Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[N:10]=[N:11][N:12]([CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:13]=1)=[O:6])([CH3:4])[CH3:3].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[F:26].C1COCC1>C(Cl)Cl>[F:19][C:20]1[CH:21]=[C:22]([CH:8]([C:9]2[N:10]=[N:11][N:12]([CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:13]=2)[NH:7][S:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: CC(C)(C)S(=O)/N=C/c1cn(C[Si](C)(C)C)nn1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC(c1ccc(F)c(F)c1)c1cn(C[Si](C)(C)C)nn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a 25 ml round bottom flask containing −78° C. solution of 2-methyl-N-((1E)-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methylene)propane-2-sulfinamide (0.286 g, 0.998 mmol) in 4.0 ml of CH2Cl2 was added dropwise 0.5N 3,4-difluorophenylmagnesium bromide in THF (4.990 ml, 1.495 mmol). The resulting solution was stirred at −78° C. for 30 min, then −20° C. for 16 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the crude title compound as a light yellow liquid (0.498 g, 93% crude). ES-MS [M+1]+: 401.1. This intermediate was carried over to the next step without further purifications and characterizations.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][C@@H:7]([C:11]([OH:13])=[O:12])[C@H:8]([CH3:10])[OH:9].[C:14](Cl)(=[O:26])[O:15][C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>C1COCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:9][C@@H:8]([CH3:10])[C@@H:7]([NH:6][C:14]([O:15][C:16]12[CH2:25][CH:20]3[CH2:19][CH:18]([CH2:24][CH:22]([CH2:21]3)[CH2:23]1)[CH2:17]2)=[O:26])[C:11]([OH:13])=[O:12]
Reactant: O=C(Cl)OC12CC3CC(CC(C3)C1)C2
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](NC(=O)OC12CC3CC(CC(C3)C1)C2)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
In a round bottom flask, NaHCO3 (1.78 g, 21.2 mmol) was suspended in THF (4.5 mL) and H2O (9 mL), then D-threonine was added (1.0 g, 8.39 mmol). Tricyclo[3.3.1.13,7]dec-1-yl chlorocarbonate (2.0 g, 9.33 mmol) was added slowly, followed by a catalytic amount (0.1 g) of tetrabutylamonium bromide. After stirring 18 h at rt, the mixture was diluted with water, washed twice with Et2O and pH of aqueous phase adjusted to 2 with 2M HCl solution. The aqueous phase was extracted four times with AcOEt, the collected organic phases were dried over Na2SO4, filtered, and the solvent removed under vacuum to give the title compound (0.250 g, 10%) as white solid. Rf=0.38 (AcOEt+1% CH3COOH, detection: ninhydrin). FTIR (cm−1): 3421, 2911, 2852, 1718, 1509, 1254, 1068.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([O:16][CH2:17][CH3:18])[CH2:15][CH2:14]2)=[C:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:8]=1)(=O)=O.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>C(N(CC)CC)C.CN(C=O)C.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>[CH2:17]([O:16][C:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:8][C:9]=2[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH3:18]
Reactant: CCOC1(c2ccc(OS(=O)(=O)C(F)(F)F)cc2C(C)(C)C)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC1(c2ccc(C#C[Si](C)(C)C)cc2C(C)(C)C)CC1
Temperature: 95 °C

