Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16])([CH3:4])[CH3:3].[NH:18]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:27]=O)[C:21]=2[CH:20]=[CH:19]1.[OH-].[Na+]>C(O)C.O>[CH3:4][C:2]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH:16]=[CH:27][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[CH:20]=[CH:19][NH:18]2)([CH3:1])[CH3:3]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(=O)c1ccccc1OCCNC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NCCOc1ccccc1C(=O)C=Cc1cccc2[nH]ccc12
Reaction time: 4 h
Yield: 89.1 %

Procedure:
A solution of 5.4 g of 1-[2-{2-(1,1-dimethylethylamino)-ethoxy}-phenyl]-ethanone in 75 ml of ethanol was added with stirring under an inert atmosphere to a mixture of 3.339 g of indole-4-carboxaldehyde and 6 ml of 50% sodium hydroxide solution and after stirring for 4 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried over a deshydrant and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 7.41 g of 1-[2-{2-(1,1-dimethylethylamino)-ethoxy}-phenyl]-3-[1H-indol-4-yl]-2-propen-1-one (E).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]1)=[O:5])C.[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.[Cl-].C[Al+]C>C1(C)C=CC=CC=1.CCCCCC.CCOC(C)=O>[F:17][C:18]([F:27])([F:28])[O:19][C:20]1[CH:21]=[CH:22][C:23]([N:24]2[CH2:14][CH2:13][C:6]3([CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]3)[C:4]2=[O:5])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1(CCOC)CCNC(=O)C1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 25 °C

Procedure:
4-(2-Methoxy-ethyl)-2-oxo-piperidine-4-carboxylic acid ethyl ester (2 g) and 4-(trifluormethoxy)aniline (3.09 g) were dissolved in toluene (100 ml) under an argon atmosphere at RT, dimethylaluminium chloride in hexane (1 molar, 39.25 ml) was added and the mixture was refluxed for 8 hours. The reaction mixture was then cooled to RT, diluted with AcOEt, quenched with water (9 ml), dried over MgSO4, filtered and the solvent was evaporated off. The residue was adsorbed on silica gel and purified by flash chromatography on silica gel (acetone/CH2Cl2, gradient from 0 to 40%) to give 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione as light brown solid. MS (ESI): 329.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-methylimidazole (100 mg, 0.30 mmol) from Step C in THF (4 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.22 mL, 0.36 mmol). The reaction was stirred for 1 hr and then ethyl chloroformate (0.060 mL, 60 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (2×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound. HPLC/MS: 409 (M+1), 411 (M+3); Rt=4.19 min.
Reaction SMILES: [F:1][C:2]1[N:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH3:19][C:20]1[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=1>C(#N)C>[F:1][C:2]1[N:9]=[C:8]([NH:25][C:22]2[CH:21]=[C:20]([CH3:19])[NH:24][N:23]=2)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(F)nc1F
Reactant: Cc1cc(N)n[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(F)c(C#N)cc2F)n[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 2,5,6-trifluoronicotinonitrile (1.0 g, 6.3 mmol) and triethylamine (0.83 g, 8.2 mmol) in ACN (30 ml) at 0° C. was added 5-methyl-1H-pyrazol-3-amine (0.67 g, 6.9 mmol). The reaction was stirred at 0° C. for 1 hour, at which point the reaction was filtered. The resulting solid was washed with cold ACN, dried and collected to give the title compound (0.44 g, 29%). MS: Calcd.: 235. Found: [M+H]+ 236.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].I[C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Reactant: Cn1ccnc1I
Product: Cc1cc(-c2nccn2C)cc(C)c1Cl

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-iodo-1-methyl-imidazole following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.80 min; Mass spectrum (ESI+): m/z=221/223 (Cl) [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C1CCCCC=1>[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CC1CN(c2ccc([N+](=O)[O-])c(C(=O)O)c2)CC(C)O1
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CC1CN(c2ccc(N)c(C(=O)O)c2)CC(C)O1

