Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH:27]([F:29])[F:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)/[CH:21]=[CH:22]/[N:23](C)C)=[CH:16][CH:15]=3.C(O)(=O)C(O)=O.[CH2:40]([NH:42]N)[CH3:41]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH:27]([F:28])[F:29])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:42]([CH2:40][CH3:41])[N:23]=[CH:22][CH:21]=1)=[CH:16][CH:15]=3
Reactant: CN(C)/C=C/C(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C(F)F
Reactant: CCNN
Agent: O=C(O)C(=O)O
Product: CCn1nccc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C(F)F

Procedure:
The process is carried out as indicated in Example 37 above, with compound B, 3-(2,4-dichlorophenyl)-9-difluoromethyl-6-((E)-3-dimethylaminoacryloyl)-1-methyl-1,9-dihydropyrido[2,3-b]indol-2-one, and ethylhydrazine oxalate.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([C:24]([NH:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:32]=2[N:33]2[CH2:38][C@H:37]([CH3:39])[C@H:36]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:35]([NH:45]C(=O)OC(C)(C)C)[CH2:34]2)=[O:25])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([CH:22]=[CH2:23])[CH:16]=2)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:45][C@H:35]1[C@@H:36]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@@H:37]([CH3:39])[CH2:38][N:33]([C:32]2[CH:31]=[CH:30][N:29]=[CH:28][C:27]=2[NH:26][C:24]([C:13]2[C:12]([NH2:11])=[CH:21][C:20]3[C:15](=[CH:16][C:17]([CH2:22][CH3:23])=[CH:18][CH:19]=3)[N:14]=2)=[O:25])[CH2:34]1
Reactant: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3C[C@H](C)[C@H](NC(=O)OC)[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2cc(N)c(C(=O)Nc3cnccc3N3C[C@@H](N)[C@@H](NC(=O)OC)[C@@H](C)C3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution of tert-butyl methyl [(3R,4S,5S)-1-(3-{[(3-{[(benzyloxy)carbonyl]amino}-7-vinylquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (92 mg, 0.13 mmol) in MeOH (4.0 mL), 10% Pd on carbon (21 mg) was added. The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under hydrogen for 1 h. The mixture was then filtered and concentrated under reduced pressure. The resulting residue was dissolved in DCM (2 mL), and TFA (2 mL) was added. The mixture then was stirred at room temperature for 1 h before being concentrated under reduced pressure. The residue was purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a yellow powder (45 mg, 73%). LCMS calc. for C25H32N7O3 (M+H)+: m/z=478.3. Found: 478.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])O)=[O:5])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])[NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[C:26]([Cl:25])[CH:27]=1)=[O:5])[CH3:2]
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cccc(Cl)c1)c1ccc(Cl)cc1C

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 with the intermediate C and the 3-chloroaniline. The reaction mixture was diluted in DCM/water and the phases were separated. The organic phase was dried (Na2SO4) and concentrated. The product was purified by flash chromatography (heptane/EtOAc, 9:1) to give the title compound. tR: 1.47 min (LC-MS 2); ESI-MS: 524.0/526.0/528.2 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[CH:20]=[CH:19][C:18]([N+]([O-])=O)=[CH:17]C=3)=[N:9][C:8]=2[N:7]([CH2:24][CH2:25][CH3:26])[C:5]1=[O:6])[CH2:2][CH3:3].C(N1C(N)=C(N)C(=O)N(CCC)C1=O)CC.[N+:43](C1C=CC(C=O)=CC=1)([O-:45])=[O:44].C(O)(=O)C>C(O)C>[CH2:24]([N:7]1[C:8](=[N:9][C:10]2[CH:15]=[CH:20][C:19]([N+:43]([O-:45])=[O:44])=[CH:18][CH:17]=2)[CH:12]([NH2:11])[C:13](=[O:14])[N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:6])[CH2:25][CH3:26]
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2n(CCC)c1=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCN1C(=O)C(N)C(=Nc2ccc([N+](=O)[O-])cc2)N(CCC)C1=O

