Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:11]2[C:6](=[CH:7][C:8]([O:31][CH3:32])=[C:9]([O:29][CH3:30])[CH:10]=2)[N:5]=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>ClCCl>[CH2:33]([N:35]([CH2:2][CH2:3][C:4]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:11]2[C:6](=[CH:7][C:8]([O:31][CH3:32])=[C:9]([O:29][CH3:30])[CH:10]=2)[N:5]=1)[CH2:36][CH3:37])[CH3:34]
Reactant: CCOC(=O)c1c(CCBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CCNCC
Solvent: ClCCl
Product: CCOC(=O)c1c(CCN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 25.5 %

Procedure:
A mixture of ethyl 2-(2-bromoethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (0.45 g), diethylamine (0.326 g) and dichloromethane (10 ml) was stirred under reflux for 14 hours. The reaction mixture was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-methanol (20:1, v/v) gave ethyl 2-[2-(N,N-diethylamino)ethyl]-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (0.113 g, 26%). This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 76°-78° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:14][CH2:13]3)[C:9]2=[NH:12])=[CH:4][CH:3]=1.O=[C:16]([CH3:20])[C:17](=[S:19])[NH2:18]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([C:9]42[NH:18][C:17](=[S:19])[C:16]([CH3:20])=[N:12]4)[CH2:14][CH2:13]3)=[CH:4][CH:3]=1
Reactant: N=C1c2cc(Br)ccc2CCC12CC2
Reactant: CC(=O)C(N)=S
Solvent: CO
Product: CC1=NC2(NC1=S)c1cc(Br)ccc1CCC21CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
7′-Bromo-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-naphthalen]-1′-imine (Intermediate 11, 717 mg, 2.87 mmol) and 2-oxopropanethioamide (970 mg, 9.40 mmol) were dissolved in dry MeOH (25 mL) and heated at 60° C. under argon for 24 h. After standing at r.t. overnight the formed precipitate was filtered and washed with MeOH. Drying in vacuo afforded the title compound (688 mg, 65% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.27-0.35 (m, 1 H), 0.35-0.45 (m, 2 H), 0.47-0.53 (m, 1 H), 1.69-1.79 (m, 1 H), 2.03-2.12 (m, 1 H), 2.27 (s, 3 H), 2.90 (t, 2 H), 6.73 (d, 1 H), 7.24 (d, 1 H), 7.47 (dd, 1 H), 12.28 (s, 1 H); MS (ES+) m/z 335.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][CH:14]=[C:13]2[CH2:17][OH:18])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:26]([Si:30](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:29])([CH3:28])[CH3:27]>ClCCl.CN(C)C1C=CN=CC=1>[Si:30]([O:18][CH2:17][C:13]1[N:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[CH:16]=[CH:15][CH:14]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1ccc(-n2cccc2CO)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-n2cccc2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 5 °C

Procedure:
To a solution of 1-(4-ethoxycarbonylphenyl)-2-hydroxymethylpyrrole (8.97 g) in dichloromethane (90 ml) was added triethylamine (12.1 ml), 4-dimethylaminopyridine (100 mg) and tert-butylchlorodiphenylsilane (10.6 ml) in that order at 5° C. under nitrogen atmosphere. After stirring for half an hour at 5° C., the mixture was allowed to warm to ambient temperature and stirred for 13.5 hours. The mixture was washed with water and brine, dried, concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution by ethyl acetate/n-hexane=1/7) to yield 2-tert-butyldiphenylsilyloxymethyl-1-(4-ethoxycarbonylphenyl)pyrrole (18.67 g) as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:8](=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[C:12]([O:21]C)[CH:11]=[CH:10]4)[CH:7]=[CH:6][C:5]=2[CH:4]=1.C(Cl)Cl.B(Br)(Br)Br>O>[CH:4]1[C:5]2[CH:6]=[CH:7][C:8]3[C:17](=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]([OH:21])=[CH:13]4)[C:18]=2[CH:19]=[CH:20][C:3]=1[OH:2]
Reactant: COc1ccc2c(ccc3c4ccc(OC)cc4ccc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc2c(ccc3c4ccc(O)cc4ccc23)c1
Temperature: -60 °C
Reaction time: 18 h