Procedure:
The mixture of 6 g 2-nitro-5-(2,6-dimethylmorpholin-4-yl)benzoic acid, 15 ml cyclohexene and 3 g Pd/C (10%) is heated under reflux for 6 hours. The hot reaction mixture is filtered through a celite pad. After evaporation of the filtrate 4.8 g title product is obtained (MH+: 251).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([F:19])[C:17]=4[CH:18]=[C:5]3[C:4]=2[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:19][C:16]1[C:17]2[CH:18]=[C:5]3[C:4]4[N:3]=[C:2]([C:37]5[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]6[O:28][C:27]([C:24]7[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=7)=[C:31]([C:32]([NH:34][CH3:35])=[O:33])[C:30]=6[CH:36]=5)[CH:11]=[CH:10][C:9]=4[CH2:8][CH2:7][N:6]3[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a degassed solution of 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, 0.18 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (120 mg, 0.24 mmol) in 1,4-dioxane (8 mL) and water (200 μl) was added CS2CO3 (119 mg, 0.37 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (20 mg, 0.03 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred for 4 hours. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. Preparative TLC (eluted with 30% EtOAc/DCM) provide 5-(11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (90 mg, yield: 80%) MS (M+H)+: 613.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][CH2:15]CO>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH2:13][O:14][CH3:15])=[O:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COCCO
Agent: [Na]
Product: COCCOC(=O)c1ccc(O)cc1

Procedure:
In the first step (as in the Example 4) 1 g (43 mmol) of sodium was dissolved in 25 ml of 2-methoxyethanol. An amount of 3.0 g (22 mmol) of methyl 4-hydroxy-benzoate was added, producing 2-methoxyethyl 4-hydroxybenzoate, as a colourless oil, in essentially quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:11])=[N:6][CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([N:6]1[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c([N+](=O)[O-])c(O)ccn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a solution of 3-nitro-pyridine-2,4-diol (5.0 g, 32.3 mmol) in DMF (50 mL) at 0° C. was added NaH (2.6 g, 64.0 mmol 60% in mineral oil). After stirring at 0° C. for 15 min, benzyl bromide (6.03 g, 35.2 mmol) was added and the reaction was stirred at 55° C. for 17 h. The mixture was cooled to room temperature, poured into ice water, and filtered to remove insoluble material. The filtrate was acidified with 1 N HCl, extracted with CH2Cl2, dried with MgSO4, and concentrated. The product was washed with EtOH to give 1-benzyl-4-hydroxy-3-nitro-1H-pyridine-2-one (3.30 g, 42% yield). 1H-NMR (DMSO): δ 7.90 (d, 1H, J=7.6 Hz), 7.27-7.38 (m, 5H), 6.12 (d, 1H, J=7.6 Hz), 5.08 (s, 2H). MS: calculated for C12H10N2O4+H 247.1; found: 247.2.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[K+].[K+].[CH2:21](Cl)[O:22][CH3:23]>CO.C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:21][O:22][CH3:23]
Reactant: COCCl
Reactant: COc1ccc2c(Br)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COCOc1ccc2cc(OC)ccc2c1Br
Temperature: 20 °C
Reaction time: 48 h
Yield: 55.6 %

Procedure:
To a solution of 1-bromo-6-methoxynaphthalen-2-ol (described in U.S. 61/423,799) (2.90 g, 11.5 mmol) in MeOH (20 mL) and THF (20 mL) was added K2CO3 (3.18 g, 23.0 mmol) and MOMCl (1.10 g, 13.8 mmol). The resulting mixture was stirred at 20° C. for 48 hours and stirred at 30-40° C. for 5 days. An aqueous/EtOAc workup was followed by purification by silica gel column chromatography (PE to PE/EtOAc=200/1) to give the product (1.90 g, yield 56%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:24][C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]([OH:23])=O)[C:15]=2[CH:14]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:58][C:59]([CH3:63])([CH3:62])[CH2:60][OH:61]>CN(C)C=O>[OH:61][CH2:60][C:59]([NH:58][C:21]([C:20]1[C:15]2[CH:14]=[C:13]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH3:12])[CH:7]=3)[NH:24][C:16]=2[N:17]=[CH:18][CH:19]=1)=[O:23])([CH3:63])[CH3:62]
Reactant: COc1ccc2c(c1)c(-c1cc3c(C(=O)O)ccnc3[nH]1)cn2C
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(C(=O)NC(C)(C)CO)ccnc3[nH]1)cn2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(5-methoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine-4 carboxylic acid [32 mg, Example 41(a)] in dry dimethylformamide (10 mL), under nitrogen, was treated with diisopropylethylamine (35 μL) followed by O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (38 mg). After stirring at room temperature for 1 hour this mixture was treated with a solution of 2-amino-2-methyl-1-propanol (10.5 μL) in dry dimethylformamide (1 mL) and stirring was then continued for a further 2 hours. The reaction mixture was evaporated and the residue was treated with saturated aqueous sodium bicarbonate solution (15 mL). This mixture was stirred for 1 hour and the resulting yellow solid was filtered, then washed well with water and then dried at 100° C. under vacuum to give the title compound (34 mg) as a yellow solid, m.p. 210-212° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:17][O:18]C(Cl)Cl.Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]([C:6]1[C:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:10][C:11]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:18]
Reactant: CCOC(=O)c1cc2cccc(OC)c2o1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(C=O)ccc(OC)c2o1
Reaction time: 0.5 h

