Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.S(=O)(=O)(O)O.CCOCC>[N+](C1C=CC=CC=1)([O-])=O>[O:14]=[C:3]1[C:2]2[N:1]=[C:20]([C:19]3[CH:23]=[CH:24][C:16]([F:15])=[CH:17][CH:18]=3)[O:21][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2oc(-c3ccc(F)cc3)nc21
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of 6.22 g (30 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphthalene in 60 mL of nitrobenzene, 18.00 mL (150 mmol) of 4-fluorobenzoic acid chloride are added with protection from light. After 10 min of stirring with reflux, 0.20 mL of concentrated sulfuric acid is added. After 12 h and complete cooling, ether is added to obtain a yellow precipitate which is filtered through fritted glass, washed with ether and purified on a flash column (support: silica; conditioning: heptane; eluant: dichloromethane/heptane, 60/40). The yellow powder obtained after evaporation of the solvent is uncolored, recrystallized in dichloromethane to produce 2.90 g of 4,9-dihydro-4,9-dioxo-2-(4-fluorophenyl)-naphtho[2,3-d]oxazole in the form of yellow crystals.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:26][CH:27]1[C:28]([O:70]C(OCC)C)([CH3:69])[CH2:29][CH2:30][CH:31]([O:63]C(OCC)C)[CH2:32][C:33]([O:35][CH:36](/[C:41](/[CH3:62])=[CH:42]/[CH:43]=[CH:44]/[CH:45]([CH3:61])[CH2:46][CH:47]2[O:60][CH:48]2[CH:49]([CH3:59])[CH:50]([O:53]C(OCC)C)[CH2:51][CH3:52])[CH:37]([CH3:40])[CH:38]=[CH:39]1)=[O:34])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[C:18]([O:26][CH:27]1[C:28]([OH:70])([CH3:69])[CH2:29][CH2:30][CH:31]([OH:63])[CH2:32][C:33]([O:35][CH:36](/[C:41](/[CH3:62])=[CH:42]/[CH:43]=[CH:44]/[CH:45]([CH3:61])[CH2:46][CH:47]2[O:60][CH:48]2[CH:49]([CH3:59])[CH:50]([OH:53])[CH2:51][CH3:52])[CH:37]([CH3:40])[CH:38]=[CH:39]1)=[O:34])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)c2ccccc2)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(=O)c2ccccc2)/C=C/C1C
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)c2ccccc2)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(=O)c2ccccc2)C=CC1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyridinium p-toluenesulfonate (2 mg, 7.5 μmol) was added to a solution of (8E,12E,14E)-7-benzoyloxy-3,6,21-tri(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (6.1 mg, 7.48 μmol) in methanol (1 mL), followed by stirring at room temperature for one hour. The reaction solution was evaporated, ethyl acetate, water and a saturated sodium bicarbonate aqueous solution were added to the resulting residue, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and then evaporated. The resulting residue was purified by thin layer chromatography (MERCK Silica gel 60 F254, 0.2 mm, developing solution; ethyl acetatehexane=2:1) to obtain the title compound (3.3 mg, 74%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.O1CCCC1.Cl[CH2:23][C:24]([O:26][CH3:27])=[O:25].C[O-].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]2[O:14][CH:23]2[C:24]([O:26][CH3:27])=[O:25])=[CH:11][CH:10]=1
Reactant: COC(=O)CCl
Reactant: O=Cc1ccc(COc2ccccn2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1OC1c1ccc(COc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(pyridin-2-yloxymethyl)-benzaldehyde (24.8 g) described in Manufacturing Example 1-1-2 and tetrahydrofuran (160 mL) was added methyl chloroacetate (10.2 mL) at −15° C., and then sodium methoxide (23.7 mL, 28% methanol solution) was added thereto at the same temperature. The reaction mixture was stirred for 1 hour at 0° C., and then stirred for 2 hours at room temperature. The reaction mixture was added to 800 mL of an ice water containing acetic acid (6 mL), and the reaction mixture was warmed to room temperature. Ethyl acetate was added to the reaction mixture for extraction, and then the organic layer was separated, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure to obtain the title compound (30.2 g).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10]
Reactant: Clc1ccccc1CBr
Reactant: O=C1NCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1Cc1ccccc1Cl
Temperature: 70 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.066 g, 0.5 mmol), 1-bromomethyl-2-chloro-benzene (0.123 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (3 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(2-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.035 g, 27%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.94 (s, 2H), 7.16-7.52 (m, 7H), 7.90 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][C:14]([CH:17]([CH3:19])[CH3:18])=[N:13][C:12]=3[CH:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[Cl-].[Na+].Cl.[CH3:26][C:27]1[N:31]=[C:30]([CH:32]([NH2:34])[CH3:33])[O:29][N:28]=1.CN1CCOCC1.Cl.CN(C)CCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[O:15][C:14]([CH:17]([CH3:19])[CH3:18])=[N:13][C:12]=3[CH:11]=[C:10]([C:20]([NH:34][C@@H:32]([C:30]3[O:29][N:28]=[C:27]([CH3:26])[N:31]=3)[CH3:33])=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2cc(C(=O)O)cc(-c3ccc(F)cc3)c2o1
Reactant: Cc1noc(C(C)N)n1
Agent: CCN=C=NCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3)c3oc(C(C)C)nc3c2)n1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 7-(4-fluorophenyl)-2-isopropyl-1,3-benzoxazole-5-carboxylic acid with three equivalents of sodium chloride (8.5 mg, 16.0 μmol), R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride (3.35 mg, 17.0 μmol) and N-methylmorpholine (8.8 μL, 0.08 mmol) in N,N-dimethylformamide (0.16 mL) were added N-[2-(dimethylamino)ethyl]-N′-ethylcarbodiimide hydrochloride (5.35 mg, 28.0 μmol), 1-hydroxy-7-azabenzotriazole (1.09 mg, 8.0 μmol). The mixture was stirred at 50° C. for 18 h. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% ammonium hydroxide) gave the title compound (2 mg). HRMS [M+1] found=409.1662. 1H NMR (500 MHz, DMSO-d6): δ 9.23 (1H, m), 8.16 (3H, m), 7.99 (1H, s), 7.37 (2H, m), 5.44, 1H, m), 3.90 (3H, s), 3.44 (1H, m), 2.34 (3H, s), 1.65 (3H, d, J=7.11 Hz), 1.37 (6H, d, J=6.75 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CC1C=CC(S(O[CH2:51][C@@H:52]2[CH2:56][O:55][C:54]([CH3:58])([CH3:57])[O:53]2)(=O)=O)=CC=1>CN(C=O)C.O>[Cl:21][C:20]1[C:15]([C:13]2[C:12]([Cl:30])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:51][C@@H:52]4[CH2:56][O:55][C:54]([CH3:58])([CH3:57])[O:53]4)[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:18][CH:19]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](CN[C@H]2CC[C@H](Nc3cc(-c4nc(NCC5CCOCC5)ccc4Cl)c(Cl)cn3)CC2)O1
Temperature: 75 °C

