Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=O)(C)(C)C.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:33]2[CH:37]=[N:36][N:35]=[N:34]2)=[C:22]([CH:32]=1)[CH2:23][NH:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:13][C:10]([CH3:11])([CH3:12])[C@H:9]([C:14]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:25]([NH:24][CH2:23][C:22]1[CH:32]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=1[N:33]1[CH:37]=[N:36][N:35]=[N:34]1)=[O:31])=[O:16])[NH2:8]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](N)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1

Procedure:
The title compound was prepared from N-(tert-butoxycarbonyl)-3-methyl-D-valine (53 mg, 0.23 mmol), N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 87 mg, 0.23 mmol, 1.0 equiv), EDC (66 mg, 0.34 mmol, 1.5 equiv) and HOAt (16 mg, 0.11 mmol, 0.5 equiv) in DMF (1 mL) followed by deprotection in TFA-CH2Cl2 essentially according to the procedure described in Example 26, Step C. Purification by reverse phase chromatography [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 50:50 water (+0.1% TFA)/CH3CN (+0.1% TFA)] followed by lyophilization of the fractions afforded the title compound as a white powder. 1H NMR (300 MHz, CDCl3): δ 9.22 (s, 1 H), 8.32–8.29 (m, 3 H), 7.85 (d, J=1.8 Hz, 1 H), 7.43 (dd, J=2.1, 8.4 Hz, 1 H), 7.15 (d, J=8.4 Hz, 1 H), 4.45 (app d, J=8.1 Hz, 1 H), 4.35–4.27 (m, 2 H), 3.95–3.79 (m, 2 H), 3.62–3.56 (m, 1 H), 2.31–2.25 (m, 1 H), 2.10–1.87 (m, 3 H), 1.18 (s, 9 H). HRMS (APCI) M+H: calculated for (C19H26N7O2Cl)+ 420.1910, found 420.1915.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[CH:12]=[C:11]([C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:27])=[O:26])([CH3:24])[CH3:23])[N:10]=1.C(O)C.CN(C=O)C>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:21][C@H:16]1[CH2:17][O:18][CH2:19][CH2:20][N:15]1[C:13]1[CH:12]=[C:11]([C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:27])=[O:26])([CH3:24])[CH3:23])[N:10]=[C:9]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:14]=1
Reactant: Nc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccn2)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccccn2)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.773 g, 3.53 mmol) and 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(2-pyridin-2-ylsulfonylpropan-2-yl)pyrimidine (1.4 g, 3.53 mmol) were suspended in a mixture of DME (10 mL), ethanol (10.00 mL), DMF (10.00 mL) and water (10 mL) at RT under nitrogen. The mixture was purged with nitrogen and bis(triphenylphosphine)palladium(II) chloride (0.124 g, 0.18 mmol) was added. The resulting suspension was stirred at 80° C. for 90 minutes under an atmosphere of nitrogen. The reaction mixture was concentrated and diluted with ethyl acetate (150 mL), and washed with water (2×150 mL) and saturated brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% ethyl acetate in DCM, to give the desired material as a yellow foam (1.210 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=3[O:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([O:28][CH3:29])[CH2:24][CH2:23]3)=[CH:10][N:9]([CH3:30])[C:8]=12>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=3[O:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[NH2:18])=[CH:10][N:9]([CH3:30])[C:8]=12
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3O[C@H]3CC[C@H](OC)CC3)cn(C)c12
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1nccc2c(-c3cc(N)ccc3O[C@H]3CC[C@H](OC)CC3)cn(C)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Example 6B (0.025 g, 0.061 mmol) in tetrahydrofuran (10 mL) was added to 10% palladium on carbon (0.005 g, 0.047 mmol) in a 50 mL pressure bottle and stirred at ambient temperature under hydrogen at 30 psi for 2 hours. The solid was removed by filtration, and the filtrate was concentrated to provide the title compound (0.023 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[C:3]=1[C:12]#[CH:13].FC1C=CC(P(C2C=CC(F)=CC=2)C2C=CC(F)=CC=2)=CC=1>CN(C=O)C.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:13]=[CH:12][C:3]=12
Reactant: C#Cc1c(N)ncc([N+](=O)[O-])c1Cl
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: Fc1ccc(P(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Solvent: C1=CCCC=CCC1
Product: O=[N+]([O-])c1cnc2[nH]ccc2c1Cl
Temperature: 80 °C
Yield: 82.5 %

