Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:11][CH2:10][C@@H:9]([CH2:12][NH:13]C(=O)OC(C)(C)C)[CH2:8]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:11][CH2:10][C@@H:9]([CH2:12][NH2:13])[CH2:8]1)=[O:44]
Reactant: Cn1ncc(N)c1N1CC[C@@H](CNC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](CN)C1
Yield: 33 %

Procedure:
Following the procedures as described in Example 113, (S)-tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)methylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 137 as a white solid (56 mg, 33%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 7.61-7.45 (m, 3H), 7.41 (d, J=5.1, 1H), 7.28 (t, J=8.6, 2H), 3.62 (s, 3H), 3.31-3.20 (m, 4H), 2.98 (dt, J=19.0, 9.5, 1H), 2.61 (d, J=6.9, 1H), 2.34-2.19 (m, 1H), 1.96 (tt, J=29.5, 14.8, 1H), 1.60 (dq, J=14.3, 7.2, 1H). ESIMS m/z=434.1 (M+1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:2]=1>N.CO.[Ni]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][NH2:11])[CH:2]=1
Reactant: N#Cc1ccccc1Oc1cccnc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccccc1Oc1cccnc1
Reaction time: 6 h

Procedure:
To a solution of Example 94A (4.28 g, 21.84 mmol) in 7N NH3 in methanol (200 ml) was added Raney nickel (12 g) under argon atmosphere. The reaction mixture was kept on a shaker under 60 psi H2 atmosphere. After 6 hours at room temperature, the reaction mixture was filtered through a micro pore filter and concentrated to give the title compound. MS (ESI+) m/z 201 (M+H)+.
Reaction SMILES: O[C:2]1[C:7]([I:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[NH:12][C:13](=[O:19])[O:14]C(C)(C)C.C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[I:8][C:7]1[C:2]2[O:19][C:13](=[O:14])[NH:12][C:3]=2[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1cc([N+](=O)[O-])cc(I)c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cc([N+](=O)[O-])cc(I)c2o1
Yield: 716.4 %

Procedure:
A solution of tert-butyl (2-hydroxy-3-iodo-5-nitrophenyl)carbamate (1.0 g, 2.6 mmol) and N,N-carbonyldiimidazole (0.47 g, 2.9 mmol) in THF (6 mL) was stirred at reflux for 1 h. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL), washed with 1 N HCl (50 mL), water (20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude solid. This material was concentrated from hexanes (2×) to give the desired product (5.7 g, 91%) as an orange solid. This material was purified by flash column chromatography to give the desired product (0.66 g, 82%) as a yellow solid. LCMS for C7H41N2O4 (M+H)+: m/z=306.8.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[NH:8][N:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1.O>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[NH:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccc(O)cc2)[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2ccc(O)cc2)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a stirred solution of 5-(4-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (5.8 g, 0.018 mole) in a mixture of methanol (50 mL) and THF (180 mL) was added 10% Pd/C (2 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 5 hours. The reaction mixture was then filtered through celite, and the celite was washed with methanol. The filtrate was collected and concentrated under reduced pressure afford 4.05 g (97%) of 5-(4-Benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 233.08 (M+1)+, 97%. To a stirred solution of 5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (4 g, 0.01724 mol) in a mixture of 1,4-dioxane (88 mL) and H2O (88 mL) was added NaOH (1.57 g, 0.03793 mol) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then acidified with concentrated HCl solution. The mixture was concentrated and the resulting precipitate was isolated by filtration and dried to afford 3.1 g (76%) of 5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid. LCMS: 205.05 (M+1)+, 91.6%.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.Cl[S:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=1)(=[O:32])=[O:31]>>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][S:30]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=3)(=[O:32])=[O:31])=[C:19]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(OS(=O)(=O)c4ccc(C(=O)O)c(O)c4)c(C4CCCC4)c3)c2c1C

