Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:3]1=[O:19].C(Cl)Cl>C(O)=O>[F:20][C:2]1([F:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([OH:14])=[O:13])[C:3]1=[O:19]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(F)(F)c2ccccc21
Solvent: O=CO
Solvent: ClCCl
Product: O=C(O)CN1C(=O)C(F)(F)c2ccccc21
Reaction time: 16 h

Procedure:
A 30 mL reaction vial was charged with tert-butyl 2-(3,3-difluoro-2-oxoindolin-1-yl)acetate (275 mg, 1 mmol) as a yellow oil. DCM (3 mL) was added, followed by an equal volume of formic acid. The reaction was stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give 2-(3,3-difluoro-2-oxoindolin-1-yl)acetic acid as a yellow solid. The desired M+H (228) was observed in the LCMS using the method [1] with a retention time of 1.652 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH2:8][C:9]1[N:10]=[C:11]2[CH:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]([CH3:29])[CH:19]=3)[N:15]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[N:13][CH:14]=1)=[O:6].N1C(C)=CC=CC=1C.[Si:46](OS(C(F)(F)F)(=O)=O)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>C(Cl)Cl>[Si:46]([O:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH2:8][C:9]1[N:10]=[C:11]2[CH:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]([CH3:29])[CH:19]=3)[N:15]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:12]2=[N:13][CH:14]=1)=[O:6])([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)CCCO)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)CCCO[Si](C)(C)C(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: -5 °C
Reaction time: 0.03 h
Yield: 74 %

Procedure:
A flask was charged with 4-hydroxy-N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)butanamide (0.130 g, 0.248 mmol) and DCM (5 mL). The mixture was cooled to about −5° C. To the mixture was added 2,6-lutidine (0.064 mL, 0.54 mmol). After about 2 min, TBDMSOTf (0.063 mL, 0.273 mmol) was added. The mixture was stirred at about −5 to 0° C. for about 2 h. The mixture was concentrated under reduced pressure and the residue was purified using silica gel chromatography with an elution gradient of 0 to 80% EtOAc/heptane to give 4-(tert-butyldimethylsilyloxy)-N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)butanamide (0.117 g, 74%): LC/MS (Table 2, Method a) Rt=3.40 min; MS m/z 638 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[O:36][C:35]([CH3:38])([CH3:37])[CH:34]=[CH:33][C:16]2=[C:17]2[C:26]=1[C:25](=[O:27])[C:24]1[C:19](=[CH:20][CH:21]=[C:22]3[CH:31]=[CH:30][CH:29]=[CH:28][C:23]3=1)[N:18]2[CH3:32].Cl>ClCCl>[C:1]([C:34]1[C:35]([CH3:37])([CH3:38])[O:36][C:15]2[C:16](=[C:17]3[C:26](=[C:13]([O:12][CH3:11])[CH:14]=2)[C:25](=[O:27])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]4[CH:31]=[CH:30][CH:29]=[CH:28][C:23]4=2)[N:18]3[CH3:32])[CH:33]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C=CC(C)(C)O2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC(=O)C1=Cc2c(cc(OC)c3c(=O)c4c5ccccc5ccc4n(C)c23)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 0.81 mmol of butyryl chloride and 0.673 mmol of AlCl3 in 2 ml of anhydrous dichloromethane is added, in small portions, to 0.135 mmol of the product of Example 3 in 2 ml of dichloromethane at 0° C. The reaction mixture is stirred for 4 hours at ambient temperature and then poured into a 10% HCl solution. After conventional treatment of the organic phases and evaporation thereof under reduced pressure, chromatography of the residue over silica gel (dichloromethane/methanol) allows the expected product to be isolated.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([S:16][CH2:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])(=[O:15])[CH3:14]>>[C:13]([S:16][CH2:17][CH:18]([CH3:22])[C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:20])(=[O:15])[CH3:14]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(=O)SCC(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Following the procedure of Example 16, L-phenylalanine is reacted with 3-acetylthio-2-methylpropanoyl chloride to give (±)-N-[3-(acetylthio)-2-methyl-1-oxopropyl]-L-phenylalanine.
