Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH3:2].C1C=CC=CC=1.C1CCCCC1.[N+:16]([C:19]1[C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:27][O:28][C:23]=2[CH:22]=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCCC1>[CH2:1]([C:26]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:25][C:24]2[C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=[CH:22][C:23]=2[O:28][CH2:27]1)[CH3:2]
Reactant: [Li]CC
Reactant: O=[N+]([O-])c1cccc2c1N=C(c1ccccn1)CO2
Solvent: C1CCCCC1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.5 M Ethyl lithium in benzene-cyclohexane (1.8 mL, 0.88 mmol) was added drop-wise to a solution of 5-nitro-3-pyridin-2-yl-2H-1,4-benzoxazine (0.025 g, 0.88 mmol) in tetrahydrofuran (4 mL), cooled to −78° C. The reaction was stirred for 1 h at −78° C. and was then quenched with methanol. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude product. The product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient to give 3-ethyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine as a solid (0.021 g. 84%). LCMS calculated for C15H16N3O3 (M+H)+: m/z=286.1. found: 286.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:15])C2C=CC=CC=2)=[N:6][CH:7]=1.Cl[C:17]1[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:15][C:17]2[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=2)=[N:6][CH:7]=1
Reactant: OC(c1ccccc1)c1ccc(Cl)cn1
Reactant: [O-][n+]1ccc(Cl)cc1
Product: [O-][n+]1ccc(OCc2ccc(Cl)cn2)cc1
Yield: 41 %

Procedure:
5-Chloro-2-pyridylbenzylalcohol (4.9 g, 34 mmol) and 4-chloropyridine-N-oxide (2.94 g, 22.7 mmol) were reacted according to Example 34 (step a) to provide the title compound (2.2 g, 40%) as a tan solid: 1H NMR (300 MHz, CDCl3) δ 8.58 (d, J=2.2 Hz, 1H), 8.13 (d, J=7.7 Hz, 2H), 7.76-7.72 (dd, J=8.4, 2.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[C:6]([OH:10])[C:5](Br)=[CH:4][C:3]=1[CH2:12][C:13]([CH3:21])([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C(O)C.[Pd]>[OH:10][C:6]1[CH:5]=[CH:4][C:3]([CH2:12][C:13]([CH3:20])([CH3:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:2][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)CC(C)(C)Cc1cc(Br)c(O)c(OC)c1Br
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(C)(C)Cc1ccc(O)c(OC)c1
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A mixture of the product of STEP 5 (0.525 g, 1.3 mmol), 20% Pd/C, triethylamine (0.39 g, 3.9 mmol) in ethanol was subjected to hydrogenation conditions at 40 psi and room temperature for 1 h. The reaction was filtered through a short column of Celite® and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/3) to afford 0.19 g colorless oil. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:6][CH:7]=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][N:6]=1)[CH3:23]
Reactant: Nc1ccc(CC(=O)O)nc1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
To a solution of (5-amino-2-pyridinyl)acetic acid (1.46 g, 9.6 mmol, Daisley; R. W.; Hanbali, J. R., Synthetic Communications., 1981, 11 (9), 743.) in ethanol was added conc. H2SO4 and stirred for 16.5 h under hydrogen atmosphere at room temperature. The mixture was neutralized with saturated NaHCO3 aqueous solution and the solvent was removed. The mixture was diluted with water and extracted with ethyl acetate (5×20 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to give 1.2 g of title compound as brown oil.
Reaction SMILES: Cl[C:2]1[C@@H:3](N)[CH2:4][CH2:5][CH2:6][CH:7]=1.C1(=O)[N:13](N[C@H](C(O)=O)CC2C=CC=CC=2)[C:12](=[O:26])[C:11]2=CC=CC=[C:10]12>>[C:2]1([CH2:10][CH2:11][C:12]([NH2:13])=[O:26])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCCC=C1Cl
Reactant: O=C(O)[C@H](Cc1ccccc1)NN1C(=O)c2ccccc2C1=O
Product: NC(=O)CCc1ccccc1

Procedure:
In Scheme A step f, (S)-2-chloro-cyclohex-2-enylamine is reacted with an appropriate phthalimido-L-phenyalanine derivative to give (S)-N-(2-chloro-cyclohex-2-enyl)-2- 2(S)-1,3-dihydro-1,3-dioxo-isoindol-2-yl)-3-phenyl-propionamide.
