Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.CCOCC>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (60% weight dispersion in mineral oil, 1.35 g, 33.8 mmol) in PhMe (35 mL) at 0° C. was added ethyl 2-(diethoxyphosphoryl)acetate (7.57 g, 33.8 mmol, 6.7 mL). The reaction mixture was stirred at 0° C. for 20 min and a solution of bis(4-fluorophenyl)methanone (5.65 g, 25.9 mmol) in PhMe (35 mL) was added. The reaction mixture was warmed to room temperature, stirred for 1 h, and heated to 50° C. for 3 d. The reaction mixture was diluted with Et2O, washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated to give ethyl 3,3-bis(4-fluorophenyl)acrylate which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24])=[CH:13][C:12]([Cl:27])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:27][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:24])[F:25]
Reactant: CCOC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1Cc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1Cc1ccccc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 12 step B from a mixture of 6-chloro-2-piperidin-1-yl-4-(2-trifluoromethyl-benzyl)-quinoline-3-carboxylic acid ethyl ester and 1N NaOH in ethanol. Pale yellow solid. MS (ESI): 449 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.CC1(C)C[O:20][B:19](B2OCC(C)(C)CO2)[O:18]C1.C([O-])(=O)C.[K+].Cl>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].CS(C)=O>[B:19]([C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1)([OH:20])[OH:18]
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: O=C(O)CCCOc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(O)CCCOc1ccc(B(O)O)cc1
Temperature: 80 °C

Procedure:
A resealable tube was charged with 4-(4-bromophenoxy)butyric acid (259 mg, 1.0 mmol), 5,5,5′,5′-Tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] (249 mg, 1.1 mmol), potassium acetate (245 mg, 2.5 mmol), and DMSO (2 mL). The resulting orange suspension was deoxygenated by sparging with nitrogen gas. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (30 mg, 0.041 mmol) was added, and the tube was sealed tightly and heated at 80° C. overnight. Hydrochloric acid (1N) was added, and the mixture was extracted with EtOAc (2×), washed with water (2×) and brine (1×), and dried (MgSO4). The organic layer was concentrated in vacuo and the residue purified by flash chromatography (0 to 15% MeOH in DCM) to give the 2,2-dimethyl-1,3-propanediol boronic ester of 1A. This material was dissolved in diethyl ether and washed with NaOH (2 N, 2×). The aqueous layers were washed with diethyl ether, combined, and acidified to pH 4 with hydrochloric acid (6 N). The resulting solid precipitate was collected by filtration to afford 1A (210 mg, 94%) as a beige solid. 1H NMR (400 MHz, CD3OD) δ 2.06 (m, 2H), 2.48 (t, J=7.5 Hz, 2H), 4.02 (t, J=6.6 Hz, 2H), 6.88 (br s, 2H), 7.62 (br d, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10][N:9]1[C:18]([O:20][CH3:21])=[O:19])=[O:7])(C)(C)[CH3:2].[O-]CC.[Na+]>CCO>[CH2:1]([O:5][C:6]([CH:8]1[CH:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10][N:9]1[C:18]([O:20][CH3:21])=[O:19])=[O:7])[CH3:2]
Reactant: COC(=O)N1CCC2CCCCC2C1C(=O)OC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1C2CCCCC2CCN1C(=O)OC
Yield: 95.2 %

Procedure:
To a solution of 2-methoxycarbonyl-(1RS,4aSR,8aSR)-perhydoisoquinoline-1-carboxylic acid t-butyl ester (81.2 g, 273 mmol) in EtOH (500 mL) was added sodium ethoxide (21% in ethanol) (88.4 mL, 273 mmol) and the reaction mixture was refluxed (24 h). The organic solvent was evaporated in vacuo, ethyl acetate (400 mL) and water (100 mL) was added to the residue. The organic layer was separated, washed twice with water, dried (MgSO4), filtered, and the filtrate was concentrated in vacuo to afford an oil of pure title compound (70 g,0.95%); FAB-MS 270 (MH+); TLC Rf (A) 0.61.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][C:10]2[C:11](=[O:23])[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[C:17]([OH:21])[CH:16]=[CH:15][C:14]=3[F:22])=[CH:7][CH:6]=1)=[O:4].[CH3:28][O:29][C:30](=[O:33])[CH2:31]Br>>[CH3:28][O:29][C:30](=[O:33])[CH2:31][O:21][C:17]1[CH:16]=[CH:15][C:14]([F:22])=[C:13]2[C:18]=1[C:19]([CH3:20])=[C:10]([CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])[C:2]([CH3:27])([CH3:26])[CH3:1])=[CH:25][CH:24]=1)[C:11](=[O:23])[NH:12]2
Reactant: Cc1c(Cc2ccc(C(=O)C(C)(C)C)cc2)c(=O)[nH]c2c(F)ccc(O)c12
Reactant: COC(=O)CBr
Product: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 7a using 3-[4-(2,2-dimethylpropionyl)benzyl]-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one and bromoacetic acid methyl ester.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O1C[CH2:14][N:13]([C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=O)[CH2:12]C1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:45])=[C:30]([NH:32][C:33]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][CH:39]=[CH:38]3)=[O:34])[CH:31]=1.CN(C=O)C>O>[CH3:14][N:13]([CH3:12])[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:45])=[C:30]([NH:32][C:33]([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][CH:39]=[CH:38]3)=[O:34])[CH:31]=1)=[O:21]
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Reactant: O=C(O)c1cccc(N2CCOCC2)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc2ncccc2c1
Yield: 101.4 %