Reaction SMILES: Cl[CH:2]=[C:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[Na].C[O-].[Na+].N1C=CN=C1>C(#N)C.CO>[N:18]1([CH:2]=[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(=O)C(=CCl)Oc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)C(=O)C(=Cn1ccnc1)Oc1ccc(F)cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
256.7 g (1 mol) of 1-chloro-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one in 150 ml of acetonitrile were added dropwise to a suspension of 90 g (1 mol) of sodium imidazole, prepared from sodium methylate and imidazole in methanol, in 2,500 ml of acetonitrile, while stirring. Thereafter, the reaction mixture was heated to the boiling point for 6 hours. It was allowed to cool to room temperature and was concentrated by distilling off the solvent in vacuo. The residue was taken up in 1,000 ml of ethyl acetate, the mixture was washed three times with 200 ml of water each time and the organic phase was dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. 272.4 g (94.5% of theory) of crude 1-(imidazol-1-yl)-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one were obtained as a brown oil, which was purified in the customary manner, via the nitrate, and then had a refractive index of nD20 =1.5590. ##STR52##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:23]([N:4]1[CH2:5][CH2:6][NH:1][CH:2]([C:7]([NH2:9])=[O:8])[CH2:3]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC(=O)C1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.29 g (10 mmol) of piperazine-2-carboxamide were dissolved in 20 ml of absolute methylene chloride, 1.01 g (10 mmol) of triethylamine were added, a solution of 2.79 g (10 mmol) of triphenylmethyl chloride in 20 ml of absolute methylene chloride was added dropwise and the mixture was subsequently stirred at room temperature for 5 hours. The reaction solution was washed twice with water, dried and concentrated and the crude product was purified by flash chromatography on silica gel with CH2Cl2 /CH3OH 95:5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](OCC2C=CC=CC=2)=O)[CH:5]=[CH:4][C:3]=1[C:19]1[CH2:20][CH2:21][S:22][CH2:23][CH:24]=1.C([Li])CCC.[C:30]([O:35][CH2:36][C@@H:37]1[O:39]C1)(=[O:34])CCC.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[S:22]1[CH2:21][CH:20]=[C:19]([C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:9][C@H:36]([CH2:37][OH:39])[O:35][C:30]3=[O:34])=[CH:7][C:2]=2[F:1])[CH2:24][CH2:23]1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1ccc(C2=CCSCC2)c(F)c1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1ccc(C2=CCSCC2)c(F)c1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
4-(2-Fluoro-4-benzyloxycarbonylaminophenyl)-3,6-dihydro-2H-thiopyran (15.3 g, 44.6 mM) was dissolved in dry tetrahydrofuran (175 ml) and stirred under nitrogen at −70° C. n-Butyllithium (1.6M in hexanes, 30 ml, 175 mM) was run in over 20 minutes, keeping the temperature below −60°, and the mixture then stirred a further 10 minutes at −70° C. A solution of (R)-glycidyl butyrate (6.42 g, 44.62 mM) dissolved in dry tetrahydrofuran (10 ml) was added dropwise over 10 minutes keeping temperature below −60°, and the mixture left to warm to ambient temperature over 18 hours. Methanol (29 ml) was added, and the mixture stirred for 10 minutes only. Saturated aqueous sodium bicarbonate (200 ml) was added, and the mixture extracted with ethyl acetate (400 ml). The extract was washed with saturated aqueous sodium bicarbonate (100 ml), brine (100 ml), dried (magnesium sulfate). Filtered and evaporated. The crude product was purified on a 300 g silica sinter column, eluting with a gradient from 0% to 100% ethyl acetate in dichloromethane. Relevant fractions were combined, reduced to a small volume, and diluted with an excess of isohexane to precipitate the desired product (11.3 g). MS (ESP): 310 (MH+) for C15H16FNO3S
