Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C1(C)C=CC(S([CH:15]([N+:23]#[C-:24])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(=O)=O)=CC=1.[Br-].[Li+].[N:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:30][CH:29]=1>CCCCCC.O1CCCC1>[CH2:39]([O:38][C:36]([C:35]1[C:34]([C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)=[C:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[NH:23][CH:24]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)C=Cc1ccncc1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
36 ml (54.7 mmol) of a 1.53 N solution of butyllithium in hexane were added to 240 ml of tetrahydrofuran. A solution of 15.90 g (54.7 mmol) of α-(p-toluenesulfonyl)-4-fluorobenzylisonitrile in 120 ml of tetrahydrofuran was then added to the resulting solution at −45° C., followed by stirring of the resulting mixture for 10 minutes at the same temperature. At the end of this time, 25.00 g (273 mmol) of 95% lithium bromide were added, the resulting mixture was stirred for 30 minutes and then a solution of 8.73 g (49.2 mmol) of ethyl 3-(4-pyridyl)acrylate in 120 ml of tetrahydrofuran was added. The resulting mixture was stirred at the same temperature for 1 hour and then the cooling bath was removed and the mixture was stirred at room temperature for a further 1 hour. At the end of this time, 500 ml of water were added and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and then dried over anhydrous sodium sulfate, after which it was concentrated by evaporation under reduced pressure to afford a solid. The solid was washed with diethyl ether to give 13.61 g (yield 89%) of the title compound as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:19])[NH:14][C:15](=O)[CH2:16]Cl>CN(P(N(C)C)(N(C)C)=O)C>[CH3:10][S:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:16]=[C:15]([NH:14][C:13]([O:12][CH3:11])=[O:19])[N:1]=2)[CH:4]=1)=[O:9]
Reactant: CS(=O)c1ccc(N)nc1
Reactant: COC(=O)NC(=O)CCl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Nc1cn2cc(S(C)=O)ccc2n1

Procedure:
A suspension of 2-amino-5-(methylsulfinyl)pyridine (7.9 mmol) and methyl(chloroacetyl)carbamate (11.6 mmol) in 12 ml of HMPT is treated in a manner similar to that described in Example 1D to yield the product.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])#[N:4]
Reactant: CN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CCO
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Reaction time: 2.5 h

Procedure:
A solution of methylamine in ethanol (33%, 75 ml.) was added to a solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (10.1 g.) in ethanol (30 ml.). The reaction mixture was set aside at room temperature for 2.5 hours. Following concentration under reduced pressure, the residue was recrystallised twice from isopropyl alcohol/petroleum ether, affording N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (8.6 g.), m.p. 141°-143°. (Found: C, 47.5; H, 6.3; N, 33.2; S, 12.9. C10H16N6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][CH3:12])[C:4]=1[NH2:5].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C1(C)C=CC=CC=1>[C:13]1(=[N:5][C:4]2[C:6]([O:11][CH3:12])=[CH:7][C:8]([CH3:10])=[CH:9][C:3]=2[O:2][CH3:1])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCCCC1
Reactant: COc1cc(C)cc(OC)c1N
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C)cc(OC)c1N=C1CCCCC1