Procedure:
Diisopropylethylamine (0.174 ml) was added to a stirred mixture of 3-morpholinobenzoic acid (0.104 g), N-(5-amino-2-methylphenyl)quinoline-6-carboxamide (0.14 g), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.23 g) and DMF (1 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured into water and the resultant solid was isolated, washed with a saturated aqueous sodium bicarbonate solution and dried in a vacuum oven. There was thus obtained the title compound (0.216 g); NMR Spectrum: (DMSOd6) 2.25 (s, 3H), 3.18 (m, 4H), 3.75 (m, 4H), 7.14 (d, 1H), 7.25 (d, 1H), 7.36 (m, 2H), 7.44 (s, 1H), 7.62 (m, 2H), 7.86 (s, 1H), 8.13 (d, 1H), 8.28 (d, 1H), 8.52 (d, 1H), 8.65 (s, 1H), 9.0 (s, 1H), 10.14 (m, 2H); Mass Spectrum: M+H+ 467.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1>C1COCC1>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][OH:10]
Reactant: Cc1cccc(CC(=O)O)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1cccc(CCO)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 95 %

Procedure:
A round bottomed flask was charged with 1.2 g (6 mmol) 3-methyl-2-nitro-phenylacetic acid and 24 mL anhydrous THF. The reaction was cooled to 0° C. and then treated with 4.0 mL 2M BH3-DMS in THF (7.8 mmol) over 5 m. The reaction was allowed to warm to rt overnight. The volatile solvents were removed in vacuo and the resulting material was partitioned between EtOAc/1 M NaHCO3. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 1.06 g (95% yield) as a light, orange oil. 1H NMR (400 MHz, CDCl3) δ 7.32–7.16 (m, 3H), 3.84 (t, J=6.4 Hz, 2H), 2.81 (t, J=6.4 Hz, 2H), 2.30 (s, 3H).
Reaction SMILES: N.O1CCOCC1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:34][CH2:33][C:28]4(OCC[O:29]4)[CH2:27][CH2:26]3)[CH:16]=2)=[CH:11][C:10]=1[O:35][CH3:36].Cl>CC(C)=O>[NH2:24][C:22]1[C:23]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH2:8])=[C:10]([O:35][CH3:36])[CH:11]=3)=[CH:16][N:17]([CH:25]3[CH2:34][CH2:33][C:28](=[O:29])[CH2:27][CH2:26]3)[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: COc1cc(-c2cn(C3CCC4(CC3)OCCO4)c3ncnc(N)c23)ccc1N
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
tert-Butyl N-4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenylcarbamate (5.7 g, 0.011 mol), conc. ammonia solution (100 mL) and dioxan (100 mL) were heated in a pressure vessel for 20 hr at 120° C. The solvent was evaporated and the residue reconstituted in EtOAc/water (250 mL/100 mL). The organic layer was separated , dried (sodium sulphate), filtered and evaporated to give a solid which by HPLC (conditions: 5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) was observed to be a 2:1 mixture of tert-butyl N-4-[4-amino-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenylcarbamate and 5-(4-amino-3-methoxyphenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. The mixture was dissolved in acetone (200 mL) and HCl (SN, 100 mL) was added dropwise over 0.5 hr. The resulting solution was stirred at room temperature overnight and the solvent was then evaporated. The acidic solution was basified with 2N NaOH (ice-cooling) and extracted with EtOAc (3×150 mL). The combined organics were washed with water (2×100 mL). During the extraction process a solid precipitated. This solid was filtered and triturated in hot EtOAc/MeOH. The insolubles were filtered, the filtrate evaporated and then resulting solid triturated with diethylether/ethyl acetate to give a yellow solid. The organic layers from the original extraction were dried (sodium sulphate), filtered and evaporated. The resulting solid was triturated with diethyl ether/ethyl acetate (5:1) and filtered to give 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone as a yellow solid. (2.3 g, combined yield=78%). 1H NMR (d6 DMSO, 400 MHz): 8.17(1H, s), 7.32(1H, s), 6.88(1H, s), 6.77(1H, m), 6.73(1H, m), 6.71(1H, m), 6.07(2H, bs), 5.14(1H, m), 3.81 (3H, s), 2.72(2H, m), 2.35(4H, m), 2.18 (2H, m). HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=11.24 min, 95%
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.[F:36][C:37]1(C(O)=O)[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:39][CH2:38]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:27][N:25]([CH3:26])[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([NH:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([NH:7][C:6]([C:46]3[CH:45]=[CH:44][C:43]([C:40]4[CH:39]=[CH:38][C:37]([F:36])=[CH:42][CH:41]=4)=[CH:48][CH:47]=3)=[O:5])[CH2:9][CH2:10]2)[N:24]=1