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[O:9]1[CH2:13][CH2:12][N:11]=[C:10]1[C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[N:3]=[N:4][C:5]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:18][C:17]3[CH:16]=[CH:15][C:14]([C:10]4[O:9][CH2:13][CH2:12][N:11]=4)=[CH:29][CH:28]=3)[CH2:23][CH2:24]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nn1
Reactant: c1cc(C2=NCCO2)ccc1OCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(N2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)nn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
A mixture of 4.1 parts of 3,6-dibromopyridazine, 4.34 parts of 1-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]piperazine, 6.4 parts of sodium carbonate and 1878 parts of N,N-dimethylformamide was stirred overnight at 65° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol 98.5:1.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 1.1 parts (16.4%) of 3-bromo-6-[4-[3-[4(4,5-dihydro-2-oxazolyl)phenoxy]propyl]-1-piperazinyl]pyridazine; mp. 169.1° C. (comp. 75).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CCCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCC(=O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 59 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (210 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 1-bromo-2-pentanone (170 mg) was added to the mixture. The mixture was stirred at room temperature for 3 hours, and the reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 2% methanol) to obtain the title compound (130 mg, 41%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:5]=[C:4](SC)[N:3]=1>[Ni].CO>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][N:3]=1
Reactant: CSc1nc(C)n(-c2ccc(N)cc2)n1
Agent: [Ni]
Solvent: CO
Product: Cc1ncnn1-c1ccc(N)cc1
Reaction time: 4 h
Yield: 47 %

Procedure:
A mixture of 20 parts of 4-[5-methyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]benzenamine, 15 parts of Raney-nickel catalyst and 400 parts of methanol is stirred and refluxed for 2 hours. The Raney-nickel is filtered off and another 15 parts of the catalyst are added. Stirring at reflux is continued for 4 hours. The reaction mixture is filtered, washed on the filter with methanol and the filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone, 2,2'-oxybispropane and petroleumether. The product is filtered off and dried, yielding 7.6 parts (47%) of 4-(5-methyl-1H-1,2,4-triazol-1-yl)benzenamine; mp. 145° C.
Reaction SMILES: [C:1]1([CH3:50])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][N:13]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH2:14][CH2:15][N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:54][CH2:55][O:56][CH2:57][CH2:58]Cl.O>CN(C=O)C>[C:26]1([CH3:29])[CH:27]=[CH:28][C:23]([S:20]([N:19]2[CH2:18][CH2:17][N:16]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[CH2:15][CH2:14][N:13]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:41])=[O:42])[CH2:12][CH2:11][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:50])=[CH:2][CH:3]=3)(=[O:8])=[O:9])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)NCCN(CCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCOCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a stirred solution of 1,4,7,10-tetra(p-toluenesulfonyl)-1,4,7,10-tetraazadecane prepared as in Example 15B (35.3 g, 0.0463 mole) in anhydrous DMF (460 ml) was added sodium hydride (2.77 g-80% in mineral oil, 0.0925 mole) in portions and the resulting mixture was stirred for 30 minutes under a dry argon atmosphere. The solution was then heated to 100° C. and a solution of 2-chloroethyl ether (6.61 g, 0.0463 mole) in anhydrous DMF (90 ml) was added dropwise over a 1.5 h period, maintaining the temperature at 100° C. After stirring the solution an additional 1.5 h at 100° C., H2O (3 l) was added while cooling (ice bath) to crystallize the product. The resulting tan solid was filtered and dried in vacuo. The crude product was purified by crystallization from CH2Cl2 -hexane to give 13.2 g (34% yield) of the product as an off-white solid: mp 197.5°-201°C.; 1H NMR (CDCl3) δ 2.44 (s, 12H), 3.28 (m, 16H), 3.57 (m, 4H), 7.35 (m, 8H), 7.69 (m, 8H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[NH:15][C:11]=3[CH:10]=2)O1.BrC1C=CC2NC(=O)NC=2C=1.