Procedure:
4.2 g of 2,6-dimethoxy-4-methylaniline are dissolved in 50 ml of toluene, 2.45 g of cyclohexanone are then added and the reaction mixture is heated at reflux for 18 hours. The water which is formed is removed as it is formed in the reaction mixture using a Dean and Stark apparatus. The toluene is evaporated and the oily N-cyclohexylidene-2,6-dimethoxy-4-methylaniline residue obtained is used without addition of purification in the following stage.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([OH:25])=[C:17]2[C:26](=[O:38])[N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:28](=[O:29])[C:16]=12)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([O:25][CH3:39])=[C:17]2[C:26](=[O:38])[N:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C:28](=[O:29])[C:16]=12)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc3c2O)C(=O)N1Cc1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Into a flask containing 5-benzhydryloxy-7-(4-fluoro-benzyl)-9-hydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione 245 (350 mg, 0.69 mmol, 1 equiv.) was added DMF (20 mL) followed by K2CO3 (478 mg, 3.46 mmol, 5 equiv.). To this was added MeI (983 μL, 6.93 mmol, 10 equiv.) under a nitrogen atmosphere and stirred for 16 hours. To the reaction was then added water (50 mL) and extracted with ethyl acetate (2×40 mL). The organic layer was washed several times with water (3×30 mL), saturated NaHCO3 (40 mL), brine solution (30 mL). It was dried over Na2SO4, filtered and concentrated in vacuo before being purified by silica gel chromatography using 3/2 Hexanes/ethyl acetate to obtain 5-benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dione 246 (78%, 280 mg, 0.54 mmol) as a yellow solid. 1H NMR (300 MHz) CDCl3 δ 9.03 (d, J=1.5 Hz, 1 H), 8.97 (d, J=1.5 Hz, 1 H), 7.75 (s, 1 H), 7.60 (dd, J1=1.5 Hz, J2=8.4 Hz, 4 H), 7.43-7.48 (m, 2 H), 7.19-7.27 (m, 7 H), 7.03-7.20 (m, 1H), 4.86 (s, 2 H), 4.37 (s, 3 H). MS: 542.0 (M+23). TLC Rf: 0.5 Hexanes/Ethyl acetate (1/1)
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:9][NH:8][N:7]=1.[F:24][C:25]([F:35])([F:34])[C:26](=O)[CH2:27][C:28](OCC)=[O:29]>CCOCC>[OH:29][C:28]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[CH:13][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:26]([C:25]([F:35])([F:34])[F:24])[CH:27]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1n[nH]cc1-c1ccc(Sc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Oc1cc(C(F)(F)F)nc2c(-c3ccc(Sc4ccccc4)cc3)cnn12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In an 8 ml acetic acid solution of 1.07 g of 3-amino-4-(4phenylthiophenyl)pyrazole, 0.6 ml of ethyl 4,4,4-trifluoroacetoacetate was added and stirred for 2 hours at 100° C. After allowing to cool, ether was added, and the precipitate was filtered and dried, and the title compound was obtained (200 mg, 13%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.C([O-])([O-])=O.[Na+].[Na+]>[N+]([O-])(O)=O>[C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1c[nH]c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: O=Cc1c[nH]c(-c2ccccc2)n1
Temperature: 0 °C

Procedure:
A 17.4 gm. portion of 2-phenyl-4-imidazolemethanol and 13.4 ml. of concentrated HNO3 are heated on a steam bath for 21/2 hours. Three drops of fuming HNO3 are added to start the reaction. The pH is adjusted to 8 with concentrated aqueous Na2CO3 and the mixture is cooled to 0° C. overnight. The solid is recovered, washed with water and recrystallized from a mixture of 70 ml. of ethyl acetate and 20 ml. of petroleum ether giving a yellow solid. Treatment of the mother liquor with petroleum ether gives an additional tacky substance which is triturated with isopropanol giving a second solid. These two solids are taken up in hot isopropanol and recrystallized as a yellow solid. This solid is recrystallized from ethanol:water (1:1) giving yellow crystals, m.p. 169°-171.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[OH-].[Na+].[OH:11][CH:12]1[CH2:15][NH:14][CH2:13]1>O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:14]2[CH2:15][CH:12]([OH:11])[CH2:13]2)[CH:7]=1
Reactant: OC1CNC1
Reactant: Clc1cc(Cl)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1CN(c2cc(Cl)ncn2)C1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
7.3 g (48.7 mmol) of 4,6-dichloropyrimidine are suspended in 140 ml of water, and 47 ml 1 N aqueous sodium hydroxide solution are added. 5.3 g (48.7 mmol) of 3-hydroxyazetidine are added, and the reaction mixture is stirred at 90° C. for 3 d. After cooling to RT, the reaction mixture is concentrated under reduced pressure and reacted further without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])/[C:3](/[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]>[Pd]>[F:1][C:2]([F:17])([F:18])[CH:3]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C(\Cc1ccccc1)C(F)(F)F
Agent: [Pd]
Product: CCOC(=O)CC(Cc1ccccc1)C(F)(F)F
Yield: 89.7 %

