7.33.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14]([C@H:16]1[CH2:21][C@H:20]2[C@H:18]([CH2:19]2)[C@@H:17]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[O:15])C1C=CC=CC=1.[OH:30]O.O.[OH-].[Li+]>C1COCC1.O>[Si:23]([O:22][C@@H:17]1[C@@H:16]([C:14]([OH:15])=[O:30])[CH2:21][C@H:20]2[C@@H:18]1[CH2:19]2)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: OO
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1[C@H]2C[C@H]2C[C@@H]1C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@H]2C[C@H]2C[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of (R)-4-benzyl-3-((1S,2S,3S,5S)-2-(tert-butyldimethylsilyloxy)bicyclo[3.1.0]hexane-3-carbonyl)oxazolidin-2-one (40 g, 96.4 mmol) in THF (200 mL) and water (50 mL) was added 30% aqueous hydrogen peroxide (88 mL, 771 mmol) dropwise at 0° C., followed by the addition of a solution of lithium hydroxide monohydrate (16 g, 386 mmol) in water (100 mL). After stirring for 1 hour at 0° C., the reaction mixture was stirred at room temperature overnight. The excess hydrogen peroxide was completely consumed by the addition of saturated aqueous sodium bisulfate. The mixture was then adjusted to pH=14 with 1 N NaOH and washed with ether (400 mL). The aqueous layer was then acidified to pH=3 with 1 M aqueous potassium hydrogen sulfate, and extracted with ethyl acetate (3×400 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (22 g, 88%) as a colorless oil.
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:27])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=3[CH3:26])=[N:13]2)=[O:8])[N:6]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>N1C=CC=CC=1>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([NH:32][CH2:31][CH2:30][O:29][CH3:28])[O:3][CH:4]=3)=[O:8])[CH3:27])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: COCCN
Reactant: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3coc(Br)n3)n2)ccc(C#N)c1Cl
Solvent: c1ccncc1
Product: COCCNc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)co1
Temperature: 120 °C
Yield: 15.65 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamide (0.180 g, 0.401 mmol) was added into a microwave vial with dry pyridine as a solvent. The mixture was bubbled with nitrogen. 2-Methoxyethylamine (0.129 ml, 2.407 mmol) was added and the mixture was heated with microwaves at 120° C. for 2 h. The product was purified by Flash-chromatography. Yield 15.65%. 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 2.58 (s, 3H), 3.39 (s, 3H), 3.44 (t, 2H), 3.51 (t, 2H), 4.30 (dd, 1H), 4.40 (dd, 1H), 4.51-4.60 (m, 1H), 5.07 (t, 1H), 6.44 (d, 1H), 7.40 (d, 1H), 7.51 (d, 1H), 7.52-7.58 (m, 2H), 7.67 (s, 1H).