Procedure:
Using 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenol (0.289 g, 0.641 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.717 g, 3.03 mmol) the title compound was prepared according to the procedure in Example 1, step 9. Purification on Dynamax C18 eluting with 100% CH3CN (0.1% TFA added) gave 0.25 g (60%) of the title compound as a yellow solid, mp >225° C.; 1H NMR (DMSO-d6) δ 1.31-1.36 (m, 2 H), 1.49-1.59 (m, 5 H), 1.61-1.63 (m, 3 H), 1.78-1.82 (m, 1 H), 2.44 (s, 3 H), 3.04-3.10 (m, 1 H), 7.25-7.31 (m, 3 H), 7.34-7.37 (m, 3 H), 7.50 (t, 1 H), 7.66 (t, 1 H), 8.02 (d, 1 H), 8.21 (d, 1 H). IR (KBr): 3425, 2900, 1650, 1400 and 1175 cm-1. mass spectrum (-ESI), m/z 649/651 (M-H). Anal. Calcd. for C32H27BrO6S2.0.6H2O: C, 58.02; H, 4.29 N, 0.00. Found: C, 57.98; H, 4.35 N, 0.10.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:17][NH:18][O:19][CH3:20].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[CH3:17][N:18]([O:19][CH3:20])[C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of 30 g Boc-proline and 13.6 g N,O-dimethylhydroxylamine hydrochloride in 250 ml of dichloromethane was added 26.73 g 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 18.83 g N-hydroxy-benzotriazol and 49.34 g N-methyl-morpholine at 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was washed sequentially with saturated sodium bicarbonate, a 5% aqueous solution of citric acid and brine. The organic phase was dried over sodium sulfate. After filtration, the solvent was removed in vacuo to give 22.9 g N-methyl-N-methoxy-(Boc-proline)-amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=1)(=[O:37])[CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 101 was prepared from 1-(4-fluorophenyl) cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.37–7.24 (m, 6H), 7.02–6.95 (m, 2H), 6.51 (br s, 1H), 3.28 (dd, 2H, J=5.6, 11.6 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.53–2.48 (m, 3H), 2.37–2.30 (m, 4H), 1.98–1.92 (m, 4H), 1.82–1.59 (m, 12H), 1.02 (t, 3H, J=7.6 Hz); ESMS m/e: 494.3 (M+H)+.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=1[CH2:20][NH:21][C:22](=O)[CH2:23][CH3:24])(=O)CC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:16]([C:8]1[C:7]([CH2:20][NH:21][CH2:22][CH2:23][CH3:24])=[C:6]([OH:5])[CH:11]=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[CH:9]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CCC(=O)NCc1c(OC(=O)CC)cc(C(C)(C)C)cc1C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCNCc1c(O)cc(C(C)(C)C)cc1C(C)(C)C

Procedure:
Using the procedure described in Example 20, the product of Step A from was reduced with lithium aluminum hydride to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:13][C:11]1([CH3:12])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][C:9](=[O:14])[CH2:10]1
Reactant: CC(C)=CC(=O)Nc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)CC(=O)Nc2ccc(Br)cc21
Temperature: 130 °C
Reaction time: 16 h

Procedure:
To 6.7 g (26.02 mmol) of molten N-(4-bromophenyl)3,3dimethylacrylamide (Compound 92) (heated to 135 degrees C.) was added 4.15 g (31.09) of aluminum chloride over 25 min. The reaction mixture was stirred at 130 degrees C. for 16 h and then treated with a further 1 g (7.5 mmol) of aluminum chloride. The reaction mixture was heated at 130 degrees C. for a further 9 h and then cooled to room temperature: The reaction was then quenched by the slow addition of 100 ml of ice cold water with slight warming of flask to facilitate mixing. The mixture was extracted with 1×100 ml and 4×50 ml of ether. The organic extracts were combined and washed with 25 ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 30% ethyl acetate in hexanes) to give the title compound as a pale yellow solid. PMR (CDCl3): & 1.37 (6H, s), 2.53 (2H, s), 6.85 (1H, d, J~8.4 Hz), 7.32 (1H, dd, J~8.4 Hz, 2.1 Hz), 7.43 (1H, d, J~2.1 Hz), 10.12 (1H, broad s).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.ClCCl.[OH-].[Na+]>[CH3:9][C:4]1[CH:3]=[C:2]([O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6][C:5]=1[CH:7]=[O:8]
Reactant: Oc1ccccc1
Reactant: Cc1cc(Br)sc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccccc2)sc1C=O
Yield: 19.5 %