Procedure:
1,3-Dipropyl-8-(4-nitrophenyl)xanthine, was prepared by treatment of 1,3-dipropyl-5,6-diaminouracil (1.01 g, 4.5 mmol) with 4-nitrobenzaldehyde (0.85 g, 5.6 mmol) in absolute ethanol (50 ml) in the presence of acetic acid (0.6 ml) and heated at reflux for 1 hour to yield 1,3-dipropyl-5-amino-6-(4-nitrophenyl)iminouracil. Treatment of 1,3-dipropyl-5-amino-6-(4-nitrophenyl)iminouracil (1.2 g, 3.3 mmol) with diethyl azodicarboxylate (7 ml) at 90° C. in toluene (40 ml) gave after dilution with ethanol a precipitate. This precipitate was recrystallized from ethanol yielding 0.95 g of pure product (81%). IR (KBr) 3180 (N--H), 1710(C=O), 1650(C=O), 1520(C=C) cm-1 ; Anal. Calcd. for C17H19N5O4 : MW 357.38: C, 57.14; H, 5.36; N, 19.60. Found: C, 57.22; H, 5.42; N, 19.50.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][N:50]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][N:50]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1ccc(N)nc1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution triphenylphosphine (177 mg, 0.68 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (132 mg, 0.74 mmol) in small portions. The reaction mixture was allowed to warm to 25° C. over 30 min and then was treated with 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (prepared as in Example 3A, 200 mg, 0.68 mmol). The reaction mixture was stirred at 25° C. for 30 min and then treated with 2-amino-5-methylpyridine (154 mg, 1.42 mmol). The resulting reaction mixture was stirred at 25° C. for 1 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 hexanes/ethyl acetate) to afford impure 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamide as a red solid. The impure product was further purified by precipitation from 1/1 hexanes/ethyl acetate to afford pure 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamide (80 mg, 31%) as an off-white solid: mp 184–185° C.; EI-HRMS m/e calcd for C21H26N2O3S (M+) 386.1664, found 386.1664.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:20](/[CH:30]=[CH:31]\[CH3:32])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:33][CH2:34][C:35](Br)=[O:36]>ClCCl>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:35](=[O:36])[CH2:34][Br:33])[CH2:26][CH2:25]2)=[C:20](/[CH:30]=[CH:31]\[CH3:32])[CH:19]=1)([C:10]([F:12])([F:13])[F:11])[C:14]([F:15])([F:16])[F:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCNCC1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Product: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)CC1
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
(Z)-1-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazine (38 mg, 0.0595 mmol) was dissolved in dichloromethane (1.0 mL). Under ice-cold conditions, N,N′-dimethylaniline (9.0 μL, 0.0714 mmol) and bromoacetylbromide (5.5 μL, 0.0625 mmol) were added, and the mixture was stirred under ice-cold conditions for 0.5 hours. Then, under ice-cold conditions, N,N′-dimethylaniline (9.0 μL, 0.0714 mmol) and bromoacetylbromide (5.5 μL, 0.0625 mmol) were added, and the mixture was stirred under ice-cold conditions for 0.5 hours. The reaction solution was concentrated in vacuo, and the obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (16 mg (yield 47%)) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromopyridin-2(1H)-one (2.01 g, 11.55 mmol) in DMF (30 mL) at 0° C. was added sodium hydride (0.924 g, 23.10 mmol). The reaction mixture was stirred for 1 h at room temperature. To this, (2-(chloromethoxy)ethyl)trimethylsilane (2.89 g, 17.33 mmol) was added slowly. The reaction mixture was stirred overnight. LCMS—0.26 min, MH+ 304.1 (non-polar method). The reaction was quenched with sat. aq. NH4Cl, and then diluted with ethyl acetate. The reaction mixture was extracted with EtOAc. The combined organics were washed with water and brine, then dried over sodium sulfate, filtered off and concentrated in vacuo. The crude product was purified by flash chromatography column using 0-50% EtOAc/heptane. 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)pyridin-2(1H)-one was obtained as a yellow viscous liquid. LCMS (m/z): 304/306 (MH+), 0.95 min.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[C:14]1([N:13]2[C:5](=[O:7])[C:4]3=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]3[CH2:2][C:1]2=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: CCOC(C)=O
Product: O=C1Cc2ccccc2C(=O)N1c1ccccc1
Reaction time: 1 h
Yield: 68 %

