Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:40])[CH2:10][CH2:11][NH:12][C:13](=[O:39])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:38])[C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:37])[NH:26]C(OCC2C=CC=CC=2)=O)=[CH:21][CH:20]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]([NH:17][CH2:16][CH2:15][CH2:14][C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:40])=[O:8])=[O:39])=[O:38])=[CH:24][CH:23]=1)(=[NH:26])[NH2:37]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(C(=O)NCCCC(=O)NCCC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc(C(=O)NCCCC(=O)NCCC(=O)O)cc1
Yield: 79.4 %

Procedure:
512 mg of N-[4-[p-[N-(benzyloxycarbonyl)amidino]benzamido]butyryl]-β-alanine benzyl ester and 170 mg of Pd/C in 10 ml of acetic acid were stirred under hydrogen. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in water and the solution was evaporated. The residue was suspended in water, adjusted to pH 7 using ammonia, filtered with suction, washed with water and dried. 239 mg of N-[4-(p-amidinobenzamido)butyryl]-β-alanine, m.p. >250° C., MS: 321 (12, M+H), were obtained.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[C:22](=[O:26])[CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 56 h
Yield: 50.4 %

Procedure:
To a solution of 5-fluoro-2-nitrotoluene (1.00 g, 6.44 mmol) in DMF (6.5 mL) was added 4-benzyloxy-pyridin-2(1H)-one (1.11 g, 5.55 mmol) and Na2CO3 (0.588 g, 5.55 mmol). After stirring at 120° C. for 56 hours, the reaction mixture was cooled, and the solids were collected by filtration and washed with EtOAc (100 ml) and H2O (100 mL). The solids were triturated with hot H2O (50 mL) and then washed with Et2O (50 mL) to yield the title compound (0.94 g, 50%) as a light yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 8.08 (d, J=8.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.50 (dd, J=9.0, 2.5 Hz, 1H), 7.47-7.37 (m, 5H), 6.16 (dd, J=8.0, 3.0 Hz, 1H), 6.01 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 2.55 (s, 3H); ESI MS m/z 337 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:9](=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=2)[CH:21]=1>CS(C)=O>[CH3:2][N:3]1[C:9](=[O:10])[CH2:8][CH2:7][N:6]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]3[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=3)[CH:21]=2)[CH2:5][CH2:4]1
Reactant: CN1CCNCCC1=O
Reactant: N#Cc1cnc(Nc2cc(CCl)ccn2)s1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccnc(Nc3ncc(C#N)s3)c2)CCC1=O
Reaction time: 20 h

Procedure:
4-Methyl-[1,4]diazepan-5-one hydrochloride (0.394 g, 2.39 mmol) was dissolved in 3 mL DMSO. Triethylamine (0.33 mL, 2.4 mmol) was added followed by the addition of 2-(4-chloromethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.200 g, 0.798 mmol). The solution as stirred for 20 h. The reaction mixture was purified directly by loading the solution onto a reverse phase preparative column. The fractions containing pure product were concentrated and the white solid that resulted was characterized as the TFA salt. 1H NMR (CD3OD) δ8.47 (d, 1H, J=5.1 Hz), 8.02 (s, 1H), 7.09 (s, 1H), 7.07 (d, 1H, J=5.0 Hz), 3.78 (bs, 2H), 3.61 (bs, 2H), 2.98 (s, 3H), 2.83-2.67 (bs, 6H). [M+H]+=343.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([CH2:16][C@@H:17]2[C@H:20]([N:21]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:22](=[O:31])[O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19](=[O:41])[N:18]2CC2C=CC(OC)=CC=2OC)[N:13]=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([CH2:16][C@@H:17]2[C@H:20]([N:21]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)[C:22](=[O:31])[O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19](=[O:41])[NH:18]2)[N:13]=[N:12]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H]2C(=O)N(Cc3ccc(OC)cc3OC)[C@@H]2Cc2cn(CCNC(=O)OC(C)(C)C)nn2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H]2C(=O)N[C@@H]2Cc2cn(CCNC(=O)OC(C)(C)C)nn2)cc1