Procedure:
To a stirred solution of N2′-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (68 mg, 0.151 mmol) in DMF (0.2 ml) was added DIPEA (80 μL, 0.458 mmol) followed by (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (42 mg, 0.147 mmol). The mixture was heated at 75° C. for 19 hours. The mixture was allowed to cool, then diluted with water and then extracted with EtOAc (×3). The organics were combined then washed with water (×2), saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC and lyaphllized to yield 3,5′-dichloro-N2′-(trans-4-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)aminocyclohexyl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (4.4 mg), LCMS (m/z): 564.4/566.3 (bis-chloro isotopic signature for MH+) retention time=0.65 min as a TFA salt.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]2[N:13](N=N[N:17]=2)[CH:14]=1)[OH:8])([CH3:4])[CH3:3].Cl.Cl[Sn]Cl.[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26]>CO.C(Cl)Cl.C(O)C>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]\[C:25]([OH:27])=[O:26].[NH2:17][C:12]1[N:13]=[CH:14][C:9]([C@H:7]([CH2:6][NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])[OH:8])=[CH:10][CH:11]=1
Reactant: CC(C)(C)NC[C@H](O)c1ccc2nnnn2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CC(C)(C)NC[C@H](O)c1ccc(N)nc1
Yield: 92.6 %