Procedure:
0.871 g (5.37 mmol) of homophthalic anhydride and 0.4 g (4.30 mmol) of aniline were mixed, and melted at a temperature of 200° C. for 1 hour. The reactant was dissolved in ethyl acetate, washed with aqueous NaHCO3 solution, with water and then with saturated aqueous sodium chloride, dried over anhydrous MgSO4, and subjected to filtration with a folded filter paper. The filtrate was concentrated and evaporated to dryness. The residue was recrystallized by using a mixture of CH2Cl2 and hexane, to obtain 0.565 g (yield 68%) of the specified substance as light yellow granulated crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:23])=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]3)[N:12]=2)=[CH:4][CH:3]=1.[N:24]1([CH2:31][CH2:32][CH2:33][NH:34][CH3:35])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[N:24]1([CH2:31][CH2:32][CH2:33][N:34]([CH3:35])[C:20]([CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH3:23])[CH2:15][CH2:16]2)=[O:22])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CNCCCN1CCCCCC1
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CN1CCC(C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccc(Cl)cc2)nc1CN1CCC(C(=O)N(C)CCCN2CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.4 %

Procedure:
To a solution of 1-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methyl)piperidine-4-carboxylic acid (A-3, 70 mg, 0.52 mmole), 3-(azepan-1-yl)-N-methylpropan-1-amine (20 mg) and DIPEA (0.05 mL) in DMF (2 mL) was added EDC (35 mg). The reaction solution was stirred at room temperature for 12 hours. The reaction was diluted with EtOAc (30 mL). The organic layer was washed with saturated sodium bicarbonate (10 mL), water (10 mL) and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified through chromatography (CH2Cl2:MeOH 10:1) to give N-(3-(azepan-1-yl)propyl)-1-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methyl)-N-methylpiperidine-4-carboxamide (42 mg, 82%). H1NMR (300 MHz, CDCl3), ppm: 7.97 (d, 2H), 7.48 (d, 2H), 3.80 (m, 1H), 3.63 (m, 2H), 3.45 (m, 2H), 3.31-3.14 (m, 7H), 2.75 (s, 3H), 2.44 (m, 4H), 2.01 (m, 2H), 1.85 (m, 10H), 1.30 (m, 2H), 1.26 (m, 2H). MS (ESI+) M/z: 487, 489 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@:10]2([CH2:18][C@H:17]2[C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[C:9]1=[O:35])C1C=CC=CC=1.CS([O:40][C@@H:41](C1C=C2C(C=NN2CC2C=CC(OC)=CC=2)=CC=1)COS(C)(=O)=O)(=O)=O.CN1C2C(=CC=CC=2)CC1=O>>[CH3:41][O:40][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:25]2[C:26]3[C:22](=[CH:21][CH:20]=[C:19]([C@H:17]4[C@@:10]5([C:11]6[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=6)[N:8]([CH3:1])[C:9]5=[O:35])[CH2:18]4)[CH:27]=3)[CH:23]=[N:24]2)=[CH:34][CH:33]=1
Reactant: O=C1N(Cc2ccccc2)c2ccccc2[C@]12C[C@H]2c1ccc2cnn(Cc3ccccc3)c2c1
Reactant: COc1ccc(Cn2ncc3ccc([C@@H](COS(C)(=O)=O)OS(C)(=O)=O)cc32)cc1
Agent: CN1C(=O)Cc2ccccc21
Product: COc1ccc(Cn2ncc3ccc([C@@H]4C[C@@]45C(=O)N(C)c4ccccc45)cc32)cc1
Yield: 80 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (S)-1-(1-(4-methoxybenzyl)-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (2.03 g, 4.47 mmol) and 1-methylindolin-2-one (658 mg, 4.47 mmol). Purification using Biotage Isolera (silica gel, 20-50% EtOAc in hexane) yielded the title compound as a yellowish crystalline solid (1.47 g, 80%); 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.13-7.06 (m, 3H), 6.97 (d, J=7.8 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.80 (d, J=8.3 Hz, 2H), 6.50 (t, J=7.6 Hz, 1H), 5.78 (d, J=7.6 Hz, 1H), 5.58-5.47 (m, 2H), 3.72 (s, 3H), 3.36-3.30 (m, 4H), 2.22-2.19 (m, 1H), 2.16-2.12 (m, 1H); MS ESI 410.2 [M+H]+, calcd for [C26H23N3O2+H]+ 410.19.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][NH:27]3)[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2].Br[CH2:31][C:32]1[O:33][C:34](=[O:38])[O:35][C:36]=1[CH3:37].C(=O)(O)[O-].[K+]>CN(C)C=O>[C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][C:32]3[O:33][C:34](=[O:38])[O:35][C:36]=3[CH3:37])[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:14][CH2:15]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2]
Reactant: Cc1oc(=O)oc1CBr
Reactant: N#Cc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1CN1CCC[C@H]2CN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3C#N)C[C@H]21