Procedure:
Prepared in analogous manner to example 82 step 5, using benzyl ((2R,3S)-2-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)(4-methoxybenzyl)carbamate (57.2 mg, 0.080 mmol), CH3CN (762 μl), water (381 μl), potassium peroxydisulfate (31 mg, 0.12 mmol), and potassium phosphate, dibasic (19 mg, 0.109 mmol). 20.2 mg. LCMS: Rt=0.89 min, m/z=565.3 (M+1). Method 2m_acidic.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[NH:14][N:13]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[F:22][C:11]([F:10])([F:21])[C:12]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]([C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)[N:13]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: OCc1ccc(I)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: OCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 130 °C
Reaction time: 23 h
Yield: 85.7 %

Procedure:
A mixture of 4-iodobenzylalcohol (1.23 g, 5.25 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (950 mg, 5 mmol), copper (I) iodide (10 mol %, 95 mg, 0.5 mmol), N,N-dimethylglycine (20 mol %, 103 mg, 1 mmol) and potassium carbonate (1.45 g, 10.5 mmol) in dimethylsulfoxide (30 ml) was stirred at 130° C. in an oil bath for 23 h. The reaction mix was cooled and partitioned between dichloromethane (30 ml) and brine (150 ml). The organic layer was removed filtered and the solvent removed under reduced pressure. The resulting product was purified by flash column chromatography on a Biotage 40+M column eluting from 0-60% ethyl acetate in pentane to give the title compound as a yellow oil (1.27 g, 86%).
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([OH:17])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][CH3:33])(=[O:31])[C:29]#[CH:30]>C(Cl)Cl.C1N2CCN(CC2)C1>[CH2:1]([C@H:8]1[CH2:9][O:10][CH2:11][C@H:12]([NH:20][C:21]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:27])[C:13](=[O:19])[O:14][C@@H:15]([CH3:18])[C@@H:16]1[O:17]/[CH:30]=[CH:29]/[C:28]([O:32][CH3:33])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Reactant: C#CC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COC(=O)/C=C/O[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo−1,5-dioxonan-3-yl)carbamate (280 mg, 0.738 mmol, 1.00 equiv) in CH2Cl2 (7.4 mL) were added methyl propiolate (0.098 mL, 1.11 mmol, 1.50 equiv) and DABCO (4 mg, 0.04 mmol, 0.05 equiv). This solution was stirred at room temperature for 1 h, concentrated, and purified by automated silica gel column chromatography (5-25% acetone in hexanes) to provide (E)-methyl 3-(((3S,6S,7R,8S)-8-benzyl-3-((tert-butoxycarbonyl)amino)-6-methyl-4-oxo-1,5-dioxonan-7-yl)oxy)acrylate (312 mg, 91%) as a white solid: mp slow melt from 50-80° C., recrystallized at 98° C., remelt at 128-129° C.; IR (neat film) 3342, 2980, 2949, 1753, 1703, 1639, 1497, 1329, 1132, 910, 731 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=12.2 Hz, 1H), 7.32-7.27 (m, 2H), 7.23-7.18 (m, 1H), 7.15-7.11 (m, 2H), 5.40 (d, J=12.2 Hz, 1H), 5.10 (d, J=8.3 Hz, 1H), 5.02 (dd, J=9.3, 6.4 Hz, 1H), 4.64 (dd, J=15.3, 7.5 Hz, 1H), 3.92 (dd, J=11.6, 7.6 Hz, 1H), 3.74 (d, J=9.1 Hz, 1H), 3.71 (s, 3H), 3.51 (d, J=11.1 Hz, 1H), 3.43 (dd, J=10.5, 6.4 Hz, 1H), 3.29 (dd, J=11.3, 7.5 Hz, 1H), 2.92 (dd, J=13.8, 3.5 Hz, 1H), 2.34 (t, J=12.5 Hz, 1H), 2.06 (s, 1H), 1.42 (s, 9H), 1.41 (d, J=6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.16, 167.97, 162.94, 154.91, 138.54, 129.09, 128.57, 126.48, 98.50, 89.01, 80.31, 73.94, 72.57, 71.33, 52.70, 51.26, 46.47, 35.18, 28.25, 18.73; HRMS-ESI (m/z) [M+Na]+ calc'd for C24H33NO8Na, 486.2098. found, 486.2104.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[NH2:19][C:20]([NH2:22])=[S:21].C([O-])(O)=O.[Na+]>CCO>[NH2:22][C:20]1[S:21][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][CH:6]=2)[N:19]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2csc(N)n2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-bromoacetyl)-N-tert-butylbenzenesulfonamide (8.71 g, 26.1 mmol) in EtOH (45 mL) was added thiourea (2.38 g, 31.3 mmol). The reaction mixture was heated to 70° C. for 15 h and poured into an aqueous solution of NaHCO3. The mixture was stirred for 30 min. The precipitate that formed was collected by filtration, washed with water, and dried under high vacuum to give 4-(2-aminothiazol-4-yl)-N-tert-butylbenzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:30]=[CH:29][C:13]([C:14]([NH:16][NH:17][C:18]4C=[CH:27][CH:26]=[CH:25][C:19]=4[C:20]([O:22][CH2:23][CH3:24])=[O:21])=O)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.C(Cl)(Cl)(Cl)Cl.C([N:41](C(C)C)CC)(C)C.C(P(CC)CC)C>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:14]4[N:41]5[CH:27]=[CH:26][CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]5=[N:17][N:16]=4)=[CH:29][CH:30]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1ccccc1NNC(=O)c1ccc(Nc2nc3ccc(Cl)cc3s2)cc1
Agent: CCP(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccn2c(-c3ccc(Nc4nc5ccc(Cl)cc5s4)cc3)nnc12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
To a solution of ethyl 2-(2-(4-(6-chlorobenzo[d]thiazol-2-ylamino)benzoyl)hydrazinyl)benzoate (142 mg, 0.3 mmol) in a mixed solvent of CCl4 (0.6 mL), THF (0.8 mL) and CH2Cl2 (1.2 mL) cooled to 0° C. was added diisopropylethylamine (392 mg, 3 mmol) under argon atmosphere and then triethylphosphine (179 mg, 1.52 mmol). The mixture was stirred at 0° C. for 45 min, and then quenched with water (2.5 mL). The resulting precipitate was isolated by filtration and air dried to yield the title compound as a brown solid (108 mg). The filtrate was concentrated in vacuo to yield additional product (15 mg) (total 123 mg, 90% yield). HPLC/MS (Method C): retention time=2.21 min, [M+H]+=450.3.
Reaction SMILES: [CH:1]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[O-:19][C:20]#[N:21].[Na+]>O>[NH2:21][C:20]([N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:1]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: CCOC(=O)C1NCCc2c1[nH]c1ccccc21
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1c2[nH]c3ccccc3c2CCN1C(N)=O
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
56.2 g (0.2 mol) of ethyl 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate are heated to about 60° C. in 1,000 ml of water. A solution of 15.2 g (0.234 mol) of pulverulent sodium cyanate in 200 ml of water is added all at once. The mixture is stirred for 15 minutes and then cooled to about 10° C. The aqueous reaction phase is decanted and the compound is washed with water and recrystallised from ethanol.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:32])[C:7]([CH2:20][NH:21][S:22]([C:25]2[C:26](C)=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:8][C:9](=[O:19])[C:10]=1[O:11]CC1C=CC=CC=1)=[O:4].[C:33]1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:32])[C:7]([CH2:20][NH:21][S:22]([C:25]2[CH:30]=[C:29]([CH3:33])[CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:24])=[CH:8][C:9](=[O:19])[C:10]=1[OH:11])=[O:4]
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2C)n1C
Product: CNC(=O)c1c(O)c(=O)cc(CNS(=O)(=O)c2cccc(C)c2)n1C
Yield: 16.76 %