Reactant: CN(C)c1nc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Reactant: O=C(O)C1(F)C=CC(c2ccccc2)=CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc(N[C@H]2CC[C@H](NC(=O)c3ccc(-c4ccc(F)cc4)cc3)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-[4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (0.76 g, 0.20 mmol) in CH2Cl2 (20 mL) was added TFA (304 μL, 0.39 mmol). The solution was stirred at ambient temperature for 4 hr. The resulting mixture was concentrated and the residue was dissolved in CH2Cl2. The organic layer was washed with a dilute aqueous NaOH and aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (twice) and the organic layers combined, dried over MgSO4, and concentrated. To a solution of the residue (0.1 g) and 4-fluoro-biphenyl-4-carboxylic acid (76 mg, 0.35 mmol) in CH2Cl2 were added HOAt (62 mg, 0.46 mmol), WSC—HCl (87 mg, 0.46 mmol), and diisopropylethylamine (31 uL, 0.18 mmol). The mixture was stirred for 1 hr at ambient temperature and the reaction was quenched with water. The aqueous layer was extracted with CH2Cl2 (twice). The organic layers were combined, dried over MgSO4, concentrated and the residue purified by column chromatography (silica gel, 2% to 4% 2 M NH3/MeOH in CH2Cl2) to give trans-4′-fluoro-biphenyl-4-carboxylic acid [4-(4-dimethlyamino-quinazolin-2-ylamino)-cyclohexyl]-amide (35 mg, 0.072, 21%) as a white solid.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][C:12]1[CH2:13][S:14](=[O:46])[C@@H:15]2[CH:35]([NH:36][C:37](=[O:44])[CH2:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:34](=[O:45])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C(Cl)Cl>[F:7][CH2:11][C:12]1[CH2:13][S:14](=[O:46])[C@@H:15]2[CH:35]([NH:36][C:37](=[O:44])[CH2:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:34](=[O:45])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS(=O)[C@H]12
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CF)CS(=O)[C@H]12
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
To a solution of 0.483 g (3.0 mmoles) of diethylaminosulfur trifluoride in 10 ml of CH2Cl2 at -78° under N2 was added a solution of 1.61 g (3.0 mmoles) of benzhydryl 3-hydroxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide in 50 ml of CH2Cl2 and the mixture was stirred at -78° for 0.5 hrs, then poured into 100 ml of water. The CH2Cl2 layer was dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel with 9:1 CH2Cl2 -acetone to yield 0.095 g of benzhydryl 3-fluoromethyl-7-(2-thienyl-acetamido)-3-cephem-4-carboxylate-1-oxide in fractions 12-15, rf = 0.60 on tlc with 9:1 CH2Cl2 -acetone; ir (CHCl3) 3450 (amide N-H), 1805 (β-lactam C=O), 1725 (ester C=O), 1680 (amide C=O), 1495 ("amide II" band), and 700 (aromatic) cm-1 ; mp 205.5°-207.5° d.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:20]([OH:22])[CH3:21])[C:15]=2[O:16][CH2:17][O:18][CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:20]([CH3:21])=[O:22])[C:15]=2[O:16][CH2:17][O:18][CH3:19])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1c(C(C)O)csc1-c1ccc(C(C)(C)C)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COCOc1c(C(C)=O)csc1-c1ccc(C(C)(C)C)cc1
Yield: 83.2 %

Procedure:
2-(4-t-Butylphenyl)-3-methoxymethyloxy-4-(1-hydroxyethyl)thiophene (0.64 g, 2.0 mmol) in dichloromethane (13 mL) was stirred with celite (2.0 g) and pyridinium chlorochromate (0.86 g, 4.0 mmol) at room temperature for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to give the desired product as a brown solid (0.53 g, yield 83%).
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]([OH:22])(=[S:21])[CH3:20].CN(C)C=O>C(OCC)C>[C:19]([S:21][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)(=[O:22])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Mixture of tert-butyl 3-iodoazetidine-1-carboxylate (STEP B, 2.05 g, 7.24 mmol), cesium carbonate (4.72 g, 14.5 mmol), thioacetic acid (1.10 g, 14.5 mmol) and dimethyl formamide (10 mL) was stirred at 70° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with diethyl ether (200 mL). The resulting mixture was washed with water (80 mL×3) and brine (50 mL), then dried over magnesium sulfate.
Reaction SMILES: [F:1][C:2]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:15](Cl)(Cl)=[O:16]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[N:4]=[C:15]=[O:16]
Reactant: CCOc1ccc(N)c(F)c1OCC
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1ccc(N=C=O)c(F)c1OCC
Temperature: 25 °C