Procedure:
Ethyl (2E)-4,4,4-trifluoro-3-(phenylmethyl)-2-butenoate (175-E) (0.85 g, 3.30 mmol) was hydrogenated at room temperature with 10% Pd/C under a hydrogen balloon to yield 0.77 g (90%) of the title compound (176) as a colorless oil. From ethyl (2Z)-4,4,4-trifluoro-3-(phenylmethyl)-2-butenoate (175-Z) (0.35 g, 1.36 mmol), 0.31 g (88%) of the title compound (176) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.18 (t, J=7.2 Hz, 3H), 2.35 (dd, J1=16.4 Hz, J2=6.3 Hz, 1H), 2.55 (dd, J1=16.5 Hz, J2=6.2 Hz, 1H), 2.60-2.70 (m, 1H), 3.00-3.15 (m, 2H), 4.00 (q, J=7.2 Hz, 2H), 7.15-7.25 (m, 3H), 7.26-7.35 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1C(O)=O.C([N:17](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CC(O)(C)C.Cl[Cu]>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[NH2:17]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1F
Agent: Cl[Cu]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: Nc1ccc(C(F)(F)F)cc1F
Temperature: 50 °C
Yield: 57.9 %

Procedure:
To the solution of 2-fluoro-4-(trifluoromethyl)benzoic acid (1 kg, 4.805 mol, 1.00 equivalent “eq.”) and CuCl (14.26 g, 0.144 mol, 0.03 eq.) in t-BuOH (11.7 L) was added triethylamine (TEA, 533.8 g, 5.286 mol, 1.10 eq.) dropwise at room temperature (rt). Then the solution was heated to 50° C. and diphenylphosphoryl azide (DPPA, 1393 g, 5.045 mol, 1.05 eq.) was added dropwise to the solution at 50-60° C. After heating at 80˜85° C. overnight the solution was concentrated under vacuum. The residual was dissolved in H2O and filtered. The filtrate was extracted with ethyl acetate. The organic layers was dried with Na2SO4, filtered and concentrated under vacuum. The residual was dissolved in tert-Butyl methyl ether (TBME) and HCl (gas) was bubbled in for 2 hours. The filtrate was collected and dissolved in water and basified with 2 M NaOH. The solution was extracted with TBME. The organic layers were dried and concentrated under vacuum to give 2-fluoro-4-(trifluoromethyl) aniline (498 g, 58%) as a red oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[O:13]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a cooled (−78° C.) solution of 3-(tert-butoxycarbonylamino)propanoic acid (1.0 g, 5.3 mmol) in THF (53 mL) was added phenyllithium (9.9 mL, 16 mmol, 1.6 M solution in cyclohexane/ether). After warming slowly to 0° C. and then stirring for 1 hour, the reaction mixture was quenched with saturated NH4Cl (10 mL), diluted with water (70 mL) and extracted with ether. The combined organics were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed (20% ethyl acetate in hexanes) to provide the product (0.69 g, 59%) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:26])[CH2:24][OH:25])[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:26])[CH2:24][O:25][S:36]([CH3:35])(=[O:38])=[O:37])[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CO)c3Cl)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)COS(C)(=O)=O)c3Cl)c2n1
Reaction time: 0.5 h