Procedure:
100 mg (0.25 mmol) of 8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 59 mg (0.30 mmol) of 4-bromomethyl-5-methyl-1,3-dioxol-2-one and 30 mg of potassium bicarbonate are heated at 140° C. in 2 ml of dimethylformamide for 30 minutes. The reaction solution is concentrated in vacuo, the residue is taken up in methylene chloride and the mixture is washed with water. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The resulting residue is stirred with water, filtered off with suction and dried.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Sn](CCCC)(CCCC)CCCC)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[O:40]([CH:47]1[CH2:52][CH2:51][C:50](OS(C(F)(F)F)(=O)=O)=[CH:49][CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:50]2[CH2:51][CH2:52][CH:47]([O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:48][CH:49]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:21][CH2:22][C@H:23]([OH:26])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](O)CC2)c(C(=O)OC)s1
Reactant: O=S(=O)(OC1=CCC(Oc2ccccc2)CC1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(C2=CCC(Oc3ccccc3)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1

Procedure:
To a stirred solution of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-tributylstannanyl-thiophene-2-carboxylic acid methyl ester (150 mg, 0.23 mmol) in toluene (5 mL) were added (PPh3)4Pd (26 mg), CuBr (2 mg, catalytic) and trifluoro-methanesulfonic acid 4-phenoxy-cyclohex-1-enyl ester (87 mg, 0.27 mmol) under nitrogen. The reaction mixture was stirred and heated to reflux during 5 h. The progress of the reaction was monitored by TLC. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by silica gel column chromatography using ethyl acetate and hexane (4:1) afforded 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4-phenoxy-cyclohex-1-enyl)-thiophene-2-carb-oxylic acid methyl ester (30 mg, 24%) as a syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](Cl)=[N:9][OH:10])=[N:6][CH:7]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([CH3:15])=[CH2:14].C(N(CC)CC)C.CCCCCC>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:14][C:13]([CH3:15])([C:12]([O:17][CH2:18][CH3:19])=[O:16])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: C=C(C)C(=O)OCC
Reactant: ON=C(Cl)c1ccc(Br)cn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1(C)CC(c2ccc(Br)cn2)=NO1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.3 %

Procedure:
To the solution of 5-bromo-N-hydroxy-pyridine-2-carboximidoyl chloride (0.6 g, 2.56 mmol) in EtOAc (15 mL) was added ethyl methacrylate (1.5 mL, 13.33 mmol) at 0° C. The mixture was stirred at the same temperature for 10 min followed by addition of triethyl amine (0.35 mL, 2.82 mmol) then stirred at 0° C. for 1 h. After completion (by TLC), the residue was poured into 100 mL of ice-cold water followed by extraction with EtOAc (3×100 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 5.0% EtOAc:hexane to obtain a white solid product (0.70 g, 88% yield). 1H NMR (DMSO-d6): δ 1.19 (t, J=7.20 Hz, 3H), 1.60 (s, 3H), 3.41 (m, 1H), 3.86 (m, 1H), 4.16 (q, J=7.20 Hz, 2H), 7.87 (d, J=8.4 Hz, 1H), 8.14 (d, J=2.4 Hz, 1H) and 8.79 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]3[CH:12]([CH3:16])[CH2:13][CH2:14][CH2:15][C:9]=3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1.Cl.[CH3:29][CH:30]([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:31](O)=[O:32].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:29][CH:30]([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:31]([O:1][C:2]1[C:11]2[C:10]3[CH:12]([CH3:16])[CH2:13][CH2:14][CH2:15][C:9]=3[C:8]([CH3:17])([CH3:18])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1)=[O:32]
Reactant: CC(CCN1CCOCC1)C(=O)O
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2C(C)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)C(C)CCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2C(C)CCC1

