Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]4C=C(F)C(F)=C(F)C=4)=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=1)[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=[O:29].[F:33][C:34]1[CH:41]=[C:40]([OH:42])[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]>>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:15]([C:14]3[CH:13]=[CH:12][C:11]([C:18]([O:42][C:40]4[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([F:33])[CH:41]=4)=[O:29])=[CH:10][C:9]=3[CH:8]=[CH:7]2)=[CH:16][CH:17]=1)[CH2:2][CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc(O)cc1F
Reactant: CCCc1ccc2c(c1)CCc1cc(-c3cc(F)c(F)c(F)c3)ccc1-2
Product: CCCc1ccc2c(ccc3cc(C(=O)Oc4ccc(C#N)c(F)c4)ccc32)c1

Procedure:
2-iodo-7-propylphenanthrene produced in Example 1 was reacted with oxalyl dichloride, and subsequently reacted with 2-fluoro-4-hydroxybenzonitrile to yield 4-cyano-3-fluorophenyl 7-propylphenanthrene-2-carboxylate
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][C:8]1([CH3:16])[C:10]([CH3:12])([CH3:11])[CH:9]1[C:13]([OH:15])=O.[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH3:23].CC(C)=O>ClCCl>[Cl-:4].[CH3:23][C:19]1[N:20]([C:13]([CH:9]2[C:10]([CH3:11])([CH3:12])[C:8]2([CH3:7])[CH3:16])=[O:15])[CH:21]=[CH:22][N+:18]=1[CH3:17]
Reactant: Cc1nccn1C
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)C(C(=O)O)C1(C)C
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1n(C(=O)C2C(C)(C)C2(C)C)cc[n+]1C
Product: [Cl-]
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
Oxalyl chloride (360 ml, 4.1 mol) was added over 65 min to a stirred solution of 2,2,3,3-tetramethylcyclopropane carboxylic acid (600 g, 4.2 mol) in dichloromethane (3.6 L) at 34° C. The solution was then heated to reflux for 30 min and then cooled to 5° C. A solution of 1,2-dimethylimidazole (490 g, 5.1 mol) in dichloromethane (1.2 L) was added over 45 min maintaining the internal temperature around 5° C. The resulting suspension was then warmed to 18° C. and acetone (4.8 L) was added over 45 minutes maintaining the internal temperature around 18° C. The slurry was cooled to 5° C. over 30 minutes, stirred at 5° C. for 30 minutes and then filtered. The product was collected by filtration, washed with acetone:dichloromethane (3:1, 3×1.2 L), sucked dry and then dried in a vacuum oven at 25-30° C. for 10 hours to give Intermediate 25 as a white solid (890 g) 1 H nmr: δH (CDCl3, 400 MHz) 8.45 (d, J 2.4 Hz, 1 H), 8.11 (d, J 2.4 Hz, 1 H), 4.21 (s, 3 H), 2.96 (s, 3 H), 2.21 (s, 1 H), 1.43 (s, 6 H), 1.33 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH:7]=1.[CH3:41][C:42]([C:45]([NH2:47])=[O:46])([CH3:44])[NH2:43]>>[NH2:47][C:45](=[O:46])[C:42]([NH:43][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N:17]2[C:18]3[C:14](=[C:13]([NH:12][CH2:11][C:10]([OH:36])([C:32]([F:33])([F:34])[F:35])[CH2:9][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:39][CH3:40])([CH3:38])[CH3:37])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:15]=[N:16]2)[CH:24]=1)([CH3:44])[CH3:41]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Reactant: CC(C)(N)C(N)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)NC(C)(C)C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and 2-methylalaninamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].[N+](N[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:19][N:18]=1)([O-])=O.N1C=CC=[CH:34][CH:33]=1>>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:19][N:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:33][CH3:34]
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: CN(CCCN)c1ccccn1
Reactant: c1ccncc1
Product: CCCN(CCCNc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (1.33 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.5 g) were heated together under reflux in pyridine (10 ml) for 24 hr. The mixture was stripped and the residue triturated with wet ether. Recrystallisation three times from ethanol/water gave 2-[3-(N-propyl-N-pyrid-2-ylamino) propylamino)-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one 0.9H2O, 1.45 g (62%) mp 83°-90° C. (softens).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:23]([CH3:24])=[N:22][C:21]3[C:16](=[C:17]([C:25]4[NH:33][C:32]5[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=5[CH:26]=4)[CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][C:23]1[C:14]([NH:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[N:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[C:25]2[NH:33][C:32]3[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=3[CH:26]=2)[N:22]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
Prepared according to Example 53, using (R)-tert-butyl-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)pyrrolidine-1-carboxylate (Ex. 48, 150 mg, 0.506 mmol), and TFA (940 μl, 12.66 mmol) in DCM (20 mL), stirring at 25° C. for 1.5 h. Purification by column chromatography (silica gel: 0 to 10% MeOH/DCM) provided (R)-2-(2-methyl-3-(pyrrolidin-3-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (140 mg, 76%). 1H NMR (DMSO-d6) δ: 12.20 (s, 1H), 7.85-7.92 (m, 1H), 7.54-7.61 (m, 1H), 7.28-7.37 (m, 1H), 7.12 (s, 1H), 6.95 (s, 2H), 4.40-4.52 (m, 1H), 3.40-3.51 (m, 3H), 3.09-3.14 (m, 1H), 2.94-3.07 (m, 2H), 2.88 (s, 3H), 2.58-2.69 (m, 1H), 2.11-2.23 (m, 1H), 1.81-1.95 (m, 1H). m/z (ESI, +ve) 363.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:6][C:7](O)=[O:8])[C:3](O)=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:12].[Cl-:17]>>[CH3:1][C:2]([CH3:10])([CH2:6][C:7]([Cl:12])=[O:8])[C:3]([Cl:17])=[O:4]
Reactant: [Cl-]
Reactant: CC(C)(CC(=O)O)C(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CC(C)(CC(=O)Cl)C(=O)Cl
Yield: 67.8 %

