Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].C1(C)C=CC=CC=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>CN(C)C=O>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CN(C)CCCCl
Reactant: COc1ccc(O)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(OCCCN(C)C)c(C=O)c1

Procedure:
2-Hydroxy-5-methoxybenzaldehyde (31.2 g) in 170 ml of dimethylformamide is treated first with 10.1 g of 50% sodium hydride, then with 160 ml of a 2 N toluene solution of 3-dimethylaminopropyl chloride, following the procedure described in Example 1A, yielding 34.1 g of the title compound, boiling point 149°-155° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(C)(C)C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cccc(CBr)c1
Temperature: 25 °C

Procedure:
Dissolve 3-tert-butyltoluene (0.5 mL, 2.9 mmol) in carbon tetrachloride (20 mL). Add NBS (530 mg, 3 mmol) and irradiate the reaction mixture with a 250 watt sun-lamp with simultaneous heating to reflux for 1 h. Cool to ambient temperature, filter, and concentrate filtrate to dryness to give crude 1-bromomethyl-3-tert-butylbenzene. Dissolve crude 1-bromomethyl-3-tert-butylbenzene (600 mg) in anhydrous DMF. Add portion wise sodium azide (260 mg, 4 mmol) and stir at room temperature for 2 h. Pour the mixture into water (250 mL), extract with EtOAc (3×50 mL), wash combined organic extracts with brine, dry over MgSO4, filter and evaporate solvent to give crude 1-azidomethyl-3-tert-butylbenzene, that was used without further purification. Dissolve crude 1-azidomethyl-3-tert-butylbenzene in methanol containing 10% Pd/C (75 mg) at 5° C., and stir the resulting slurry under 1 atm H2 for 1 h. Filtrate, concentrate in vacuo and purify by chromatography on silica gel eluting sequentially with hexane/EtOAc (4:1 and 1:1), EtOAc, methanol and 2M ammonia in methanol to give the title compound (255 mg, 53% overall). MS (ES+) m/z: 164 (M+H)+.
Reaction SMILES: [Cl-].[Li+].[CH3:3][N:4]1[C:8]2=[N:9][CH:10]=[C:11](Br)[CH:12]=[C:7]2[C:6]([CH3:15])([CH3:14])[C:5]1=[O:16].[CH2:17]([O:19]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:18]>C1(C)C=CC=CC=1.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>[CH3:3][N:4]1[C:8]2=[N:9][CH:10]=[C:11]([C:17](=[O:19])[CH3:18])[CH:12]=[C:7]2[C:6]([CH3:15])([CH3:14])[C:5]1=[O:16]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CN1C(=O)C(C)(C)c2cc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc2c(c1)C(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Under argon, suspend 482 mg (11.37 mmol) of lithium chloride and 90 mg (7.84×10-5 mol) of tetrakis(triphenylphosphine)palladium in 10 ml of anhydrous toluene. Add to that suspension a solution of 1 g (3.92 mmol) of 1,3-dihydro-1,3,3-trimethyl-5-bromo-2H-pyrrolo[2,3-b]pyridin-2-one and 1.46 mg (4.04 mmol) of (1-ethoxyvinyl)tributyltin in 20 ml of anhydrous toluene. After 5 hours at reflux, evaporate off the solvent and take up the residue in a 1:1 mixture (30 ml) of dioxane and 10% hydrochloric acid. After 30 minutes' stirring at room temperature, evaporate off the dioxane. Filter off the resulting tin salts over Celite. Extract the filtrate with dichloromethane and dry over magnesium sulfate. After purification on a silica column, 780 mg of the title product are obtained in a yield of 90% ##STR59##
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8](C(OC(C)(C)C)=O)[N:9]=[CH:10][C:5]2=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.CNC>CO.O>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]=12
Reactant: CC(C)(C)OC(=O)n1ncc2c(-c3ccco3)nc(N)nc21
Agent: CNC
Solvent: O
Solvent: CO
Product: Nc1nc(-c2ccco2)c2cn[nH]c2n1
Yield: 69.4 %

Procedure:
A solution of tert-butyl 6-amino-4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate (204 mg, 0.68 mmol) in MeOH (2 mL) was treated with dimethylamine in water (0.5 mL, 40%), refluxed for 1 h, cooled and the resulting solid filtered and washed with water to give the title compound (95 mg, 70%) as a cream solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.O[C@@H]([C@H]1CN([C@@H]([C:31]2[CH:36]=[CH:35][C:34](OC)=[CH:33][CH:32]=2)C)C(=O)C1)C.B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].CO[CH2:51][CH2:52]OC>O>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:31]3[CH:32]=[CH:33][C:34]([N:7]4[CH2:52][CH2:51][NH:17][CH2:5][CH2:6]4)=[CH:35][CH:36]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: COCCOC
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Cs+]
Solvent: O
Product: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C