Procedure:
2-Fluoro-3,4-diethoxyaniline (1.99 g) in toluene (20 ml) was dropwise added to a toluene solution containing 10 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 2-fluoro-3,4-diethoxyphenyl isocyanate. The thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and isopropanol (1.0 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(2-fluoro-3,4-diethoxyphenyl)carbamate (Compound No. 1) (1.99 g) in a yield of 69.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[CH:35]=[C:36]([C:39]([F:40])([F:41])[F:42])[CH:37]=[CH:38][C:32]=3[F:31])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3cc(C(F)(F)F)ccc3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 9.8 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.100 g, 0.268 mmol), thionyl chloride (3.0 mL), 2-fluoro-5-(trifluoromethyl) aniline (0.053 g, 0.296 mmol), THF (10.0 mL) and DIPEA (3 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.014 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 2.25 (s, 3H), 3.15 (s, 2H), 7.32 (m, 4H), 7.54 (m, 3H), 8.98 (s, 1H), 10.25 (s, 1H), 11.50 (s, 1H); MS [M+H]+: 533.37.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH2:10][CH2:9]2.[CH2:15]([OH:20])[CH:16]([OH:19])[CH2:17]Cl>CO>[OH:19][CH:16]([CH2:15][OH:20])[CH2:17][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH2:10][CH2:9]2
Reactant: OCC(O)CCl
Reactant: O=C1CCc2cccc(O)c2N1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2cccc(OCC(O)CO)c2N1
Yield: 33.8 %

Procedure:
0.8 g of potassium hydroxide was dissolved in 50 ml of methanol, and 1.63 g of 8-hydroxy-3,4-dihydrocarbostyril and 1.4 g of glycerol α-monochlorohydrin were added to the resulting solution followed by refluxing the mixture for 3 hours. The raction mixture was then concentrated to dryness, and the resulting residue was extracted with 50 ml of chloroform. The extract was washed with a 2% aqueous sodium hydroxide solution and then water, and then dried over anhydrous sodium sulfate. The chloroform was then removed by distillation and the resulting residue was recrystallized from ethanol to give 0.8 g of 8-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as a light yellow amorphous solid having a melting point of 182° - 184° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].O.[OH-].[Li+]>CS(C)=O>[CH3:20][C:18]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:19]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1ccc(C#N)c(N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(C#N)c(Nc2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-fluoro-2-nitro-benzene (5.34 g, 37.83 mmol), 2-amino-4-methyl-benzonitrile (5.00 g, 37.83 mmol), lithium hydroxide monohydrate (3.17 g, 75.66 mmol) and DMSO (70.0 ml) and stir at 55° C. Afer 16 hours; cool to ambient temperature, pour the mixture onto ice chips and stir. After 1 hour, remove the resulting yellow precipitate by vacuum filtration. Dry the precipitate under vacuum, recrystallize in ethanol to give 5.15 g (54%) of fine, amber colored needles: mp 162-164° C.; mass spectrum (ion spray): m/z 254.0 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[C:2]=1[NH2:8].O[CH2:10][CH:11]([CH2:13]O)O.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].S(=O)(=O)(O)O.[OH-].[Na+]>O>[N:7]1[C:3]2[C:4](=[CH:5][CH:6]=[N:1][C:2]=2[NH2:8])[CH:13]=[CH:11][CH:10]=1
Reactant: Nc1cccnc1N
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Nc1nccc2cccnc12
Temperature: 135 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
A mixture of pyridine-2,3-diamine (5.0 g, 45.9 mmol), glycerol (21.1 g, 229 mmol), sodium 3-nitrobenzenesulphonate (20.6 g, 91.7 mmol), sulfuric acid (20 mL) and water (30 mL) was heated to 135° C. and stirred for 16 h. The mixture was cooled to room temperature and then poured into ice/water (150 g). The mixture was adjusted to pH ˜9 with saturated NaOH aqueous solution. Then the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduce pressure to give the crude product, which was purified by silica gel column (eluting with PE/EtOAc v/v 2:1) to give 1,7-naphthyridin-8-amine as a yellow solid (2.6 g, yield 39%). ESI MS: m/z 146.1 [M+H]+.