Procedure:
To a solution of 8-[2,6-dichloro-3-(N-hydroxyacetyl-N-methylamino)benzyloxy]-2-methylquinoline (200 mg) and triethylamine (99.9 mg) in dry dichloromethane (2 ml) was added methanesulfonyl chloride (62.2 ml) under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was washed with water, saturated sodium bicarbonate solution and brine,dried over magnesium sulfate and concentrated in vacuo to give 8-[2,6-dichloro-3-(N-methanesulfonyloxyacetyl-N-methylamino)benzyloxy]-2-methylquinoline (220 mg) as colorless amorphous.
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:41]=[CH:40][C:39]([O:42]CC4C=CC=CC=4)=[CH:38][CH:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[OH:42][C:39]1[CH:38]=[CH:37][C:36]([C:19]2[N:20]=[C:21]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]4[N:32]=[CH:33][CH:34]=[CH:35][C:23]=4[N:22]3[C:18]=2[C:15]2[CH:16]=[CH:17][C:12]([C:8]3([NH:7][C:6](=[O:50])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:9][CH2:10][CH2:11]3)=[CH:13][CH:14]=2)=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(OCc5ccccc5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of tert-butyl[1-(4-{2-[4-(benzyloxy)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamate (236 mg, 0.36 mmol) in THF (10 mL) and MeOH (20 mL) was added 10%-Pd/C (100 mg). The reaction mixture was stirred under atomospheric hydrogen at room temperature for 19 hours. The reaction mixture was filtered through Celite and concentrated. The title compound was gave 125 mg as a white solid. LCMS: 572 [M+H].
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.Cl[C:17]([O:19][CH:20]([Cl:22])[CH3:21])=[O:18]>CCOCC>[C:17](=[O:18])([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:19][CH:20]([Cl:22])[CH3:21]
Reactant: CCCCCCCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a stirring solution of dry n-octanol (6.42 g, 49.3 mmol) and pyridine (3.90 g, 49.3 mmol) in anhydrous ether (75 mL) was added at 0° C. alpha-chloroethyl chloroformate (prepared according to U.K. Pat. No. 1,426,717; 7.00 g, 49.3 mmol). The mixture was stirred vigorously for three hours at 25° C. then filtered. The filtrate was concentrated in vacuo and distilled at 102°-107° C. (2 mm) affording 8.1 g title product as a clear oil (34.2 mmol, 69.4%): 1H NMR (CDCl3) delta 0.44-2.03 (m, 15H), 1.60 (d, J=6 Hz, 3H), 3.94 (t, J=7 Hz, 2H), 6.18 (q, J=6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([CH3:12])=[N:6][C:5]=2[S:4][C:3]=1[CH3:13].CC(C)([O-])C.[K+].[Cl:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:12])=[CH:8][C:9]=2[NH:11][S:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)(=[O:29])=[O:28])[S:4][C:3]=1[CH3:13]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Cc1cc(N)c2c(Br)c(C)sc2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reaction time: 0.08 h
Yield: 48.4 %

Procedure:
To a solution of 3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-amine (1.6 g, 6.22 mmol) (Description 8) in THF (30 mL) was added potassium tert-butoxide (2.79 g, 24.89 mmol) and the mixture stirred for 5 min before adding 3-chlorobenzenesulfonyl chloride (2.190 mL, 15.56 mmol). The mixture was stirred for 1 h and the solvent was then removed in vacuo. Ethyl acetate (50 mL) was added and the mixture washed with water (3×30 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, afforded the title compound (1.3 g). LCMS (A) m/z: 431/433 [M+1]+, Rt 1.38 min (acidic).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25](OCC)=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][C:36]4=[O:40])=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:21])([F:22])[F:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCCN1CCCC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Product: O=C(NCCCN1CCCC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Yield: 54 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate (23 mg, 0.0542 mmol) and 1-(3-aminopropyl)-2-pyrrolidinone (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (15 mg, 54% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.05 (br s, 1 H), 8.59 (s, 1 H), 7.38 (s, 1 H), 7.16-7.13 (m, 2 H), 7.05-7.01 (m, 2 H), 4.86 (br s, 2 H), 4.14 (s, 2 H), 3.49-3.37 (m, 6 H), 2.40 (m, 2 H), 2.04 (m, 2 H), 1.87 (m, 2 H); MS m/z 521 (M+1).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[C:13](Cl)(=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:14][C:13]([NH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc(C(=O)O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.2 %