[N+](C1C=C(C=CC=1)C=C1OC2C=CC=CC=2CC2C=CC=CC1=2)([O-])=O.Br[CH:57]=[C:58]1[C:64]2[CH:65]=[CH:66][C:67]([F:69])=[CH:68][C:63]=2[CH2:62][CH2:61][C:60]2[CH:70]=[C:71]([F:74])[CH:72]=[CH:73][C:59]1=2.C([O-])([O-])=O.[Na+].[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.O1CCOCC1>[F:69][C:67]1[CH:66]=[CH:65][C:64]2[C:58](=[CH:57][C:9]3[CH:18]=[CH:17][C:12]4[NH:13][C:14](=[O:16])[NH:15][C:11]=4[CH:10]=3)[C:59]3[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:60]=3[CH2:61][CH2:62][C:63]=2[CH:68]=1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reactant: Fc1ccc2c(c1)CCc1cc(F)ccc1C2=CBr
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: O=[N+]([O-])c1cccc(C=C2Oc3ccccc3Cc3ccccc32)c1
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(C=C3c4ccc(F)cc4CCc4cc(F)ccc43)cc2[nH]1
Yield: 44.5 %

Procedure:
Following procedures essentially as described in Example 219, mix 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (535 mg, 2.06 mmol) (prepared from 5-bromo-1,3-dihydro-benzoimidazol-2-one (Preparation 27) according to the procedure reported by M Murata, T Takashi, S Watanabe and Y Yusuru, J. Org. Chem.; 65 (1) 164-168 (2000)), 5-bromomethylene-2,8-difluoro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (550 mg, 1.71 mmol), 2N Na2CO3 (2 mL), dioxane (14 mL) and (Ph3P)4Pd (200 mg, 0.17 mmol). Purify the crude product by column chromatography using dichloromethane/ethyl acetate to give 285 mg white solid, mp 257° C. HPLC (ISO80-10M) t=2.62 (97%), MS (ES) 373 (M−1). H NMR 10.55 (s, 1H), 10.45 (s, 1H), 7.48 (dd, 1H, J=8.4, 6.2 Hz), 7.21 (dd, 1H, J=9.7, 2.2 Hz), 7.01 (td, 1H, J=12.2, 4.2 Hz), 6.94 (dd, 1H, J10.1, 2.2 Hz), 6.90 (d, 2H, J=6.2 Hz), 6.85 (dd, 1H, J=8.6, 2.4 Hz), 6.78 (s, 1H), 6.72 (d, 1H, J=8.4 Hz), 6.67 (d, 1H, J=7.9 Hz), 6.51 (s, 1H), 3.30 (s, 2H), 2.89 (s, 2H), 6.90 (d, 1H, J=6.2 Hz).
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][NH:30][N:29]=3)[CH:25]=[C:24]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:23]=2)[C:10]=1[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])C.[OH-].[Na+]>>[C:39]([CH2:38][CH2:37][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][NH:30][N:29]=3)[CH:25]=[C:24]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:44])=[O:3])([OH:41])=[O:40]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3cc[nH]n3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cc[nH]n2)c1
Yield: 83.8 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-(2-(2-ethoxycarbonyl-ethyl)-3-{6-[3-methanesulfonyl-5-(1H-pyrazol-3-yl)-phenoxy]-hexyl}-phenoxy)-butyric acid ethyl ester (35 mg, 0.05 mmol) and 1.0 N aqueous sodium hydroxide (0.4 mL) to afford 4-(2-(2-carboxy-ethyl)-3-{6-[3-methanesulfonyl-5-(1H-pyrazol-3-yl)-phenoxy]-hexyl}-phenoxy)-butyric acid (24 mg, 75%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C29H36N2O8S (M+Na)+ 595.2084, found 595.2080.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2[CH2:27][CH2:28][CH2:29][CH2:30][C:22]1=2>C(O)(=O)C>[F:20][C:3]1[C:2]([N:1]2[C:24](=[O:25])[C:23]3[CH2:27][CH2:28][CH2:29][CH2:30][C:22]=3[C:21]2=[O:26])=[CH:19][C:6]2[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: Nc1cc2c(cc1F)OCC(=O)N2Cc1ccccn1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1Cc1ccccn1
Yield: 80.5 %

Procedure:
A mixture of 6-amino-7-fluoro-4-(pyridin-2-ylmethyl)-2H-1,4-benzoxazin-3(4H)-one (2 g), 3,4,5,6-tetrahydrophthalic anhydride (1.2 g) and acetic acid (50 ml) was heated under reflux for 1 hour. The acetic acid was distilled off under a reduced pressure, and the residue was dissolved in toluene (100 ml), washed in a saturated aqueous solution of sodium bicarbonate and then in water, and dried over anhydrous sodium sulfate. The toluene was distilled off under a reduced pressure, and the resultant residue was recrystallized from ethanol, whereby the aimed product, namely, 7-fluoro-4-(pyridin-2-ylmethyl)-6-(4,5,6,7-tetrahydro-2H-isoindole-1,3-dion-2-yl)-2H-1,4-benzoxazin-3(4H)-one (2.4 g) was obtained. m.p. 188°-190° C.