Procedure:
2,2-Dimethylsuccinyl dichloride was prepared by reacting 2,2-dimethylsuccinic acid with PCl5 in the presence of a solvent at 20° C. After the work-up a yellow liquid was obtained which had a purity of 97.5% according to chloride content. The corrected yield was 67.8%.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:43][O:44][CH2:45][CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl.C(N(CC)CC)C>[C:50]([O:49][C:48](=[O:54])[NH:47][CH2:46][CH2:45][O:44][NH:43][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCCON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of the carboxylic acid (6b, 1.34 g, 4.87 mmol) of Example 9 or 16 in methylene chloride (35 mL) were added triethylamine (2.71 mL), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g), 1-hydroxybenzotriazole.monohydrate (1.15 g), and tert-butyl 2-(aminooxy)ethylcarbamate (1.12 g) described in Reference Example 9, followed by agitating at room temperature overnight. To the residue resulting from concentrating the reaction solution under reduced pressure was added water, followed by extracting with ethyl acetate. The resulting organic layer was washed with 0.1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtrated, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/2-0/10) to afford 1.77 g of the title compound (yield 84%).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH2:11].[CH3:12][CH2:13][O:14][C:15]([CH3:17])=[O:16]>CN(C=O)C>[CH2:3]([O:11][CH:4]1[CH2:5][CH2:6][C:15]2([O:16][CH2:12][CH2:13][O:14]2)[CH2:17][CH2:3]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h

Procedure:
To a mixture of 1,4-dioxaspiro[4.5]decan-8-01 (1.18 g, 7.46 mmol) and NaH (0.358 g, 8.96 mmol) in DMF (5 mL) at 0° C. was added benzyl bromide (1.06 mL, 8.95 mmol). After being stirred overnight under N2, water and EtOAc were added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed using 10% EtOAc/hexane to give 1.524 g of the title compound. MS (EI) calcd: (M+1)+=249.1; found: 249.2. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.35 (5H, m), 4.52 (2H, s), 3.95 (4H, m), 3.5 (1H, m), 1.95-1.50 (8H, m).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:44][C:45](=[O:49])[CH2:46][CH2:47][NH2:48])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:48][CH2:47][CH2:46][C:45]([OH:44])=[O:49])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)NCCC(=O)O)cc2)cc1

Procedure:
The product from Example 100 and β-alanine ethyl ester hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.96 (s, 1 H), 7.88 (br.s, 1 H), 7.12-7.35 (m, 8 H), 7.02 (m, 4 H), 6.89 (m, 4 H), 4.04 (m, 4 H), 3.22 (m, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.37 (m, 5 H), 2.05 (m, 2 H), 1.76 (m, 2 H); MS (APCI) m/z 630 (M+H+).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH2:20])[CH:14]=1.NC[C@@H]1CCCN1CC.C(=O)C>>[NH2:8][CH2:9][C:10]([NH:20][CH2:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCc1cccnc1
Agent: CC=O
Agent: CCN1CCC[C@H]1CN
Product: NCC(=O)NCc1cccnc1

