Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:25])[C:26]1[CH:31]=[CH:30][C:29]([C:13]2[CH:12]=[N:11][C:7]3[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]4[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:2]=4[F:1])[C:6]=3[CH:14]=2)=[CH:28][CH:27]=1)[CH3:22]
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1
Yield: 63 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (500 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as an off-white solid (63% yield). M.p. 173-174° C., LCMS: m/z=410.30 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.39 (t, J=7.1 Hz, 3H), 3.45 (t, J=5.0 Hz, 2H), 3.61-3.66 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 4.49 (s, 2H), 5.32 (bs, 1H), 6.78 (d, J=1.5 Hz, 1H), 6.89-6.96 (m, 1H), 6.99-7.08 (m, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.76 (d, J=1.8 Hz, 2H), 8.02 (d, J=8.6 Hz, 2H).
Reaction SMILES: Br.CNC(O[N:7]1[C:11]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:10]=2[N:9]=[C:8]1[C:18]([F:21])([F:20])[F:19])=O>CO>[Cl:17][C:13]1[C:14]([Cl:16])=[CH:15][C:10]2[N:9]=[C:8]([C:18]([F:21])([F:19])[F:20])[NH:7][C:11]=2[CH:12]=1
Reactant: CNC(=O)On1c(C(F)(F)F)nc2cc(Cl)c(Cl)cc21
Agent: Br
Solvent: CO
Product: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2[nH]1

Procedure:
HBr was passed into a cooled (0° -5° C.) solution of 1.05 grams of 1-(methylcarbamoyloxy)-5,6-dichloro-2 -(trifluoromethyl) benzimidazole in 40 milliliters of methanol. The reaction mixture was permitted to stand for twenty minutes, then evaporated to obtain as a residue 5,6-dichloro-2-(trifluoromethyl) benzimidazole. After recrystallization from chloroform, it melted at 233° -5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH3:13])[NH:8][C:7](=[O:14])[C:6]=2[CH:15]=1>[Pt].C(O)C>[NH2:16][C:4]1[C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH3:13])[NH:8][C:7](=[O:14])[C:6]=2[CH:15]=[C:2]([Cl:1])[CH:3]=1
Reactant: C[C@@H]1NC(=O)c2cc(Cl)cc([N+](=O)[O-])c2NC1=O
Agent: [Pt]
Solvent: CCO
Product: C[C@@H]1NC(=O)c2cc(Cl)cc(N)c2NC1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
A mixture of 298.42 parts of (S)-7-chloro-3,4-dihydro-3-methyl-9-nitro-1H-1,4-benzodiazepine-2,5-dione (prepared as interm. 44) and 3324 parts of ethanol was hydrogenated at 50° C. and normal pressure with 21.04 parts of platinum-on-charcoal catalyst 5%. At the end of the hydrogenation, the temperature was raised to 70° C. The reaction mixture was filtered while hot and the catalyst was washed with boiling ethanol. The filtrate was stirred overnight in an ice-bath and was then concentrated. The residue was cooled on ice. The precipitate was filtered off, washed with methylbenzene and dried in vacuo at 50° C., yielding 187.7 parts (74.6%) of (S)-9-amino-7-chloro-3,4-dihydro-3-methyl-1H-1,4-benzodiazepine-2,5-dione (interm. 77).
Reaction SMILES: [C:1]([O:5][C:6](=[O:56])[N:7]([CH2:22][CH2:23][CH2:24][N:25]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:26][CH2:27][CH2:28][CH2:29][N:30]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][CH2:9][CH2:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[C:1]([O:5][C:6](=[O:56])[N:7]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:22][CH2:23][CH2:24][N:25]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:26][CH2:27][CH2:28][CH2:29][N:30]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCN(CCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCN(CCCCN(CCCN(CCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 88 %