Procedure:
Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-tert-butyl-phenyl 1,1,1-trifluoromethansulfonate (Intermediate 110, 260.0 mg, 0.71 mmol) in triethylamine (4 mL) and DMF (6 mL) was sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (40.0 mg, 0.06 mmol). The resulting reaction mixture was heated to 95° C. for 18 hours. The title compound, 215.0 mg (96%), was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[Cl:16])(=[O:3])[CH3:2].C(OC(=O)C)(=[O:19])C.S(=O)(=O)(O)O.O>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([NH:4][C:5]1[C:14]([CH:15]=[O:19])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C)c(NC(C)=O)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c(C=O)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a cooled solution (ice bath) of 10.8 g of methyl 4-acetamido-3-chloro-5-methylbenzoate in 73.8 ml of glacial acetic acid; and 73.8 ml of acetic anhydride were added dropwise 11 mL of concentrated sulfuric acid followed by the portion wise addition of 12.96 g (0.1295 mole) of chromium trioxide over a 25 minute period. The reaction mixture was stirred at 0° C. for 2.5 hours and then poured into a mixture of 612 g of ice and 162 ml of water. The resulting aqueous mixture was extracted with methylene chloride (4×250 ml). The combined organic layers were washed sequentially with water (3×250 ml), 5% aqueous sodium bicarbonate (2×250 ml) and then brine (1×250 ml) and dried over anhydrous magnesium sulfate. The solvent was removed in a rotary evaporator. The resulting residue was purified by chromatographic column (silica gel, ethyl acetate:hexane 30:70 followed by ethyl acetate:hexane 50:50), yielding 2.5 g methyl 4-acetamido-3-chloro-5-formylbenzoate.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N+:23]([O-])=O)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33]N[CH2:31][CH2:30]1>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N:23]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc3c([N+](=O)[O-])c(Br)cc(c23)C(=O)N1OCc1ccccc1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(c2c(Br)cc3c4c(cccc24)C(=O)N(OCc2ccccc2)C3=O)CC1
Yield: 38.2 %

Procedure:
Following the procedure of Example U1, 2-benzyloxy-5-bromo-6-nitro-benzo[de]isoquinoline-1,3-dione (0.50 g, 1.2 mmol, from Example S1-A) and 1-methylpiperazine (0.46 g, 4.7 mmol) in DMF (5 mL) were reacted to give 0.22 g of the title compound.
Reaction SMILES: [C:1]([N:5]1[C:10]2[CH:11]=[C:12]([Cl:15])[N:13]=[CH:14][C:9]=2[CH2:8][N:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:23]([O-])=O)[CH:17]=2)[C:6]1=[O:26])([CH3:4])([CH3:3])[CH3:2].Cl>[Fe].CCO.O>[NH2:23][C:18]1[CH:17]=[C:16]([N:7]2[CH2:8][C:9]3[CH:14]=[N:13][C:12]([Cl:15])=[CH:11][C:10]=3[N:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:6]2=[O:26])[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CC(C)(C)N1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(Cl)cc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)N1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(Cl)cc21
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
Iron powder was added (5.2 g, 93 mmol) in portions to a solution of 1-tert-butyl-7-chloro-3-(4-fluoro-3-nitrophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (3.5 g, 9.3 mmol) and conc. HCl (0.35 mL, 4.2 mmol) in 10/1 EtOH/H2O (11 mL). The resulting mixture was stirred at 40° C. for 30 min. The reaction mixture was filtered and the filter cake was washed with EtOH. The ethanolic filtrate was concentrated and the residue was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×80 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by chromatography on silica gel to afford 3-(3-amino-4-fluorophenyl)-1-tert-butyl-7-chloro-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2.0 g, 62% yield). 1HNMR (400 MHz, DMSO-d6): δ 8.20 (s, 1 H), 7.26 (s, 1 H), 6.92 (m, 1 H), 6.62 (m, 1 H), 6.34 (m, 1 H), 5.17 (s, 2 H), 4.50 (s, 2H), 1.55 (s, 9 H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]4[CH:29]5[CH2:30][C:25]6([C:32](O)=[O:33])[CH2:26][CH:27]([CH2:31][CH:23]4[CH2:24]6)[CH2:28]5)=[O:20])[CH2:15]3)=[N:12][CH:13]=2)=[CH:4][C:3]1=[O:35].C1C=CC2N(O)N=[N:42]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]4[CH:23]5[CH2:24][C:25]6([C:32](=[O:33])[NH2:42])[CH2:26][CH:27]([CH2:28][CH:29]4[CH2:30]6)[CH2:31]5)=[O:20])[CH2:15]3)=[N:12][CH:13]=2)=[CH:4][C:3]1=[O:35]
Reactant: Cn1ccc(-c2cnc(C3CCN(C(=O)OC4C5CC6CC4CC(C(=O)O)(C6)C5)C3)nc2)cc1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ccc(-c2cnc(C3CCN(C(=O)OC4C5CC6CC4CC(C(N)=O)(C6)C5)C3)nc2)cc1=O

