Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[N:4][C:3]1=O.P(Cl)(Cl)([Cl:23])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:23][C:3]1[N:2]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(-c2ccccc2)c(-c2ccccc2)cnc1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
A solution of 1-methyl-5,6-diphenyl-1H-pyrimidin-2-one (106, 314 mg, 1.20 mmol), phosphorus oxychloride (0.6 ml, 6.4 mmol) and phosphorus pentachloride (55 mg, 0.26 mmol) was heated at 120° C. for 3 hours. The excess amount of phosphorus oxychloride was removed under reduced pressure and cold water was added to the residue. The resulting precipitate was extracted with CH2Cl2. The organic layer was washed with brine, and dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (20% ethyl acetate in hexane) to produce the title compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34](=O)[C:35]1[C:36]([O:41][CH3:42])=[CH:37][CH:38]=[CH:39][CH:40]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][CH3:42])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: COc1ccccc1C=O
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CN1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-(4-Methanesulfonyl-phenoxy)-1-[1-(2-methoxy-benzyl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 25) with o-anisaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.89-1.98 (m, 2H), 2.19-2.26 (m, 4H), 2.95-3.03 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.55 (s, 2H), 3.79 (s, 3H), 4.74-4.80 (m, 1H), 6.93-7.00 (m, 2H), 7.22-7.26 (m, 1H), 7.36-7.38 (m, 2H), 7.62-7.64 (m, 2H), 8.04-8.07 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=494.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5]1.N1C(C)=CC=CC=1C.[CH:36]([S:39](Cl)(=[O:41])=[O:40])([CH3:38])[CH3:37].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:37][CH:36]([S:39]([NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=2)[CH2:8][CH2:9]1)(=[O:41])=[O:40])[CH3:38]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (70 mg, 0.18 mmol) and 2,6-lutidine (123 μL, 0.882 mmol) in CH2Cl2 (2 mL) was treated with isopropylsulfonyl chloride (49.9 mg, 0.35 mmol). The reaction was stirred overnight and then transferred to a test tube containing saturated aqueous NaHCO3 (4 mL) and EtOAc (4 mL). The biphasic mixture was mixed vigourously and allowed to separate for 15 min. After separation, the mixture was cooled to −20° C. until the aqueous layer was frozen. The organic layer was then poured off and the solvent was removed under reduced pressure at 50° C. The resulting residue was purified by HiTOPs
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](O)=[O:22])[N:4]=1)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:38]([O:42][C:43](=[O:49])[C@@H:44]([CH3:48])[C@H:45]([NH2:47])[CH3:46])([CH3:41])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[C:38]([O:42][C:43](=[O:49])[C@@H:44]([CH3:48])[C@H:45]([NH:47][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=2)=[O:22])[CH3:46])([CH3:39])([CH3:41])[CH3:40]
Reactant: C[C@H](C(=O)OC(C)(C)C)[C@@H](C)N
Reactant: N#Cc1nc(C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](C(=O)OC(C)(C)C)[C@@H](C)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A flask was charged with 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid (40 mg, 0.13 mmol), HOBt (18 mg, 0.13 mmol) and CH2Cl2 (2 mL). EDC (35 mg, 0.18 mmol) was added, and the mixture was stirred for 10 min. (2S,3R)-3-Amino-2-methyl-butyric acid tert-butyl ester (22 mg, 0.13 mmol) and Hunig's base (0.050 mL, 0.26 mmol) were then added, and the resulting mixture was stirred for 16 h at r.t. Hydrochloric acid (0.1 M) was added to acidify the mixture, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-10% EtOAc/hexanes+2% AcOH) to give 32 mg of the title compound as a white solid. MS: (−) m/z 460.31 (M−1).