Procedure:
Under an argon gas flow, 24 g (0.083 mol) of 2,8-dimethoxychrysene and 2 L of methylene chloride were charged into a 3 L glass flask equipped with a condenser, and cooled to −60° C. Successively, 4.1 g (0.17 mol) of boron tribromide was slowly dropped into the flask, and then the contents of the flask were stirred at room temperature for 18 h. After completion of the reaction, 1 L of water was added to the flask to separate an organic layer from the reaction solution. The resultant crude crystal was short-passed through silica gel (using THF (tetrahydrofuran) as a developing solvent). The obtained product was concentrated under reduced pressure, and the resultant crude product (25 g) was directly used in the subsequent reaction.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.C(N(CC)C(C)C)(C)C.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>ClCCl.CN(C)C1C=CN=CC=1>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH:4]2[N:3]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[CH:29][CH:28]=1)#[N:27]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 40 mg, 0.10 mmol) in dichloromethane (1.0 mL) is treated with N,N-diisopropylethylamine (70 μL, 0.4 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol). Ethyl chloroformate (11 μL, 0.11 mmol) is added and the mixture is stirred at room temperature for 2 h. All volatiles are evaporated pi and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 46 mg; ESI mass spectrum [M+H]+=470; Retention time HPLC: 0.90 min (Z011_S03).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1>CN(C=O)C>[O:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5ccccc5)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
To NaH (60 wt % in mineral oil; 0.047 g, 1.176 mmol) in 1 mL DMF was added phenol (0.111 g, 1.176 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1, 0.050 g, 0.168 mmol) was added and the reaction became dark red. After 30 min at RT, the reaction was heated to 70° C. The reaction was judged complete after 5 h at 70° C., and was cooled to RT and quenched with saturated aq. NH4Cl and EtOAc. The organic layer was sequentially washed with water, and saturated aq. NaCl, then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-50%-90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 2-(2-phenoxyquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.048 g, 0.135 mmol, 80% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.04 (1H, br. s), 8.49 (1H, d, J=8.8 Hz), 8.12 (1H, dd, J=7.6, 1.6 Hz), 7.74-7.87 (1H, m), 7.56-7.66 (2H, m), 7.33-7.52 (5H, m), 6.84-7.01 (2H, m), 3.31-3.38 (2H, m), 2.39 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 356.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[N:4]=[C:5]1[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1.CC(C)([O-])C.[K+]>>[Cl:1][C:2]1[C:3]2[N:4]=[C:5]3[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]3[C:12]=2[C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(N=C2NCCCCN2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(Cl)c2nc3n(c12)CCCCN3
Temperature: 60 °C
Yield: 68.3 %

Procedure:
2-Chloro-N-1,3-diazepan-2-ylidene-5-nitroaniline (5.0 g, 18.6 mmol) and potassium t-butoxide (417 mg, 3.7 mmol) were dissolved in N,N-dimethylsulfoxide (100 mL), and heated at 60° C. for 24 hr. After cooling to room temperature, the reaction mixture was directly purified by silica gel column chromatography eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give the title compound (3.38 g, 12.7 mmol, 68%) as a yellow amorphous.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]#[N:28])[N:18]=1>CN1C(=O)CCC1.O>[C:27]([C:19]1[N:18]=[C:17]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2)#[N:28]
Reactant: N#Cc1cc2ccccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccccc23)C1
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.906 g, 10.18 mmol) in NMP (10 mL) at 0° C. was added NaH (0.339 g, 8.48 mmol). The mixture was stirred for 5 minutes and then 1-chloroisoquinoline-3-carbonitrile (1.6 g, 8.48 mmol) was added. The reaction mixture was heated at 160° C. for 30 minutes in a microwave reactor and was subsequently diluted with water and extracted with EtOAc (2×). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica column chromatography eluting with a gradient of 0-75% EtOAc in hexane to give the title compound as a yellow solid (1.61 g, 55.9%). ESI-MS m/z [M+H-tert-butyl]+ 284.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[O:9]=[C:10]([CH3:14])[C:11](Cl)=[O:12].Cl>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:11](=[O:12])[C:10](=[O:9])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(=O)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)C(=O)Nc1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
26.3 g of 4-chlorophenylamine in 150 ml of dichloromethane and 35 ml of triethylamine are added, at −60° C., to 22 g of 2-oxopropionyl chloride (prepared according to Synthesis, 1975, 163-164 from 2-oxopropionic acid and 1,1-dichlorodimethyl ether) in 350 ml of dichloromethane. The reaction mixture is stirred at −60° C. for 2 hours and then 200 ml of a 0.15N aqueous hydrochloric acid solution and 500 ml of dichloromethane are added at −30° C. The organic phase is extracted, washed with a 0.25N aqueous hydrochloric acid solution and dried over sodium sulphate. The solvents are evaporated under reduced pressure and the residue obtained is crystallized from dichloromethane;
Reaction SMILES: BrC1C=C2C(=CC=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])C(C)=C2.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[CH2:40][C:41](=O)[CH3:42]>>[C:27]([O:26][C@@H:20]([C:7]1[C:41]([CH3:42])=[CH:40][C:34]2[C:35](=[CH:36][C:37]([F:39])=[CH:38][C:33]=2[F:32])[C:8]=1[O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(=O)Cc1ccc(F)cc1F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(F)cc(F)cc2c1OS(=O)(=O)C(F)(F)F