Procedure:
By using N-(t-butoxycarbonyl)glycine (1.0 g) and 3-picolylamine (577 μl) as starting materials, the title compound (892 mg) was obtained in the same manners as those of Reference Example 88, (1) and Reference Example 78, (3).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([CH3:11])=[CH:9][C:8]([NH2:12])=[CH:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1>C(O)CCC>[Cl:13][C:14]1[N:15]=[CH:16][N:17]=[C:18]([NH:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH:19]=1
Reactant: Cc1nc2cc(N)cc(C)c2o1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCCCO
Product: Cc1nc2cc(Nc3cc(Cl)ncn3)cc(C)c2o1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
600 mg (1.90 mmol) 2,7-dimethyl-benzoxazol-5-ylamine, 400 mg (2.70 mmol) 4,6-dichloropyrimidine and 1.50 mL (11.0 mmol) TEA were combined in 8.0 mL 1-butanol and stirred for 2 h at 90° C. The reaction mixture was cooled to RT and purified by preparative HPLC. The product-containing fractions were combined, evaporated down and the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1>C(O)CCC.O1CCOCC1>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[C:19]([F:24])[CH:18]=1
Reactant: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Reactant: Nc1ccc(Br)cc1F
Solvent: CCCCO
Solvent: C1COCCO1
Product: Fc1cc(Br)ccc1Nc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 90 °C
Yield: 58.1 %

Procedure:
In a 250-mL round-bottom flask, 2-chloro-6-trifluoromethoxy-1,3-benzothiazole (5.36 g, 21.14 mmol) and 4-bromo-2-fluoroaniline (4.82 g, 25.36 mmol) were combined in 100 mL n-butanol containing 1% 4.0 M HCl in dioxane, and heated at 90° C. overnight. The mixture was cooled to rt and the solvent was removed under reduced pressure. Ethyl acetate (50 mL) was added, and the mixture was ultrasonicated by suspending the flask in an ultrasonication bath for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Acetonitrile (50 mL) was added to the mixture, which was then ultrasonicated for 30 minutes and then filtered to provide the product as a white solid (5 g, 58%). LC-MS m/z 409.1 (MH+), ret. time 4.02 min.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C(N(CC)CC)C>C(O)C>[C:19]1(=[O:28])[N:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: Sc1cccc2nccn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.4 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (1.50 g, 10 mmoles) and N-[6-(bromo)hexyl]phthalimide (3.10 g, 10 mmoles) in ethanol (100 ml) was added triethylamine (2.1 ml, 15 mmoles) and the mixture was stirred at room temperature for 12 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.86 g of the desired product (75.5%, light tan solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([O:18]C)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:5][C:4]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29].[OH-].[Na+].CO.Cl>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:5][C:4]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:27][C:28]=1[CH3:29]
Reactant: COC(=O)Cc1cccc(OCc2ccc(OC)c(OCc3nc(-c4ccccc4)oc3C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2cccc(CC(=O)O)c2)cc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3-[4-methoxy-3-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]phenylacetate (420 mg), 1N sodium hydroxide (2 mL), methanol (5 mL) and tetrahydrofuran (5 mL) was stirred at room temperature for 3 hrs. The reaction mixture was poured into water, and the mixture was neutralized with 2N hydrochloric acid to give crystals of 3-[4-methoxy-3-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]phenylacetic acid. Recrystallization from ethyl acetate gave colorless prism crystals (350 mg, 86%). melting point: 114-115° C.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC(O)C>CCCCCCC>[CH3:10][C@@H:7]1[N:6]2[C:5]3[C:14]([C:13]([C:12]([C:17]([OH:19])=[O:18])=[CH:11]2)=[O:16])=[CH:15][C:2]([F:1])=[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:4]=3[O:9][CH2:8]1
Reactant: CN1CCNCC1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CC(C)O
Solvent: CCCCCCC
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 80 °C
Yield: 76.2 %

Procedure:
5 g (17.79 mmole) of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4]benzoxazine-6-carboxylic acid was put in suspension in 6.8 mL (0.06 mole) of N-methyl piperazine. The reaction mixture was heated to reflux for 40 minutes until completion of the reaction. The mixture was then cooled to 80° C. IPA (10 mL) and n-heptane (10 mL) were added at this temperature. The solid was filtrated under vacuum and rinsed with n-heptane. The mother liquor also gave a precipitate after addition of n-heptane. Both precipitates were filtrated under vacuum and dried overnight to yield 4.9 g (76%) levofloxacin.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]=3[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29].[OH-].[Na+]>ClCCl.CO>[NH:2]1[C:3]2[C:11]3[CH:12]=[CH:13][N:14]=[CH:6][C:7]=3[N:8]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[CH2:9][CH2:10][C:4]=2[CH:5]=[N:1]1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1cnc2c(c1)NCCc1cn[nH]c1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ccncc32)cn1