Reaction SMILES: [NH2:1][C@H:2]([C:14]([NH:16][C@H:17]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(C(O)=O)(F)F.[NH:38](C(OC(C)(C)C)=O)[CH2:39][C:40](ON1C(=O)CCC1=O)=[O:41].CN1CCOCC1>C(OCC)(=O)C>[NH2:38][CH2:39][C:40]([NH:1][C@H:2]([C:14]([NH:16][C@H:17]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:41]
Reactant: CC(C)[C@H](NC(=O)[C@@H](N)CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CN)C(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A solution of 4.2 g. of H-Asp(OBzl)-Val-OBzl.TFA in 50 ml of ethyl acetate is treated in succession with 2.72 g of Boc-Gly-OSu and 0.88 ml of N-methylmorpholine and then stirred at 20° C. for 72 hours. The reaction mixture is partitioned between ethyl acetate and water and the organic phase is washed with 5% KHSO4 /10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution. After drying the solution is concentrated. The residue is dissolved in 30 ml of trifluoroacetic acid held at 20° C. for 20 minutes and then concentrated. After crystallization from ethyl acetate/hexane there are obtained 3.5 g of H-Gly-Asp(OBzl)-Val-OBzl, TFA (1:1), m.p. 150°-151° C.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[NH2:2].[CH:5]([N:7]1[CH2:12][CH2:11][CH2:10]N[C:8]1=[O:13])=[O:6].C(Cl)(Cl)=O>>[Cl:4][C:1]([N:2]1[CH2:10][CH2:11][CH2:12][N:7]([CH:8]=[O:13])[C:5]1=[O:6])=[O:3]
Reactant: O=CN1CCCNC1=O
Reactant: NC(=O)Cl
Agent: O=C(Cl)Cl
Product: O=CN1CCCN(C(=O)Cl)C1=O

Procedure:
This carbamic acid chloride was produced as described in Example 27 B from 5 parts by weight of 1-formyl-2-oxo-1,3-diaza-cyclohexane and 6 parts by weight of phosgene. The substance, an oil, was used without further purification for the production of the penicillin of Example 35 A. IR-bands at 1790, 1685, 1300 and 1165 cm-1.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[C:13]1([NH:19][C:20]([O:12][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4][N:2]([CH3:1])[CH3:3])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=Nc1ccncc1O
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CN(C)C=Nc1ccncc1OC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a warm solution of 4-[[(dimethylamino)methylene]amino]-3-pyridinol (3.0 g) in dry tetrahydrofuran (60 mL) was added phenyl isocyanate (2.05 mL). The reaction mixture was stirred at room temperature for 1.5 hours and filtered. The solid was washed with dry diethyl ether, air dried, and dried under high vacuum and refluxing ethanol for 4 hours to yield 4.19 g of solid, m.p. 151° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.Cl.[F:23][C:24]1([F:32])[CH2:29][CH2:28][CH2:27][C@@H:26]([NH2:30])[C@H:25]1[NH2:31].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:31][C@H:25]1[C:24]([F:32])([F:23])[CH2:29][CH2:28][CH2:27][C@H:26]1[NH:30][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(C)c1
Reactant: N[C@@H]1CCCC(F)(F)[C@@H]1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a screw-cap vial was added methyl 6-chloro-4-cyano-2-(m-tolylamino)nicotinate (200 mg, 0.663 mmol), cis-3,3-difluorocyclohexane-1,2-diamine hydrochloride (148 mg, 0.795 mmol), and DIPEA (347 μL, 1.989 mmol) in DMF (3.9 mL). The resulting brownish-yellow mixture was stirred at RT for 2 h and then at 60° C. for 12 h. The reaction mixture was cooled to RT, diluted with EtOAc (30 mL) and washed with water (2×10 mL) and brine (20 mL). The organic layer was collected, dried over Na2SO4, and concentrated to give a thick brown oil, which included the title compound and isomers (328 mg, 119%). The crude product was used without further purification. [M+H] calc'd for C21H23F2N5O2, 416. found, 416.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:15]=[C:16]([C:20]([NH:22][CH2:23][C:24]([NH:26][CH:27]([C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)[CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[O:21])[CH:17]=[CH:18][CH:19]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[NH:13][C:14]1[CH:15]=[C:16]([C:20]([NH:22][CH2:23][C:24]([NH:26][CH:27]([C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCN2)c1)c1cc(Cl)cc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCN2)c1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
To the product from Example 190 (200 mg, 0.00032 mole) in H2O (10 mL) and CH3CN (10 mL) was added LiOH (54 mg, 0.0013 mole). The reaction mixture was stirred at room temperature for 1.5 hours. The pH was lowered to ~2.5 with TFA and the product was isolated by RPHPLC to yield the title product (190 mg after lyophilization) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH2:33][CH:32]([CH2:34][OH:35])[O:31][N:30]=2)=[N:27][CH:28]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[C:23]1[CH:28]=[N:27][C:26]([C:29]2[CH2:33][CH:32]([CH2:34][OH:35])[O:31][N:30]=2)=[CH:25][CH:24]=1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)nc1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NOC(CO)C3)nc2)c(F)c1