Procedure:
A solution of 538 mg (2.29 mmol) of (R)-α-[[(1,1-dimethylethyl)amino]methyl]tetrazolo[1,5-a]- pyridine-6-methanol in 15 ml of methanol was treated with 0.19 ml (2.29 mmol) of concentrated hydrochloric acid and 1.03 g (4.58 mmol) of SnCl2 ·2H2O. The reaction mixture was heated at reflux for one hour at which point tlc (silica gel) indicated completion. The mixture was reduced in volume under reduced pressure and then diluted with methylene chloride. The organic solution was washed with 15 ml of 2.5 N NaOH solution. The aqueous layer was back washed with a 20% methanolic methylene chloride solution until all product had been recovered. The combined organic layers were washed with saturated sodium chloride solution (2X), dried with anhydrous magnesium sulfate, and concentrated to dryness. The crude product was chromatographed on silica gel with 80:20:2 methylene chloride:methanol:concentrated aqueous ammonia as eluent to five 434 mg of pure product. To a solution of this free base (2.07 mmol) in 3 ml of absolute ethanol, a solution of 506 mg (4.36 mmol) of maleic acid in 5 ml of absolute ethanol was added slowly. The heterogeneous mixture was permitted to stir for an additional hour. The precipitate was collected by filtration and washed with ethanol-ether and then ether to give 690 mg of salt. The filtrate was diluted with ether to afford additional solid which was collected and rinsed with ethanol-ether and ether to afford 110 mg of product (total yield, 88%). A sample was recrystallized from ethanol, m.p. 167°-68° C. (dec.); [α]25D=-35.0 (MeOH); Analysis: Calc'd. for C11H19N3O·2C4H4O4 :
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH2:23]([CH:27]([Sn])C=C(CCCC)CCCC)[CH2:24]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+]>[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:27][CH:23]=[CH2:24])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(I)ccc1Cl
Reactant: CCCCC(=CC([Sn])CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reaction time: 0.42 h
Yield: 84.4 %

Procedure:
2-Chloro-5-iodo-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (prepared as described in WO 99/29661) (7.74 g), tri-n-butylallyltin (5.99 g), dichlorobis(triphenylphosphine)palladium(II) (1.24 g), triphenylphosphine (1.86 g), lithium chloride (6.11 g) and N,N-dimethylformamide. (260 mL) were heated together under nitrogen from 110° C. to 130° C. over 20 minutes, and then at 130° C. for 25 minutes. The mixture was then cooled, poured into brine (500 mL), extracted into ethyl acetate (3×250 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. The crude mixture was purified by column chromatography eluting with 9:1 isohexane/ethyl acetate to give the sub-titled compound (5.23 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:26]([O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl.CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:35](=[O:36])[CH2:34][NH:33][C:31](=[O:32])[O:30][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:22][CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(N3CCNCC3)c12)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
The above NMP solution of N-(5-bromo-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.200 g, 0.498 mmol), 2-(tert-butoxycarbonylamino)acetic acid (0.114 g, 0.648 mmol), HOBT-H2O (0.107 g, 0.698 mmol), and EDCI (0.124 g, 0.648 mmol) were placed in DCM (3 mL). DIEA (d 0.742; 0.434 mL, 2.49 mmol) was then added, and the reaction was stirred at room temperature for 4 hours. The reaction was then quenched with saturated Na2CO3 and extracted into DCM. The organic fractions were combined, dried, filtered, and concentrated to give the crude residue. Purification by column chromatography (500:15 to 500:25 DCM:MeOH) gave tert-butyl 2-(4-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-oxoethylcarbamate (0.112 g, 40.2% yield).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH:6]1[C:19]2[C:10](=[S+:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1.[C-:20]#[N:21].[K+]>O.C(Cl)Cl>[C:20]([CH:18]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11][C:10]2[C:19]1=[CH:6][CH:7]=[CH:8][CH:9]=2)#[N:21]
Reactant: [C-]#N
Reactant: c1ccc2[s+]c3ccccc3cc2c1
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: N#CC1c2ccccc2Sc2ccccc21
Reaction time: 1 h
Yield: 91.2 %

