Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].O1CCCC1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[C:13]=1[CH3:19]>O>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:2]([O:4][CH3:5])=[O:3])[C:13]=1[CH3:19]
Reactant: COC(=O)Cl
Reactant: Cc1c(N)cccc1Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Nc1cccc(Cl)c1C
Temperature: 25 °C

Procedure:
Under cooling, to a mixture of methyl chloroformate 30 mL and tetrahydrofuran 50 mL was added dropwise 1-chloro-2-methyl-3-aminobenzene 5.00 g and the mixtures were stirred at 25° C. for a half hour. To the reaction mixtures was added water and the resulting mixtures were extracted with ethyl acetate. The organic layers were washed with aqueous saturated sodium bicarbonate solution and were dried over anhydrous sodium sulfate. The mixtures were concentrated under reduced pressure to give 1-chloro-2-methyl-3-methoxycarbonylaminobenzene 5.80 g.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[C:9](=N)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.O>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[N:6]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](C)N
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](C)N=C(c1ccccc1)c1ccccc1
Reaction time: 15 h

Procedure:
To a solution of alanine methyl ester hydrochloride (10.0 g, 71.6 mmol) in 100 mL CH2Cl2 was added benzophenone imine (12.0 mL, 71.6 mmol). A white ppt gradually came out of solution as the reaction was allowed to proceed at rt for 15 h. The reaction was diluted with H2O and CH2Cl2, and the layers were separate, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford methyl-N-(diphenylmethylene)alaninate as a viscous oil which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.62 (m, 2H), 7.47-7.29 (m, 6H), 7.19-7.16 (m, 2H), 4.16 (q, J =6.8 Hz, 1H), 3.7 (s, 3H, 1.40 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:11][CH3:12]>C(O)(=O)C.O.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[S:11][CH3:12])[NH2:8]
Reactant: CSc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(N)cc1Cl
Reaction time: 1.5 h
Yield: 96.1 %

Procedure:
To a mixture of the compound from stage (i) (14.08 g, 69 mmol) in acetic acid (300 mL) and water (60 mL) was added Fe powder (23 g, 412 mmol) and the reaction mixture was swirled until all the starting material had dissolved. The mixture was left to stand for 1.5 h and the acetic acid was then removed under reduced pressure. The residue was taken up in sat NaHCO3 (aq) (500 mL) and EtOAc (500 mL) and filtered through Arbacel®. The layers were separated, the aqueous phase was extracted with EtOAc (300 mL) and the combined organics were washed with brine, dried (MgSO4) and the solvent was removed in vacuo to give the title compound (11.52 g, 96%) as a beige solid; δH (400 MHz, CDCl3) 2.38 (3H, s), 3.66 (2H, br), 6.53 (1H, dd), 6.70 (1H, d), 7.12 (1H, d); MS m/z (ES+) 174 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.[NH:14]1[C:18]([C:19]2[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=2)=[N:17][N:16]=[N:15]1>>[NH:17]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=4)[N:3]=3)=[CH:21][CH:20]=2)=[N:14][N:15]=[N:16]1
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: OB(O)c1ccc(-c2nnn[nH]2)cc1
Product: Oc1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)ccc2c1

Procedure:
Followed Scheme 2, A conditions: Starting materials: 2-chloro-6-methoxyquinoline (Intermediate 1) and (4-(1H-tetrazol-5-yl)phenyl)boronic acid. 1H NMR (DMSO-d6, 400 MHz): δ 10.15 (s, 1H), 8.45 (d, 2H), 8.31-8.28 (d, 1H), 8.22-8.12 (m, 3H), 7.98-7.95 (d, 1H), 7.39-7.35 (dd, 1H), 7.21 (s, 1H). MS (ESI): m/z 290.08 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[S:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[C:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[N:18][C:19]3[C:24]([N:25]=1)=[CH:23][C:22]([C:26]([O:28]C)=[O:27])=[CH:21][CH:20]=3)[CH2:11][CH2:10][CH2:9]2)(=[O:5])=[O:4].[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH3:37])[S:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[C:17]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[N:18][C:19]3[C:24]([N:25]=1)=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][CH:20]=3)[CH2:11][CH2:10][CH2:9]2)(=[O:4])=[O:5]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(S(=O)(=O)N(C)C)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of methyl 3-[6-(dimethylsulfamoyl)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate (120 mg, 0.23 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (36.9 mg, 0.92 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 5 with hydrogen chloride (3 N). The solids were collected by filtration to afford 3-[6-(dimethylsulfamoyl)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (43.5 mg, 37%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br-:7].C[C:9]1[S:13][CH:12]=[CH:11][S+:10]=1>C(O)C>[Br-:7].[S:10]1[CH:11]=[CH:12][S:13][C:9]1=[N+:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Cc1scc[s+]1
Reactant: C1COCCN1
Agent: [Br-]
Solvent: CCO
Product: c1csc(=[N+]2CCOCC2)s1
Yield: 71.5 %

