Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:19][C:20]1[N:29]=C(C)C2C(=O)CC(C3C=CC(F)=CC=3)CC=2[N:21]=1>>[NH2:29][C:20]1[N:21]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:6][C:5]=2[N:19]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Reactant: CC(=O)C1C(=O)CC(c2ccc(C)cc2)CC1=O
Product: Cc1ccc(C2CC(=O)c3c(C)nc(N)nc3C2)cc1

Procedure:
The title compound was prepared from 2-acetyl-5-p-tolyl-cyclohexane-1,3-dione (850 mg, 3.50 mmol), stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/a stage 2/3).
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[N:6]=[C:7]([Cl:10])[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:10][C:7]1[N:8]=[CH:9][C:4]2[CH:3]=[C:2]([C:17]3[CH:16]=[C:15]([O:14][CH3:13])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=3)[CH:12]=[N:11][C:5]=2[N:6]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: Clc1ncc2cc(Br)cnc2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2cnc3nc(Cl)ncc3c2)c1
Temperature: 85 °C
Yield: 46.2 %

Procedure:
A mixture of 6-bromo-2-chloropyrido[2,3-d]pyrimidine (800 mg, 3.3 mmol), 3,5-dimethoxyphenylboronic acid (655 mg, 3.6 mmol), bis(tri-tert-butylphosphine)palladium (83 mg, 0.16 mmol) and cesium carbonate (1.06 g, 3.3 mmol) in THF (30 mL) and water (6 mL) was degassed with nitrogen for three times and then heated at 85° C. for 0.5 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate=3/1) to get the title product as a yellow solid (460 mg, 47%) as a yellow solid. MS (ES+) C15H12ClN3O2 requires: 301, 302, found: 302, 304 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: NCc1ccncc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccncc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[(4-pyridyl)methylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-aminomethylpyridine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].CCO>O>[CH3:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:25]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
The mixture of 2-(2,3-dimethyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (235) (290 mg, 0.86 mmol), KOH (50% aqueous solution, 1.92 g, 17.2 mmol), EtOH (10 mL) and water (1 mL) are stirred in a 20 mL vial at 50° C. for 30 min. After concentration in vacuo, the residue is dissolved in water (5 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The filtration gives 2-(2,3-dimethyl-benzoylamino)-indan-2-carboxylic acid (236) as white solid (240 mg, 90%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1([C:44]2[CH:60]=[CH:59][CH:58]=[CH:57][C:45]=2[CH2:46][O:47][CH2:48][CH2:49][C:50]([CH3:56])([CH3:55])[C:51]([O:53]C)=[O:52])[CH2:10][CH2:9][N:8]([C:11]([C@:13]2([O:34][C:35]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[S:37][CH:36]=3)[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:30])[C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=3)[C@@H:14]2[CH2:31][CH2:32][CH3:33])=[O:12])[CH2:7][CH2:6]1)#[N:4]>C1COCC1.CO>[C:3]([C:5]1([C:44]2[CH:60]=[CH:59][CH:58]=[CH:57][C:45]=2[CH2:46][O:47][CH2:48][CH2:49][C:50]([CH3:56])([CH3:55])[C:51]([OH:53])=[O:52])[CH2:10][CH2:9][N:8]([C:11]([C@:13]2([O:34][C:35]3[CH:39]=[C:38]([C:40]([F:41])([F:43])[F:42])[S:37][CH:36]=3)[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:30])[C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=3)[C@@H:14]2[CH2:31][CH2:32][CH3:33])=[O:12])[CH2:7][CH2:6]1)#[N:4]
Reactant: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(C#N)(c2ccccc2COCCC(C)(C)C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(C#N)(c2ccccc2COCCC(C)(C)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2 N Aqueous sodium hydroxide (5.5 mL) was added to methyl 4-(2-(4-cyano-1-((2R,3S)-2-propyl-1-(3-(trifluoromethyl)picolinoyl)-3-(5-(trifluoromethyl)thiophen-3-yloxy)piperidine-3-carbonyl)piperidin-4-yl)benzyloxy)-2,2-dimethylbutanoate (312 mg, 0.37 mmol) in THF/methanol (1:3, 12 mL). The reaction was stirred for 8 h at room temperature then concentrated. The residue was diluted ethyl acetate (30 mL) and the pH adjusted to 1 with 1 N hydrochloric acid. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by C18 semi-prep HPLC to obtain A60 (300 mg, 99% yield) as a white powder after lyophilization from water/acetonitrile: 1H NMR (CDCl3, 300 MHz) δ 8.81-8.82 (d, J=3.9 Hz, 1H), 8.06-8.08 (d, J=8.1 Hz, 1H), 7.24-7.50 (m, 5H), 6.84-6.87 (d, J=8.1 Hz, 1H), 6.53-6.56 (m, 1H), 4.65-5.57 (m, 5H), 3.48-3.75 (m, 6H), 3.08-3.20 (m, 3H), 1.22 (s, 6H), 0.93-2.47 (m, 17H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:31][C:32]([NH:34][C@@H:35]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([OH:38])=O)=[O:33])[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].CCN(C(C)C)C(C)C.