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)C.C(O)CO.[OH-].[K+]>O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc(-c2nc3cccnc3n2CC(=O)O)cc1
Yield: 1.7 %

Procedure:
A mixture of N-[3-[(4-methoxybenzoyl)amino]-2-pyridinyl] glycine ethyl ester (32 g, 0.1 mole) and 167 ml of ethylene glycol was heated at reflux for 11/2 hr. After cooling, potassium hydroxide (8.4 g) in 40 ml of water was added, and the reaction mixture was heated at reflux for 1 hr. The solution was filtered to remove yellow precipitate, the filtrate was diluted with 650 ml of water, and acidified with 3N hydrochloric acid. The solid which formed, was collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight to give 25.5 g (90.1% yield). A 0.5-g sample was recrystallized from ethanol, collected by filtration, washed with cold ethanol and water, and dried under high vacuum at 70° C. over 2 days to give 0.47 g of crystals, mp 260°-63° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:4]=1[CH:5]=[CH:6][S:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([NH2:19])[CH:12]=1)(=[O:9])=[O:8].[O-:28][C:29]#[N:30].[K+].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:4]=1/[CH:5]=[CH:6]/[S:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([NH:19][C:29]([NH2:30])=[O:28])[CH:12]=1)(=[O:9])=[O:8]
Reactant: COc1cc(OC)c(C=CS(=O)(=O)Nc2ccc(OC)c(N)c2)c(OC)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Nc2ccc(OC)c(NC(N)=O)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,4,6-trimethoxystyryl-N-(3-amino-4-methoxyphenyl)-sulfonamide (1 mmol) in glacial acetic acid (10 mL) is added an aqueous solution of potassium cyanate (1 mmol in 2 mL of de-ionized water). The reaction mixture is stirred for 3 h at room temperature. The reaction mixture is then poured into de-ionized water (100 mL) and extracted with ethyl acetate for 3 times. The combined organic layer is then washed with sodium bicarbonate to neutralize acetic acid and then with brine. The organic layer is then dried over anhydrous magnesium sulfate and the solvent is removed under vacuum to yield the title compound which is purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:37])([CH2:31][N:32]1[CH:36]=[N:35][N:34]=[N:33]1)[C:10]([F:30])([F:29])[C:11]1[CH:16]=[CH:15][C:14]([CH:17](O)[C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:13][N:12]=1.C([SiH](CC)CC)C>CCO.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:37])([CH2:31][N:32]1[CH:36]=[N:35][N:34]=[N:33]1)[C:10]([F:30])([F:29])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)=[CH:13][N:12]=1
Reactant: OC(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CCO
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Cc2ccc(C(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 30.5 %

Procedure:
To a stirred solution of 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(hydroxy(4-(trifluoromethyl)phenyl)methyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (72; 100 mg, 0.19 mmol) in EtOH (5 mL) was added triethylsilane (˜0.18 mL, 1.13 mmol) and Pd(OAc)2 (20 mg, 0.02 mmol) at RT under inert atmosphere. The reaction mixture was stirred under reflux conditions for 7-8 h; progress of the reaction was monitored by TLC. The reaction mixture was allowed to cool to RT, filtered through a pad of Celite®, and the Celite® cake was washed with EtOH (3×25 mL). The filtrate was concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 40% EtOAc/hexanes) afforded 73 (30 mg, 0.058 mmol, 31%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.35 (s, 1H), 7.63-7.52 (m, 5H), 7.40-7.35 (m, 1H), 7.25-7.23 (m, 1H), 6.78-6.74 (m, 1H), 6.69-6.66 (m, 1H), 5.50 (d, J=14.5 Hz, 1H), 5.14 (d, J=14.5 Hz, 1H), 4.08 (s, 2H). MS (ESI): m/z 512 [M+H]+. HPLC: 91.7%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2[C:13](=[O:16])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@H:13]([OH:16])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Temperature: -40 °C