Procedure:
Aqueous NaOH (2N, 1.93 g, 48.3 mmol) was added to a solution of 4-aminobenzoic acid (3.0 g, 21.90 mmol) in H2O at 0° C. A clear solution appeared within 5 min. Then, benzyl carbonochloridate (4.45 g, 26.28 mmol) was added dropwise to the mixture and it was heated to room temperature and stirred for 2 h. The reaction mixture was diluted with water and separated with ether. The aqueous layer was cooled to 0° C. temperature and acidified with 6M HCl. The solid was collected by filtration, washed with water and dried. The crude solid was recrystallized from ethyl acetate-hexane to furnish 4-(benzyloxycarbonylamino)benzoic acid 10 (5.0 g, 84%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10]C)[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ccc(Br)cc1O
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
To a stirred solution of 4-bromo-2-methoxy-benzonitrile (4.60 g, 21.7 mmol) in methylene chloride (20 mL) was added aluminum chloride (14.5 g, 108 mmol). After stirring under an argon atmosphere for 10 min, more methylene chloride (30 mL) was added, and the mixture left to reflux under argon overnight. The reaction was then diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure, providing (4.09 g, 95.2%) of 4-bromo-2-hydroxy-benzonitrile as a slightly gray-colored product. 1H-NMR (CDCl3) δ 7.35 (d, J=8.4 Hz, 1H), 7.19 (d, J=1.4 Hz, 1H), 7.14 (dd, J=8.4, 1.4 Hz, 1H), 6.15 (s, 1H); TLC Rf=0.78 (50% ethyl acetate—hexane).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>>[CH2:14]([NH:17][C:11]([CH:2]1[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1]1)=[O:13])[CH:15]=[CH2:16]
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: C=CCN
Product: C=CCNC(=O)C1CCc2ccccc2O1

Procedure:
3 Was prepared as white crystals, mp: 76°-77° C. from the ethyl ester of chroman-2-carboxylic acid (Witiak et al. (1971)) and 2-propenamine, by the procedure described in the last paragraph of Example 2.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:50]=[CH:51][CH:52]=1)[C:12]([NH:14][C:15]1[C:16]([CH3:49])=[C:17]([C:24]([C:26]2[CH:27]=[CH:28][C:29]([NH:42][C:43](=[O:48])[C:44]([F:47])([F:46])[F:45])=[C:30]([CH:41]=2)[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=[O:25])[N:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)=[O:13])=[O:4].[CH2:53]([O:60][C:61]([C:63]1[CH:64]=[C:65]([CH:92]=[CH:93][C:94]=1[NH:95][C:96](=[O:101])[C:97]([F:100])([F:99])[F:98])[C:66]([C:68]1[N:76]2[C:71]([CH:72]=[CH:73][CH:74]=[CH:75]2)=[C:70]([NH:77][C:78]([C:80]2[CH:81]=[C:82]([CH:88]=[CH:89][CH:90]=2)[O:83][CH2:84][C:85](O)=[O:86])=[O:79])[C:69]=1[CH3:91])=[O:67])=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[CH2:53]([O:60][C:61]([C:63]1[CH:64]=[C:65]([CH:92]=[CH:93][C:94]=1[NH:95][C:96](=[O:101])[C:97]([F:100])([F:99])[F:98])[C:66]([C:68]1[N:76]2[C:71]([CH:72]=[CH:73][CH:74]=[CH:75]2)=[C:70]([NH:77][C:78]([C:80]2[CH:81]=[C:82]([CH:88]=[CH:89][CH:90]=2)[O:83][CH2:84][C:85]([NH:1][CH2:2][C:3]([NH:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:50]=[CH:51][CH:52]=2)[C:12]([NH:14][C:15]2[C:16]([CH3:49])=[C:17]([C:24]([C:26]3[CH:27]=[CH:28][C:29]([NH:42][C:43](=[O:48])[C:44]([F:45])([F:46])[F:47])=[C:30]([CH:41]=3)[C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])=[O:25])[N:18]3[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]3)=[O:13])=[O:4])=[O:86])=[O:79])[C:69]=1[CH3:91])=[O:67])=[O:62])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: Cc1c(NC(=O)c2cccc(OCC(=O)O)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Reactant: Cc1c(NC(=O)c2cccc(OCCNC(=O)CN)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Product: Cc1c(NC(=O)c2cccc(OCCNC(=O)CNC(=O)COc3cccc(C(=O)Nc4c(C)c(C(=O)c5ccc(NC(=O)C(F)(F)F)c(C(=O)OCc6ccccc6)c5)n5ccccc45)c3)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1

Procedure:
By following the process described in stage G of Example 42, the coupling of the amine obtained in stage A above with (3-{[(3-{3-[(benzyloxy)carbonyl]-4-[(trifluoroacetyl)amino]benzoyl}-2-methylindolizin-1-yl)amino]carbonyl}phenoxy)acetic acid (described in stage D of Example 44) is carried out.