Procedure:
To a solution of 4-chloro-3-ethynyl-5-nitropyridin-2-amine (0.16 g, 0.81 mmol) in DMF (3 mL) was added chloro(1,5-cyclooctadiene)rhodium (I) dimer (0.02 g, 0.04 mmol) and tris(4-fluorophenyl)phosphine (0.128 g, 0.405 mmol). The reaction mixture was degassed by bubbling argon for 15 min. The reaction mixture was heated at about 80° C. for about 45 min. The solvent was removed under reduced pressure and the residue was suspended in ether (10 mL). The precipitate was collected by filtration and dried to give 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.132 g, 83%, contains approximately 6% mol of DMF and approximately 3% mol of tris(4-fluorophenyl)phosphine) as a brown solid: LC/MS (Table 1, Method a) Rt=2.05 min; MS m/z 198 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O-:19])=[O:18])[O:11][C:10]=2[C:9]([CH2:20][CH2:21][CH3:22])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[Na+].Cl>O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[O:11][C:10]=2[C:9]([CH2:20][CH2:21][CH3:22])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CCCc1c2ccccc2c(O)c2c(=O)cc(C(=O)[O-])oc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCc1c2ccccc2c(O)c2c(=O)cc(C(=O)O)oc12

Procedure:
The product of step (b) (0.2 g) was dissolved in hot water (20 ml) and acidified with hydrochloric acid. The title acid precipitated as an orange solid (0.18 g) mp 283° (decomp).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=O)=[CH:4][CH:3]=1.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]=[CH:16][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: O=CCc1ccc(Br)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=CCc1ccc(Br)cc1
Reaction time: 16 h

Procedure:
To a cold solution (-78° C.) of 15 g (62 mmol) of ethyl (4-bromophenyl)acetate (Compound A) in 150 ml of CH2Cl2 was added dropwise (over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at -78° C. for an additional hour. The reaction was quenched by the dropwise addition of methanol (10 ml), followed by water (10 ml) and 10% HCl (40 ml). The mixture was then warmed to 0° C., stirred for 10 minutes and then washed with water (15 ml), 10% aqueous NaHCO3 (10 ml) and brine (10 ml). The organic phase was dried over MgSO4 and the solvent distilled off at ambient temperature to give crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) of this crude aldehyde in 150 ml of CH2Cl2 was added a solution of 26 g (74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml of CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over 1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH3:13])[O:4][CH:5]([Cl:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COCCOCCOCCO
Reactant: O=C(Cl)OC(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOCCOCCOC(=O)OC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
α-Chlorobenzyl chloroformate (1 g) was added to an ice-cold solution of triethyleneglycol monomethylether (0.7 ml) in dichloromethane (5 ml) followed by pyridine (0.43 ml) at such a rate that the temperature was kept below 10° C. After stirring overnight at room temperature the reaction mixture was washed twice with 0.5 M HCl followed by water and aqueous sodium bicarbonate. Drying over magnesium sulfate, filtration, evaporation in vacuo followed by chromatography on silica gel with hexane/ethyl acetate (1:1) as eluent gave the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([OH:26])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccc(Cl)cc1Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Cl)cc1Oc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A solution of 4-chloro-2-(2-fluoro-phenoxy)-benzaldehyde (0.8 g, 3.2 mmol) in chloroform (10 mL) is treated with m-CPBA (2.75 g, 16 mmol). The reaction is heated to reflux and stirred for about 2 hr. The reaction is cooled to room temperature and quenched with 10% aqueous NaHSO4. The aqueous is extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, and the solvent is removed. The crude is diluted in methanol (20 mL) and treated with potassium carbonate (1.32 g, 9.6 mmol). The reaction stirred for 30 minutes at room temperature. The reaction is filtered and the solvent removed. The crude is purified by silica gel column chromatography using 4:1 hexanes:acetone to elute the pure product. The solvent is removed to afford about 0.64 g (84%) of product. 1H NMR (400 MHz, CDCl3). MS (ES−) m/z mass calcd for C12H8ClFO2 238, found 237 (M−1, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][CH:64]1[CH2:69][CH2:68][CH2:67][CH2:66][NH:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:65]1[CH2:66][CH2:67][CH2:68][CH2:69][CH:64]1[CH3:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-methyl-piperidine in DMSO at ambient temperature.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.NC1C=CC=CC=1.[SH2]=N.[CH3:35][S:36]([CH3:38])=O>C(N(CC)CC)C.C(Cl)Cl>[CH3:35][S:36][CH2:38][C:6]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[C:4]=1[NH2:5]
Reactant: CS(C)=O
Reactant: Nc1ccccc1C(F)(F)F
Agent: N=[SH2]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1cccc(C(F)(F)F)c1N
Reaction time: 3 h