Procedure:
A solution of 4-((3-(5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2-yl)pyrrolidine-1-carbonyl)oxy)adamantane-1-carboxylic acid (20 mg, 0.04 mmol), HOBt (11.3 mg, 0.08 mmol), EDCl (16.5 mg, 0.08 mmol) and i-Pr2NEt (27 mg, 0.21 mmol) in dichloromethane (5 mL) was stirred overnight under ammonia gas. The reaction mixture was concentrated to afford an oil which was purified by basic preparative HPLC to afford two isomers:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:10][C:11]([O:13]C)=O)[NH2:9])[CH:5]=[CH:6][CH:7]=1.[CH3:15][N:16]=[C:17]=[O:18]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:10][C:11](=[O:13])[N:16]([CH3:15])[C:17](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN(N)c1cccc(Br)c1
Reactant: CN=C=O
Solvent: CC#N
Product: CN1C(=O)CN(c2cccc(Br)c2)NC1=O
Reaction time: 1 h

Procedure:
A solution of methyl [1-(3-bromophenyl)hydrazino]acetate (2.5 g) and methyl isocyanate (1.46 ml) in acetonitrile (20 ml) was heated under reflux for 2 h. The solvent was removed in vacuo and methanol (20 ml) was added to the residue which was then treated with a solution of sodium methoxide in methanol (30 ml; from 556 mg of sodium). After 1 h at 20° the solution was neutralised with acetic and the solvent was removed in vacuo. The residue was taken into ethyl acetate (250 ml), washed with pH 6 phosphate buffer solution (250 ml), dried and evaporated. Crystallisation of the residue from System B gave the title compound (316 mg). The mother liquor was evaporated, and the resulting solid was triturated with ether to give a further quantity of the title compound (335 mg), m.p. 165°-166°, t.l.c. (ether) Rf 0.41.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20](Cl)=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][Al](C)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([CH3:35])=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)nc(Cl)nc32)CC1
Reactant: C[Al](C)C
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccc(S(C)(=O)=O)cc2)c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Yield: 42.4 %

Procedure:
A mixture of 4-[6-chloro-4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 172; 230 mg, 0.45 mmol), trimethylaluminum (2 M in toluene; 0.5 mL, 1 mmol), and tetrakis(triphenyl-phosphine)palladium(0) (58 mg, 0.05 mmol) in tetrahydrofuran (5 mL) was heated at reflux for 2 h. The solvent was evaporated and the residue was purified by column chromatography to give 4-[4-(4-methanesulfonyl-phenoxy)-6-methyl-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (93 mg, 42%) as a white foam/solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.S(=O)(=O)(O)O.[CH3:19]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:19])=[O:12])=[CH:2]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c[nH]c2ccccc12

Procedure:
Indole-3-acetic acid (25 g, 143 mmol) was dissolved in 500 mL of methanol and 5 mL of concentrated sulfuric acid was added. The resulting solution was heated under reflux overnight. TLC analysis indicated the absence of starting material and the reaction mixture was concentrated in vacuo. The residue was dissolved in 300 mL of ethyl ether, washed with 5% aqueous sodium bicarbonate (2×150 mL), dried over magnesium sulfate, filtered and concentrated to 24.09 g (89.1%) of the ester as a burgandy colored oil.
Reaction SMILES: [Na].[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:20]=[CH:19][C:14]([CH:15]=[CH:16][C:17]#[N:18])=[CH:13][CH:12]=1>C(O)C>[NH2:18][C:17]1[CH2:16][CH:15]([C:14]2[CH:13]=[CH:12][C:11]([CH3:10])=[CH:20][CH:19]=2)[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: NNc1ccccc1
Reactant: Cc1ccc(C=CC#N)cc1
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(C2CC(N)=NN2c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
A 1.0 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 20.0 ml. of phenylhydrazine is added followed in 5 minutes by 24.0 ml. of (mixed cis and trans) 4-methyl cinnamonitrile. The reaction mixture is refluxed for 4 hours then is cooled. The precipitate is collected by filtration then is recrystallized from acetone-hexane after treatment with activated charcoal to give 14.25 g. of the desired product as pale orange needles, m.p. 165°-166.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[C:15]([CH2:18][NH:19]C(=O)OC)=[CH:16][O:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[C:15]([CH2:18][NH2:19])=[CH:16][O:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)NCc1coc2ccc(-c3cc(F)cc(F)c3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NCc1coc2ccc(-c3cc(F)cc(F)c3)nc12
Yield: 55.1 %