[CH3:52][O:53][C@:54]1([C:63]2[CH:68]=[CH:67][C:66]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[CH:75]=[CH2:76])=[CH:65][CH:64]=2)[CH2:58][NH:57][C@H:56]([C:59]([O:61][CH3:62])=[O:60])[CH2:55]1>C(Cl)Cl>[CH2:25]([O:31][C:32]([NH:34][C@@H:35]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36]([N:57]1[CH2:58][C@:54]([O:53][CH3:52])([C:63]2[CH:64]=[CH:65][C:66]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[CH:75]=[CH2:76])=[CH:67][CH:68]=2)[CH2:55][C@H:56]1[C:59]([O:61][CH3:62])=[O:60])=[O:38])=[O:33])[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30]
Reactant: C=Cc1ccccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Reactant: C=CCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
HATU (139 mg, 0.365 mmol) was added to a solution of (S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (128 mg, 0.498 mmol), DIEA (0.174 mL, 0.996 mmol) and (2S,4R)-methyl 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (112 mg, 0.332 mmol) in DCM (5 mL). The reaction was stirred at r.t. overnight. The reaction was evaporated and purified on the Biotage (10-40% EtOAc in hexanes) to give (2S,4R)-methyl 1-((S)-2-((hex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (151 mg, 79% yield) as a clear oil. LCMS: rt=2.05 min. [M+Na]30 =599; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[CH:14][NH:13][N:12]=2)=[CH:3]1.[H-].[Na+].Br[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>C1COCC1>[C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:13]1[CH:14]=[N:15][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[N:12]1)(=[O:21])[CH3:19]
Reactant: O=C(CBr)N1CCCCC1
Reactant: Cn1cc(-c2nc[nH]n2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CCCCC1n1cnc(-c2cn(C)c3ccccc23)n1
Reaction time: 4 h
Yield: 25.8 %

Procedure:
3-(1-Methyl-1H-indol-3-yl)-1,2,4-triazole (0.190 g, 0.960 mmol) was dissolved with stirring in dry THF (5 ml) and was treated with sodium hydride (80%) (0.032 g, 1.05 mmol), followed by 1-(bromoacetyl)piperidine (Bull. Soc, Chim. Fr. 1964, 5, 1063-9) (0.232 g, 1.05 mmol) in dry THF (1 ml). After 4 h, the reaction mixture was evaporated under reduced pressure and partitioned between EtOAc and water. The organic layer was then dried (Na2SO4) and evaporated under reduced pressure to give a yellow oil, which was purified by silica-gel chromatography (EtOAc→EtOAc:MeOH 100:1 as eluant) to give the title compound (D5b) as a white solid (0.080 g, 26%).
Reaction SMILES: C([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]([CH3:14])[CH2:5]1)(=O)C.C(O[CH:18]=[C:19]([C:25]([O:27]CC)=O)[C:20]([O:22]CC)=[O:21])C.O.[OH-].[Na+]>C(O)(=O)C>[CH3:14][CH:6]1[N:7]2[CH:18]=[C:19]([C:20]([OH:22])=[O:21])[C:25](=[O:27])[C:9]3[C:8]2=[C:13]([CH:12]=[CH:11][CH:10]=3)[NH:4][CH2:5]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(=O)N1CC(C)Nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC1CNc2cccc3c(=O)c(C(=O)O)cn1c23
Temperature: 120 °C

Procedure:
A mixture of 0.0894 mole (1.7 g) of optically purified (+) 1-acetyl-3-methyl-1,2,3,4-tetrahydroquinoxaline and 0.009 mole (1.9 g) diethyl ethoxymethylenemalonate was heated over one hour to 200° C. and maintained at that temperature for 1.5 hours. After cooling, 5 g of polyphosphoric acid were added and the mixture was heated at 120° C. until foaming stops. The mixture was stirred into water and the solution was made strongly basic with 25 percent sodium hydroxide. The solution was stirred and heated on a steam bath for one hour, then neutralized with acetic acid. Cooling, followed by filtration provided an olive green solid R(+) 2,3-dihydro-3-methyl-7-oxopyrido-[1,2,3-de]quinoxaline-6- carboxylic acid, m.p. >250° C. Analysis: Calculated for C13H12N2O3 : %C, 63.9; %H, 5.0; %N, 11.5; Found: %C, 63.4; %H, 5.0; %N, 11.6. Optical rotation [α]21 D = 93±3° (C=0.594, N,N-dimethylformamide:ethanol, 1/1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH:6]=[CH:5][CH2:4]1.N1C=CN=C1.C(Cl)Cl.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH:6]=[CH:5][CH2:4]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: OC[C@H]1CC=C[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC=C[C@H]1O

Procedure:
To a solution of rel-(1R,5R)-5-(hydroxymethyl)cyclopent-2-en-1-ol (47.20 g, 0.4135 mol), N,N-dimethylaminopyridine (2.52 g, 0.0207 mol) and 1H-imidazole (30.97 g, 0.4549 mol) in methylene chloride (800 mL, 10 mol) at 0° C. under an atmosphere of nitrogen was added tert-butyldimethylsilyl chloride (28.0 g, 0.186 mol). The reaction was stirred for at 0° C. for 2.5 h, at which time tert-butyldimethylsilyl chloride (28.0 g, 0.186 mol) was added. The reaction was stirred for 2 additional hours. The reaction was quenched by addition of saturated aqueous NaCl solution (200 mL) and water (200 mL). The layers were separated and the organic layer was washed with water (3×200 mL) and brine (1×200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The material was used without further purification in the next step.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:27].[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl>CC(O)C.[OH-].[Na+].O>[CH3:27][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])[CH:6]=[C:7]([CH3:8])[C:2]=1[O:1][CH2:28][CH:30]1[CH2:31][O:32]1
Reactant: ClCC1CO1
Reactant: CCCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCc1sc(C(=O)CCc2cc(C)c(OCC3CO3)c(C)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (250 mg, 0.661 mmol) in 2-propanol (2 mL) and 3 N aq. NaOH (1 mL) is treated with epichlorohydrine (122 mg, 1.32 mmol) and the mixture is stirred at rt for 18 h, then diluted with water and extracted with EA. The solvent of the organic extract is evaporated to give crude 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (257 mg) as a yellow oil; LC-MS: tR=1.18 min, [M+1]+=435.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[CH2:22][NH+:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:24])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH3:26])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.[I-].[C:28]([Mg]Br)#[C:29][CH3:30].O1CCCC1>C(OCC)C>[CH3:1][O:2][C:3]1[C:23]2[CH:22]([C:28]#[C:29][CH3:30])[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:24])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH3:26])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4
Reactant: COc1ccc2c(c1OC)C[NH+]1CCc3cc4c(cc3C1=C2C)OCO4
Reactant: CC#C[Mg]Br
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC#CC1c2c(ccc(OC)c2OC)C(C)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a suspension of 9,10-dimethoxy-13-methyl-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (200 mg, 0.4 mmol) in anhydrous diethyl ether (5 mL) at 0° C. was added a solution of 1-propynylmagnesium bromide in tetrahydrofuran (0.5 M, 17 mL, 8.5 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 9,10-dimethoxy-13-methyl-8-prop-1-ynyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (100 mg, 61%). LC/MS m/e calcd for C24H23NO4 (M+H)+: 390.46, observed: 390.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (d, J=1.52 Hz, 3 H) 2.22 (s, 3 H) 2.59-2.69 (m, 1 H) 2.89-2.99 (m, 1 H) 3.16-3.27 (m, 2 H) 3.81 (d, J=7.58 Hz, 6 H) 5.38 (d, J=1.77 Hz, 1 H) 6.04 (d, J=2.78 Hz, 2 H) 6.84 (s, 1 H) 6.96 (m, 2 H) 7.06 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:14]([CH3:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:32][Mg]Cl.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:17]3[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=3)[C:14]([CH3:32])([OH:15])[CH3:16])[CH2:10]2)=[CH:30][CH:29]=1
Reactant: C[Mg]Cl
Reactant: CC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 230 mg (0.5 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)acetone in 10 mL of THF was added slowly a solution of 0.42 mL (1.25 mmol) of methylmagnesium chloride (3.0M solution in THF) at −78° C. and stirred for 1 h. The reaction mixture was warmed to 0° C. for 1 h, followed by adding 1 g of sodium sulfate decahydrate to quench the reaction, and stirring for 1 h at rt. The quenched reaction mixture was filtered and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/acetone=8:1 to afford racemic 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol as a white solid. The enantiomers were separated by a chiral column (OJ Column with hexanes/ethyl alcohol); 1H NMR (CDCl3) δ 1.06 (s, 3H), 1.15 (S, 3H), 2.29 (t, 1H, J=7.5 Hz), 2.74 (d, 1H, J=10.7 Hz), 2.82 (t, 1H, J=7.5 Hz), 3.10-3.16 (m, 2H), 3.62 (m, 1H), 4.20 (s, 11H), 6.67-6.73 (m, 3H), 7.21-7.33 (m, 8H); Mass Spectrum: m/e=476 (M+1 35Cl, 35Cl) and 478 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].ClC1C=C(O)C=CC=1C=O.C(CC(Br)(C)C([O-])=O)C.[CH:38]1([C:41]2[C:46]([C:47](O)=[O:48])=[CH:45][N:44]=[C:43]([C:50]3[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=3)[N:42]=2)[CH2:40][CH2:39]1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:47]([C:46]2[C:41]([CH:38]3[CH2:40][CH2:39]3)=[N:42][C:43]([C:50]3[CH:51]=[CH:52][C:53]([C:56]([F:58])([F:59])[F:57])=[CH:54][CH:55]=3)=[N:44][CH:45]=2)=[O:48])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)c(Cl)c1