Procedure:
8.0 g (27.0 mmol) of thioxanthylium perchlorate [C. C. Price et al, J. Amer. Chem. Soc. 85, 2278 (1963)] are added to a well-stiffed mixture of 3.5 g (53.8 mmol) of potassium cyanide in 4 ml of water and 30 ml of methylene chloride under a nitrogen atmosphere. After one hour, the mixture is dried over potassium carbonate and filtered and the flitrate is concentrated on a vacuum rotary evaporator. Crystallization of the residue from isopropanol gives 5.5 g (91%) of 9-cyano-thioxanthene, melting point 103°-105° C., colourless needles (compound (103), Table I).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4]C=[C:6]2[C:11](=O)[NH:10]C(=O)[C:7]=12.CS(O)(=O)=O.[C:18](O)([C:20](F)(F)F)=[O:19]>[Pd]>[NH2:1][C:2]1[CH:7]=[C:6]2[C:20](=[CH:4][CH:3]=1)[C:18](=[O:19])[NH:10][CH2:11]2
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cccc2c1C(=O)NC2=O
Agent: [Pd]
Agent: CS(=O)(=O)O
Product: Nc1ccc2c(c1)CNC2=O

Procedure:
A solution of 16.2 g (100 mmol) of 6-aminophthalimide, 9.6 g (100 mmol) of methanesulfonic acid, and 4.0 g of 10% Pd/C in 140 mL of TFA was hydrogenated overnight at 50 psi. The catalyst was filtered off and and the filtrate concentrated on a rotary evaporator. The residue was diluted with 70 mL of ice water, adjusted to pH 8 with K2CO3, and chilled in an ice bath. The resulting solid was filtered to give 6.7 g of a 5:4 ratio of 5-amino:6-amino lactam isomers. Recrystallization from hot ethanol/water afforded 1.45 g of undesired isomer. The filtrate was preabsorbed onto silica gel and chromatographed with TEA:MeOH:methylene chloride (1:2:47). The resulting solid was slurried in methylene chloride/MeOH and filtered to afford a low yield of 5-amino-2,3-dihydro-isoindol-1-one: 1H NMR (DMSO-d6): δ 4.13 (s, 2H), 5.67 (s, 2H), 6.55 (dd, J=8.7, 1.9 Hz, 1H), 6.55 (d, J=1.9 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.83 (s, 1H); APCI−MS m/z 149 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.Cl>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.[OH-].[Na+]>[C:9]([C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#[N:10]
Reactant: ClCCOCCCl
Reactant: N#CCc1cccc(I)c1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Product: N#CC1(c2cccc(I)c2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of 3-iodophenylacetonitrile (2.43 g, 10 mmol), bis-(2-chloroethyl)ether (1.57 g, 11 mmol), hexadecyltributylphosphonium bromide (250 mg, 0.5 mmol) and 50% aqueous sodium hydroxide (20 ml) was stirred vigorously for 1 h at room temperature. The mixture was neutralized with 6 N aqueous HCl, transferred to a separatory funnel and extracted with ethyl acetate (50 ml×3). The combined extracts were washed with 2 N aqueous HCl (50 ml), water (50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo. The residual crude solids were collected and washed with cold Et2O (30 ml) to afford 2.38 g (76%) of the titled compound as white solids.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][CH:6]=1)=[O:4].C1COCC1.[OH-].[Li+].Cl>O.C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[C:3]([C:5]1[N:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)N(C)C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(C(=O)O)cn1
Reaction time: 1 h
Yield: 96 %

