Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.[H-].[Na+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:34])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]([S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:13])=[O:14])([F:34])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(F)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a stirred solution of 10 g (0.032 mol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester in 110 mL of DMF at 0° C., 1.42 g (0.035 mol, 1.1 eq) of NaH (60%) were added. The reaction mixture was stirred at this temperature for one hour, and 15.71 g (0.048 mol, 1.5 eq) of N-fluorobenzenesulfonimide were added. After 2 hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with heptane/EtOAc 2:1, yielding 3.06 g (27%) of (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-acetic acid methyl ester as a white solid, MS: 329 (MH+) and 3.2 g (28%) of (RR,SS)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-acetic acid methyl ester as a white solid, MS: 329 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19][C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: NCC1Cc2cccc(-c3ccc(F)cc3F)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccc(F)cc3F)c2O1)OCc1ccccc1
Yield: 80.5 %

Procedure:
Treatment of (±)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.0 g, 6.72 mmol) with diisopropylethylamine (1.30 g, 10.07 mmol) followed by benzyl chloroformate (1.26 g, 7.37 mmol) generally according to the procedure described for Intermediate 12 gave 2.14 g (81%) of (±)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. mp 78-80° C.; Anal. calcd. for C23H19F2NO3: C, 69.87; H, 4.84; N, 3.54. Found: C, 69.76; H, 4.8; N, 3.35. Chiral HPLC separation of (±)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralpak AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=9.117 min, Chiralpak AD, ethanol:hexane 1:1); Fraction 2 (Rt=9.424 min, Chiralpak AD ethanol:hexane 1:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[NH2:25][CH:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:25][CH2:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[S:8][CH:9]=3)[C:13](=[O:24])[NH:14]2)=[CH:19][CH:18]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: CC(C)C(N)CO
Product: CC(C)C(CO)NCc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 2-amino-3-methyl-butan-1-ol to give a yellow solid. MS m/z: 421.3 (M+1).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:18]#[N:19])=[C:11]2[CH2:20][CH:21]([CH3:23])[CH3:22])=O)C.Cl>CCOCC.CO.O>[OH:5][CH2:6][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]([C:18]#[N:19])[CH:11]2[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(CC(C)C)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CC(C)CC1C(C#N)=CNc2ccc(CO)cc21
Yield: 43.2 %

Procedure:
To the suspension of lithium borohydride (93 mg, 4.3 mmol) and methanol (170 uL, 4.3 mmol) in ether (20 mL) was added the solution of 3-cyano-4-isobutyl-quinoline-6-carboxylic acid ethyl ester (example 46d, 600 mg, 2.1 mmol) in ether (5 mL). The mixture was stirred at reflux overnight. The mixture of water and methanol (v/v 1:1, 40 mL) was added to the above solution. Then 1 N HCl (3 mL) was added to quench the reaction. The product was extracted with ethylacetate. The combined organic layers were successively washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 5%-50% ethyl acetate in hexanes in 50 min) afforded 6-hydroxymethyl-4-isobutyl-1,4-dihydro-quinoline-3-carbonitrile (220 mg, 43%) as a yellow solid. LC-MS m/e 243 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13](Cl)=[O:14])=[CH:6]2)[CH3:2].[NH3:16]>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([NH2:16])=[O:14])=[CH:6]2)[CH3:2]
Reactant: N
Reactant: CCc1ccc2nnc(C(=O)Cl)cc2c1
Product: CCc1ccc2nnc(C(N)=O)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aqueous ammonia solution (specific gravity 0.88; 10 ml.) was added to 6-ethylcinnolin-3-yl carbonyl chloride (1 g.). The resulting suspension was stirred overnight at room temperature. The resulting mixture was filtered and the solid residue was crystallised from aqueous ethanol to give 6-ethylcinnolin-3-ylcarboxamide, m.p. 215°-216° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[I:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[NH:15][C:14](=[O:21])[C:13]2=[CH:22]OC>CN(C)C=O>[I:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[NH:15][C:14](=[O:21])[C:13]2=[CH:22][NH:1][CH2:2][CH:3]1[CH2:4][CH2:5][C:6](=[O:8])[NH:7]1
Reactant: NCC1CCC(=O)N1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: O=C1CCC(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)N1
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
5-Aminomethyl-pyrrolidin-2-one (140 mg, ˜80-90% pure, 1.04 mmol) is stirred with 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (150 mg, 0.46 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The suspension become clear in 10 minutes and further stirring gave a pale yellow precipitate. The precipitate is filtered and washed with MeOH, Et2O and dried to provide the title compound (110 mg, 58%). MS (ESI): 411.8 (M+1)+1.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[C:10]2[C:17]([CH3:18])=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[Br:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[N:35][C:36]#[N:37])OC2C=CC=CC=2)[CH:23]=[CH:24][CH:25]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:26]/[C:27](/[N:6]2[CH2:7][CH:2]([CH3:1])[N:3]([C:9]3[C:10]4[C:17]([CH3:18])=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:4][CH:5]2[CH3:8])=[N:35]\[C:36]#[N:37])[CH:23]=[CH:24][CH:25]=1
Reactant: N#CN=C(Nc1cccc(Br)c1)Oc1ccccc1
Reactant: Cc1c[nH]c2ncnc(N3C[C@@H](C)NC[C@@H]3C)c12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CC(C)N(/C(=N/C#N)Nc4cccc(Br)c4)CC3C)c12
Temperature: 150 °C
Yield: 19 %