Procedure:
A mixture of 1.2 g. (3.24 mmole) of 1-hydroxy-3-(3-methyl-2-octyl)-7,8,9,10-tetrahydro-6,6,10-trimethyl-6H-dibenzo[b,d]pyran, 0.73 g. (3.24 mmole) of 2-methyl-4-morpholinobutyric acid hydrochloride, 0.71 g. (3.46 mmole) of dicyclohexylcarbodiimide and 50 ml. of methylene chloride was stirred at room temperature for 16 hrs. The reaction mixture was cooled and the byproduct of dicyclohexylurea was removed by filtration. The solvent was evaporated to give a foamy residue which was chromatographed using activated magnesium silicate and methanol/chloroform solvent mixtures. The fractions were monitored by thin layer chromatography and the desired material was obtained from the 2% methanol/chloroform fractions. The appropriate fractions were collected and evaporated to give 0.9 g. (51%) of light purple gum.
Reaction SMILES: Cl[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:22]([O:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)[CH3:23].C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(=O)NC4C=CC(C)=C(I)C=4)=CN=3)CC2)=CC=1)C>CCOC(C)=O>[CH2:22]([O:24][C:25](=[O:38])[C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:33][CH2:34][N:35]([C:2]3[CH:21]=[CH:20][C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:17]=[C:16]5[C:12]([CH:13]=[CH:14][N:15]5[CH2:18][CH3:19])=[CH:11][CH:10]=4)=[CH:4][N:3]=3)[CH2:36][CH2:37]2)=[CH:30][CH:31]=1)[CH3:23]
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc5ccn(CC)c5c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(1-Ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]piperazin-1-yl}-benzoic acid ethyl ester was prepared from 6-chloro-N-(1-ethyl-1H-indol-6-yl)-nicotinamide and 4-(piperazin-1-yl)-benzoic acid ethyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester above. The product was isolated after silica gel column chromatography with 20-50% EtOAc in hexanes gradient. HRMS m/z calcd for C29H31N5O3 [M+H]+: 498.2500. Found: 498.2501.
Reaction SMILES: [Cl-].[Cl-].[Ca+2].C(S)[C@@H](O)[C@H]([OH:9])CS.[Na+].[Cl-].C(O)C(N)(CO)CO.Cl.C([O:25][C:26](=[O:44])[C@H:27]([CH2:37][CH2:38][CH2:39][NH:40][C:41](=N)[NH2:42])[NH:28]C(=O)C1C=CC=CC=1)C>>[NH2:28][C@H:27]([C:26]([OH:25])=[O:44])[CH2:37][CH2:38][CH2:39][NH:40][C:41]([NH2:42])=[O:9]
Reactant: O[C@H](CS)[C@H](O)CS
Reactant: CCOC(=O)[C@H](CCCNC(=N)N)NC(=O)c1ccccc1
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Ca+2]
Product: NC(=O)NCCC[C@H](N)C(=O)O
Reaction time: 0.25 h

Procedure:
IC50 values were determined by pre-incubating various amounts of the potential inhibitor in Reaction Buffer (10 mM CaCl2, 2 mM DTT, 50 mM NaCl, 100 mM Tris HCl pH 7.6) and 0.2 μM PAD4 at 37° C. After 15 minutes, Benzoyl Arginine Ethyl Ester (BAEE; 1 mM final; 0.74×Km) was added and the reaction was allowed to proceed for 15 minutes (60 μL total volume). Reactions were quenched by flash freezing in liquid N2. The amount of Cit produced was then quantified according to methods known in the art. IC50 values were determined by fitting the data to equation 1, FracionalActivity=1/(1+[I]/IC50)   (1) using GraFit version 5.0.11. Inhibition Studies.