Procedure:
To a flask charged with methyl (5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methylcarbamate (680 mg, 2137 μmol) was added MeOH (20 mL), then aqueous NaOH (18 mL, 6 N, 106 mmol). The solution was heated at reflux for 60 h. The solution was concentrated to remove MeOH, then partitioned between CH2Cl2 (30 mL) and NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (1×10 mL), then EtOAc (4×25 mL). The combined organic layers were concentrated to give a total of (5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methanamine (306.6 mg, 55% yield) as a brown foam. LRMS (ESI) m/z calcd for C14H11F2N2O (M+H) 261.1. found 261.2.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH3:7][C:8]1[CH:32]=[C:31]([C:33]([N:35]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]3[CH:42]=[CH:43][CH:44]=[CH:45][C:36]2=3)=[O:34])[CH:30]=[CH:29][C:9]=1[CH2:10][NH:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[F:24])[N:17]([CH2:25][C:26]#[N:27])[C:16](=[O:28])[CH2:15]1)=[O:13]>CN(C=O)C>[CH3:7][C:8]1[CH:32]=[C:31]([C:33]([N:35]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]3[CH:42]=[CH:43][CH:44]=[CH:45][C:36]2=3)=[O:34])[CH:30]=[CH:29][C:9]=1[CH2:10][NH:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[F:24])[N:17]([CH2:25][C:26]2[NH:27][N:3]=[N:2][N:1]=2)[C:16](=[O:28])[CH2:15]1)=[O:13]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CC#N)c2cccc(F)c21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(Cc2nnn[nH]2)c2cccc(F)c21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Sodium azide (78 mg, 1.2 mmol) and ammonium chloride (21 mg, 0.40 mmol) were added to a solution of 4-cyanomethyl-8-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid 2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylamide from Example 13 (210 mg, 0.40 mmol) in DMF (5 ml) and the mixture was stirred at 100° C. for 18 h. The mixture was cooled and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant CHCl3 100% to CHCl3:methanol;triethylamine 97:2:1 to CHCl3:methanol;triethylamine 94:4:2). The product was partitioned between chloroform and potassium hydrogen sulphate, separated and the organic phase was dried and evaporated in vacuo; yield 33 mg, 15%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:22]([O:24][CH3:25])=[O:23])[C:5]2[CH:6]=[C:7]([C@@:11]3([CH3:21])[CH2:15][CH2:14][CH2:13][N:12]3[CH2:16][C:17](OC)=[O:18])[NH:8][C:9]=2[CH:10]=1.CS(O)(=O)=O.C([O-])(O)=O.[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([C:22]([O:24][CH3:25])=[O:23])[C:5]2[C:6]3[C:17](=[O:18])[CH2:16][N:12]4[C@:11]([CH3:21])([CH2:15][CH2:14][CH2:13]4)[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: COC(=O)CN1CCC[C@]1(C)c1cc2c(C(=O)OC)cc(F)cc2[nH]1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(F)cc2[nH]c3c(c12)C(=O)CN1CCC[C@]31C
Temperature: 60 °C
Yield: 33 %

Procedure:
In a 25-mL flask, (R)-methyl 6-fluoro-2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (100 mg) was treated with anhydrous MeSO3H (6 mL). The flask was fitted with a reflux condenser and heated at 60° C. for 1 h. Then, the reaction mixture was cooled in an ice-bath and diluted with distilled water (6.0 mL). The pH of the solution was increased to pH ˜10 by the addition of saturated aq. NaHCO3. The reaction mixture was then extracted with EtOAc (3×5 mL). The organic extracts were combined and washed with brine (1×5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Pre-TLC to give (R)-methyl 9-fluoro-11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-7-carboxylate (30 mg). 1H NMR (CDCl3-d) δ 7.14-7.224 (m, 2H), 4.03 (s, 3H), 3.81-3.84 (m, 1H), 3.57-3.59 (m, 1H), 3.22-3.24 (m, 1H), 2.92-2.94 (m, 1H), 2.39-2.40 (m, 1H), 2.16-2.17 (m, 1H), 1.93-1.94 (m, 1H), 1.63 (s, 3H), and 1.56-1.57 (m, 1H). MS (ESI) m/e [M+1]+ 317.0.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]([CH3:39])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=1)=[O:25]>>[C:16]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH2:12][N:36]3[CH2:37][CH2:38][CH:33]([C:29]4[CH:28]=[C:27]([NH:26][C:24](=[O:25])[CH:23]([CH3:39])[CH3:22])[CH:32]=[CH:31][CH:30]=4)[CH2:34][CH2:35]3)=[CH:10][CH:9]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(N(c4ccccc4)c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(diphenylamino)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 504.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH2:19].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([F:13])[CH:15]=2)[N:11]=1
Reactant: NCCc1cccc(F)c1
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)nc1NCCc1cccc(F)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 54.8 %