Procedure:
3-Hydroxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (16-04) (35.0 mg, 16.76%, purified by Prep-HPLC) was synthesized as an off white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (14-11) (260.0 mg, 0.571 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: ClC1C=CC(C2C3C=CC(N)=NC=3C3C(C)=NOC=3C[N:14]=2)=CC=1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[C:29]3[C:45]([CH3:46])=[N:44][O:43][C:30]=3[CH2:31][N:32]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[C:34]=2[N:35]=1.ClC1C=CC2C(C3C=CC(Cl)=CC=3)=NCC3ON=C(C)C=3C=2N=1>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:33]2[C:34]3[N:35]=[C:25]([NH2:14])[CH:26]=[CH:27][C:28]=3[C:29]3[C:45]([CH3:46])=[N:44][O:43][C:30]=3[CH2:31][N:32]=2)=[CH:37][CH:38]=1
Reactant: Cc1noc2c1-c1nc(N)ccc1C(c1ccc(Cl)cc1)=NC2
Reactant: Cc1noc2c1-c1ccc(Cl)nc1C(c1ccc(Cl)cc1)=NC2
Agent: Cc1noc2c1-c1nc(Cl)ccc1C(c1ccc(Cl)cc1)=NC2
Product: Cc1noc2c1-c1ccc(N)nc1C(c1ccc(Cl)cc1)=NC2