Procedure:
1.0 g of morpholine and 2.3 g of 2-methyl-1,3-dithiolium bromide were treated in the same manner as in Example 26, and the product was recrystallized from ethanol, whereby 2.2 g (yield: 86.6%) of 4-(1,3-dithiol-2-ylidene)morpholinium bromide (Compound No. 28) was obtained as crystals having a melting point of 274° to 276° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:16]1([CH:12]2[O:13][CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[C:23]([F:34])([F:33])[F:22])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=C(c1ccc(Br)cc1)N1CCOC(c2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(c1ccc(-c2ccccc2C(F)(F)F)cc1)N1CCOC(c2ccccc2)C1
Temperature: 120 °C
Yield: 97 %

Procedure:
100 mg of (4-Bromo-phenyl)-(2-phenyl-morpholin-4-yl)-methanone was combined with 82 mg of 2-(Trifluoromethyl)phenyl boronic acid, 33 mg of tetrakis(triphenylphosphine)palladium(0), 0.968 mL of 2M sodium carbonate solution, 2.6 mL toluene and 1.3 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 412, 97% yield.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCOCC1.O>[CH2:21]([O:20][C:18]([NH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCOc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
Sodium hydroxide (222 mg) was added to a solution of 2-[4-(2-aminoethoxy)-phenyl]acetic acid (394 mg) (see DE-A-2250400) in 1,4-dioxane: water (1:1, by volume) (20 ml) at 0° C. The reaction mixture was stirred for 20 minutes then benzyl chloroformate (319 mg) was added to the mixture and the solution was stirred for 4 hours. Additional benzyl chloroformate (70 mg) was added to the reaction mixture and it was stirred for a further 1 hour. The solvent was removed under reduced pressure. The resulting solid was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution and the product was extracted with ethyl acetate. The organic solution was dried over magnesium sulphate and the solvent removed under reduced pressure to afford 2-[4-(2-[benzyloxycarbonylamino]ethoxy)phenyl]acetic acid (375 mg) as a solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:15][C:16]1[CH:40]=[CH:39][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:25]([C:35]([F:38])([F:37])[F:36])[CH:24]=3)[S:22][C:18]=2[CH:17]=1>CN(C=O)C.CCOC(C)=O>[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH:10][CH2:15][C:16]1[CH:40]=[CH:39][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[C:25]([C:35]([F:36])([F:37])[F:38])[CH:24]=3)[S:22][C:18]=2[CH:17]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: FC(F)(F)c1cc(-c2nc3ccc(CBr)cc3s2)ccc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCNCc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
To a solution of β-alanine tert-butyl ester hydrochloride (47 mg, 1.1 eq.) in DMF (2 ml) is added NaH (60% in mineral oil) (28 mg, 3 eq.) at room temperature. The mixture is stirred at room temperature for 15 minutes before a solution of 6-bromomethyl-2-(2-trifluoromethyl-biphenyl-4-yl)benzothiazole (105 mg, 0.234 mmol) in DMF (1 ml) is added. The mixture is stirred at room temperature overnight, diluted with EtOAc, washed with 10% Na2S2O3, brine, dried over MgSO4, filtered and concentrated. Column chromatography (CH2Cl2/CH3OH, 95/5) gave 31 mg (26%) of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzothiazol-6-ylmethyl]-amino}-propionic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:13](Cl)(=[O:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[C:13]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[S:5][CH2:4][CH2:3][C:2]2([CH3:12])[CH3:1])(=[O:15])[CH3:14]
Reactant: CC1(C)CCSc2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 10 h
Yield: 87.8 %