Procedure:
A solution of 5-bromo-3-methyl-thiophene-2-carbaldehyde (example 1.a, 30.8 g, 150 mmol), phenol (28.2 g, 300 mmol), cesium carbonate (97 g, 300 mmol), copper(I) trifluoromethanesulfonate benzene complex (90%, 7.5 g, 15 mmol), and ethyl acetate (750 μL, 7.5 mmol) in 150 mL of anhydrous toluene was heated at reflux temperature for 48 hours. The resultant mixture was diluted with dichloromethane and 2 N NaOH(aq) and filtered through a small pad of celite, the solid was washed with additional dichloromethane and NaOH solution. The biphasic mixture was separated and the organic fraction was successively washed with 2 N NaOH and brine. The organic fraction was dried over anhydrous magnesium sulfate and concentrated to a residue. The crude product was purified by column chromatography, eluting the desired product from silica gel with a gradient of 5-30% ethyl acetate in hexanes to provide 6.4 g of product; MS: (+) m/z 219.4 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](B(O)O)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][C:19]1[O:20][CH2:21][C:22]2([C:36]3[C:31](=[N:32][CH:33]=[C:34]([O:37][CH2:38][C:39](=[O:41])[CH3:40])[CH:35]=3)[O:30][C:29]3[C:24]2=[CH:25][C:26](Br)=[CH:27][CH:28]=3)[N:23]=1.O1CCOCC1>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.O>[NH2:18][C:19]1[O:20][CH2:21][C:22]2([C:36]3[C:31](=[N:32][CH:33]=[C:34]([O:37][CH2:38][C:39](=[O:41])[CH3:40])[CH:35]=3)[O:30][C:29]3[C:24]2=[CH:25][C:26]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:11])=[CH:27][CH:28]=3)[N:23]=1
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: CC(=O)COc1cnc2c(c1)C1(COC(N)=N1)c1cc(Br)ccc1O2
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)COc1cnc2c(c1)C1(COC(N)=N1)c1cc(-c3cc(Cl)ccc3F)ccc1O2
Temperature: 80 °C

Procedure:
A vial charged with 5-chloro-2-fluorophenylboronic acid (0.431 g, 2.474 mmol), palladiumtetrakis (0.057 g, 0.049 mmol), potassium carbonate (0.684 g, 4.95 mmol), and 1-(2′-amino-7-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yloxy)propan-2-one (0.400 g, 0.990 mmol) was treated with 5 mL dioxane followed by 1 mL water. The vial was flushed with argon and was heated to 80° C. for 3 hours. The reaction mixture was diluted with EtOAc (25 mL) and dried over MgSO4. The organic layers were combined and concentrated, and the crude residue was purified by column chromatography yielding 1-(2′-amino-7-(5-chloro-2-fluorophenyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yloxy)propan-2-one. MS m/z=454.0 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[Cl:14].[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[Cl:14]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(N)cc1Cl

Procedure:
2-(4 nitro-2-chlorophenyl )acetic acid methyl ester was reduced with tin chloride in methanol at reflux for 2 h. The solution was poured over ice and neutralized with saturated sodium bicarbonate. The mixture was extracted with methylene chloride, dried (MgSO4), and concentrated. The oil was purified by silica gel chromatography eluted with hexane/ethyl acetate(9:1 to 8:2) to yield the title compound (0.81 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[CH:8]1[CH2:13][CH:6]([CH2:7]1)[C:5]2=O.CO.[NH2:17][OH:18].Cl.[OH-].[K+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]1[CH2:13][CH:6]([CH2:7]1)[C:5]2=[N:17][OH:18]
Reactant: O=C1c2cc(Br)c(F)cc2C2CC1C2
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: ON=C1c2cc(Br)ccc2C2CC1C2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
Into a 20-L 4-necked round-bottom flask was placed 6-Bromo-7-fluoro-2,3-dihydro-1H-1,3-methano-naphthalen-4-one (920 g, 3.88 mol, 1.00 equiv), methanol (7.5 L), tetrahydrofuran (2.5 L), NH2OH.HCl (538.2 g, 2.00 equiv), and KOH (655.2 g, 3.00 equiv, 50%). The resulting solution was stirred at 80° C. for 2.5 h and cooled to 25° C. The solids were filtered out and washed with 3×1 L of DCM. The filtrate was concentrated under vacuum and the residue was diluted with 5 L of H2O and 8 L of EA. The pH value of the solution was adjusted to 7 with HCl (3 M). The organic layer was washed with 1×2 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 980 g (crude) of 6-Bromo-2,3-dihydro-1H-1,3-methano-naphthalen-4-one oxime as a dark red solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([NH:33][C:34](=[O:37])[O:35][CH3:36])[C:4](=[O:32])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:14][C:13]2[C:15]3[C:20]([CH:21]=[CH:22][C:12]=2[N:11]=1)=[CH:19][C:18](B1OC(C)(C)C(C)(C)O1)=[CH:17][CH:16]=3.Br[C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[C:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[C:45]([NH:58][C:59](=[O:61])[O-:60])[CH:44]=[CH:43]2.C([O-])(O)=O.[Na+]>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.COCCOC>[CH3:36][O:35][C:34](=[O:37])[NH:33][C@@H:3]([CH:2]([CH3:1])[CH3:38])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]2[C:22]3[C:17]([CH:16]=[CH:15][C:13]=2[N:14]=1)=[CH:18][C:19]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([NH:58][C:59]([O:60][C:2]([CH3:38])([CH3:3])[CH3:1])=[O:61])[C:46]=2[NH:50][C:51]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:57])[CH:41]=1)=[CH:20][CH:21]=3)=[O:32]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)Nc1c(NC(=O)[O-])ccc2cc(Br)ccc12
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: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)ccc5c4)ccc3c2[nH]1)C(C)C
Temperature: 120 °C
Yield: 151.7 %