Procedure:
A procedure similar to 5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-2-amine (Compound 228) was followed, except that 8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine (Compound 240) was used as starting material instead of 2-chloro-5-(4-chlorophenyl)-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine. LC/MS m/z 325 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=8.72 Hz, 1H), 7.38 (td, J=2.10, 8.70 Hz, 2H), 7.33 (td, J=1.90, 8.70 Hz, 2H), 6.76 (d, J=8.7 Hz, 1H), 6.39 (s, 2H), 4.60 (br. s, 2H), 2.46 (s, 3H).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([O:31][CH3:32])=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[CH:17]=[C:16]2[NH:22][C:23]1[C:28]([Cl:29])=[CH:27][N:26]=[CH:25][C:24]=1[Cl:30]>>[Cl:30][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:29])[C:23]=1[NH:22][C:16]1[C:15]2[C:20](=[C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:1]#[N:2])[C:12]([O:31][CH3:32])=[CH:13][CH:14]=2)[O:19][C:18](=[O:21])[CH:17]=1
Reactant: [C-]#N
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Agent: [K+]
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC#N

Procedure:
The title compound was prepared from potassium cyanide and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 3.98 (t, 2H), 3.92 (s, 3H), 2.51 (t, 2H), 1.75-1.55 (m, 6H); MS (ESI): 447.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[C:11]1([C@H:17](O)[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C@H:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: C[C@@H](O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn([C@@H](C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 20 mL microwave vial was charged with 1H-pyrazole-4-carboxylic acid ethyl ester (1 g, 7.1 mmol), (R)-1-phenylethanol (1.31 mL, 10.7 mmol), triphenylphosphine (3 g, 11.4 mmol) and tetrahydrofuran (15 mL). The reaction was stirred at ambient temperature for 10 minutes before adding diisopropyl azodicarboxylate (2.25 mL, 11.14 mmol) with cooling. The vial was heated under microwave irradiation at 140° C. for 15 mins. After cooling, the solvent was removed in vacuo and the residue purified by flash chromatography on SiO2 with hexane—30% ethyl acetate/hexane (gradient) to afford intermediate (6f), 1((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester as an oil, 1.646 g, 94%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[F:7][C:8]([F:14])([F:13])[C:9](OC)=[O:10]>CO>[F:7][C:8]([F:14])([F:13])[C:9]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[O:10]
Reactant: NCCCCO
Reactant: COC(=O)C(F)(F)F
Solvent: CO
Product: O=C(NCCCCO)C(F)(F)F
Yield: 85.4 %