Procedure:
To an appropriate sized container charged with a magnetic stir bar, aryl halide 2.06, 2.58 or 2.62 (1 equiv), boronic acid or ester (1.2 equiv), cesium carbonate (3 equiv), and PEPPSI-IPr catalyst (0.1 equiv) were added and reagents were taken up in 2:1 DME:water. After evacuating and backfilling with argon, mixture was heated at 100° C. for one hour. After cooling to room temperature, mixture is poured into water and extracted with ethyl acetate. Combined organics were dried, filtered, and concentrated under reduced pressure and resulting residues were purified by silica gel column chromatography or reverse phase HPLC to yield Examples 3B.01-3B.31.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[NH2:10][C:11]1[N:15]([C:16]2[CH:17]=[C:18]([S:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:20][CH:21]=2)[N:14]=[C:13]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1.O>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:14]=[C:13]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(SCCO)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(SCCO)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
2,2,2-Trichloroethyl chloroformate (0.10 mL, 0.78 mmol) was added to a solution of Intermediate 35b (176 mg, 0.60 mmol) and DIPEA (0.31 mL, 1.81 mmol) in THF (10 mL) and the mixture stirred at RT for 3 h. The mixture was diluted with water (15 mL), extracted with EtOAc (3×20 mL), then the combined organic extracts dried (Na2SO4) and concentrated in vacuo. The residue was suspended in cyclohexane, and filtered to give the title compound as a yellow solid (280 mg, 100%). LCMS (Method 1): Rt 3.93 min, m/z 466, 468 [MH+]
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCO[C:42]2[CH:50]=[C:49]3[C:45]([C:46](C4C=CC=CC=4)=C(Br)C3=O)=[CH:44][CH:43]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:42]2[CH:50]=[CH:49][C:45]([CH3:46])=[CH:44][CH:43]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1
Yield: 52 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 of Example 96 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, p-tolylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (52%).
Reaction SMILES: [CH2:1]([C@@H:3]1[O:5][CH2:4]1)Cl.[CH3:6][C:7]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2[CH:12]=[C:11]([OH:17])[CH:10]=[CH:9][C:8]1=2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:6][C:7]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2[CH:12]=[C:11]([O:17][CH2:1][C@@H:3]3[CH2:4][O:5]3)[CH:10]=[CH:9][C:8]1=2
Reactant: CC1(C)CCCc2cc(O)ccc21
Reactant: ClC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CCCc2cc(OC[C@@H]3CO3)ccc21
Temperature: 45 °C
Reaction time: 168 h
Yield: 66.6 %

Procedure:
To a mixture of (R)-epichlorohydrin (2.2 g, 23.8 mmol) and 5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (2.1 g, 11.9 mmol) in acetone (30 ml) was added potassium carbonate (1.65 g, 11.9 mmol). The mixture was stirred at 45° C. for 7 days. The reaction mixture was then concentrated. The residue was partitioned between ethyl acetate and water and extracted twice with ethyl acetate. The organic extracts were combined and washed with water, brine, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by flash chromatography (silica, methylene chloride/heptane) to give 1.84 g (67%) of (S)-2-(5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-oxirane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([Cl:14])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([OH:23])[CH2:16]2>>[ClH:14].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([O:23][CH:17]3[CH:18]4[CH2:21][CH2:22][N:15]([CH2:20][CH2:19]4)[CH2:16]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1(c2ccc(Br)cc2)CCC1
Reactant: OC1CN2CCC1CC2
Product: Cl
Product: O=C(OC1CN2CCC1CC2)C1(c2ccc(Br)cc2)CCC1