Temperature: 90 °C
Yield: 44.1 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (342 mg, 0.88 mM), {3-[5-(trimethylstannyl)pyridin-2-yl)-4,5-dihydroisoxazol-5-yl}methanol (300 mg, 0.88 mM), tris(dibenzylideneacetone) dipalladium (0)-chloroform adduct (91 mg, 0.088 mM, 0.1 equiv.) and tri-2-furylphosphine (41 mg, 0.176 mM, 0.2 equiv) were placed in a flask. The contents of the flask were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the mixture was heated at 90° C. for 5 hours and then cooled to room temperature. Solvent was evaporated under reduced pressure and the residue was purified by chromatography (silica gel; elution with 5% methanol in dichloromethane) to give the title compound (170 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=4[NH:14][C:13]3=[O:22])[CH:10]=1)[N:7]([CH3:23])[C:6]([CH3:24])=[C:5]2[CH3:25].[C:26]([O:32][CH3:33])(=[O:31])[CH:27]=[CH:28][CH2:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:33][O:32][C:26](=[O:31])[CH2:27][CH:28]([N:14]1[C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[N:7]([CH3:23])[C:6]([CH3:24])=[C:5]3[CH3:25])[C:13]1=[O:22])[CH2:29][CH3:30]
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2Cc1cc(Cl)cc2c(C)c(C)n(C)c12
Reactant: CCC=CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCC(CC(=O)OC)n1c(=O)n(Cc2cc(Cl)cc3c(C)c(C)n(C)c23)c2ccc(C)cc21
Temperature: 120 °C
Yield: 77.7 %

Procedure:
To a solution of 1-(5-Chloro-1,2,3-trimethyl-1H-indol-7-ylmethyl)-5-methyl-1,3-dihydro-benzimidazol-2-one (40 mg, 0.11 mmol) in DMA (2 mL) were added Methyl 2-pentenoate (26 mg, 0.23 mmol) and K2CO3 (31 mg, 0.23 mmol). The reaction mixture was heated to 120° C. for 20 min in a microwave. When the reaction was completed, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 4:1 Hexane:ethyl acetate to afford 40 mg of the desired product. LCMS (ESMS): m/z 468.36 (M+H+).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1.[CH3:17][N:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[C:21]2[CH:33]=[CH:34][N:35]([S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:20]=2[C:19]1=[O:46]>>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:22]2[C:21]3[CH:33]=[CH:34][N:35]([S:36]([C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=4)(=[O:38])=[O:37])[C:20]=3[C:19](=[O:46])[N:18]([CH3:17])[CH:23]=2)=[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(Br)c(OCC2CC2)c1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c([N+](=O)[O-])c4OCC4CC4)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 4-bromo-3-(cyclopropylmethoxy)-2-nitroaniline and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C25H25N4O6S (M+H)+: m/z=509.1. found: 509.1.
Reaction SMILES: C(OC1C=CN(C2C=CC(O)=CC=2)C(=O)C=1)C1C=CC=CC=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[C:32](=[O:43])[CH:31]=2)=[CH:26][CH:25]=1.[F:46][CH2:47][C@@H:48]1[CH2:52][CH2:51][CH2:50][N:49]1[CH2:53][CH2:54]O>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:54][CH2:53][N:49]4[CH2:50][CH2:51][CH2:52][C@H:48]4[CH2:47][F:46])=[CH:38][CH:37]=3)[C:32](=[O:43])[CH:31]=2)=[CH:44][CH:45]=1
Reactant: OCCN1CCC[C@H]1CF
Reactant: O=c1cc(OCc2ccc(F)cc2)ccn1-c1ccc(O)cc1
Agent: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Product: O=c1cc(OCc2ccc(F)cc2)ccn1-c1ccc(OCCN2CCC[C@H]2CF)cc1

Procedure:
Step (3) of Example 12 was repeated except that 4-benzyloxy-1-(4-hydroxyphenyl)-1H-pyridin-2-one and 2-(1-pyrrolidine)ethanol were replaced with 4-(4-fluorobenzyloxy)-1-(4-hydroxyphenyl)-1H-pyridin-2-one (Step (2) of Example 28) and 2-[(S)-2-fluoromethyl-1-pyrrolidinyl]ethanol, respectively, to provide the title compound.
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:20].[Na+].I>C(C(C)=O)C>[CH2:1]([C:8]1[C:9]([I:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc(Cc3ccccc3)c(Cl)nc2c1
Reactant: [I-]
Agent: I
Agent: [Na+]
Solvent: CCC(C)=O
Product: Clc1ccc2cc(Cc3ccccc3)c(I)nc2c1
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 3-benzyl-2,7-dichloroquinoline (3.0 g, 10.4 mmol) and sodium iodide (15.6 g, 104 mmol) in 30 mL of methyl ethyl ketone was heated to 80° C. To this was added hydroiodic acid (1.13 ml, 13.2 mmol). The reaction mixture was heated at 80° C. for 1.5 hours and then cooled to ambient temperature. The reaction was quenched with H2O. Excess ethyl acetate was added to the reaction mixture and the organic layer was washed with saturated NaHCO3, saturated Na2S2O3, brine, dried over MgSO4, filtered and the solvent was removed in vacuo to yield 3.9 g (10.3 mmol, 99%) of 3-benzyl-7-chloro-2 iodo-quinoline 23 as a tan solid.