Procedure:
In a 2-liter flask with stirrer is placed 147 g o-(trifluoromethyl)aniline, 250 g P2O5 and 1 liter CH2Cl2. With vigorous stirring simultaneously and separately, 250 mL dimethyl sulfoxide and 200 g triethyl amine were added dropwise at such a rate as to create gentle reflux; addition time ca 1 hour with reflux at 41°-42° C., and final temp 52° C. Fifteen minutes after completion of addition, temperature was still 51° C., but external heat was applied for 3 hours, then let stand overnight. Monitoring the reaction by glc was only partially successful; there was decrease in starting aniline and an increase in product peak (sulfilimine decomposing on column to ortho-rearranged product). After reaction, 10% caustic was added to fill flask, then layers separated. Caustic layer washed once with more CH2Cl2, then combined organic layers washed with water (salt added). The organic layer was stripped of solvent, heated (in kugelrohr) to ca 140°-150° C. for ca 1/2 hour. The material was distilled through 6" vigreux to give 100 g distillate, bp 60°-100° C. (0.3 mm). A more viscous oil 9.2 g was collected bp 140° C. (0.25-0.45 mm). A second distillation gave 80 g of 2-methylthiomethyl-6-trifluoromethyl aniline, bp 68°-78° C. (0.1 mm Hg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.C=O.[C:11](O)(C(F)(F)F)=O>C(O)C>[CH2:11]1[NH:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][CH:6]=[C:5]12
Reactant: NCCn1cccc1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: CCO
Product: c1cc2n(c1)CCNC2
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a ethanol solution (20 ml) of 1-(2-aminoethyl)pyrrole (9 mmol) and 37% formaldehyde (9 mmol) was added TFA (0.5 ml) and the resulting reaction mixture was allowed to stir at 50° C. for 15 minutes. It was then cooled to come to 25° C. and stirred at this temperature for 4 hrs. Solvent was removed under reduced pressure, residue was dissolved in ethyl acetate, basified with aqueous sodium carbonate solution, organic layer was separated and dried over sodium sulfate. Evaporation of the organic layer gave the crude 1,2,3,4-Tetrahydro-pyrrolo[1,2-a]pyrazine which was dissolved in dichloromethane (90 ml) at to it DIPEA (12.15 mmol) and boc anhydride (8.9 mmol) were added at 0° C. The resulting reaction mixture was allowed to stir for 16 hrs at 25° C. Organic layer was washed with sodium carbonate, water and brine and finally dried over sodium sulfate. Evaporation of the organic layer gave the crude product which was purified by column chromatography (1% ethyl acetate in dichloromethane) or (10% ethyl acetate in hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:32]1([N:38]=[C:39]=[S:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)C>[C:32]1([NH:38][C:39]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:3]=2)=[S:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: S=C=Nc1ccccc1
Reactant: COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=S)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
0.8 g (0.0023 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. While cooling the obtained solution in a dry ice-acetone bath in an argon atmosphere, 1.5 ml of a 1.69M-hexane solution of BuLi (0.0023×1.1 mol) was added thereto, followed by stirring the solution for about 10 minutes. After 0.62 g (0.0023×2.0 mol) of phenyl isothiocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the solution was removed from the bath and stirred at room temperature for about 30 minutes. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then precipitated with hexane, thereby obtaining an aimed product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]([OH:22])[C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:13]2[CH2:12][O:22]2)=[CH:15][N:16]=1
Reactant: COc1ccc([C@@H](O)COS(=O)(=O)c2ccc(C)cc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc([C@@H]2CO2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a stirred solution of (R)-2-hydroxy-2-(6-methoxypyridin-3-yl)ethyl 4-methylbenzenesulfonate in MeOH (150 mL) at 0° C. was added potassium carbonate (4.4 g, 0.032 mol) and the mixture was stirred at rt overnight. The mixture was filtered through Celite and the filter cake was washed with MeOH. The filtrate was concentrated and the residue was treated with EtOAc (150 mL) and aq. Na2CO3. The organic layer was separated and washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column to give the desired expoxide as a colorless oil (1.02 g, 42%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([CH:29]=O)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:39][CH:40]1[CH2:43][NH:42][CH2:41]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([CH2:29][N:42]5[CH2:43][CH:40]([F:39])[CH2:41]5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: FC1CNC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C=O)cccc4c3=O)cc2)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(CN5CC(F)C5)cccc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {1-[4-(8-formyl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (81 mg, 0.163 mmol) and 3-fluoroazetidine hydrochloride (23 mg, 0.245 mmol) in dichloroethane (5 mL) was stirred for 10 min. Sodium triacetoxyborohydride (87 mg, 0.409 mmol) was added and the reaction stirred at RT for 18 h. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution, diluted with DCM, filtered through a phase separation cartridge and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 50% EtOAc in DCM) to give the title compound as a gummy solid. LCMS (Method G): RT=2.71 min, [M+H]+=555.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][CH:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>C(#N)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:26]3[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH:20]([CH3:21])[CH3:19])[CH2:25]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: CC(C)NCC1CCNC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CNC(C)C)C3)nc21
Yield: 17.7 %

