Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].F[C:15]1[CH:16]=[C:17]([C:24]2[S:28][C:27]([N:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:30][C@@H:31]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[N:26][N:25]=2)[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22]>O1CCOCC1>[C:46]([O:45][C:44]([NH:43][C@@H:31]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:38]=1)[CH2:30][N:29]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[C:27]1[S:28][C:24]([C:17]2[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:15]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:16]=2)=[N:25][N:26]=1)=[O:50])([CH3:47])([CH3:48])[CH3:49]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
Diethyl malonate (2.83 mL, 18.7 mmol) in 30 mL of 1,4-dioxane was added to sodium hydride (0.748 g, 60% dispersion in mineral oil, 18.7 mmol) in 10 mL of 1,4-dioxane at room temperature under nitrogen. The mixture became a clear solution within 5 minutes. The mixture was stirred for another 15 minutes followed by addition of the tert-butyl (S)-1-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate as described in Schemes 1a and 1b (3.0 g, 4.7 mmol). After overnight stirring, the solvent was removed. The residue was partitioned between EtOAc and saturated NH4Cl. The combined organic portions were washed with brine and dried over sodium sulfate. The crude product was used in the following reaction without purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]C(O)=O)([O-:18])=[O:17].N1CCCCC1>C1(C)C(C)=CC=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N+:16]([O-:18])=[O:17])[CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Solvent: Cc1ccccc1C
Solvent: C1CCNCC1
Product: CC(C)c1cc(C=Cc2ccccc2[N+](=O)[O-])cc(C(C)C)c1O
Yield: 86.8 %

Procedure:
To a solution of 3,5-diisopropyl-4-hydroxybenzaldehyde (0.95 g, 4.6 mmol) and 2-nitrophenyl acetic acid (1.1 g, 6.2 mmol) in xylene (10 ml) was added piperidine (0.05 ml) and the mixture was heated under reflux for 8 hrs while removing water producing with the progress of reaction. After distilling off the solvent followed by purification of the residue by a silica gel column chromatography, recrystallization from hexane gave 2,6-diisopropyl-4-(2-nitrostyryl)phenol (1.3 g, 87%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.C(NC(C)C)(C)C.[C:20](=[O:22])=[O:21].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:20]([OH:22])=[O:21]
Reactant: Fc1cccnc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1ccncc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
3-Fluoropyridine (25 g, 257 mmol) was added to a solution of butyllithium (270 mmol) and diisopropylamine (27.4 g, 271 mmol) in tetrahydrofuran (600 mL) at −78° C. After stirring for one hour, crushed dry ice was added to the solution and the solution was warmed to room temperature during one hour. Aqueous hydrogen chloride was added to the solution to acidify the solution to pH 5. The resulting precipitate was filtered and dried. The title compound (25.2 g, 179 mmol, 70%) was obtained as colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[CH:5]=[O:6].B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cc(Br)cc(C=O)c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1cc(O)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.7 %

Procedure:
3-Bromo-5-methoxybenzaldehyde (1 g, 4.65 mmol) was dissolved in 20 mL dichloromethane. A solution of boron tribromide (1M in dichloromethane, 23 ml, 23 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. A mixture of ethyl ether and diisopropyl ether was added and the precipitate was filtered to give 1.1 g (68% yield) of the title compound as an orange solid. Purity 99%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19][CH2:20][CH3:21])=[CH2:18])CCC>O1CCOCC1.C(OCC)(=O)C.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>[CH2:20]([O:19][C:17]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[CH2:18])[CH3:21]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc(C(=O)OC)nc1
Yield: 100.1 %