Procedure:
Ethyl 7-methoxybenzofuran-2-carboxylate (10 g) was dissolved in anhydrous methylene chloride (200 ml), to which were dropwise added dichloromethyl methyl ether (8.2 ml) and titanium tetrachloride (10 ml) with cooling with ice, and directly stirred for 30 minutes. After having been restored to be at room temperature, the mixture was stirred for further 1.5 hours. Then, an aqueous HCl (1 mol/liter) solution was dropwise added thereto to decompose the remaining titanium tetrachloride, and thereafter the mixture was extracted with chloroform. The extract was washed with an aqueous NaOH (1 mol/liter) solution and a saturated saline solution, and dried over sodium sulfate, and the solvent was thereafter evaporated. The residue was suspended in ether, and taken out therefrom through filtration to obtain Compound IIbz-s (8.9 g, 79%) as colorless crystals.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9]C(C#N)=[CH:7][CH:6]=1)=[O:4].[OH-:13].[Na+].[O:15]1[CH2:20][CH2:19]OCC1>O>[C:3]([C:5]1[CH:10]=[CH:9][C:19]([C:20]([OH:15])=[O:13])=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:1]
Reactant: C1COCCO1
Reactant: [OH-]
Reactant: CCC(=O)c1ccc(C#N)cc1
Agent: [Na+]
Solvent: O
Product: CCC(=O)c1ccc(C(=O)O)cc1
Yield: 98 %

Procedure:
4-Cyanopropiophenone (4.67 g, 29.3 mmol) was refluxed with 2N NaOH (90 mL, 180 mmol) and dioxane (90 mL) at 95° C. overnight. The mixture was diluted with water (150 mL), washed with ether (75 mL), acidified to pH 2 with concentrated HCl, and extracted with ether (3×75 mL). The organic phase was washed with saturated aqueous NaCl (3×75 mL), dried, and concentrated to give a yellow solid (5.12 g, 98%).
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]1[C:17]([O:18][CH3:19])=[C:16]2[C:12]([C:13]3[CH:30]=[C:29]([CH3:31])[CH:28]=[N:27][C:14]=3[N:15]2C(OC(C)(C)C)=O)=[C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH:33]=2)[CH:10]=1)=O)(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([S:38]([C:34]1[CH:33]=[C:32]([C:11]2[CH:10]=[C:9]([NH:8][CH3:6])[C:17]([O:18][CH3:19])=[C:16]3[C:12]=2[C:13]2[CH:30]=[C:29]([CH3:31])[CH:28]=[N:27][C:14]=2[NH:15]3)[CH:37]=[CH:36][CH:35]=1)(=[O:40])=[O:39])[CH3:42]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(N(C)C(=O)OC(C)(C)C)c(OC)c3c2c2cc(C)cnc2n3C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CCS(=O)(=O)c1cccc(-c2cc(NC)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
The crude residue from previous step (Compound 251) was dissolved in 3 mL CH2Cl2 and to were sequentially added 0.2 mL of anisole and 1 mL of TFA. The mixture was stirred at room temperature for 2 h. Solvent was removed in vacuum and the residue was basified with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and finally purified flash chromatography to furnish Compound 252 (287 mg, 70%, for 2 steps).
Reaction SMILES: [CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2.C(N(CC)CC)C.CCCP(=O)=O.[CH:37]([C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1)([CH3:39])[CH3:38]>ClCCCl>[CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:44][C:43]2[CH:45]=[CH:46][C:40]([CH:37]([CH3:39])[CH3:38])=[CH:41][CH:42]=2)=[O:15])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Agent: CCCP(=O)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(NC(=O)c2cccc(N3CCc4c(cnc5ccccc45)C3)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
To a mixture of 3-(1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid (0.20 mmol, 61 mg) and triethylamine (0.40 mmol, 0.056 mL) in 2.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.24 mmol, 0.143 mL). After 10 min at rt, 4-isopropylaniline (0.30 mmol, 0.043 mL) was added and the reaction stirred at rt for 1 hour. Then an additional 0.015 mL 4-isopropylaniline was added, the reaction heated at 60° C. for 5 min, then continued at rt for 3 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, dilute aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was recrystallized from EtOAc/hexane to give the title compound as an off-white solid (52 mg, 62%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:12][CH2:13][CH3:14])[CH:4]=1)#[N:2].[CH3:15][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[O:12][CH2:13][CH3:14]
Reactant: CCOc1cc(C#N)ccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: CCOc1cc(C#N)ccc1C(=O)OC
Yield: 74 %