Procedure:
The dimethyl piperazine from step A (80 mg, 0.32 mmol), phenyl N-3-bromophenyl-N′-cyanocarbamimidate, from Example 5, step A, (100 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.20 ml) were added to isopropanol (10 ml). The mixture was heated at 150° C. for 20 min in a microwave, then concentrated under vacuum. The material was purified prep HPLC (Sunfire C18 30×250 mm column, 10-100% MeCN:H2O (10 mM NH4OAc), 18 min., 45 ml/min) to give (E)-N-(3-bromophenyl)-N′-cyano-2,5-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide (29 mg, 0.062 mmol, 19%).
Reaction SMILES: O.[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=O)[C:8]2[CH:14]=[CH:15][C:16]([CH3:18])=[N:17][C:7]=2[O:6]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1>C1(C)C=CC=CC=1>[OH2:6].[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[S:28])[C:8]2[CH:14]=[CH:15][C:16]([CH3:18])=[N:17][C:7]=2[O:6]1
Reactant: Cc1ccc2c(n1)OC(CCCl)CN(C)C2=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(n1)OC(CCCl)CN(C)C2=S
Reaction time: 1 h

Procedure:
To a suspension of 17.4 g (0.043 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diposphetane-2,4-disulfide in ~300 ml of toluene was added 20 g (0.078 mole) of 2-(2-chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one hydrate [1:1]. The mixture was heated to reflux for 3 hr and 4.0 g (0.01 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide was added and heating was continued for 1 hr. After cooling, toluene was decanted off and washed with 3×100 ml 1N sodium hydroxide and 100 ml water. The organic layer was then extracted with 2×100 ml of 2N hydrochloric acid. The aqueous layer was made basic to litmus with conc. sodium hydroxide causing the product to precipitate out. Of the 25 g of crude collected, 2 g were recrystallized from diisopropyl ether to give pale yellow crystals, m.p. 80°-86° C.
Reaction SMILES: P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[Mg+2].[Cl-].[Cl-].[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](COP(OP(OCC([C@H](C(NCCC(NCCS)=O)=O)O)(C)C)(O)=O)(O)=O)[C@@H](OP(O)(O)=O)[C@H]1O.O[C@H](CCCCC)CC([O-])=O.[OH:94][C@H:95]([CH2:147][CH2:148][C:149]1C=CC(F)=[CH:151][CH:150]=1)[CH2:96][C:97]([S:99][CH2:100][CH2:101][NH:102][C:103](=[O:146])[CH2:104][CH2:105][NH:106][C:107](=[O:145])[C@H:108]([OH:144])[C:109]([CH3:143])([CH3:142])[CH2:110][O:111][P:112]([OH:141])(=[O:140])[O:113][P:114]([OH:139])(=[O:138])[O:115][CH2:116][C@H:117]1[O:121][C@@H:120]([N:122]2[C:131]3[N:130]=[CH:129][N:128]=[C:126]([NH2:127])[C:125]=3[N:124]=[CH:123]2)[C@H:119]([OH:132])[C@@H:118]1[O:133][P:134]([OH:137])([OH:136])=[O:135])=[O:98]>>[OH:94][C@H:95]([CH2:147][CH2:148][CH2:149][CH2:150][CH3:151])[CH2:96][C:97]([S:99][CH2:100][CH2:101][NH:102][C:103](=[O:146])[CH2:104][CH2:105][NH:106][C:107](=[O:145])[C@H:108]([OH:144])[C:109]([CH3:143])([CH3:142])[CH2:110][O:111][P:112]([OH:141])(=[O:140])[O:113][P:114]([OH:139])(=[O:138])[O:115][CH2:116][C@H:117]1[O:121][C@@H:120]([N:122]2[C:131]3[N:130]=[CH:129][N:128]=[C:126]([NH2:127])[C:125]=3[N:124]=[CH:123]2)[C@H:119]([OH:132])[C@@H:118]1[O:133][P:134]([OH:137])([OH:136])=[O:135])=[O:98]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@H](O)CCc1ccc(F)cc1
Agent: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS
Agent: CCCCC[C@@H](O)CC(=O)[O-]
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: CCCCC[C@@H](O)CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O