Procedure:
To a solution of methyl 5-bromopyridine-2-carboxylate (5.0 g, 23.1 mg) in dioxane (80 ml) was added Pd(PPh3)4 (1.34 g, 1.16 mmol) and tributyl(1-ethoxyethenyl)stannane (8.60 ml, 25.5 mmol). After stirring the reaction mixture at reflux temp for overnight, the mixture was diluted with ethyl acetate, washed with 10% KF solution (aqueous), filtered though celite, dried, concentrated, and separated by HPLC (8-70% EtOH in hexane) to give methyl 5-(1-ethoxyethenyl)pyridine-2-carboxylate (4.8 g). LCMS: [M+H]+=208.2
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]([NH:18][C:19]([NH2:21])=[NH:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CN(C=O)C>[NH2:21][C:19]1[N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[N:20]=1
Reactant: CCCCCCC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC(=N)N
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reaction time: 48 h
Yield: 57.3 %

Procedure:
1-bromooctan-2-one (1.00 g, 4.83 mmol) was placed in a 50 mL round bottomed flask with a stir bar and dissolved in 10 mL of DMF. Boc guanidine (2.31 g, 14.89 mmol) was then added to the reaction mixture and it was allowed to stir for 48 hours. Water was then added to the reaction mixture and it was placed in a separatory funnel. The mixture was then extracted twice with ethyl acetate, washed twice with water, washed twice with brine, concentrated de vacuo and then purified via column chromatography (5% methanol/95% dichloromethane) to provide tert-butyl 2-amino-4-hexyl-1H-imidazole-1-carboxylate as a hygroscopic light yellow solid (0.74 g, 57% yield). 1H NMR (300 MHz, CDCl3) δ 6.69 (s, 2H), δ 6.34 (s, 1H), δ 2.20 (t, J=7.5 Hz, 2H), δ 1.44 (bs, 11H), 1.17 (s, 6H), δ 0.76 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 151.1, 149.6, 139.3, 105.7, 84.1, 31.8, 29.2, 28.4, 28.3, 28.0, 22.7, 14.2 ppm; IR νmax (cm−1) 3421, 2109, 1644, 1442, 1204, 1142; HRMS (ESI) calcd for C14H25N3O2 (M+) 267.1946, found 267.1940. Then, tert-butyl 2-amino-4-hexyl-1H-imidazole-1-carboxylate was dissolved in a 1:4 mixture of trifluoroacetic acid/dichloromethane and allowed to stir for five hours and then concentrated de vacuo. The sample was then dissolved with a dilute HCl/methanol (5 drops HCl/50 mL of methanol) and then concentrated in vacuo to provide 4-(5phenylpentyl)-1H)-imidazol-2-amine hydrochloride as a hygroscopic light yellow solid (0.57 g, 57% overall yield). 1H NMR (300 MHz, CD3OD) δ 6.34 (bs, 3H), δ 2.41 (t, J=7.5 Hz, 2H), δ1.56 (m, 2H), δ 1.28 (bs, 6H), δ 0.82 (t, J=6.6 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 151.4, 131.9, 111.9, 35.3, 32.4, 31.9, 28.3, 26.3, 17.1 ppm; IR νmax (cm−1) 3411, 2099, 1638; HRMS (ESI) calcd for C9H17N3 (M+) 167.1422, found 167.1416.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH2:8][CH:7]([NH:22][C:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][N:26]=2)=[O:24])[C:6]1=[O:35].[Li+].[OH-]>C1COCC1.O>[C:14]([NH:13][CH2:12][C:10]1[CH2:11][N:5]([CH2:4][C:3]([OH:36])=[O:2])[C:6](=[O:35])[CH:7]([NH:22][C:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][N:26]=2)=[O:24])[CH2:8][CH:9]=1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)CN1CC(CNC(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1CC(CNC(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution containing {6-(benzoylamino-methyl)-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 30, (84 mg, 0.17 mmol) in THF/H2O (4 mL of 3:1) is treated with excess LiOH and the solution stirred for 2.5 hours at room temperature. The solution is then acidified and extracted with EtOAc. The EtOAc layer was dried (Na2SO4) and concentrated to the crude product which is used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[C:24]1([N:30]2[C:34]([CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:33][C:32]([OH:43])=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:43][C:32]3[CH:33]=[C:34]([CH2:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: Oc1cc(CCc2ccccn2)n(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2cc(CCc3ccccn3)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (0.30 g), 1-phenyl-5-[2-(pyridin-2-yl)ethyl]-1H-pyrazol-3-ol (0.43 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}ethyl)pyridine as a colorless oil (0.47 g, yield 76%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 104-105° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[N:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[N:33][CH:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cncc(-c2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyrazine.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.S(Cl)(Cl)=O.[C:16]([Cl:26])(=O)C1C=CC=C(OC)C=1.C=O>[Cl-].[Zn+2].[Cl-]>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([O:11][CH2:16][Cl:26])=[O:10]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1cccc(C(=O)O)c1
Agent: C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=S(Cl)Cl
Product: COc1cccc(C(=O)OCCl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
A similar procedure (Lu, M. C. et al. J. Med. Chem. 1987, 30, 273-278 and Iyer, R. P. et al. Synth. Commun. 1995, 25, 2739-2749) to that described for the preparation of 50 was followed using m-anisic acid (4.1 g, 26.9 mmol) and thionyl chloride (4 mL), under reflux for 1 h. A mixture of crude m-anisoyl chloride, paraformaldehyde (808 mg, 26.9 mmol) and zinc chloride (28 mg, 0.21 mmol) was then stirred at 80° C. for 16 h. Purification by flash chromatography (hexane/ethyl acetate 19:1) afforded chloromethyl m-methoxybenzoate (47) as a pale green oil (1.4 g, 6.86 mmol, 26%). 1H NMR 3.86 (3H, s, OMe), 5.95 (2H, s, CH2), 7.14-7.17 (1H, m, Ar), 7.36-7.40 (1H, m, Ar), 7.58-7.59 (1H, m, Ar), 7.66-7.69 (1H, m, Ar).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:12])([CH3:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+:13]([O-])([OH:15])=[O:14].[OH:17][S:18]([OH:21])(=[O:20])=[O:19]>>[S:18]([OH:21])([OH:20])(=[O:19])=[O:17].[NH2:2][C:3]([CH3:12])([CH3:11])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CC(C)(N)Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Product: CC(C)(N)Cc1ccc([N+](=O)[O-])cc1