Procedure:
The compound from Stage 2 above (1.49 g, 1.88 mmol, 1 eq) is refluxed in 50 mL of EtOH in the presence of hydrazine hydrate (0.5 mL, 16.1 mmol, 8.5 eq) for 6 hrs. The cooled medium is filtered, washed with EtOH, and evaporated. The residue is flash chromatographed on SiO2 (gradient elution pure CH2Cl2 up to 80:18:2 CH2Cl2:MeOH:NH4OH). After evaporation of the pure fractions, 1.09 g of a colorless oil is obtained (yield 88%). TLC SiO2 (90:9:1 CH2Cl2:MeOH:NH4OH) Rf=0.34. MS: m/z=660 (M-H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH3:12][CH:13](O)[CH2:14][CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:13]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[Cl:11])([CH2:14][CH3:15])[CH3:12]
Reactant: CCC(C)O
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
2,6-dichloropurine (5.3 mmol), 2-Butanol (9.01 mmol), triphenylphosphine (7.95 mmol) in 40 ml anhydrous tetrahydrofuran, to which was added drop-wise diisoproplyazidodicarboxylate (7.95 mmol) at room temperature over a period of 30 minutes. The reaction mixture was stirred at room temperature for 24 hrs. The reaction is monitored by TLC or LC/MS. The reaction mixture was poured in to a beaker containing ice-cold water. Extraction of the aqueous layer, using 3×100 ml portions of ethyl acetate, afforded the crude product. This was purified on the silica gel column (10-80% ethyl acetate in petroleum ether, gradient elution), to give the desired compound in a yield of 50%.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[CH3:9].[C:10]([N:13]1[CH2:17][C:16](=O)[N:15]=[CH:14]1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[CH2:17][CH2:16][N:15]=[C:14]1[NH:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[CH3:9])(=[O:12])[CH3:11]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: Cc1cnn(C)c1N
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1c(C)cnn1C

Procedure:
5-amino-1,4-dimethyl pyrazole hydrochloride (Z. Chem. 388, 1970) (5.72 g.) and 1-acetyl-2-imidazolinone (5.54 g.) were reacted as described in Example I to give 4.723 g. product mp 199°-202° (crystallized from CH3CN)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:31][CH2:30][CH:27]2[CH2:28][CH2:29][CH:24]([N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[C:10]([C:11]4[CH:16]=[CH:15][C:14]([O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:13][CH:12]=4)=[CH:9]3)[CH2:25][CH2:26]2)[CH2:36][CH2:35]1
Reactant: CN1CCNCC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(CCC2CCC(n3cc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
A mixture of 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}acetaldehyde (0.025 g, 0.059 mmol), N-methylpiperazine (0.0083 g, 0.083 mmol) and acetic acid (0.0035 g, 0.059 mmol) in 1,2-dichloroethane (0.4 mL) was stirred for 10 min at ambient temperature and sodium triacetoxyborohydride (0.019 g, 0.089 mmol) was added. The mixture was stirred at ambient temperature under an atmosphere of nitrogen for 6 hours and the solvent removed under reduced to yield a yellow oil. The compound was purified by preparative RP-HPLC to yield 7-{4-[2-(4-methylpiperazino)ethyl]cyclohexyl}-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.016 g, 0.031 mmol) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.27(s, 1H), 7.45(d, 2H), 7.37(t, 2H), 7.16(t, 1H), 7.09(m, 5H), 5.57(br, 2H), 4.73(m, 1H), 2.33(s, 3H), 2.49-1.65(m, 19H); RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 8.15 min. MS: MH+ 511.
Reaction SMILES: O.[OH-].[Na+].[CH3:4][C:5]1([CH3:20])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[CH:16]C=O)[CH:13]=2)[S:8][CH2:7][CH2:6]1>O1CCOCC1>[CH3:4][C:5]1([CH3:20])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[CH:16])[CH:13]=2)[S:8][CH2:7][CH2:6]1
Reactant: CC1(C)CCSc2ccc(C(Cl)=CC=O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C#Cc1ccc2c(c1)C(C)(C)CCS2
Yield: 87.68 %