Procedure:
4-amino-1-butanol (15.0 g, 168.27 mmol) and methyl trifluoroacetate (82.96 mL, 824.55 mmol) were combined in methanol (250 mL) and heated at reflux for 2 hours. The reaction was concentrated to yield the title compound (26.6 g, 85.4%) as a clear oil which had the following properties: 1H NMR CDCl3 δ: 7.08 (brd s, 1H), 3.71 (t, J=5.4 Hz, 2H), 3.40 (q, J=6.2 and 6.2 Hz, 2H), 1.75-1.61 (m, 4H).
Reaction SMILES: [CH:1]([N:4]([CH2:13][CH:14]1[CH2:18][O:17][C:16]2([CH:26](Br)[CH2:25][CH2:24][C:23]3[N:22]([S:28]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[CH:21]=[CH:20][C:19]2=3)[O:15]1)[C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:3])[CH3:2]>C1CCN2C(=NCCC2)CC1.CN(C)C=O.C(OCC)(=O)C>[CH:1]([N:4]([C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:13][CH:14]([OH:15])[CH2:18][O:17][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][N:22]2[S:28]([C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1)(=[O:30])=[O:29])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CN(C(=O)c3ccccc3)C(C)C)O2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(OCC(O)CN(C(=O)c4ccccc4)C(C)C)cccc32)cc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
In a three necked flask equipped with a stirrer and a thermometer is added 4'-(N-isopropyl-N-benzoylaminomethyl)-1-p-toluenesulfonyl-5-bromo-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane (100 parts) and dissolved in a mixture of 1,5-diazabicyclo[5,4,0]-5-undecene (51 parts) and N,N-dimethylformamide (319 parts). After stirring for 24 hours at 85° C., the solution is cooled, diluted with ethyl acetate (300 parts) and washed thrice with water (50 parts). Aqueous washings are combined and washed with ethyl acetate (50 parts). The ethyl acetate solution and ethyl acetate washings are combined, washed with water (30 parts) and dried over anhydrous sodium sulfate (50 parts). After 1 hour, the drying reagent is filtered off and filtrate concentrated to dryness under reduced pressure. Obtained residue (83 parts) is dissolved in ethyl acetate (200 parts), stirred for 30 minutes with active charcoal (10 parts) and filtered through diatomaceous filter-bed. The filtrate concentrated under reduced pressure. The residue is triturated with a small amount of hexane to separate amorphous powder. This is collected by filtration and dried to afford 4-(N-isopropyl-N-benzoyl-3-amino-2-hydroxypropoxy)-1-p-toluenesulfonylindole (35 parts) in 41% yield.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][C:29]1([CH3:32])[CH2:31][O:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:28][C:29]([OH:30])([CH3:32])[CH3:31])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)CO1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C)n(CC(C)(C)O)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 2,2-dimethyloxirane (2.5 mL), cesium carbonate (1.83 g) and N,N-dimethylacetamide (10 mL) was stirred at 100° C. for 24 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.92 g, 76%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:22])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O[CH2:24][NH:25][C:26](=[O:29])[CH2:27][Cl:28].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:28][CH2:27][C:26]([NH:25][CH2:24][C:6]1[C:7]([OH:22])=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4])=[O:29]
Reactant: O=C(CCl)NCO
Reactant: CC(C)(C)c1cc(O)c(-c2ccc(Cl)cc2)c(C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(C)(C)C)c(-c2ccc(Cl)cc2)c(O)c1CNC(=O)CCl
Reaction time: 8 h

Procedure:
To a solution of 3.0 g (9.5 mmol) of the product of Step B and 1.25 g (10.1 mmol) of N-hydroxymethyl-2-chloroacetamide in 20 mL CH2Cl2 was added 25 mL of trifluoroacetic acid. The reaction mixture was stirred under a nitrogen atmosphere overnight and then concentrated in vacuo. The residue was partitioned between EtOAc and excess saturated aqueous NaHCO3. The aqueous layer was separated and re-extracted with EtOAc. The organic layers were then combined, dried (Na2SO4), filtered and evaporated in vacuo to afford the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1.[OH-].[Na+].CN([CH:32]=[O:33])C>>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[CH:17]=[C:16]([CH:32]=[O:33])[NH:15][C:14]=2[C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=2)=[CH:20][CH:21]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc[nH]c2-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc(C=O)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To 25 ml DMF at 0° was added dropwise with stirring 30 g of phosphorus oxychloride. The mixture was stirred for 15 minutes at room temperature, then a solution of 5.6 g (0.02 mole) of 2,3-bis(4-methoxyphenyl)pyrrole in 40 ml DMF was added dropwise with cooling in an ice bath. The mixture was then heated at 70°-80° for one hour, then cooled. Aqueous sodium hydroxide (50%) was added until the mixture was basic. The reaction mixture was then heated again at 70° for 15 minutes. The cooled reaction mixture was poured into ice water. The precipitated material was collected and purified by chromatography on 600 g Silic AR CC-7 (eluting with toluene containing 1-2% ethyl acetate) to give 3.4 g (55%) of product, m.p. 165°-6° (methylcyclohexane/toluene).