Procedure:
A slight modification in the procedure described previously [Lavin et al, J. Biol. Chem., Vol. 256, p. 11944 (1981)] enables direct isolation of the product instead of column chromatographic separation of ortho (20%) and para (80%) isomers, both of which are products of the nitration. 2-Amino-2-methyl-1-phenylpropane hydrochloride (97 g, 0.41 mol) was dissolved in concentrated H2SO4 (195 ml) and the solution was cooled in an ice bath. Nitric acid (70%, 40 ml, 56 g, 0.6 mol) was added with stirring while the temperature was kept under 10° C. and then the solution was stirred for an additional 20 min. Next the mixture was poured on ice (4 l), and after 16 h white crystals were filtered, washed with cold water and methanol, and dried in air. Yield: 71.3 g (56%); mp 293°-298° C. dec; Rf 0.24 (dichloro-methane-methanol-ammonia, 4:1:0.03).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8]N)[CH:5]=[CH:6][CH:7]=1.[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(N(CC)CC)C>C(O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:19]3[CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:22][CH2:21][C:20]=3[NH:8][C:4]=2[CH:3]=1
Reactant: NNc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Br)ccc3c2C1
Reaction time: 18 h
Yield: 41.7 %

Procedure:
3-Bromophenylhydrazine (40.0 g, 0.179 mol) and N-Boc-4-oxo-piperidine (35.4 g, 0.179 mol) were dissolved in ethanol (368 mL), and conc. HCl (72 mL) was added. The reaction mixture was then heated to reflux for 18 h, concentrated and basified using 10% NH4OH in methanol (10%, 100 mL). The solvent was removed, and the residue was suspended in CH2Cl2 (1.2 L). Boc2O (39.2 g, 0.179 mol) followed by DMAP (195 mg, 1.6 mmol) and triethylamine (46.4 mL, 0.358 mol) were then added, and the reaction progressed at room temperature for 18 h. The mixture was washed with 0.5 N HCl, and the organic phase was removed, dried over Na2SO4, filtered and concentrated to dryness. The resulting mixture of regioisomers was purified by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 then 25:75) to give the more polar title compound (26.2 g, 42%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.16 (br s, 1H), 7.42 (s, 1H), 7.28 (d, J=8.1 Hz, 1H, partially masked by solvent), 7.18 (d, J=8.1 Hz, 1H), 4.60 (s, 2H), 3.80 (t, J=5.5 Hz, 2H), 2.79 (t, J=5.6 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[C:10]([F:30])=[C:11]([F:29])[CH:12]=[C:13]2[C:18]=1[N:17]([NH:19][CH2:20][CH:21]=[O:22])[CH:16]=[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:14]2=[O:28])C1C=CC=CC=1>C(Cl)(Cl)Cl.CO.[Pd]>[F:29][C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([OH:8])[C:10]=1[F:30])[N:17]([NH:19][CH2:20][CH:21]=[O:22])[CH:16]=[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:14]2=[O:28]
Reactant: CCOC(=O)c1cn(NCC=O)c2c(OCc3ccccc3)c(F)c(F)cc2c1=O
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1cn(NCC=O)c2c(O)c(F)c(F)cc2c1=O
Yield: 92.4 %

Procedure:
Ethyl 8-benzyloxy-6,7-difluoro-1-(formylmethylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (330 mg) was hydrogenated over 5% Pd/C (50 mg) in chloroform (14 ml) for 4 hours. The reaction mixture was diluted with methanol (14 ml) and filtered. The filtered cake was washed with chloroform/methanol (1:1). The combined filtrate was evaporated and the residue was recrystallized from ethanol to give 239 mg of ethyl 6,7-difluoro-1-(formylmethylamino)-8-hydroxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate, mp 221°-225° C. (dec.); MS m/z 326 (M+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[C:9]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1.[F:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:27]=[CH:26][C:25]=1[OH:37]>CN1C(=O)CCC1>[F:23][C:24]1[CH:29]=[C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:27]=[CH:26][C:25]=1[O:37][C:8]1[C:9]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1F
Reactant: CC(=O)N1CCC(c2nccnc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccccn3)cc2F)CC1
Temperature: 120 °C

Procedure:
To a mixture of cesium carbonate (1.11 g, 3.41 mmol), 1-(4-(3-chloropyrazin-2-yl)piperidin-1-yl)ethanone (0.336 g, 1.40 mmol), and 2-fluoro-4-(pyridin-2-ylamino)phenol (0.547 g, 2.68 mmol) was added NMP (3 mL). The reaction mixture was degassed and heated to 120° C. for 1.5 h. The reaction mixture was diluted with EtOAc and the organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (40% to 100% EtOAc in hexanes) gave 1-(4-(3-(2-fluoro-4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as a white solid. MS (ESI, pos. ion) m/z: 408.2 (M+1). IC50 (uM) 0.008056.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[S:5][C:4](=[C:8]([C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])[C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])[S:3]1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>N1C=CC=CC=1>[CH3:21][N:22]([CH3:26])[C:23]([O:7][CH:6]1[CH:2]([O:1][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])[S:3][C:4](=[C:8]([C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])[C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])[S:5]1)=[O:24]
Reactant: CN(C)C(=O)Cl
Reactant: CCCOC(=O)C(C(=O)OCCC)=C1SC(O)C(O)S1
Solvent: c1ccncc1
Product: CCCOC(=O)C(C(=O)OCCC)=C1SC(OC(=O)N(C)C)C(OC(=O)N(C)C)S1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.0 g (3.1 m mole) of di-n-propyl 4,5-dihydroxy-1,3-dithiolane-2-ylidenemalonate was dissolved in 5 ml of pyridine, 1.33 g of N,N-dimethylcarbamoyl chloride was dropped into the solution, which was stirred for 18 hours at room temperature.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[C:8]([C:10]1[CH:14]=[N:13][N:12]([CH3:15])[C:11]=1[NH:16][C:17]([C:19]1[C:27]2[S:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:24][C:23]=2[C:22]([O:34][CH3:35])=[CH:21][CH:20]=1)=[O:18])#[N:9].C=O.C([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[C:8]([C:10]1[CH:14]=[N:13][N:12]([CH3:15])[C:11]=1[NH:16][C:17]([C:19]1[C:27]2[S:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH3:2])[CH2:30][CH2:29]3)=[N:24][C:23]=2[C:22]([O:34][CH3:35])=[CH:21][CH:20]=1)=[O:18])#[N:9]
Reactant: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(N3CCNCC3)nc12
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(N3CCN(C)CC3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.1 %