Procedure:
A solution of 10.0 g (0.056 mol) of 4,4-dimethylthiochroman and 4.4 g (0.056 mol) of acetyl chloride in 150 mL of CS2 was added dropwise over a 45-minutes period to a stirred CS2 suspension of AlCl3 (11.22 g, 0.084 mol) in a 500-mL, round-bottom flask equipped with a condenser and nitrogen inlet. The resulting yellowish-orange mixture was allowed to stir for 10 hours at room temperature; 80 mL of ice water was added and the two layers separated. The aqueous layer was extracted with ether (3×50 mL); the ether layers were combined and dried (Na2SO4, 6 h). After evaporation, the resulting light yellow oil was vacuum distilled to give 10.83 grams (87.6%) of 6-acetyl-4,4-dimethylthiochroman as a yellowish viscous oil: bp 168°-173° C./1.0 mm; IR (neat) 1680 cm-1 ; 1H NMR (DCCl3 δ1.31 [s, 6 H, (CH)3)2 C], 1.89 [m, 2 H, ArSCH2CH2 ], 2.52 [s, 3 H, CH3C=O]3.01 [m, 2 H, ArSCH2CH2 ], 7.11 [d, 1 H, J=8.1 Hz, H(8)], 7.57 [dd, 1 H, J=1.7 Hz, J=8.1 Hz, H(7)], 8.00 [d, 1 H, J=1.7 Hz, H(5)]; 13C NMR ppm 23.1 [ArSCH2CH2 ]26.2 [CH3C=O], 29.8 [(CH3)2C], 32.8 [(CH3)2C], 36.8 [ArSCH2CH2 ], 125.8, 126.2, 132.9, 139.4, 141.7, 196.7 [CH3C=O]. ##STR14##
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[O:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=2)[CH2:47][CH2:46]1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:55][C:54]4[CH:56]=[CH:57][C:51]([N:48]5[CH2:47][CH2:46][O:45][CH2:50][CH2:49]5)=[CH:52][CH:53]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(N5CCOCC5)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-morpholinoaniline as the aniline component. (13%, MS=541.3 (M+H))
Reaction SMILES: C(O)(=[O:3])C.[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH3:20])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.OO.O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19]([CH3:20])=[O:3])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: OO
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
To an acetic acid solution (30 ml) of 4-chloro-4'-methylmercaptomethylbenzophenone (8.3 g), aqueous 30% hydrogen peroxide solution (3.5 ml) was added, and the mixture was stirred for 2 hours while keeping at 10° C. To the reaction solution, water (200 ml) and toluene (200 ml) were added, and then the organic layer was separated, and washed successively with water, an aqueous sodium bicarbonate solution and an aqueous saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate. After distilling off the solvent, the crude product was purified by silicagel column chromatography (developing solvent: acetone:n-hexane=50:50) to obtain 4-chloro-4'-methylsulfinylmethylbenzophenone (5.3 g).
Reaction SMILES: [OH:1][P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3].[CH2:15](O)[CH2:16][OH:17]>>[OH:3][P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:4][CH2:5][C:6]([O:8][CH2:15][CH2:16][OH:17])=[O:7])=[O:1]
Reactant: OCCO
Reactant: O=C(O)CCP(=O)(O)c1ccccc1
Product: O=C(CCP(=O)(O)c1ccccc1)OCCO

Procedure:
Except that the recrystallization-purified 3-[hydroxy(phenyl)phosphinyl]propionic acid obtained in Comparative Example 3 was used in lieu of the rinse-purified 3-[hydroxy(phenyl)phosphinyl]propionic acid, the procedure of Comparative Example 4 was repeated to provide 102.81 g of an ethylene glycol solution of hydroxyethyl 3-[hydroxy(phenyl)phosphinyl]propionate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:26])[CH2:24][CH3:25]>>[CH2:23]([NH:26][C:20]([C@@H:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:22])[CH2:24][CH3:25]
Reactant: CCCN
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1C(=O)OCc1ccccc1
Product: CCCNC(=O)[C@@H]1Cc2ccccc2N1C(=O)OCc1ccccc1

