Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC=C2C=1C=C(C(OCC)=O)N2.[CH3:16][C:17]1[CH:25]=[CH:24][C:23]2[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH2:30][N:21]3[C:22]=2[C:18]=1[CH:19]=[C:20]3[C:32]([O:34][CH2:35][CH3:36])=[O:33].[Br:37]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:37][CH2:16][C:17]1[CH:25]=[CH:24][C:23]2[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH2:30][N:21]3[C:22]=2[C:18]=1[CH:19]=[C:20]3[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2c(C)ccc3c2n1CCCCC3=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCOC(=O)c1cc2c(C)cccc2[nH]1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2c(CBr)ccc3c2n1CCCCC3=O

Procedure:
In accordance with the process described in Example 22(a)-(c) except for using ethyl 4-methyl-1H-indole-2-carboxylate as a starting material, ethyl 5,6,7, 8-tetrahydro-11-methyl-8-oxo-4H-azocino[3.2.1-hi]indole-2-carboxylate (m.p. 98° C., recrystallized from isopropyl alcohol) was synthesized. Ethyl 5,6,7,8-tetrahydro-11-methyl-8-oxo-4H-azocino[3.2.1-hi]indole-2-carboxylate (2.50 g, 8.76 mmol) was then dissolved in carbon tetrachloride (80 ml) and N-bromosuccinimide (1.72 g, 9.64 mmol) and 2,2'-azobisisobutyronitrile (43 mg) were added therein under refluxing condition to heat at reflux for 2 hours. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the obtained residue was purified with silica gel column chromatography (eluated with ethyl acetate/n-hexane=1/10) to give ethyl 5,6,7,8-tetrahydro-11-bromomethyl-8-oxo-4H-azocino[3.2.1-hi]indole-2-carboxylate (3.12 g).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10]([CH:12]=[O:13])[N:11]=1)=[O:5].S([CH2:39][N+:40]#[C-:41])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[C:10]([C:12]2[O:13][CH:41]=[N:40][CH:39]=2)[N:11]=1)=[O:5]
Reactant: O=Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1nc(-c2cnco2)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Temperature: 65 °C
Yield: 72.4 %