Procedure:
A suspension of 4-methoxy-2-(piperazin-1-yl)benzothiazole-7-carboxylic acid (4-cyano-2-methyl-2H-pyrazol-3-yl)amide trifluoroacetic acid salt (275 mg) in acetonitrile (20 ml) was treated with formaldehyde (0.44 ml, 37% aqueous solution), sodium cyanoborohydride (102 mg), and acetic acid (0.3 ml) and the mixture stirred at room temperature of 12 hours. The solvent was evaporated in vacuao and the residue partitioned between aqueous sodium hydroxide (10 ml, 1M) and dichloromethane (100 ml). The aqueous layer was separated, was neutralised with acetic acid, and extracted with 2% methanol in dichloromethane (2×75 ml). The extracts were combined, dried over magnesium sulphate (5 g), filtered, and the filtrate evaporated in vacuo. Purification by column chromatography (eluent 5% methanol in dichloromethane) followed by trituration with diethyl ether yielded the title compound as a pale yellow solid (40 mg). TLC Rf 0.14 (10% methanol in dichloromethane); Mpt 249-251° C.
Reaction SMILES: [Br:1]Br.O[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[CH:9][CH:10]=2)[C:5]=1[CH2:15][C:16]([OH:18])=[O:17]>C(O)(=O)C>[Br:1][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH3:14])[C:5]1[CH2:15][C:16](=[O:17])[O:18][C:4]=1[CH:13]=[CH:12]2
Reactant: Cc1ccc2ccc(O)c(CC(=O)O)c2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc2c3c(ccc2cc1Br)OC(=O)C3

Procedure:
A solution of bromine (0.05 ml) in acetic acid (2 ml) was added over 5 minutes to a solution of 2-hydroxy-7-methyl-1-naphthylacetic acid (0.21 g) in acetic acid (5 ml). The solid which precipitated was collected and washed with acetic acid to give 7-bromo-8-methyl-2(1H)-naphtho[2,1-b]furanone, m.p. 238°-240°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH:7]=[CH:6]2)=[O:2].C(=O)([O-])[O-:22].[K+].[K+].CS(C)=O.OO>O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:22])=[CH:15][CH:14]=1)[CH:7]=[CH:6]2)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Cn2ccc3cc(C=O)ccc32)cc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Cn2ccc3cc(C=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 169.4 %

Procedure:
Mix 4-(5-Formyl-indol-1-ylmethyl)-benzonitrile (0.73 g, 2.8 mmol), potassium carbonate (0.19 g, 1.4 mmol), and dimethylsulfoxide (14 mL) in a flask. Cool 10 minutes in an ice bath and add hydrogen peroxide (0.95 mL, 30% wt in water) dropwise. Remove ice bath and stir at rt for 4 hrs. Pour into water (30 mL). After trituration, filter the solid formed and dry on a vacuum pump to obtain the product as a white solid (0.66 g, 88%). 1H NMR (DMSO-d6) 9.95 (s, 1H), 8.17 (s, 1H), 7.89 (bs, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.69 (d, J=3.1 Hz, 1H), 7.63-7.60 (m, 2H), 7.32 (bs, 1H), 7.23 (d, J=8.1 Hz, 2H), 6.73 (d, J=3.1 Hz, 1H), 5.54 (s, 2H).