Procedure:
In a 250 ml 4-necked round bottom flask fitted with a mechanical stirrer and reflux condenser, water (41.3 ml) and sodium hydroxide (5.22 g, 0.1305M) are added and heated to a temperature in the range of from about 80° C. to about 90° C. The reaction mixture is stirred, and a solution of 3-[4,4-dimethylthiochroman-6-yl]-3-chloro-2-propene-1-al (3.0 gm, 0.0113 M) is added dropwise in 1,4-dioxane (52.2 ml) under vigorous stirring. The reaction mixture is maintained at a temperature in the range of from about 80° C. to about 90° C. for about 2 hours. After completion of the reaction as determined by TLC, the solvents are distilled off and the product is extracted with ether (15 ml×3). The ether layer is washed with brine (15 ml×3). The organic layer is dried over sodium sulfate, and the solvent is distilled off to get an oily residue. The resulting crude oil is distilled under high vacuum and the vapors are collected at a temperature of about 126° C./0.2 mm as the main product. The main fraction appears as red viscous oil, which upon standing crystallized. Net wt of about 2.00 g, yield of about 87.68%; m.p. in the range of from about 69° C. to about 72° C., purity of about 98% (HPLC). The IR (neat) shows the following absorptions: 3200 cm−1 (C—H-str), 2950 cm−1 (—C═C—H str), 2100 cm−1 (—C═C—). The 1H-NMR (CDCl3), TMS as internal standard shows the following signals δ 1.35 (6H,s), 1.92-1.98 (2H,m), 3.02-3.08 (3H,m), 7.13 (1H,d 8.6 Hz), 7.58 (1H,dd,J 8.6 Hz,2 Hz), 7.99 (1H,d,J 2 Hz). The CI/MS shows m/z 202 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:36])=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[F:36][C:22]([CH2:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1)=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH2:26][CH2:25]1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Reactant: CC(=O)OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc3c(c2)OCO3)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 25.8 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.313 g), tetrahydrofuran. (2 ml) and magnesium (24 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(3,4-methylenedioxyphenyl) cyclopropane (Example 22) (0.138 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) to afford 1-(2-fluoro-3-(4-fluoro-3-phenoxyphenyl)prop-1-enyl)-1-(3,4-methylenedioxyphenyl)cyclopropane (52 mg, 26%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][OH:21].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CCO.ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC[C@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@@H]2CO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
A solution of 5.98 g (30.0 mmol) of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 3.55 ml=3.64 g (36.0 mmol) of (R)-(−)-pyrrolidin-2-yl-methanol in 60.0 ml of EtOH was treated with 60.0 ml of 1,2-dichloroethane, followed by 4.50 ml (36 mmol) of borane-pyridine complex (8 molar). Then, 4.46 ml=4.68 g (78.0 mmol) of acetic acid was added to this solution. After stirring at RT for 16 hours, the reaction mixture was poured into crashed ice; then, the pH was adjusted to 9-10 with sodium carbonate solution and the mixture was extracted twice with EtOAc; the combined organic phases were washed with water, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 8:2) to give 7.69 g (90%) of the title compound as light yellow oil. MS: 285.1 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[CH:21]=[CH:20][S:19][C:18]=3[C:22]([O:24]C)=[O:23])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]3[CH:21]=[CH:20][S:19][C:18]=3[C:22]([OH:24])=[O:23])(=[O:15])=[O:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Yield: 73.1 %

Procedure:
To a solution of 128 (0.55 g; 1.46 mmol) in tetrahydrofuran (20 mL) and methanol (7 mL) was added aqueous sodium hydroxide (20 mL; 2N) and then heated at 80° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and then extracted with diethyl ether (20 mL). The aqueous layer was separated and acidified with aqueous hydrochloric acid (15 mL; 2N) then extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title product as a gray solid (0.39 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O.[CH2:37]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH2:41][CH2:40][NH:39][CH2:38]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:39]2[CH2:38][CH2:37][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[CH2:41][CH2:40]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CN2CC(CN3CCc4ccccc4CC3)C(c3ccccc3)C2)cc1
Yield: 49.1 %