Procedure:
To methyl (S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (190 mg, 0.36 mmol), tert-butyl 6-bromonaphthalene-1,2-diyldicarbamate (205 mg, 0.47 mmol), Pd(PPh3)4 (42 mg, 0.036 mmol). DME (1.5 mL) was added and followed by 1.08 mL 1M NaHCO3 aqueous solution. The reaction was purged with Ar and heated to 120° C. at microwave synthesizer for 0.5 hour. The reaction was cooled to room temperature and concentrated down. EtOAc was added and washed with sat. NaHCO3 aqueous (2×) and sat. NaCl aqueous (1×). The organic layer was concentrated down after drying over sodium sulfate and subject to silica gel chromatography with an eluent of ethyl acetate and hexane at a gradient of 40-100% with an ISCO column (12 g silica gel). The fractions containing product were combined and the solvent was removed under reduced pressure to provide the desired product (205 mg, 75%). MS (ESI) m/z 752 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[C@H:19]([CH3:24])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]([F:45])=[CH:32][C:31]=1[N:46]1[CH2:58][CH2:57][N:49]2[C:50]3[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=3[CH:56]=[C:48]2[C:47]1=[O:59])(=[O:27])[CH3:26].CC([O-])=O.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:46]2[CH2:58][CH2:57][N:49]3[C:50]4[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=4[CH:56]=[C:48]3[C:47]2=[O:59])=[CH:32][C:33]([F:45])=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[C@H:19]([CH3:24])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CCN1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)[C@H](C)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 52.7 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 108e (280 mg, 0.71 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (344 mg, 0.71 mmol), PdCl2(dppf) (58 mg, 0.071 mmol), 1.0 M NaOAc (2.0 equiv), 1.0 M K3PO4 (2.0 equiv), and dioxane (5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1, V/V) to afford 108f (250 mg, 58%) as a white solid. LCMS: [M+H]+ 668
Reaction SMILES: C(=O)/C=C/C.C=C=O.Cl.NC(N)=O.[OH-].[Na+:15].[C:16]([OH:23])(=[O:22])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[CH3:21]>>[C:16]([O-:23])(=[O:22])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[CH3:21].[Na+:15]
Reactant: C/C=C/C=C/C(=O)O
Agent: C/C=C/C=O
Agent: C=C=O
Agent: Cl
Product: C/C=C/C=C/C(=O)[O-]

Procedure:
A related protocol is described in Japanese Unexamined Patent Application Publication No. 54-163516. Here, the polyester obtained from reacting crotonaldehyde and ketene is decomposed with hydrochloric acid in the presence of a urea compound. The resulting decomposition reaction mixture is filtered to yield crude sorbic acid. Aqueous sodium hydroxide solution is added to the crude sorbic acid to yield an aqueous sodium sorbate solution. The aqueous sodium sorbate solution is treated with activated carbon, neutralized, and cooled to crystallize the purified sorbic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[CH2:11](Br)[CH3:12]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:11][CH3:12])[CH:7]=1
Reactant: OCc1ccc(Cl)cc1O
Reactant: CCBr
Product: CCOc1cc(Cl)ccc1CO

Procedure:
The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol (PREPARATION 7) and ethylbromide according to the procedure for the preparation of Example 111, part A. 1H NMR (400 MHz, CDCl3): δ 1.44 (3H, t, J=6.8 Hz), 2.24 (1H, s), 4.07 (2H, q, J=6.8 Hz), 4.64 (2H, s), 6.85 (1H, d, J=1.6 Hz), 6.91 (1H, dd, J=1.6 Hz, 7.6 Hz), 7.20 (1H, d, J=8.0 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=2)[N:4]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[CH2:30]([N:32]([CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=2)[N:4]=1)[CH2:33][CH3:34])[CH3:31]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)cc1
Reactant: CCNCC
Product: CCOC(=O)c1c(CN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)cc1

Procedure:
According to the same manner as that described in Example 33, ethyl 2-chloromethyl-4-(4-methoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with diethylamine to give ethyl 2-(N,N-diethylaminomethyl)-6,7-dimethoxy-4-(4-methoxyphenyl)quinoline-3-carboxylate. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 118°-119° C.