Procedure:
(R)-3-hydroxyoctanoyl-CoA was synthesized according to Rehm B H A, Kruger N, Steinbuchel A (1998) Journal of Biological Chemistry 273 pp 24044-24051 with certain changes. Acyl-CoA synthetase (Sigma Co.) was dissolved in trishydrochloric acid buffer (50 mM, pH 7.5) containing 2 mM ATP, 5 mM MgCl2, 2 mM coenzyme A and 2 mM (R)-3-hydroxyoctanoate to a concentration of 0.1 mU/μL. It was retained in a bath of 37° C. and was sampled suitably and the proceeding of reaction was analyzed by HPLC. After the enzyme reaction was terminated by adding sulfuric acid to 0.02 N to the sampled reaction liquid, the unreacted substrate (R)-3-hydroxyoctganoate was removed by extraction with n-heptane. The HPLC analysis employed RP18 column (nucleosil C18, 7 μm, Knauser), and elusion was made under a linear concentration slope of acetonitrile, utilizing 25 mM phosphoric acid buffer (pH 5.3) as the moving phase, and the thioester compound generated by the enzymatic reaction was detected by monitoring the absorption spectrum of 200 to 500 nm with a diode array detector. (R)-3-hydroxy-5-phenylvaryl CoA and (R)-3-hydroxy-5-(4-fluorophenyl)valeryl CoA were also synthesized in a similar manner.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1Cl
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,5-dichloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:21][C:20](=O)[C:11]2[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][O:14][C:10]=2[CH2:9]1.[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:21]/[C:20](=[N:27]\[NH:26][C:23]([NH2:25])=[NH:24])/[C:11]2[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][O:14][C:10]=2[CH2:9]1
Reactant: CCOC(=O)c1coc2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1coc2c1/C(=N/NC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a mixture of 6-(2-chlorophenyl)-3-ethoxycarbonyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.14 g) and aminoguanidine hydrochloride (49 mg) were ethanol (9 ml) and 6N hydrochloric acid (0.038 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-chlorophenyl)-3-ethoxycarbonyl-4-guanidinoimino-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 56) (90 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.FC(F)(F)C(O)=[O:15].C(OO)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N+:3]=1[O-:15]
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: O=C(O)C(F)(F)F
Agent: CC(=O)OO
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(Cl)[n+]1[O-]
Temperature: 25 °C

Procedure:
2-Chloro-3-nitro-6-picoline (2 g, 11.6 mmol) was added to an ice cooled mixture of trifluoroacetic acid (6 mL) and 30% peracetic acid in acetic acid (6 mL). The mixture was allowed to warm to room temperature over 30 minutes and was heated in a 60° C. oil bath for 5 hours. The mixture was partitioned between methylene chloride (100 mL) and water (50 mL). The pH was adjusted to 8 with 2.5 N sodium hydroxide and the aqueous layer was extracted with more methylene chloride (2×50 mL). The combined methylene chloride layers were dried with magnesium sulfate, filtered and evaporated to give the title compound as a white solid (1.6g).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH:11](O)[CH2:12][Si](C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>O1CCCC1>[CH:11]([C:8]1[N:7]=[CH:6][C:5]2[O:4][CH2:3][CH2:2][O:1][C:10]=2[CH:9]=1)=[CH2:12]
Reactant: C[Si](C)(C)CC(O)c1cc2c(cn1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cc2c(cn1)OCCO2
Yield: 145.6 %