Procedure:
The title compound was prepared from 20 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 28 mg of 2, 3, 4, 5-tetrahydro-1H-benzo[d]-azepine-picrate salt, 0.013 mL of DIEA and 24 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 14.5 mg of the title compound. RF : 0.53 (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ2.42-3.02 (m, 16H), 3.67 (ABq, J=13 Hz, 2H), 7.00-7.38 (m, 14H). Mass Spectrum (ESI): 397.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([O:14]C)[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[CH3:1][O:2][C:3]([C:5]1([CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4]
Reactant: COC(=O)C1(C)Cc2cc(OC)ccc2O1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C1(C)Cc2cc(O)ccc2O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-methoxy-2-methyl-2,3-dihydro-benzofuran-2-carboxylic acid methyl ester (0.32 g, 1.4 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C. A solution of boron tribromide in dichloromethane (1.0 M, 3.5 mL, 3.5 mmol) was added. After 1 hr at 0° C., the reaction was diluted with dichloromethane and washed with brine. The organic phase was dried and concentrated. The residue was dissolved in 7:1 benzene:methanol (10 mL) and treated with TMSCHN2 (1.0 M in hexane) until gas evolution ceased. Removal of the solvent gave a residue which was chromatographed on silica gel eluting with 7:3 hexane:ethyl acetate to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[N:3]=1.[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)(=[O:19])[CH3:18].FC1C=CC(C2C=C3C(=CC=2)N=CN=C3O)=CC=1>>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]3[CH:25]=[CH:26][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[CH:22][CH:23]=3)[CH:8]=2)[N:3]=1
Reactant: CC(C)Oc1nc(N)nc2ccc(Br)cc12
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: Oc1ncnc2ccc(-c3ccc(F)cc3)cc12
Product: CC(=O)Nc1ccc(-c2ccc3nc(N)nc(OC(C)C)c3c2)cc1
Yield: 84 %

Procedure:
This compound, synthesized from 2-amino-6-bromo-4-isopropoxy-quinazoline and 4-acetamido-phenylboronic acid in 84% yield as a white solid using the procedure described for the synthesis of 6-(4-fluorophenyl)-4-hydroxy-quinazoline, was characterized by its mass spectrum as follows: MS (m/z): 298 ([M+H]+, 100).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2=[C:7]([C:11]([OH:13])=O)[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.CCOC(OC(OCC)=O)=O.[F:25][C:26]([F:42])([F:41])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[C:29]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:28]=1>C1COCC1>[F:41][C:26]([F:25])([F:42])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:4]3[O:3][C:2](=[O:1])[NH:6][C:5]=23)=[O:13])=[C:29]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:28]=1
Reactant: O=C(O)c1cccc2oc(=O)[nH]c12
Reactant: NCc1ccc(C(F)(F)F)cc1N1CCCCC1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C(F)(F)F)cc1N1CCCCC1)c1cccc2oc(=O)[nH]c12
Temperature: 80 °C
Yield: 19.2 %

Procedure:
2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxylic acid 21 (560 mg, 3.1 mmol) was dissolved in 20 ml of THF and at 0° C. DEPC (0.55 ml, 1.2 equiv) and amine 2c (964 mg, 1.2 equiv.) were added to the solution. The mixture was warmed at 80° C. overnight, then evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column using AcOEt 4/petroleum ether 6 as eluant gave 250 mg of a pale yellow solid. Yield=19% 1HNMR (DMSO, 200 MHz) δ 4.58 (2H, d, J=5.8 Hz), 7.14 (1H, t, J=8 Hz), 7.41 (4H, m), 7.68 (1H, dd, J=8 Hz, J′=0.8 Hz), 9.20 (1H, bt), 11.59 (1H, bs); [M+1] 420.2 (C21H20F3N3O3 requires 419.4).
Reaction SMILES: C1N(CC[OH:9])CCN(CCS(O)(=O)=O)C1.[Na+].[Cl-].[Cl-].[Cl-].[Ca+2].C(C(O)=O)CP(CCC(O)=O)CCC(O)=O.CC[O:39][C:40]([C@@H:42]([NH:50]C(C1C=CC=CC=1)=O)[CH2:43][CH2:44][CH2:45][N:46]=[C:47](N)[NH2:48])=[O:41]>>[NH2:50][C@H:42]([C:40]([OH:39])=[O:41])[CH2:43][CH2:44][CH2:45][NH:46][C:47]([NH2:48])=[O:9]
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Reactant: CCOC(=O)[C@H](CCCN=C(N)N)NC(=O)c1ccccc1
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Product: NC(=O)NCCC[C@H](N)C(=O)O
Reaction time: 0.25 h