Procedure:
The title compound was prepared in an analogous manner to that in Example 36. 1-(4-Bromophenyl)cyclobutanecarbonyl chloride, prepared from the compound prepared in Example 10, was refluxed with 3-quinuclidinol overnight. The crude was chromatographed on silica gel using EtOAc-Et3N 90:10 as eluent. The yield was 0.46 g (19%); mp 222-226° C.; 1H NMR (CD3OD) δ 1.73 (m, 2H), 1.82-2.15 (m, 4H), 2.23 (br, 1H), 2.53 (m, 2H), 2.85 (m, 2H), 2.95-3.10 (m, 2H), 3.20-3.35 (m, 3H), 3.66 (m, 1H), 5.06 (m, 1H), 7.25 (d, 2H), 7.50 (d, 2H). Anal. (C18H22BrNO2.HCl) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1.O>CN(C)C=O.C(OCC)(=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH:17]1[CH2:16][N:9]1[C:10]2[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:12]
Reactant: O=c1ccc2ncc(F)cc2[nH]1
Reactant: BrCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1ccc2ncc(F)cc2n1CC1OCCO1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.32 g of 7-fluoro-1,5-naphthyridin-2(1H)-one in 3 mL of N,N-dimethylformamide, 0.12 g of 60% sodium hydride was added at room temperature, and the mixture was stirred at 50 to 60° C. for 1 hour. Thereto was added 0.60 mL of 2-bromomethyl-1,3-dioxolan, the temperature was increased to 85 to 95° C., and the reaction mixture was stirred for 4 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were then added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant residue, chloroform was added, the solid was filtered off and purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=100:0 to 30:70 to obtain 0.23 g of 1-(1,3-dioxolan-2-ylmethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([O:31]CC)=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([OH:31])=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(CCOc2nccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2ncc(Cl)c(CCCC3(C(=O)O)CCN(CCOc4nccs4)CC3)c2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 0.68 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thiazol-2-yloxy)-ethyl]piperidine-4-carboxylate in 7 cm3 of dioxane, 9 cm3 of methanol and 2 cm3 of aqueous 5N sodium hydroxide solution was maintained at a temperature in the region of 60° C. for 20 hours. After cooling to about 20° C., the reaction mass was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was chromatographed under a pressure of 50 kPa of argon, on a column of silica gel (particle size 20-45μ; diameter 2.2 cm; mass 20 g), eluting with a mixture of dichloromethane/methanol (70/30 by volume). The fractions containing the expected product were combined and then concentrated to dryness under the above conditions. The residue obtained was taken up in 5 cm3 of ethyl acetate, stirred for 1 hour at room temperature and then filtered and rinsed with 3 times 3 cm3 of ethyl acetate and then 3 times 3 cm3 of pentane. 0.27 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thiazol-2-yloxy)-ethyl]piperidine-4-carboxylic acid was obtained in the form of a white solid melting at 188° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:24]=2[C:25]([OH:27])=O)[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]N[CH2:36][CH2:35]1.[CH2:47]([N:49](CC)CC)C>CN(C)C=O>[C:43]([O:42][C:40]([N:34]1[CH2:35][CH2:36][CH:47]([NH:49][C:25](=[O:27])[C:24]2[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:23]=2[CH:5]2[C:4]([C:1](=[O:3])[CH3:2])=[C:9]([CH3:10])[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[C:7](=[O:21])[N:6]2[CH3:22])[CH2:38][CH2:39]1)=[O:41])([CH3:44])([CH3:45])[CH3:46]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-[5-acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-5-cyano-benzoic acid (intermediate 6, 40.0 mg, 0.09 mmol) in N,N-dimethylformamide (1 mL) triethylamine (25.0 μL, 0.18 mmol) is added and stirred at room temperature for 5 min. Then O-(7-azabonzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (34.9 mg, 0.09 mmol) is added and stirred for 15 min. A solution of tert-butyl 1-piperazinecarboxylate (24.4 mg, 0.13 mmol) and triethylamine (25.0 μL, 0.18 mmol) in N,N-dimethylformamide (1 mL) is added and stirred at room temperature for 72 h. The reaction mixture is purified by reversed phase HPLC. ESI mass spectrum [M-Boc+H]+=526; Retention time HPLC: 1.16 min (HPLC method Z018_S04).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)C1C=CC=CC=1.[OH-].[Na+]>O.CS(C)=O>[CH2:2]([O:4][C:5](=[O:8])[CH2:6]/[N:7]=[CH:15]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C/N=C/c1ccccc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 87.2 %