Procedure:
Into a solution of Compound 67 (62 mg, 0.15 mmol) in 5 mL of dry methanol was added tosylmethyl isocyanide (35 mg, 0.18 mmol), followed by dry potassium carbonate (25 mg, 0.18 mmol). The reaction mixture was heated to 65° C. for 2 hours. The reaction mixture was dissolved in ethyl acetate, washed each with water and brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (eluted with 10-50% ethyl acetate in hexanes) to give Compound 76 (49 mg, 72%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([NH:67][CH2:68][CH2:69][CH2:70][NH2:71])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.O>[NH2:67][CH2:68][CH2:69][CH2:70][NH:71][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: NCCCNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
To a solution of example 13 (0.150 g, 0.375 mmol) in DMF (1 ml) N-ethyldiisopropylamine (0.048 g, 0.375 mmol) and HATU (0.143 g, 0.375 mmol) were added and stirred for 5 min. N-boc-1,3-diaminopropane (0.130 g, 0.751 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford N-boc-protected amide (0.200 g). The amide was dissolved in dichlomethane (1 ml) and trifluoroacetic acid (0.5 ml) was added and stirred at RT for 1 h. The reaction mixture was quenched with sodium bicarbonate solution, extracted with dichloromethane, dried over sodium sulphate and concentrated to afford the title compound as a pale brown solid (0.160 g, 93%). M.P.: 292-294° C. MS (m/z): 456.270 (M++1).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Li+].CCC[CH2-].[CH2:13]([N:20]([CH3:32])[S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.O.Cl>[CH2:13]([N:20]([CH3:32])[S:21]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])=[CH:28][CH:29]=1)(=[O:23])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CSC(=O)N1
Reactant: CN(Cc1ccccc1)S(=O)(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
2,4-Thiazolidinedione (11 mmol, 1.3 g) was dissolved in tetrahydrofuran (50 ml) and cooled to -78° C. N-Butyllithium (22 mmol, 13.8 ml of 1.6M in hexane) was added over 15 minutes. The cooling bath was removed and the reaction mixture was stirred for 20 minutes. N-Benzyl-N-methyl-4-(bromomethyl)benzenesulfonamide (10 mmol, 3.5 g) dissolved in tetrahydrofuran (50 ml) was added over 20 minutes. The reaction mixture was heated to reflux for 15 hours, cooled and diluted with water (50 ml) and 6N HCl (10 ml). The mixture was extracted with ethyl acetate (75 ml) and the organic layer was dried (Na2SO4) and removed in vacuo. The residue was purified on silica gel using 1:1 hexane:ethyl acetate to afford 3.0 g of title product as a gum; MS 390 (m+), 269, 205.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[H-].[Na+].Br[CH2:17][C:18]([CH3:27])=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.O>CN(C)C=O>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:17][C:18]([CH3:27])=[CH:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: CC(=Cc1ccc(C)cc1)CBr
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(C)cc1)COc1cc(C)c(NC=O)c(C)c1C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
To a solution of N-(4-hydroxy-2,3,6-trimethylphenyl)formamide (9.31 g, 52.0 mmol) in N,N-dimethylformamide (120 ml) was added at 0° C. under nitrogen atmosphere sodium hydride (a 60% dispersion in liquid paraffin, 2.11 g, 52.8 mmol) and the resulting mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added a solution of 1-(3-bromo-2-methyl-1-propenyl)-4-methylbenzene (12.48 g, 55.44 mmol) in N,N-dimethylformamide (20 ml) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate-isopropyl ether to obtain 7.34 g (44% yield) of the title compound. Melting point: 167-169° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(OC[CH:22]([N:28]=[N+:29]=[N-:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=O)=O.N([CH2:34]CN1C=CC=C(OC)C1=O)=[N+]=[N-]>>[N:28]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:34][N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]1=[O:15])=[N+:29]=[N-:30]
Reactant: CCCCCC(COS(C)(=O)=O)N=[N+]=[N-]
Reactant: O=c1[nH]cccc1OCc1ccccc1
Reactant: COc1cccn(CCN=[N+]=[N-])c1=O
Product: [N-]=[N+]=NCCCCCCCn1cccc(OCc2ccccc2)c1=O
Yield: 48 %

Procedure:
Reaction of 3-benzyloxypyridine-2-one (0.79 g, 3.38 mmol) and 156f (0.81 g, 4.05 mmol) within 16 h as described for synthesis of 157a gave compound 157f (0.55 g, 48%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J=7.8, 1.0 Hz, 2H), 7.31 (m, 3H), 6.85 (dd, J=6.9, 1.7 Hz, 1H), 6.61 (dd, J=7.4, 1.7 Hz, 1H), 5.99 (m, 1H), 5.09 (s, 2H), 3.93 (m, 2H), 3.23 (t, J=6.9 Hz, 2H), 1.74 (m, 2H), 1.55 (m, 2H), 1.34 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 158.32, 149.19, 136.63, 129.15, 128.74, 128.13, 127.52, 115.66, 104.69, 94.66, 70.96, 51.62, 50.03, 29.22, 28.98, 26.77, 26.72.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8]C(=O)[C:5]2=[CH:11][C:12]=1[F:13].CCCCCCCCCCCCC>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:12]=1[F:13])[C:9]([OH:10])=[O:8]
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Agent: CCCCCCCCCCCCC
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(F)c(F)c1
Temperature: 190 °C
Yield: 85 %