Procedure:
(S)-ethyl 2-tert-butoxy-2-(5,7-difluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was prepared in a similar was as (S)-ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate in Example 20, except using 1-(2,4-difluorophenyl)propan-2-one instead of 1-(3-bromophenyl)propan-2-one. 1H-NMR: 400 MHz, (CDCl3) δ: 7.82 (s, 1H), 7.39 (d, J=5.47 Hz, 1H), 6.99 (m, 1H), 5.63 (s, 1H), 4.18 (m, 2H), 2.49 (s, 3H), 1.11 (s+t, 12H). 19F-NMR: 377 MHz, (CDCl3) δ: −73.27 (s, 3F), −109.1 (m, 1F), −117.5 (m, 1F).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][CH:13](O)[C:12]=2[CH:18]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][CH:13]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:12]=2[CH:18]=1
Reactant: C1CCNCC1
Reactant: COc1ccc2c(c1)C(O)CCO2
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(N1CCCCC1)CCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methane sulfonyl chloride (14.9 ml) is added dropwise to a stirred solution of the product obtained in Step 1. (31.6 g) and triethylamine (29.3 ml) in methylene chloride (750 ml) cooled to 0° C. under nitrogen. The reaction mixture is stirred at RT for 21/2 hours and cooled to 0° C. Piperidine (175 ml) is added to the cooled reaction mixture and the solution stirred at RT overnight. Sat'd aq. sodium bicarbonate is added to the solution and the mixture is stirred for 30 minutes. The organic layer is separated, washed with sat'd NaCl and dried. The solution is filtered and the filtrate evaporated in vacuo yielding the desired product as its hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1>>[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:28])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:21]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)c1

Procedure:
62.5 mg of solid beige-coloured 3-[4-(3-m-tolylureido)phenyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and m-tolyl isocyanate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C@H:39]([NH:41][C:42]([NH2:44])=[O:43])[CH3:40])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.O1CCOCC1>[F:32][C:33]1[CH:34]=[CH:35][C:36]([C@H:39]([NH:41][C:42]([NH:44][C:2]2[N:7]=[CH:6][C:5]3[C:8]([NH:30][CH3:31])=[N:9][N:10]([C:11]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:4]=3[CH:3]=2)=[O:43])[CH3:40])=[CH:37][CH:38]=1
Reactant: C[C@@H](NC(N)=O)c1ccc(F)cc1
Reactant: CNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccc(F)cc3)ncc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Chloro-N-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (332 mg, 0.781 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (Intermediate 20C; 193 mg, 1.059 mmol), BrettPhos pre-catalyst (48.0 mg, 0.060 mmol), and cesium carbonate (759 mg, 2.330 mmol) were taken up in 1,4-dioxane (6 mL) in a 20 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction was stirred at 100° C. for 3 h. Room temperature was attained, the reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (0-100% EtOAc-DCM) gave (R)-1-(1-(4-fluorophenyl)ethyl)-3-(3-(methylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. MS ESI calc'd. For C35H31FN6O [M+1]+ 571. found 571.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH2:20][CH2:19][N:18](CC4C=CC=CC=4)[CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd]>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH2:20][CH2:19][NH:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCCC1)c1ncnc2c1CCN(Cc1ccccc1)C2
Agent: [Pd]
Product: O=C(NCC1CCCCC1)c1ncnc2c1CCNC2
Reaction time: 8 h

Procedure:
Into a 500 ml hydrogenation vessel was combined 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carboxylic acid, cyclohexylmethyl-amide (80 mg, 0.22 mmol), palladium on carbon (30 mg) and methano. The vessel was purged and evacuated with hydrogen three times and allowed to agitate overnight at 15 psi. The contents were filtered over celite and concentrated to afford the title compound (4.7 mg, 7.7%.
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.C(O)(C)C>CS(C)=O>[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: CS(C)=O
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 91.1 %