Procedure:
The process is performed as in Example 14 a), starting with N-benzyloxycarbonyl-2(S)-indolinecarboxylic acid prepared as in Example 16 a) and n-propylamine. A white solid is obtained, which is recrystallized from CCl4.
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[NH:10])[CH:3]([CH3:5])[CH3:4].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.C(O)(=O)C>C(O)C>[O:18]=[C:19]1[NH:11][C:9]([C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH2:2][CH:3]([CH3:5])[CH3:4])=[N:10][CH:26]=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(C)COc1ccccc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(-c2ccccc2OCC(C)C)[nH]c1=O

Procedure:
To a stirred sodium (3.15 g., 0.137 g-atom) in ethanol (250 ml.) was added 2-isobutoxybenzamidine (26.3 g., 0.137 mole) followed by diethyl ethoxymethylenemalonate (29.6 g., 0.137 mole). The mixture was heated under reflux for 3 hours. The cooled mixture was added to icewater (300 ml.) which was then acidified to pH 5 with glacial acetic acid. The crystalline product (36.4 g., 85%) m.p. 89°-91°, which formed on cooling was collected and a portion recrystallized from 50% aqueous ethanol to give the title compound, m.p. 92°-93°.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1([CH3:8])[CH2:7][O:6][CH2:5]1.C([Li])CCC.[CH3:15][Si:16]([CH3:19])([CH3:18])Cl>C1COCC1.CCCCCC>[CH3:15][Si:16]([CH3:19])([CH3:18])[C:2]#[C:3][C:4]1([CH3:8])[CH2:7][O:6][CH2:5]1
Reactant: CC1(C=C(Br)Br)COC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C#C[Si](C)(C)C)COC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 93.9 %

Procedure:
A 250-mL round-bottom flask was charged with 3-(2,2-dibromovinyl)-3-methyloxetane (2.177 g, 8.51 mmol) in THF (85 mL) to give a clear solution. The flask was cooled in a dry ice/acetone bath for 15 min, then n-butyllithium (7.83 mL, 19.56 mmol) (as a 2.5 M solution in hexane) was added dropwise over five min. After stirring at −78° C. for 45 min, trimethylchlorosilane (3.81 mL, 29.8 mmol) was added over 2 min. The cooling bath was removed after 30 min and the reaction was allowed to warm to RT for 30 min. The mixture was diluted with water (50 mL) and ether (50 mL). The layers were separated, and the aqueous layer was extracted with ether (25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and evaporated. The residue was dissolved in a small amount of ether and filtered through a small pad of silica gel. The filtrate was evaporated to give trimethyl((3-methyloxetan-3-yl)ethynyl)silane (1.344 g, 7.99 mmol, 94% yield) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(C(C)C)C(C)C)C>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCCO1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCO4)c23)C1
Temperature: 160 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide (225 mg, 0.686 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (412 mg, 2.06 mmol), and N-ethyl-N-isopropylpropan-2-amine (239 μL, 1.37 mmol) in n-BuOH (5 mL) was purged under N2 and stirred at 160° C. in a sealed tube for 16 hours. The solvent was then removed in vacuo, and the residue obtained was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+; C-18) on Biotage SP4 unit eluting with a gradient of 15-90% CH3CN/water (25 CV) to provide tert-butyl (3R)-1-(5-bromo-3-(tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (101 mg, 0.199 mmol, 29.0% yield) as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH:10]([OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][O:14][S:17]([CH3:16])(=[O:19])=[O:18])[CH:10]([OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CC1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCC1CN(Cc2ccccc2)CC1O
Yield: 53.5 %