Procedure:
4,5-difluorophthalic anhydride (0.5 grams, 2.7 mmole) was added to a slurry of cupric oxide (5% by weight of starting material) in 5 ml. of N-methyl-2-pyrrolidone. n-tridecane (0.25 grams) was added as an internal standard. The mixture was heated to 190° C. for 3 hours, at which time GC analysis indicated complete consumption of the starting material and conversion to 3,4-difluorobenzoic acid in an 85% yield, based upon the internal standard, corrected for response factors.
Reaction SMILES: Cl.C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([Cl:15])[CH:7]=1)(=O)C>O>[Cl:15][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13])[NH2:5]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Agent: Cl
Solvent: O
Product: Nc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To concentrated HCl (15 mL) at reflux under nitrogen was added N-acetyl-3-chloro-4-nitroaniline (3 g, 0.014 mol). The reaction mixture was stirred for 3 hours. A white precipitate formed upon cooling to room temperature. The reaction mixture was then diluted with water, extracted with ethyl acetate and dried over sodium sulfate. The solvent was then removed under reduced pressure to afford 2.1 g (87%) of the title compound, 3-chloro-4-nitroaniline, as a yellow solid; m.p. 157°-158° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[CH3:20][O:21][CH2:22]C(Cl)=O.[N:26]1[C:35]2[C:30](=[CH:31][C:32]([NH2:36])=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[CH2:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH2:22][O:21][CH3:20])[C@H:9]([C:17]([NH:36][C:32]2[CH:31]=[C:30]3[C:35](=[CH:34][CH:33]=2)[N:26]=[CH:27][CH:28]=[CH:29]3)=[O:19])[CH2:10]1)[CH3:16]
Reactant: COCC(=O)Cl
Reactant: Nc1ccc2ncccc2c1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCON=C1C[C@@H](C(=O)Nc2ccc3ncccc3c2)N(C(=O)COC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and 6-quinolinamine the title compound was obtained in 81% purity by LC/MS. MS(ESI+): m/z=371.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][CH2:12][CH2:11]O2)=[CH:5][CH:4]=1)#[N:2].Br[C:15]1[CH:20]=[CH:19]C=[CH:17][C:16]=1COCOC>>[B:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[C:17]2[CH:16]=[CH:15][CH:20]=[CH:19][C:11]=2[CH2:12][O:13]1
Reactant: N#Cc1ccc(B2OCCO2)cc1
Reactant: COCOCc1ccccc1Br
Product: N#Cc1ccc(B2OCc3ccccc32)cc1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(4-cyanophenyl)-[1,3,2]-dioxaborolane and 1-bromo-2-((methoxymethoxy)methyl)-benzene to afford white crystalline product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH3:15])[NH:7][C:6]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH3:15])[N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1CCOC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(CCOC)c(C(=O)OCC)n(-c2ccccc2)c1C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
A mixture of diethyl 3-(2-methoxyethyl)-5-methyl-1H-pyrrole-2,4-dicarboxylate (100 mg, 0.35 mmol), phenyl boronic acid (130 mg, 1.06 mmol), copper acetate (130 mg, 0.71 mmol), dry pyridine (110 mg, 1.40 mmol), molecular sieves (400 mg) and dichloromethane (10 mL) was purged with argon gas for 30 min and stirred overnight. The mixture was filtered through a celite bed, washed with dichloromethane (15 mL) and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using 20% ethyl acetate/pet ether as eluent to afford diethyl 3-(2-methoxyethyl)-5-methyl-1-phenyl-pyrrole-2,4-dicarboxylate (50 mg, 40%) as a colourless oil.
Reaction SMILES: C([O:5][C:6](=[O:31])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[F:21])[N:12]([S:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:11]=1)C)(C)(C)C.[C:32]([O:35]CC)(=[O:34])[CH3:33].Cl.[CH3:39]O>>[C:6]([OH:5])(=[O:31])/[CH:39]=[CH:33]/[C:32]([OH:35])=[O:34].[F:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[C:13]1[N:12]([S:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:11]=[C:10]([CH2:9][NH:7][CH3:6])[CH:14]=1
Reactant: CO
Reactant: CCOC(C)=O
Reactant: CN(Cc1cc(-c2ccncc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCc1cc(-c2ccncc2F)n(S(=O)(=O)c2cccnc2)c1
Product: O=C(O)/C=C/C(=O)O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
tert-Butyl{[5-(3-fluoropyridin-4-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (60 mg) was dissolved in methanol (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1.5 mL) was added and the mixture was stirred at 70° C. for 30 min. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium hydrogencarbonate solution was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (8 mL), a solution of fumaric acid (58 mg) in methanol (2 mL) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 45 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:36]1[CH2:38][CH:37]1[CH2:39][CH2:40]O.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:40][CH2:39][CH:37]3[CH2:38][CH2:36]3)=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: OCCC1CC1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2OCCC2CC2)cc1