Procedure:
A near solution of 0.82 g (3.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and 1.4 g (10 mmole) of N-(2-propyl)-3-pyrrolidinemethanamine in 50 ml of acetonitrile was heated at reflux for one hour. The solvent was removed in vacuo, the residue dissolved in water, filtered through a fiber glass pad to clarify and the filtrate adjusted to pH 2.0 with 6 M hydrochloric acid. The resulting clear solution was lyophilized and the residue recrystallized from ethanol to give 200 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-[[(1-methylethyl)amino]methyl]-1-pyrrolidinyl]-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 302°-304° C. as the hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]=1)#[N:2].C(O)C.N>[Ni].O1CCOCC1.Cl.C(OCC)C>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]=1
Reactant: N#Cc1ccc(F)cn1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CCO
Solvent: CCOCC
Product: NCc1ccc(F)cn1
Reaction time: 16 h

Procedure:
Combine a mixture of 2-cyano-5-fluoropyridine (63.2 g, 0.52 mol), 22.5 g of Raney nickel, and ethanol (1.5 L) saturated with ammonia and hydrogenate at 500 p.s.i. and 70° C. for 16 h. Chromatograph the dark purple liquid over flash silica gel (methylene chloride/methanol/ammonia hydroxide—95:4.5:0.5) to give, after concentration at 25-30° C., a yellow liquid of the pure desired free base, 25.0 g (44%); 1H NMR (DMSO-d6) δ 8.43 (d, J=2.9 Hz, 1H), 7.66 (m, 1H), 7.50 (m, 1H), 3.77 (s, 2H), 2.10 (br, 2H); MS (ESI) m/z 127 (m+H). Add to a solution of the free base (20.0 g, 159.0 mmol) in 150 ml of 1,4-dioxane, 4N HCl in dioxane (150 mL, 3.8 eq.) and a white solid separates immediately. Dilute the solid with ethyl ether (300 mL) and filter. Dry the product at 20 mm Hg, 60° C., to give the pure dihydrochloride title compound, 30.0 g (95%); 1H NMR (DMSO-d6) δ 8.61 (d, J=2.9 Hz, 1H), 8.50 (brs, 3H), 7.82 (m, 1H), 7.62 (m, 1H), 7.50 (br, 1H), 4.18 (m, 2H); MS (ESI) m/z 127 (m+H, free base).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.[ClH:26].[S:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])[CH2:29][CH2:28]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:26].[CH3:25][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][N:30]3[CH2:29][CH2:28][S:27][CH2:32][CH2:31]3)=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCSCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCSCC2)c2c(c1)OC(C)(C)C1=C2CCC1
Yield: 35 %

Procedure:
A mixture of 1.5 g. (4.4 mmole) of 4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran, 0.99 g. (4.4 mmole) of γ-thiomorpholinobutyric acid hydrochloride, and 0.99 g. (4.8 mmole) of dicyclohexylcarbodiimide in 125 ml. of methylene chloride was stirred and heated at reflux for 16 hours. The reaction mixture was cooled and the byproduct of dicyclohexylurea was removed by suction filtration. The solvents were evaporated to give a residue which crystallized from a mixture of 10 ml. chloroform/40 ml. diethyl ether to give 0.85 g. (35%) of the desired product as a beige solid, m.p. 167°-171°C. The material was pure by thin layer chromatography, and the infrared and nuclear magnetic resonance spectra were in agreement with the proposed structure.