Procedure:
To a 5° C. mixture of methyl 6-[(dimethylamino)carbonyl]-3-pyridine carboxylate (52.5 g, 0.252 mol) and THF (390 mL) was added a solution of lithium hydroxide (trihydrate, 11.6 g, 0.277 mol) in water (60 mL) over 6 minutes. After stirring for 1 h, 2 N HCl (145 mL) was added over a 15-min period. Toluene (200 mL) was added and the organic solvents were removed in vacuo. The slurry was filtered, and the solids were washed with water (2×20 mL) and dried at 75° C. in vacuo to provide 47 g (96%) of 6-[(dimethylamino)carbonyl]-3-pyridine carboxylic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[F:19])=[C:9]([F:20])[C:8](=[O:21])[NH:7][CH:6]=1)=[O:4].C1COCC1.[Li+].[OH-].Cl>CO>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][NH:7][C:8](=[O:21])[C:9]=2[F:20])=[C:13]([F:19])[CH:14]=1
Reactant: COC(=O)c1c[nH]c(=O)c(F)c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c[nH]c(=O)c(F)c1Nc1ccc(Br)cc1F
Reaction time: 8 h
Yield: 99 %

Procedure:
A stirred solution of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.10 g, 0.278 mmol) in 4:1 THF:MeOH (5 mL) was treated with 1 M LiOH solution (0.75 mL). After 8 hours, the reaction mixture was acidified to pH 1 with 1 N HCl and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give 0.095 g (99%) of desired product as a white solid. MS APCI (−) m/z 343, 345 (M−, Br pattern) detected; 1H NMR (400 mHz, DMSO) δ 12.34 (bs, 1H), 9.39 (bs, 1H), 7.95 (s, 1H), 7.59 (d, 1H), 7.36 (d, 1H), 7.12 (td, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CC(O)C.CN1C(=O)CCC1>CCOC(C)=O>[CH3:11][C:10]1[C:5]2[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][C:2]([NH:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:7][C:6]=2[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Reactant: NCCN1CCOCC1
Solvent: CC(C)O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(NCCN2CCOCC2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Temperature: 150 °C
Yield: 26.8 %

Procedure:
(see, e.g., WO2013039988A1). A pressure vessel was charged with 50 (121 mg, 0.29 mmol), 4-(2-aminoethyl)morpholine (1.0 mL, 7.6 mmol) and iPrOH (3 mL) and NMP (1 mL). The vessel was sealed and the reaction mixture was heated at 150° C. overnight. The reaction mixture was diluted with EtOAc (20 mL) and washed with H2O (10 mL×3) to remove NMP. Combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Crude was subjected to flash column chromatography on silica gel to provide the title compound (40 mg, 26%) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.29 (q, J=7.1, 6.6 Hz, 4H), 7.07 (t, J=7.1 Hz, 1H), 6.96 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H), 6.78 (s, 1H), 5.46 (s, 2H), 4.43 (q, J=7.1 Hz, 2H), 3.76-3.70 (m, 4H), 3.55 (q, J=5.0 Hz, 2H), 2.63 (t, J=5.7 Hz, 2H), 2.58 (s, 3H), 2.49 (s, 4H), 1.42 (t, J=7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.00, 157.47, 157.15, 156.51, 152.39, 141.23, 134.44, 132.67, 129.66, 129.31, 123.18, 118.83, 118.77, 107.03, 103.90, 66.92, 61.62, 57.03, 53.40, 49.37, 37.75, 16.16, 14.26.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[Si:11]([O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Br-:29].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCC.O.O1CCCC1>[Br:29][CH:24]1[CH2:25][CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:18][Si:11]([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:13])[CH3:12])[C:23]1=[O:28]
Reactant: [Br-]
Reactant: CC(C)(C)[Si](C)(C)OCCCN1CCCCC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCN1CCCC(Br)C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 10.4 %

Procedure:
Under an argon atmosphere, t-butyl lithium (a 1.50M pentane solution, 1.40 ml, 2.10 mmol) was added dropwise to a tetrahydrofuran solution (5 ml) of 1-[3-(t-butyldimethylsilyloxy)propyl]piperidin-2-one (542 mg, 2.00 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 15 minutes. After a tetrahydrofuran solution (5 ml) of tetrabutylammonium tribromide (1.16 g, 2.40 mmol) was added to the reaction mixture, the temperature of the resulting mixture was gradually raised to −40° C. under stirring. Water was added to the reaction mixture at −40° C. and then, the temperature of the mixture was raised to room temperature. The reaction mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and concentrated. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:3 eluate was concentrated to give the title compound (72.8 mg, 0.208 mmol, 10%) as a colorless oil.