Procedure:
Crude 4-cyano-2-ethoxybenzoic acid (19 g) was dissolved in a mixture of benzene (446 mL) and methanol (111 mL). At 0° C., (trimethylsilyl)diazomethane (76 mL, 2.0 M in ether, Aldrich) was added slowly and then at room temperature. Solvent was removed, and the residue was purified by flash chromatography (silica gel, eluting with 25% ethyl acetate in hexane) to give 4-cyano-2-ethoxybenzoic acid methyl ester as a solid (15.5 g, 74%).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[OH-].[K+]>C(O)C.O>[Cl:22][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[C:3]([OH:23])=[O:2])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:19])=[O:20]
Reactant: COC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.9 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (190 mg, 0.53 mmol) in ethanol (10 mL) was treated with a solution of potassium hydroxide (174 mg, 2.64 mmol) in water (4 mL). The reaction was stirred at 25° C. for 2.5 h. The reaction was then concentrated in vacuo to remove the ethanol and then acidified to pH=2 with a 1N aqueous hydrochloric acid solution. The resulting solution was then extracted with methylene chloride 3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (167 mg, 92%) as a white foam: (ES)+-HRMS m/e calcd for C15H19ClO5S (M+Na)+ 369.0534. found 369.0536.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:26][CH2:27][CH2:28][CH3:29])[NH:7][C:6](=[O:30])[CH:5]=1)([CH3:3])[CH3:2].[I:31]I>[N+]([O-])([O-])=O.[Ag+].CO>[I:31][C:5]1[C:6](=[O:30])[NH:7][C:8]([C:10]2[CH:15]=[C:14]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:26][CH2:27][CH2:28][CH3:29])=[N:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc(C(C)C)cc(=O)[nH]1
Reactant: II
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Product: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc(C(C)C)c(I)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
The compound (1.69 g, 3.9 mmol) of example 1 was added into methanol (15 ml), and added with silver nitrate (0.66 g, 3.9 mol), and then with I2 grain (0.98 g, 3.9 mmol) under stirring. The reaction mixture was stirred at room temperature for 0.5 h, and TLC showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated. The concentrate was washed with water, extracted with dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated. The residue was recrystallized from ethyl acetate to give a yellowish solid (1.52 g, yield: 70%). 1H NMR (CDCl3) δ: 8.90 (1H, d), 7.89 (1H, dd), 7.16 (1H, d), 4.27 (2H, t), 3.46 (1H, m), 3.08 (4H, t), 2.49 (4H, t), 2.27 (3H, s), 2.03 (2H, m), 1.25 (6H, d), 1.16 (3H, t).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=1>>[Cl:27][C:21]1[CH:20]=[C:19]([CH:26]=[CH:25][C:22]=1[C:23]#[N:24])[CH2:18][NH:17][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16]
Reactant: N#Cc1ccc(CN)cc1Cl
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)c(Cl)c1)c1ccc(OC)cc1F

Procedure:
(RS)-Ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid, described in example 63.1 was coupled with 4-aminomethyl-2-chlorobenzonitrile (CAS 202522-15-4) according to general procedure C to give (RS)-N-(3-chloro-4-cyano-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Yellow oil. MS 377.2 ([M+H]+)
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10](=O)[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[NH2:2][C:1]1[S:29][C:10]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[N:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C#N)NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2c(F)cccc2F)sc1N
Temperature: 95 °C
Reaction time: 48 h

Procedure:
To a solution of the ethyl 2-cyano-2-(2,6-difluorobenzamido)acetate (1 eq) in 10 mL of toluene was added Lawesson reagent. The mixture was stirred at 95° C. for 2 days. Solvents were removed under reduced pressure. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to give the ethyl 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylate, which was dissolved in 5 mL of methanol and 5 mL of THF. Then the mixture was added 1M sodium hydroxide (2 eq). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated to remove most of solvents. The residue was extracted with ethyl acetate. The aqueous layer was acidified to pH=4-5 by 1N HCl. The resulting mixture was extracted by ethyl acetate. The organic layer was separated, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. to give the pure titled compound (34%). LC/MS (m/z): 257.1 (MH+), Rt: 0.61 min.