Procedure:
The known compound, 1-benzyl-3-hydroxy-4-hydroxymethylpyrrolidine [see J. Org. Chem., 30, 740 (1965)] (110 g) was allowed to react in chloroform with methanesulfonyl chloride (60.9 g) in the presence of triethylamine to yield 1-benzyl-3-hydroxy-4-methanesulfonyloxymethylpyrrolidine (81 g) as an oil.
Reaction SMILES: N=C=N.C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)C(O)=O.[CH3:23][N:24]([S:53]([CH3:56])(=[O:55])=[O:54])[C:25]1[C:30]([CH2:31][NH:32][C:33]2[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][N:36]=[C:35]([NH:43][C:44]3[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=3)[C:47]([OH:49])=O)[N:34]=2)=[CH:29][CH:28]=[CH:27][N:26]=1.CC[N:59]([CH:63]([CH3:65])[CH3:64])C(C)C.C1(N)CC1>C(#N)C>[CH:63]1([NH:59][C:47](=[O:49])[C:46]2[CH:50]=[CH:51][CH:52]=[C:44]([NH:43][C:35]3[N:34]=[C:33]([NH:32][CH2:31][C:30]4[C:25]([N:24]([CH3:23])[S:53]([CH3:56])(=[O:54])=[O:55])=[N:26][CH:27]=[CH:28][CH:29]=4)[C:38]([C:39]([F:42])([F:40])[F:41])=[CH:37][N:36]=3)[CH:45]=2)[CH2:65][CH2:64]1
Reactant: CN(c1ncccc1CNc1nc(Nc2cccc(C(=O)O)c2)ncc1C(F)(F)F)S(C)(=O)=O
Reactant: CCN(C(C)C)C(C)C
Agent: N=C=N
Agent: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ncccc1CNc1nc(Nc2cccc(C(=O)NC3CC3)c2)ncc1C(F)(F)F)S(C)(=O)=O

Procedure:
A polymer supported carbodiimide (PS-CDI) (0.326 mmol) was allowed to swell in acetonitrile (volume of 500 μL). The resultant suspension was treated with 10 (100 mg, 0.164 mmol) and DIEA (29 μL, 0.164 mmol). The resultant solution was then treated with cyclopropylamine (19 μL, 0.164 mmol). The resultant suspension was then mixed on a shaker plate for 16 hours. The mixture was then filtered, and the solids washed with 10% MeOH in chloroform. The combined filtrates were concentrated under reduced pressure, and the resultant residue was purified over silica (99:1:0.1 CHCl3:CH3OH:NH4OH) to provide 11 as a white foam. Yield: 14.3 mg, 16%. LC Ret. Time (standard)=2.1 min., m/z 536.2 (MH+); 1H NMR (CD3OD) : 8.42 (d, J=7.8 Hz., 1H), 8.20 (s, 1 h), 7.97 (t, J=7.8 Hz., 1H), 7.81 (d, J=7.8 Hz., 1H), 1.68 (d, J=7.8 Hz., 1H), 7.39-7.34 (m, 2H), 7.26 (t, J=7.8 Hz., 1H), 4.94 (s, 2H), 3.23 (s, 3H), 3.14 (s, 3H), 2.82 (m, 1H), 0.79 (m, 2 h), 0.60 (m, 2H) ppm. FAK IC50: 0.00186 μM
Reaction SMILES: Br.[NH2:2][C:3]1([C:14]([OH:16])=[O:15])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:13])[CH:9]=2)[CH2:4]1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[NH2:2][C:3]1([C:14]([O:16][CH2:22][CH3:23])=[O:15])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:13])[CH:9]=2)[CH2:4]1
Reactant: NC1(C(=O)O)CCc2cc(O)ccc2C1
Reactant: CCO
Agent: Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(N)CCc2cc(O)ccc2C1
Reaction time: 24 h

Procedure:
2-Amino-6-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid hydrobromide (580 mg., 2.0 mM) was suspended in dry ethanol (15 ml.). Concentrated sulphuric acid (0.05 ml.) was added and the mixture was stirred under reflux. After 24 hr. reflux, more sulphuric acid (0.05 ml.) was added and the reflux was continued for 48 hr. The mixture was evaporated in vacuo. Ether (15 ml.) and ethyl acetate (20 ml.) were added to the residue, followed by water (10 ml.). The mixture was basified with dilute sodium bicarbonate solution, and then separated. The organic phase was washed successively with water (15 ml.) and saturated brine (15 ml.). The solution was dried (Na2SO4) and evaporated in vacuo, giving ethyl 2-amino-6-hydroxy-1,2,3,4-tetrahydronapthalene-2-carboxylate, Rf 0.54 [kieselgel 60, 5:1 v/v dichloromethane/methanol].