Procedure:
A mixture of (3aR,6aS)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (1.462 g, 6.79 mmol) in methanol (20 mL) was cooled in a dry ice/acetone bath to −40° C. Sodium borohydride (0.514 g, 13.58 mmol) was added in portions over 5 minutes. The reaction allowed to warm to room temperature overnight, then it was quenched with saturated aqueous ammonium chloride, diluted with water, and extracted with 3×150 mL of ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent was removed in vacuo to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.45-7.38 (m, 2H), 7.34 (dd, J=10.2, 4.7, 2H), 7.30-7.24 (m, 1H), 5.63 (s, 1H), 4.30 (dd, J=11.4, 6.2, 1H), 3.54 (q, J=13.0, 2H), 3.17 (dd, J=9.3, 3.3, 1H), 2.57 (dtd, J=10.0, 7.1, 3.2, 1H), 2.48 (dtt, J=17.5, 8.7, 4.3, 1H), 2.44-2.38 (m, 2H), 2.31 (dd, J=9.2, 7.4, 1H), 2.04-1.96 (m, 1H), 1.76-1.61 (m, 2H), 1.47-1.40 (m, 1H); MS (ESI+) m/z 217 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH2:19]([C:13]1[CH:14]=[CH:15][C:16]([C:10](=[O:12])[CH2:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:17][CH:18]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: N#Cc1cccc(CC(=O)O)c1
Reactant: CCCCCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Temperature: 0 °C
Yield: 31.2 %

Procedure:
The acid chloride prepared from 3-cyanophenylacetic acid (5 g) as described in Example 18 is added at once to 1-phenyloctane (5.9 g, 0.03 moles) in methylene chloride (20 ml). Anhydrous aluminium chloride (4.96 g, 0.037 moles) is added in 1 portion and the resulting mixture heated under reflux for 2 hours. The reaction mixture is cooled and poured into a mixture of ice water (200 ml) and concentrated hydrochloric acid (20 ml). The mixture is extracted with ether (3×50 ml) and the combined extracts dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is chromatographed on silica gel (hexane: ether; 70:30) to yield 3-(4-n-octylphenacyl)benzonitrile (3.12 g, m.p. 59°-64° C). This nitrile is heated under reflux in a mixture of concentrated hydrochloric acid (30 g) and acetic acid (30 g) for 48 hours. The reaction mixture is diluted with water (60 ml) and extracted with ether (3×50 ml). The combined ether extracts are washed with water (50 ml) then dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is recrystallized from heptane and again from aqueous ethanol to provide 3-(4-octyl-phenacyl)benzoic acid (1.5 g), m.p. 103°-110° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1CCC([CH2:49][OH:50])CC1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][CH:38]([CH2:49][OH:50])[CH2:37][CH2:36]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC1CCNCC1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCCCC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCC(CO)CC1
Yield: 15.6 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from Example 57B (200 mg, 0.37 mmol) and 4-piperidinemethanol (127 mg, 1.11 mmol) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-(4-(hydroxymethyl)piperidin-1-yl)propoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea (35.75 mg, 58%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.02 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.53-7.43 (m, 2H), 7.34-7.26 (m, 3H), 6.49 (s, 1H), 4.42-4.40 (m, 1H), 4.22-4.18 (m, 2H), 4.18 (s, 3H), 3.25-3.21 (m, 2H), 2.91 (d, 2H), 2.50-2.47 (m, 2H), 2.00-1.88 (m, 4H), 1.64 (d, 2H), 1.27 (s, 9H), 1.16-1.12 (m, 2H); LC-MS (ESI) m/z 621 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:11]2[C:6](=[C:7]3[CH:22]=[CH:21][N:20]=[C:8]3[CH:9]=[CH:10]2)[O:5][C:4]1=N)#[N:2].[OH-:24].[Na+]>Cl.O>[C:1]([CH:3]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:11]2[C:6](=[C:7]3[CH:22]=[CH:21][N:20]=[C:8]3[CH:9]=[CH:10]2)[O:5][C:4]1=[O:24])#[N:2]