Procedure:
A solution of (d) (1.6 g) in tetrahydrofuran (20 ml) was treated at 0° C. under argon with a solution of potassium t-butoxide in tetrahydrofuran (1M; 7.6 ml, 7.6 mmol). After 2 hours the mixture was partitioned between ethyl acetate—half saturated aqueous ammonium chloride solution. The organic extract was dried and evaporated affording an oil (1.5 g).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[C@H:10]([CH3:12])[OH:11].ClC(Cl)(Cl)C(=N)O[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1CCCCC1.C(Cl)Cl>[CH2:21]([O:11][C@@H:10]([CH3:12])[C:9]([O:14][CH2:15][CH3:16])=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@H](C)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CCOC(=O)[C@H](C)OCc1ccccc1
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Trifluoromethanesulfonic acid (1.13 g) was added to a stirred mixture of ethyl (S)-(−)-lactate (5.90 g) and benzyl 2,2,2-trichloroacetimidate (15.15 g) in cyclohexane (70 ml) and methylene chloride (35 ml) at room temperature under nitrogen atmosphere. After being stirred for 18 hours, the reaction mixture was filtered. The filtrate was diluted with cyclohexane, and then washed successively with saturated NaHCO3 solution (100 ml)and H2O (100 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel (260 g) chromatography eluted with hexane/ethyl acetate (30:1) to give ethyl (S)-2-(benzyloxy)propionate (6.48 g).
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44]C=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:28]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[CH:45]([CH3:46])[CH3:44]
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: CC(C)C(=O)N1CC=C(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 278, substituting isobutyryl chloride for acetyl chloride and N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.40 (s, 1H), 7.55-7.58 (m, 2H), 7.30-7.38 (m, 6H), 6.11-6.13 (bs, 1H), 4.76-4.77 (bs, 4H), 4.19-4.21 (m, 1H), 4.08-4.09 (m, 1H), 3.65-3.72 (m, 2H), 2.85-3.00 (m, 1H), 2.40-2.56 (m, 2H), 1.00-1.07 (m, 6H); MS (ESI(+)) m/e 390 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([NH2:11])=[CH:20][CH:19]=3)[CH:15]=[CH:16]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc2c(ccn2C(=O)c2ccc(F)cc2)c1
Reaction time: 18 h
Yield: 83.5 %

Procedure:
The 4-fluorobenzoyl chloride (5.2 g, 33 mmol) in 30 ml of tetrahydrofuran was added dropwise to a solution of the 5-amino-1H-indole (3.96 g, 30.0 mmol) and triethylamine (4.04 g, 40 mmol) at room temperature. The reaction was stirred for 18 hours and then poured into water. The mixture was made basic with sodium hydroxide solution then extracted with methylene chloride. The extract was dried (sodium sulfate) and concentrated. The residue was recrystallized from ethyl acetate/hexanes to give 6.37 g of product. (84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 951.9 %

Procedure:
To a solution of 3-bromo-4-hydroxybenzaldehyde (100 g, 50 mol, 1 eq) in acetone (500 mL) was added potassium carbonate (135 g, 100 mmol, 2 eq) followed by t-butyl 2-bromoacetate (100 g, 50 mmol, 1 eq). After stirring at room temperature for 2 h, the acetone was removed in vacuo and the resultant residue was washed with water to give 150 g (89%) of t-butyl 2-(2-bromo-4-formylphenoxy)acetate (1).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][OH:7].C1OCCOCCOCCOCCOC1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][C:47]=3F)[N:42]=[CH:41][N:40]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>CC(N(C)C)=O>[Cl:23][C:24]1[CH:25]=[C:26]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][C:47]=3[O:7][CH2:6][CH2:5][NH:4][CH3:3])[N:42]=[CH:41][N:40]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: Fc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CNCCO
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 100 °C
Yield: 45 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.63 g) was added to 2-(methylamino)ethanol (0.95 ml), 15-crown-5 (100 μl) and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine (1.5 g) in DMA (25 ml) and the reaction heated at 100° C. for 2 hours. The reaction was cooled, quenched with saturated aqueous ammonium chloride solution to pH 7-8. Addition of a small amount of saturated aqueous sodium hydrogen carbonate solution resulted in the formation of a precipitate, which was filtered, washed with water and dried. The solid was purified by chromatography using DCM-5% methanol/7N ammonia as eluent to give N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine as a yellow solid (0.27 g, 45%); NMR spectrum (DMSO-d6) 2.40 (s, 3H), 3.02 (t, 2H), 4.35 (t, 2H), 5.28 (s, 2H), 7.12 (d, 1H), 7.25 (d, 1H), 7.31 (d, 1H), 7.37 (m, 1H), 7.57 (d, 1H), 7.71 (dd, 1H), 7.85 (m, 2H), 8.10 (d, 1H), 8.51 (s, 1H), 8.58 (m, 1H), 10.57 (bs, 1H); Mass spectrum MH+ 436.5.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Cl:35][C:36]1[C:37]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][N:19]([C:41]([C:40]3[S:39][C:38]4[CH:44]=[CH:45][CH:46]=[C:47]([F:48])[C:37]=4[C:36]=3[Cl:35])=[O:42])[CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH2:21]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2cccc(C(C)=O)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Product: COc1ccc(-c2cccc(C(C)=O)c2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 178 (80 mg, 0.15 mmol) is treated with acid chloride 6 (53 mg, 0.21 mmol) using Method D to give the title compound.