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-cyclopropane ethanol in place of isobutanol (yield: 0.1472 g, 100%). mp 111-117° C. 1H NMR (300 MHz, DMSO d6) δ −0.01 (m, 2H), 0.31 (m, 2H), 0.60 (m, 1H), 1.49 (q, J=6 Hz, 2H), 3.29 (s, 3H), 4.48 (t, J=6 Hz, 2H), 7.37 (m, 2H), 7.65 (m, 2H), 7.91 (m, 2H), 8.06 (m, 2H), 8.17 (s, 1H). MS (DCI/NH3) m/z 429 (M+H)+, 446 (M+NH4)+. Anal. calc. for C22H21FN2O4S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.59; H, 5.02; N, 6.45.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([N+:15]([O-])=O)=[C:10]3[O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].[H][H]>O1CCCC1.[Pd]>[NH2:15][C:11]1[CH:12]=[CH:13][C:14]2[N:6]([CH2:5][CH2:4][N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])[N:7]=[C:8]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:10]=1[C:9]=23
Reactant: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Oc1ccccc1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Oc1ccccc1-2

Procedure:
A solution of 8.9 g (0.026 mole) of N,N-diethyl-5-nitro-2H-[1]benzopyrano[4,3,2-cd]indazole-2-ethanamine in 100 ml of tetrahydrofuran was hydrogenated over 1 g of 10% palladium on carbon at ambient temperature and a hydrogen pressure of 46.3-52.3 psi. The mixture was filtered and the solvent removed in vacuo. The oily residue was triturated with petroleum ether and recrystallized from n-hexane to give the product, mp 78°-80° C.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])[C:11]2=[O:24])=[CH:6][CH:5]=1.F[C:26](F)(F)[C:27]([O-])=O>>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]([NH:18][C@H:19]([CH:26]=[CH2:27])[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[C:11]2=[O:24])=[CH:6][CH:5]=1
Reactant: NN=Cc1ccc(N2CCC(NC(=O)NCCC(=O)O)C2=O)cc1
Reactant: O=C([O-])C(F)(F)F
Product: C=C[C@H](CC(=O)O)NC(=O)NC1CCN(c2ccc(C=NN)cc2)C1=O