Procedure:
Glycine ethyl ester hydrochloride (13.8 g (98.9 mmol)) and 50 g of toluene were mixed, and 10 g of dimethyl sulfoxide was flown thereinto at room temperature. Benzaldehyde (10.0 g (94.2 mmol)) was flown into the obtained mixture. The obtained mixture was adjusted to 12° C., and 16.5 g of a 25% aqueous sodium hydroxide solution (sodium hydroxide 104 mmol) was added dropwise over 3 hours. After completion of the dropwise addition, the obtained mixture was stirred at a temperature in a range from 11° C. to 13° C. for 20 hours. After completion of the reaction, the reaction mixture was cooled to 5° C., and 11.4 mL of water was added dropwise thereto. Thereafter, stirring was stopped to perform liquid separation, and the obtained organic layer was washed with 19 g of 20% by weight brine. The obtained organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure to obtain 43.6 g of a toluene solution of (E)-N-phenylmethyleneglycine ethyl ester (16.5 g of pure (E)-N-phenylmethyleneglycine ethyl ester). Yield: 92%
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25]O)[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=O)(C)C.[CH2:29]([N:31](CC)CC)[CH3:30].CS(Cl)(=O)=[O:38]>C(Cl)Cl>[O:27]=[C:21]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[C:15]([F:28])[CH:16]=2)[CH2:24][C@H:23]([CH2:25][NH:31][C:29](=[O:38])[CH3:30])[O:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (R)-(-)-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 5, 970 mg) and triethylamine (0.50 mL) in dry methylene chloride (9.5 mL) at 0° C. under N2 is treated with methanesulfonyl chloride (0.20 mL) dropwise. The resulting mixture is stirred at 0° C. for one hour, diluted with methylene chloride (40 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, mp 163-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@@:8]2([CH:16]([F:18])[F:17])[C@H:14]3[C@H:12]([CH2:13]3)[O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:20]1([CH:24]=O)[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:20]1([CH2:24][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]3([CH:16]([F:17])[F:18])[C@@H:14]4[C@@H:12]([CH2:13]4)[O:11][C:10]([NH2:15])=[N:9]3)[CH:7]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: NC1=N[C@](c2cc(N)ccc2F)(C(F)F)[C@@H]2C[C@@H]2O1
Reactant: O=CC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: NC1=N[C@@](c2cc(NCC3CCC3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (16g-B, 50 mg, 0.184 mmol) in 1,2-dichloroethane (1.2 mL) was added cyclobutanecarbaldehyde (15.51 mg, 0.184 mmol) and sodium triacetoxyborohydride (0.033 mL, 0.221 mmol). After addition, the mixture was then stirred at room temperature for 3 h. Additional cyclobutanecarbaldehyde (15.51 mg, 0.184 mmol) was added and the mixture was stirred at room temperature for additional 30 min. The mixture was quenched with saturated NaHCO3 and extracted with DCM (1×6 mL). The organic layer was collected, dried over MgSO4, and concentrated. The residue was then dissolved in MeOH and solution mixture was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give a desired product, which was dissolved in MeOH. The solution was loaded onto a PL-HCO3 MP SPE 200 mg/6 mL column and eluted with MeOH (2×2 mL). The combined eluates were concentrated and dried in vacuo to give 30 mg of the title compound as a light yellow solid. MS m/z=340.1 [M+H]+
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:13][N:14]([CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CNc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CN(C)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
To a solution of methyl 4-formylbenzoate (1 g, 6.1 mmol) and N-methylbenzenamine (650 mg, 6.1 mmol) in methanol (50 mL) was added acetic acid (2 drops) and the mixture was stirred for 0.5 hour. Then sodium cyanoborohydride (660 mg, 10 mmol) was added in portions. The mixture was stirred at room temperature for 24 hours. The mixture was washed with water (50 mL) and extracted with dichloromethane (50 mL). The organic phase was separated and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1:1) to give methyl 4-((methyl(phenyl)amino)methyl)benzoate (400 mg, 26%) as a yellow oil. LRMS (M+H+) m/z: calcd 255.13. found 255. 1H NMR (300 MHz, CD3OD): δ 7.96-7.32 (m, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.18-7.12 (m, 2H), 6.74-6.60 (m, 3H), 4.60 (s, 2H), 3.88 (s, 3H), 3.02 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:22][O:23][NH2:24].C(O)(C)C.C(O)C>C(OCC)(=O)C>[CH3:22][O:23][N:24]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[C:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1cnc2ccccc2c1Cl)c1ccccc1
Reactant: CON
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COn1c(-c2ccccc2)nc2cnc3ccccc3c21
Temperature: 80 °C

Procedure:
A mixture of N-(4-chloroquinolin-3-yl)benzamide (0.020 g, 1 eq), O-methylhydroxylamine hydrochloride (3 eq), and isopropanol was heated at 80° C. for 17 hours. The reaction was also run using ethanol in lieu of isopropanol. The two reaction mixtures were combined, diluted with ethyl acetate, washed sequentially with aqueous potassium carbonate (×2), water, and brine, dried over potassium carbonate, filtered, and then concentrated under reduced pressure. The resulting solid was dried at 80° C. for 3 days to provide 12.1 mg of 1-methoxy-2-phenyl-1H-imidazo[4,5-c]quinoline as a tan powder, mp 194.0-195° C. MS (APCI) m/z 276 (M+H)+; Anal. calcd for C17H13N3O.0.2H2O: C, 73.21; H, 4.84; N, 15.07. Found: C, 73.27; H, 4.61; N, 14.84.