Procedure:
To a solution of 2 mmol 1,4,5,6-tetrahydropyrazolo[3,4-d]pyrido[3,2-b]azepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 4.2 mmol of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride. After stirring over the mixture is worked-up as described for Example 1 and the initial solid treated with 1N NaOH in methanol as described for Example 1 to give the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[CH2:17][N:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[C:15](=[O:28])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42](O)=[O:43])[C:37]2=[O:45])=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[CH2:17][C:18]3[C:9]([O:8][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:42]([C:38]5[C:37](=[O:45])[N:36]([C:33]6[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=6)[CH:41]=[CH:40][CH:39]=5)=[O:43])=[N:7][CH:6]=4)=[CH:10][CH:11]=[N:12][C:13]=3[NH:14][C:15]2=[O:28])=[CH:21][CH:22]=1
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)nc4)ccnc3NC2=O)cc1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(Oc4ccc(NC(=O)c5cccn(-c6ccc(F)cc6)c5=O)nc4)ccnc3NC2=O)cc1
Yield: 31.8 %

Procedure:
A solution of 5-[(6-aminopyridin-3-yl)oxy]-3-(4-methoxybenzyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (100.00 mg; 0.26 mmol; 1.00 eq.), 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (67.97 mg; 0.29 mmol; 1.10 eq.), pybop (179.26 mg; 0.34 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (0.13 μl; 0.79 mmol; 3.00 eq.) was stirred at room temperature under N2 for 14 hours. The reaction was concentrated, redissolved in DMSO, and purified via prep HPLC to afford 49 mg (26%) of 282 as a peach-colored solid. LC-MS (M+H=593, obsd.=593).
Reaction SMILES: [O:1]=[S:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([N:18]3[CH2:23][CH2:22][N:21]4[CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=[C:20]4[CH2:19]3)=[N:6][C:5]=2[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C)C=O>[N:39]1([C:27]([C:25]2[N:26]=[C:20]3[CH2:19][N:18]([C:7]4[N:8]=[C:9]([NH:11][CH:12]5[CH2:13][CH2:14][O:15][CH2:16][CH2:17]5)[C:10]5[S:2](=[O:1])[CH2:3][CH2:4][C:5]=5[N:6]=4)[CH2:23][CH2:22][N:21]3[CH:24]=2)=[O:28])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cn2c(n1)CN(c1nc3c(c(NC4CCOCC4)n1)S(=O)CC3)CC2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cn2c(n1)CN(c1nc3c(c(NC4CCOCC4)n1)S(=O)CC3)CC2)N1CCOCC1
Temperature: 25 °C

Procedure:
50 mg of 7-[5-oxo-4-(tetrahydropyran-4-ylamino)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-2-yl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (see 13.1) are placed in 2 ml dimethylformamide, then 66 μl diisopropylethylamine and 54.2 mg O-(7-azabenzotriazol-1-yl+N,N,N″,N″-tetramethyluronium hexafluorophosphate (HATU) are added. After 15 min a suspension of 11.4 mg morpholine in 300 μl dimethylformamide is added. The reaction mixture is stirred at ambient temperature until there is no further reaction, and the product is purified directly by preparative HPLC (method B). 40 mg of Example 48 are obtained as a solid. Analytical HPLC-MS (method D): RT=0.79 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2C(=O)C3=CC=CC=C3[C:10]2=[O:19])[N:5]=[C:4]([C:20]2[N:21]=[C:22]([N:25]=[C:26]([NH2:28])[NH2:27])[S:23][CH:24]=2)[CH:3]=1.O.[NH2:30]N>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:30])=[O:19])[N:5]=[C:4]([C:20]2[N:21]=[C:22]([N:25]=[C:26]([NH2:28])[NH2:27])[S:23][CH:24]=2)[CH:3]=1
Reactant: NC(N)=Nc1nc(-c2cc(Cl)cc(CN3C(=O)c4ccccc4C3=O)n2)cs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NC(=O)NCc1cc(Cl)cc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 32.3 %

Procedure:
A mixture of 4-(4-chloro-6-phthalimidomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (1.10 g) and hydrazine mono-hydrate (400mg) in ethanol (200 ml) was refluxed for 5 hours. After the solvent and excess hydrazine monohydrate were removed by concentration, water (10 ml) was added to the residue and the suspension was adjusted to pH 2 with 6N-hydrochloric acid. The resulting precipitate was filtered off, washed with water (5 ml) and the filtrate and the washing solution were combined. After the solution was readjusted to pH 4 with aqueous sodium bicarbonate, potassium cyanate (320 mg) was added to the solution and the mixture was stirred for 14 hours at ambient temperature. The reaction mixture was readjusted to pH 4 with 6N-hydrochloric acid, additional potassium cyanate (215 mg) was added and the solution was further stirred for 8 hours. The mixture was made basic to pH 10 with aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of N,N-dimethylformamide and water to give 4-(4-chloro-6-ureidomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.28 g).