Reaction SMILES: ClCC#CCCl.C1(=O)NC(=O)C2=CC=CC=C12.[K].[Na].[N:20]1([CH2:25][C:26]#[C:27][CH2:28][N:29]2C(=O)C3=CC=CC=C3C2=O)[CH:24]=[CH:23][N:22]=[CH:21]1.NN.I.CS[C:45]1[C:53]2[CH:54]=[CH:55][CH:56]=[C:51]3[C:52]=2[C:47](=[CH:48][CH:49]=[CH:50]3)[N:46]=1.I>C(O)C>[N:20]1([CH2:25][C:26]#[C:27][CH2:28][NH:29][C:45]2[C:53]3[CH:54]=[CH:55][CH:56]=[C:51]4[C:52]=3[C:47](=[CH:48][CH:49]=[CH:50]4)[N:46]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: O=C1c2ccccc2C(=O)N1CC#CCn1ccnc1
Reactant: CSC1=Nc2cccc3cccc1c23
Agent: ClCC#CCCl
Agent: I
Agent: NN
Solvent: CCO
Product: C(#CCn1ccnc1)CNC1=Nc2cccc3cccc1c23

Procedure:
The sequential reaction of 1,4-dichloro-2-butyne with potassium phthalimide and then the sodium salt of imidazole leads to the formation of N-(4-(1H-imidazol-1yl)2-butyn-1-yl)phthalimide, which upon treatment with hydrazine in boiling ethanol leads to 4-(1H-imidazol-lyl)-2-butyn-1-ylamine. Reaction of the latter compound with 2-methylthiobenz(cd)indole hydriodide in ethanol solution, by the conditions of Example 52 leads to the hydriodide of the title compound which is converted to the free base by treatment with alkali hydroxide solution.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[C:18]1[S:22][C:21]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)=[N:20][N:19]=1>C(Cl)Cl.CO>[N:23]1([C:21]2[S:22][C:18]([C:8]3[CH:9]=[CH:10][C:11]([N:13]4[CH:17]=[CH:16][CH:15]=[N:14]4)=[CH:12][C:7]=3[OH:6])=[N:19][N:20]=2)[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1
Reactant: COc1cc(-n2cccn2)ccc1-c1nnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1cc(-n2cccn2)ccc1-c1nnc(N2CCNCC2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
BBr3 (1M solution in heptane, 1.56 mL, 1.56 mmol) was added to a stirred, nitrogen flushed solution of tert-butyl 4-(5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (138 mg, 0.312 mmol) in DCM (6 mL) and the resulting bright yellow suspension was stirred at room temperature for 16 hours. The reaction mixture was quenched by addition of MeOH (10 mL) to give a suspension. The solid was collected by vacuum filtration, rinsed with MeOH, and re-dissolved in a mixture of DMSO and water. The solution was loaded onto a 5 g SCX cartridge (pre-wet with MeOH) and the cartridge was washed with DMSO/water (5 mL), MeOH (20 mL), then flushed with 7M NH3 in MeOH (30 mL). The MeOH/NH3 was removed in vacuo to afford the crude product as an off-white solid. The crude material was sonicated in MeOH (5 mL) and the resulting suspension filtered under vacuum to afford the title compound as an off-white solid (69 mg, 68% yield). LC-MS: Rt 0.76 min; MS m/z 329.2 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (d, J=2.53 Hz, 1H), 8.03 (d, J=8.59 Hz, 1H), 7.77 (d, J=1.52 Hz, 1H), 7.52 (d, J=2.02 Hz, 1H), 7.42 (dd, J=8.59, 2.02 Hz, 1H), 6.55-6.61 (m, 1H), 3.42-3.48 (m, 4H), 2.80-2.91 (m, 4H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)C.[CH2:12]([C:19]1[C:20]([C:42]([NH:44][CH3:45])=[O:43])=[N:21][C:22]2[C:27]([C:28]=1[C:29]([F:32])([F:31])[F:30])=[CH:26][C:25]([C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[CH:24][CH:23]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([C:19]1[C:20]([C:42]([NH:44][CH3:45])=[O:43])=[N:21][C:22]2[C:27]([C:28]=1[C:29]([F:32])([F:30])[F:31])=[CH:26][C:25]([C:33]([C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)([OH:41])[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1)=[CH:24][CH:23]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1cncc1Br