Procedure:
IC50's for compounds 2 to 11 were determined analogously to the methods used to determine the IC50 for F3-amidine, 1. Briefly, inhibitors were pre-incubated with PAD4 (0.2 μM) for 15 min at 37° C. in a buffer containing 100 mM HEPES, pH 7.6, 50 mM NaCl, 10 mM CaCl2, and 0.25 mM TCEP. BAEE was then added to a final concentration of 10 mM to initiate the reaction. Reactions were then quenched after a further 15 min by flash freezing. The amount of Cit produced in the reaction was quantified using our assay for Cit production. IC50 values were determined by fitting the concentration-response data to Equation 3, Fractional activity of PAD4=1/(1+([I]/IC50))  (Eq. 3), using the Grafit™ version 5.0.11 software package. The concentration of an inhibitor that corresponds to the midpoint (fractional activity=0.5) is referred to as the IC50. The calcium dependence of the IC50 was determined identically, except that CaCl2 was omitted during the initial pre-incubation step and then added (10 mM final) with BAEE to initiate the reaction.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1O.N>>[O:20]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:18]1[C:16]1[CH:15]=[CH:14][C:6]2[N:7]([CH:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[C:3]([CH3:2])=[N:4][C:5]=2[CH:17]=1
Reactant: Nc1ccccc1O
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Agent: Cl
Agent: N
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 160 °C
Reaction time: 17 h
Yield: 0.2 %

Procedure:
An eggplant flask (100 mL) was charged with 2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (0.64 g, 2.46 mmol), 2-aminophenol (0.32 g, 2.95 mmol) and polyphosphoric acid (approx. 18 g), and this was heated to 160° C. and stirred for 17 hours. After being allowed to cool, ice was added and concentrated aqueous ammonia (28%) was added to the liquid to give approx. pH 9. This was extracted with chloroform (approx. 50 mL, 3 times) and dried over anhydrous magnesium sulfate. The crude product (0.08 g) obtained after the solvent was distilled off was purified by PTLC (CHCl3) with double development to yield the title compound (0.002 g, 0.2% yield) as a yellowish-brown semisolid.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[OH:15])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>>[NH2:26]/[C:4](/[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Br:1])=[C:6]1\[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[S:10]\1
Reactant: O=C(c1ccccc1Br)c1sc2ccccc2c1O
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1Br
Yield: 42 %

Procedure:
Prepared as in Example 1 from 2-(2-bromobenzoyl)-benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated aqueous ammonia with a yield of 42% of theory. M.p. 143°-144° C. (petroleum ether/ethyl acetate 1:1).
Reaction SMILES: C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O.C([O:23][C:24]1[CH:51]=[C:50]([C:52]2[CH:56]=[CH:55][O:54][CH:53]=2)[CH:49]=[CH:48][C:25]=1[C:26]([NH:28][C:29]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:38][C:30]=1[C:31]([O:33]C(C)(C)C)=[O:32])=[O:27])C1C=CC=CC=1>>[O:54]1[CH:55]=[CH:56][C:52]([C:50]2[CH:49]=[CH:48][C:25]([C:26]([NH:28][C:29]3[CH:41]=[C:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH:39]=[CH:38][C:30]=3[C:31]([OH:33])=[O:32])=[O:27])=[C:24]([OH:23])[CH:51]=2)=[CH:53]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccoc2)cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(-c2ccoc2)cc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.8 %

Procedure:
Thioanisole (0.82 mL) and trifluoroacetic acid (2.6 mL) were added to the obtained tert-butyl 2-(2-(benzyloxy)-4-(furan-3-yl)benzamido)-4-phenylbenzoate (0.076 g), followed by stirring at room temperature for 3 hours and 20 minutes. The solvent was evaporated under reduced pressure, and a 2 mol/L aqueous solution of sodium hydroxide and toluene were added to the residue. The aqueous layer was separated and adjusted to a pH of 4.5 with 6 mol/L hydrochloric acid. The solid substance was collected by filtration to obtain 0.016 g of 2-(4-(furan-3-yl)-2-hydroxybenzamido)-4-phenylbenzoic acid as a brown solid.