Procedure:
5 g (17.8 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 2.5 mL of DMSO and 4.2 mL (37.9 mmole) of N-methyl piperazine. The reaction mixture was heated to 120° C. and the suspension became soluble. After 2.5 h the reaction was completed. The mixture was then cooled to 70° C. and isopropanol (25 mL) was then added at this temperature. The reaction mixture was slurried for 1 h at ambient temperature, filtered, and dried overnight to obtain 5.86 g (91.3%) of levofloxacin.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:25]=[CH:24][C:12]([O:13][CH:14]([CH3:23])[CH2:15][NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].BrC1C=CC(O[C@H](C)CNS(C(C)C)(=O)=O)=CC=1.CC(O)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>[CH3:23][C@@H:14]([O:13][C:12]1[CH:24]=[CH:25][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[CH2:15][NH:16][S:17]([CH:20]([CH3:21])[CH3:22])(=[O:19])=[O:18]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)S(=O)(=O)NC[C@@H](C)Oc1ccc(Br)cc1
Agent: CC(O)C(C)O
Product: CC(C)S(=O)(=O)NC[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 85 °C
Yield: 113 %

Procedure:
4-Cyanobenzeneboronic acid (171 mg, 1.16 mmol, prepared in example 25), tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.063 mmol), 2 M sodium carbonate (1.6 mL), and [(2R)-2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (310 mg, 0.922 mmol) were combined in a 15 mL round bottomed flask with dimethylethylene glycol (6.15 mL, DME), fitted with a condenser, stirbar, and in a temperature regulated oil bath, and refluxed in a nitrogen system to 85° C., overnight. The reaction was allowed to cool to room temperature, and quenched with 15 mL of water, and extracted three times with 15 mL ethyl acetate. The organic layer was dried with magnesium sulfate, filtered through Celite®, and concentrated under reduced pressure, yielding 470 mg viscous black oil. This material was further purified using a 4000 uM rotor on a Chromatotron® in a 1:1 hexanes:ethyl acetate solvent system yielding the final title compound (57.5 mg, 18%) as white crystals.
Reaction SMILES: [CH2:1]([Si:3](Cl)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH2:9]([O:11][C:12]([C@@H:14]1[CH2:18][C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[C:16]([CH3:26])[C@H:15]1[OH:27])=[O:13])[CH3:10].N1C=CN=C1>C(Cl)Cl>[CH2:9]([O:11][C:12]([C@@H:14]1[CH2:18][C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[C:16]([CH3:26])[C@H:15]1[O:27][Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:13])[CH3:10]
Reactant: CCOC(=O)[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1O
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1O[Si](CC)(CC)CC
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Triethylsilyl chloride (145 μL, 0.863 mmol, 1.5 equiv) was added dropwise to a solution of alcohol 88 (150 mg, 0.575 mmol) and imidazole (17 mg, 1.72 mmol, 3 equiv) in methylene chloride (4 ml) at 0° C. After stirring at 0° C. for 2 hr, the reaction was quenched with water (2.5 ml), and extracted with ethyl acetate (3×5 ml). The organic extracts were washed with brine (3.5 ml), and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvents in vacuo furnished an oily crude product which was purified by flash column chromatography on silica (2-7% EtOAc/hexanes-) to give 93 (198 mg, 92%) as a yellow oil: [α]22D=−51.04 (c=0.7, CHCl3); TLC Rf=0.29 (silica gel, 25% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H), 7.45-7.42 (dd, 1H, 3J=1.8 Hz, 2J=8.4 Hz), 7.2-7.18 (d, 1H, 3J=7.8 Hz), 5.12 (d, 1H, 3J=4.8 Hz), 4.2-4.16 (dd, 2H, 3J=7.2 Hz, 2J=14.4 Hz), 3.17-3.12 (m, 1H), 3.0-2.89 (m, 2H), 2.3 (s, 3H), 1.97 (s, 3H), 1.29-1.26 (t, 3H, 3J=14.4 Hz), 0.98-0.95 (t, 9H, 3J=7.8 Hz), 0.67-0.63 (q, 6H, 3J=7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 175.31, 153.31, 149.87, 139.09, 136.51, 134.07, 131.15, 122.39, 84.53, 60.83, 51.58, 37.40, 18.42, 14.46, 13.31, 7.03, 5.15; HRMS calcd for C21H33NO3Si+H+376.2308; found 376.2302 [M+H+].