Reactant: CNC(=O)c1nc2ccc(C(=O)c3ccc(F)cc3)cc2c(C(F)(F)F)c1Cc1ccccc1
Agent: CC[Mg]Cl
Solvent: ClCCl
Product: CNC(=O)c1nc2ccc(C(O)(c3ccc(F)cc3)c3cncn3C)cc2c(C(F)(F)F)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
5-Bromo-1-methyl-1H-imidazole (1.36 mL, 0.5 M in DCM over 3 Å molecular sieves, 0.678 mmol) was treated with EtMgCl (0.325 mL, 2.09 M in THF, 0.678 mmol) dropwise under argon with stirring at room temperature over 1 minute, and the resulting translucent/semi-opaque reaction was stirred at room temperature for 20 minutes. This was treated dropwise over 2 minutes with a solution of 3-benzyl-6-(4-fluorobenzoyl)-N-methyl-4-(trifluoromethyl)quinoline-2-carboxamide (90.4 mg, 0.194 mmol, Intermediate 35: step f) in DCM (1.2 mL) with stirring at room temperature, and the resulting orange reaction was immediately stirred at 40° C. for 13 hours. The resulting orange opaque mixture was cooled to room temperature, partitioned with 5 M aqueous NH4Cl (3 mL), and the aqueous layer was extracted with DCM (1×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was dry load flash chromatographed using 2:3 toluene/acetone (isocratic elution) to yield the title compound as a pale yellow foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (s, 1H), 7.88 (d, J=9.09 Hz, 1H), 7.69 (d, J=10.61 Hz, 1H), 7.30-7.38 (m, 3H), 7.10-7.24 (m, 4H), 6.97-7.09 (m, 4H), 6.29 (s, 1H), 4.91 (s, 2H), 3.39 (s, 3H), 2.89 (d, J=5.05 Hz, 3H); MS m/e 549.2 [M+H]+.
Reaction SMILES: CC([CH:5]([CH:9]1[C:18]2[C:13](=[C:14]([C:19]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:33])[CH3:32])=[C:26]([Cl:34])[CH:25]=4)[O:21][N:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][NH:10]1)[C:6]([O-:8])=[O:7])(C)C>Cl.O1CCOCC1>[ClH:34].[Cl:34][C:26]1[CH:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:13]=3[CH2:12][CH2:11][NH:10][CH:9]4[CH2:5][C:6]([OH:8])=[O:7])[N:23]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH:31]([CH3:32])[CH3:33]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNC4C(C(=O)[O-])C(C)(C)C)no2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNC4CC(=O)O)no2)cc1Cl
Yield: 184.6 %

Procedure:
1,1-dimethylethyl[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1-isoquinolinyl]acetate (Preparation 5, 61 mg, 0.126 mmol) was stirred at room temperature for 18 hours in 4M HCl in 1,4-Dioxane (10 mL). Evaporation yielded the title compound (54 mg). 1H NMR (400 MHz, d6-DMSO)) δ 8.19 (1H, s), 8.11 (1H, d), 8.00 (1H, d), 7.61 (1H, d), 7.54 (1H, t), 7.46 (1H, d), 4.96-4.86 (2H, m), 1.37 (6H, d), other aliphatic signals obscured by solvent peaks; m/z (API-ES) 428, 430 [M+H]+.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[ClH:21]>C(#N)C.C(Cl)Cl.[Cu](Cl)Cl>[Cl:21][C:9]1[S:10][C:11]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Cl
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Combine tert-butyl nitrite, (35 mL, 292 mmol, technical 90%) and copper (II) chloride (31.7 g, 236 mmol) in acetonitrile (400 mL) and warm to 65° C. under nitrogen for 1 hour. Slowly add 2-amino-6-nitrobenzthiazole (41.7 g, 214 mmol) over 15 min. Continue to stir at 65° C. for 30 min. Cool to room temperature, dilute with CH2Cl2, and add 0.1 N HCl to precipitate the product. Filter and dry in a vacuum oven overnight to afford 2-chloro-6-nitrobenzthiazole (35.1 g, 77%). 1H NMR (400 MHz, DMSO-d6): δ 9.18 (d, 1H, J=2.2 Hz), 8.37 (dd, 1H, J=9.0, 2.4 Hz), 8.18 (d, 1H, J=8.8 Hz).