Procedure:
A mixture of methyl 2,6-dichloronicotinate (53.3 g, 0.26 mol), 3-fluorophenethyl amine (37.3 mL, 0.29 mol), K2CO3 (72 g 0.52 mol) and NMP (150 mL) was stirred at 100° C. for 10 hrs. The mixture was diluted with ethyl acetate (2×300 mL) and washed with brine. The organic layers were combined, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography using hexane-EtOAc (9:1) as eluant to give methyl 6-chloro-2-(3-fluorophenethylamino)nicotinate as an off-white solid (44 g, 54%). LRMS (M+H+) m/z 309.0.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-])=O.Cl>C(O)C.[Pd]>[NH2:11][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[NH:2][CH3:1]
Reactant: CNc1cc(OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNc1cc(OC)ccc1N

Procedure:
A solution of 3.7 g (20.4 mmol) N-methyl-5-methoxy-2-nitroaniline in 700 ml ethanol was added 7.4 ml 4N hydrochloric acid, and then hydrogenated at atm. pressure by using 5% Pd-C (0.5 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo to give 2-amino-5-methoxy-N-methylaniline as crystals.
Reaction SMILES: [CH3:1][NH2:2].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[N:17]=[C:16](C(Cl)(Cl)Cl)[O:15][N:14]=3)[CH:11]=2)[N:6]([S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:5]=1>O>[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[N:17]=[C:16]([NH:2][CH3:1])[O:15][N:14]=3)[CH:11]=2)[N:6]([S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:23])=[O:24])[CH:5]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(C(Cl)(Cl)Cl)n4)ccc32)cc1
Solvent: O
Product: CNc1nc(-c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)no1
Temperature: 90 °C
Yield: 94.3 %

Procedure:
N-Methylamine (1M in THF) (5 mL) was added to a sealed tube equipped with magnetic stir bar followed by the addition of 3-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(trichloromethyl)-1,2,4-oxadiazole (250 mg, 0.43 mmol). The tube was sealed and heated at 90° C. in oil bath for 12 h. After completion of the reaction, it was cooled to RT. The mixture was treated with water and extracted with EtOAc (2×20 mL). The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified with basic alumina column chromatography (eluent: 40% EtOAc in petroleum ether) to give 3-(3-iodo-1-tosyl-1H-indol-5-yl)-N-methyl-1,2,4-oxadiazol-5-amine (200 mg, 94.3%) as an off white solid. MS (ESI, pos. ion) m/z: 495.0 (M+1).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:3].Cl.[CH:15]([O:17][CH2:18][CH3:19])=[CH2:16]>>[CH2:15]([O:17][CH:18]([O:3][CH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:1]([O:11][CH2:12][CH3:13])=[O:10])[CH3:19])[CH3:16]
Reactant: CCOC(=O)CC(O)C(=O)OCC
Reactant: C=COCC
Agent: Cl
Product: CCOC(=O)CC(OC(C)OCC)C(=O)OCC

Procedure:
A mixture of 19 g. diethyl malate and 0.1 g. of 36% hydrochloric acid was added to a 50 ml. round-bottom flask equipped with an addition funnel, static nitrogen head, condensor, heating mantle, thermometer, and magnetic stirrer. Ethyl vinyl ether was then added, dropwise, at 41° to 43° C. over a one-hour period and quenched with 0.4 g. of solid sodium carbonate. Distillation was performed directly on the mixture (short path column):
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:49])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH2:40][O:41]C3CCCCO3)[CH:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:41][CH2:40][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:49])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:23])[F:21])[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:39]=[CH:38][N:37]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M262) (0.48 g, 0.67 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N.