Reaction SMILES: [Na].[F:2][C:3]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:4]=1[NH:5][C:6](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[SH:7].[C:25]([O:28][CH2:29][C:30]([CH2:32]Cl)=[O:31])(=[O:27])[CH3:26]>CN(C)C=O>[F:2][C:3]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:4]=1[NH:5][C:6](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[S:7][CH2:32][C:30](=[O:31])[CH2:29][O:28][C:25](=[O:27])[CH3:26]
Reactant: CCOC(=O)C(C(=O)OCC)=C(S)Nc1ccc(F)c(F)c1F
Reactant: CC(=O)OCC(=O)CCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)=C(Nc1ccc(F)c(F)c1F)SCC(=O)COC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Diethyl [(2,3,4-trifluoroanilino)(mercapto)methylene]malonate sodium salt (5.3 g) was dissolved in N,N-dimethylformamide (70 ml) and thereo 1-acetoxy-3-chloroacetone (2.2 g) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered to remove insoluble materials. After the filtrate was evaporated to dryness under reduced pressure, water was added to the residue and the mixture was extracted with chloroform. The extract was washed with a NaCl solution and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to give the title compound (6.0 g) as pale yellow oil.
Reaction SMILES: O[C:2]1[C:6](=[O:7])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]=1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl.[NH2:23][OH:24].O>N1C=CC=CC=1>[OH:24][N:23]=[C:2]1[C:6](=[O:7])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH:3]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: NO
Reactant: CC(C)(C)OC(=O)C1=C(O)C(=O)N(Cc2ccccc2)C1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C1CN(Cc2ccccc2)C(=O)C1=NO
Reaction time: 96 h
Yield: 83.7 %

Procedure:
To a solution of the title compound of Example I (8.07 g, 27.9 mmol) in 150 ml of pyridine was added hydroxylamine hydrochloride (9.69 g, 139 mmol) and resulting solution was stirred for 4 d. Addition of H2O resulted in the formation of precipitate which was filtered to give the title compound (7.11 g, 84%) as a colorless solid. Calculated for C16H20N2O4 1/2H2O: C, 61.35; H, 6.76; N, 8.94. Found C, 61.35; H, 6.57, N, 9.34.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27].N1C=CC=CC=1>CN(C=O)C>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1)=[O:27]
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1nc(NC(=O)CCl)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine (0.33 g, 1.0 mmol,) in dry DMF (3 mL) was cooled on an ice-water bath. Chloroacetyl chloride (0.22 g, 2.0 mmol) and pyridine (80 μL) were added. After stirring at room temperature for 18 h, the reaction mixture was concentrated, poured into ice water and extracted with CH2Cl2. The organic phases were combined, washed with brine, dried on MgSO4 and evaporated to dryness. The resulting greenish residue was purified by SiO2 chromatography (1:1 EtOAc/PE) to afford the title compound as a gray solid. Anal. RP-HPLC: tR=20.6 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>97%). 1H-NMR (DMSO-d6) δ: 2.45 (s, 3H, CH3), 4.12 (s, 2H, CH2), 7.03 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.42 (m, 1H, Ph-H), 7.63 (m, 1H, Ph-H), 8.01 (m, 1H, Ph-H), 8.41 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 8.64 (s, 1H, Ph-H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.C(OC(C)C)(C)C>O>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1cccs1
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Reaction time: 70 h
Yield: 0.1 %

Procedure:
8.32 kg (65 moles) of the 2-(2-thienyl)-ethanol obtained in 1. above are mixed with 12.68 kg (66.6 moles) paratoluene sulfonyl chloride and 6.8 kg (67.2 moles) triethylamine and with 63 liters diisopropyl ether at room temperature. After stirring during 70 hours, the reaction mixture is poured over 40 liters water. The organic phase is washed with carbonated water and then with pure water until neutral, after which it is dried over sodium sulfate. Evaporation of the solvent gives 16.62 g (Yield: 90.60%) 2-(2-thienyl)-ethyl paratoluene sulfonate.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:32])=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.18 min; [M+H]+=443.0.