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: O=Cc1ccc(O)cc1Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c(Cl)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-benzaldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[3-chloro-4-({[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1.COC(=O)OC>CS(C)=O>[CH3:22][CH:23]1[NH:24][CH2:25][CH2:26][N:27]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7](=[O:18])[C:8]3=[CH:9][C:10]=2[F:17])[CH2:28]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC1CNCCN1
Solvent: COC(=O)OC
Solvent: CS(C)=O
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 55 °C
Yield: 70 %

Procedure:
Forty grams of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid and 28.4 g (2.1 eq) of 2-methyl piperazine were suspended in DMSO (800 mL) under nitrogen atmosphere. The mixture was heated to 55° C. during 24 hours. Thereafter, dimethylcarbonate (200 mL) was added, the reaction mixture was cooled to 5° C., and held at this temperature overnight. The mixture was then filtered under vacuum and the compound was then dried under vacuum to obtain 35.5 g after assay (70% yield) of gatifloxacin.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:21]([S:24][CH2:25][CH2:26][C:27](Cl)=[O:28])(=[O:23])[CH3:22]>O.C(OCC)(=O)C>[C:21]([S:24][CH2:25][CH2:26][C:27]([N:9]1[CH:10]([C:12]([OH:14])=[O:13])[CH2:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)=[O:28])(=[O:23])[CH3:22]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: O=C(O)C1CC(c2ccccc2)=NN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)SCCC(=O)N1N=C(c2ccccc2)CC1C(=O)O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
A suspension of 8.0 g of 4,5-dihydro-3-phenyl-1H-pyrazole-5-carboxylic acid in 200 ml of distilled water is treated slowly with 2.6 g of sodium carbonate. The solution is layered with 50 ml of ethyl acetate, cooled to 5° C. and treated with 7.0 g of 3-(acetylthio)propionyl chloride in 10 ml of ethyl acetate. The pH of the reaction mixture is maintained at 7.5-8.0 by the addition of concentrated sodium carbonate solution. The mixture is stirred at room temperature for 30 minutes. The ethyl acetate layer is then discarded and the aqueous layer is washed twice with fresh ethyl acetate. Using 6 N hydrochloric acid, the pH of the aqueous layer is adjusted to 2.5 and then it is extracted with two 100 ml portions of ethyl acetate. The combined extracts are dried over magnesium sulfate and concentrated to a point where precipitation begins. Cooling affords 10.6 g of the title compound, melting point 137°-139° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=3)[NH2:15])=[CH:8][C:6]=2[N:7]=1.[C:25]([O:29][C:30]([NH:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>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.O>[NH2:15][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[N:11][C:5]3[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:3][C:2]([C:36]4[CH:37]=[N:38][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[N:34][CH:35]=4)=[N:7][C:6]=3[CH:8]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(B(O)O)cn1
Reactant: Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(N)c4)cc3n2)cn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a 50 mL sealed tube, 3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)aniline (1.1 g, 0.0032 mol), (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (1.15 g, 0.0048), potassium phosphate (2.04 g, 0.0096 mol), DMF (20 mL) and water (7 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)4 (0.23 g, 0.0002 mol) was added and degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 105° C. for 1 hour. The reaction mass was cooled to room temperature and added ice cold water. The precipitate was obtained and the solid was collected by filtration. The solid was dissolved in chloroform, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by column chromatography (60-120 silica gel, 2% methanol in chloroform) to provide the title compound (1.4 g, 87%). 1H NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.47 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.07-7.03 (m, 2H), 6.71 (d, J=8.1 Hz, 1H), 5.33 (s, 2H), 4.55 (br s, 4H), 3.83 (t, J=4.8 Hz, 4H), 1.49 (s, 9H). LC-MS (ESI): Calculated mass: 500.2; Observed mass [M+H]+: 501.1 (RT=1.09 min).