Reactant: [OH-]
Reactant: Cc1cncc(C2=c3ccc4c(c3OC(=N)C2C#N)C=CN=4)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cncc(C2=c3ccc4c(c3OC(=O)C2C#N)C=CN=4)c1
Yield: 35 %

Procedure:
A solution of 3-cyano-2-imino-4-(5-methyl-pyridin-3-yl)-2H-pyrrolo[2,3-h]chromene (83 mg, 0.28 mmol) in 10% HCl (5 mL) was stirred at room temperature for approximately 5 h. The yellow suspension was diluted with water (5 mL), neutralized to approximate pH=10 using 10% NaOH and extracted with EtOAc (3×25 mL). The EtOAc extracts were washed with brine (10 mL), dried over MgSO4, and evaporated to yield a yellow solid. The solid was purified by flash column chromatography (silica gel, EtOAc:hexanes, 50-80% EtOAc) to yield a yellow solid (27 mg, 35%). 1H NMR (DMSO-d6): 12.10 (s, 1H), 8.70 (d, J=1.8 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 7.88 (m, 1H), 7.62 (d, J=3.3 Hz, 1H), 7.45 (dd, J=0.3, 9.0 Hz, 1H), 6.91-6.88 (m, 2H), 2.45 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][C:5]([Cl:10])=[N:6][C:7]=1[CH2:8]Cl.[CH3:12][O-:13].[Na+]>CO>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][C:5]([Cl:10])=[N:6][C:7]=1[CH2:8][O:13][CH3:12]
Reactant: C[O-]
Reactant: ClCc1nc(Cl)nc(Cl)c1Br
Agent: [Na+]
Solvent: CO
Product: COCc1nc(Cl)nc(Cl)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of 5-bromo-2,4-dichloro-6-(chloromethyl)pyrimidine (2) (600 mg, 2.19 mmol) in anhydrous MeOH (15 mL) at 0° C. was added NaOMe (25% wt in MeOH, 521 mg, 2.41 mmol). The mixture was stirred at 0° C. for 30 min and then allow warm to room temperature and stirred overnight. After this time the reaction mixture was concentrated in vacuo. The residue was purified using ISCO chromatography (24 g silica gel, 0-1.5% EtOAc in hexanes in 40 min) to give the title compound (480 mg, 81%) as a white solid. 1H NMR (DMSO, 300 MHz) δ 4.77 (s, 2H), 4.04 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:19])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH3:18])[CH3:17])[N:10]=2)=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH3:22][N:23]([CH3:25])[CH:24]=[C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH3:17])[CH3:18])[N:10]=1)[C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:19]
Reactant: CC(C)Nc1nccc(CC(=O)c2ccc(Cl)s2)n1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(C)Nc1nccc(C(=CN(C)C)C(=O)c2ccc(Cl)s2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a suspension of 1-(5-chloro-2-thienyl)-2-[2-(isopropylamino)pyrimidin-4-yl]ethanon (1 eq, 13.5 mmol) in 6 mL N,N-dimethylformamide, was added of N,N-dimethylformamide dimethyl acetal (3.4 eq, 46 mmol). The mixture was stirred at 100° C. for 2 h and then allowed to cool to room temperature. The solvent was evaporated to afford 4.5 g (95% yield) of 3-(dimethylamino)-1-(5-chloro-2-thienyl)-2-[2-(isopropylamino)pyrimidin-4-yl]prop-2-en-1-one which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=S)[CH:14]=[CH:15][C:16]=1[Br:17].O[Li].O.OO>O1CCCC1>[Br:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19]2[O:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][C:11]=1[Cl:10]
Reactant: Nc1cccc(Cl)c1O
Reactant: S=C=Nc1ccc(Br)c(Cl)c1
Agent: OO
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Clc1cc(Nc2nc3cccc(Cl)c3o2)ccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ambient solution of 2-amino-6-chlorophenol (0.86 g, 6.0 mmol) and 3-chloro-4-bromophenyl isothiocyanate (1.49 g, 6.0 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0° C.), and LiOH.H2O (0.521 g, 12.41 mmol) was added, followed by the drop wise addition of 30% H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×75 mL). The combined organics were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 359[M+H]+.