Procedure:
3-[[[[1-[4-(aminoiminomethyl)phenyl]-2-oxo-3-pyrrolidinyl]amino]carbonyl]amino]propanoic acid, trifluoroacetate;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl:27][C:28]1[CH:29]=[C:30]([CH2:34][CH2:35][NH2:36])[CH:31]=[CH:32][CH:33]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:36][CH2:35][CH2:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4cccc(Cl)c4)cc3)c(Cl)cc21
Reaction time: 48 h
Yield: 91.5 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (48.8 mg, 0.130 mmol), in 1:1 DCM:DMF (0.1 M) was sequentially treated with 2-(3-chlorophenyl)ethylamine (22.2 mg, 0.143 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29.8 mg, 0.155 mmol), and 1-hydroxy-7-azabenzotriazole (5.29 mg, 0.0389 mmol) at ambient temperature. After 48 hours the reaction was applied directly to a silica gel column and eluted with a gradient (15% to 60%) of ethyl acetate-hexanes to provide the title compound (61.1 mg, 0.119 mmol, 91.7% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[NH2:22][C:23]([CH:29]1[CH2:31][CH2:30]1)([CH3:28])[CH2:24][C:25]([NH2:27])=[O:26]>>[NH2:27][C:25](=[O:26])[CH2:24][C:23]([NH:22][C:12]([C:9]1[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])[C:6]([C:2]2([F:1])[CH2:3][O:4][CH2:5]2)=[CH:11][N:10]=1)=[O:14])([CH:29]1[CH2:31][CH2:30]1)[CH3:28]
Reactant: CC(N)(CC(N)=O)C1CC1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC(C)(CC(N)=O)C2CC2)ncc1C1(F)COC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (example 142b) and 3-amino-3-cyclopropyl-butanamide (example 270c) as starting materials and isolated (55 mg, 39%); MS (ESI, m/z): 434.3 (M+H+).
Reaction SMILES: [C:1]([CH:4]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].C(O)(=O)C>N12CCCN=C1CCCCC2.C(OCC)C>[CH2:18]([O:17][C:13](=[O:16])[CH2:14][CH2:15][C:4]([C:5](=[O:7])[CH3:6])([C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH3:19]
Reactant: CC(=O)CCC(C(C)=O)C(C)=O
Reactant: C=CC(=O)OCC
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Product: CCOC(=O)CCC(CCC(C)=O)(C(C)=O)C(C)=O
Reaction time: 16 h
Yield: 57.4 %

Procedure:
10.2 g of 3-acetyl-2,6-heptandione and 5 drops of 1,8-diazabicyclo-[5.4.0]-undec-7-ene were mixed, and 9 g of ethyl acrylate was added dropwise over 15 minutes. After stirring for 16 hours, the base was neutralized with acetic acid, 30 ml of diethyl ether was added, and the solution was extracted with sodium carbonate solution and water. Fractional distillation of the dry organic layer yielded 9.3 g of 4,4-diacetyl-7-oxo-octanoic-ethyl ester (boiling point: 136° C./0.02 mbar; purity: 81%; colorless).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH2:14])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:26](O)=[O:27])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:26]([C:23]1([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:25][CH2:24]1)=[O:27])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc(N)ccc2[nH]1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C2(C(=O)Nc3ccc4[nH]c(C(C)(C)C)cc4c3)CC2)cc1
Reaction time: 3 h

Procedure:
2-tert-Butyl-1H-indol-5-amine (19 mg, 0.10 mmol) and 1-(4-methoxyphenyl)-cyclopropanecarboxylic acid (19 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1.00 mL) containing triethylamine (28 μL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl)-N,N, N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The crude reaction mixture was filtered and purified by reverse phase HPLC. ESI-MS m/z calc. 362.2, found 363.3 (M+1)+; Retention time 3.48 minutes.
Reaction SMILES: P(Br)(Br)[Br:2].[O:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[O:13][C:12]=2[CH:22](O)[CH3:23])[CH2:7][CH2:6]1>C(Cl)Cl>[Br:2][CH:22]([C:12]1[O:13][C:14](=[O:21])[C:15]2[C:20]([C:11]=1[C:8]1[CH2:7][CH2:6][O:5][CH2:10][CH:9]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:23]
Reactant: CC(O)c1oc(=O)c2ccccc2c1C1=CCOCC1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1C1=CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
1 M PBr3 in DCM (1.43 mL, 1.43 mmol) was added to 4-(3,6-dihydro-2H-pyran-4-yl)-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate B18, 130 mg, 0.477 mmol) in DCM (2 mL) and stirred for 2 hrs at RT, then the reaction mixture was adsorbed on silica pad and straightforward purified on Biotage silica cartridge eluting with a gradient of hexane and AcOEt to give the title compound (94 mg, 58.7%) as an off white solid.