Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[Br:11]N1C(=O)CCC1=O.C(OCC)(=O)C.II>C(#N)C>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: O=C1CCC(=O)N1Br
Agent: II
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 4-chloropyrrolo(2,3-d)pyrimidine (30.0 g, 195 mmol) in acetonitrile (300 mL) at 85° C. was added N-bromosuccinimide (34.8 g, 195 mmol) portion-wise during a period of 10 minutes and the reaction mixture was stirred at 40° C. for 1 hour, then at room temperature for another 30 minutes. The reaction progress was monitored by TLC using 30% ethyl acetate in petroleum ether with iodine and 254 nm UV light to visualize the spot. The reaction mixture was allowed to stand for 1 hour so that precipitation occurred completely. The resulting solid was filtered and washed with chilled water (250 mL), then dried under high vacuum to give 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as brown solid. LRMS (ESI) calc'd for C6H4BrClN3 [M+H]+, 232; found 232. 1H NMR (400 MHz, DMSO-D6,) δ: 12.98 (s, 1 H), 8.60 (s, 1H), 7.96 (d, J=2.4 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:16][CH3:17])=[C:5]([O:14][CH3:15])[CH:6]=[C:7]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:8]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)C>[NH2:2][CH2:1][C:3]1[C:4]([O:16][CH3:17])=[C:5]([O:14][CH3:15])[CH:6]=[C:7]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:8]=1
Reactant: COc1cc(C2OCCO2)cc(C#N)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C2OCCO2)cc(CN)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(5-cyano-3,4-dimethoxyphenyl)-1,3-dioxolane (50) (FIG. 22) (0.555 g, 2.23 mmole) was predissolved in 2 ml dry THF and 10 ml anhydrous diethyl ether. To this solution under an argon atmosphere at room temperature was added 2.23 ml of 1.0M lithium aluminum hydride in diethyl ether solution. The reaction was then stirred at room temperature for 4 hours. The reaction was then cooled to 0° C. and the excess hydride destroyed with H2O. The reaction mixture was subsequently quenched with 10% NaOH and extracted with diethyl ether. The organic layer was dried over MgSO4, and concentrated to an oil in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=1[F:43])=[O:34])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[O:16])[S:14][C:7]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]([C:13]1[S:14][C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:29]=[CH:30][C:31]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=3[F:43])=[O:34])=[C:2]([F:1])[CH:3]=2)[CH:12]=1)=[O:16]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCNC(=O)OC(C)(C)C)sc34)cc2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of tert-butyl {3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate (300 mg, 0.49 mmol) in 10 ml of methylene chloride was added 3 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 10 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as yellow solid. Yield: 250 mg, 100%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:33])=[C:17]([C@@:19]2([CH3:32])[N:28]=[C:27]([NH2:29])[C:22]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[S:21](=[O:31])(=[O:30])[CH2:20]2)[CH:18]=1>>[NH2:29][C:27]1[C:22]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[S:21](=[O:30])(=[O:31])[CH2:20][C@:19]([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:33])([CH3:32])[N:28]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Yield: 45.6 %

Procedure:
Prepared from 5-cyanopicolinic acid (27.3 mg, 184 μmol, Eq: 1.2) and (R)-8-(5-amino-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-9-en-10-ylamine (50 mg, 154 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (32 mg, 70.3 μmol, 45.7% yield) as a white foam. MS (ISP): m/z=456.5 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:7]2=[N:8][C:9](=O)[N:10]=[C:6]2[CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:19])=O>>[N+:1]([C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:7]2[N:8]=[C:9]([Cl:19])[NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1N=c2cc([N+](=O)[O-])c([N+](=O)[O-])cc2=N1
Product: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1[N+](=O)[O-]
Yield: 64.7 %

Procedure:
As represented in the following synthesis scheme, 10 g of 2-benzoimidazolone was heated and stirred in 100 mL of nitric acid (1.38) at 70° C. for 1 hour, followed by diluting with cold water, to thereby obtain yellow green 5,6-dinitro-2-benzoimidazolone (yield 76.5%). The thus obtained 5,6-dinitro-2-benzoimidazolone was refluxed in phosphorous oxychloride at 140° C. for 7 hours, followed by evaporating the excessive phosphorous oxychloride under reduced pressure, and neutralizing with an aqueous solution of sodium hydrogen carbonate, to thereby obtain yellow 5,6-dinitro-2-chlorobenzimidazole the 2-position of which was chloridized (yield 64.7%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) and piperidine in DMSO at 23° C. according to the general procedure C. Obtained as a yellow solid (1.173 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:6]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=1)[S:3]([C:2]([F:15])([F:14])[F:1])(=[O:4])=[O:5]
Reactant: c1ccncc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=S(=O)(Oc1ccccn1)C(F)(F)F
Yield: 68 %

Procedure:
In a modification to GP 2, reaction of 1.5 g Intermediate 1.4 (5.3 mmol, 1 eq.), and 2.69 ml trifluoromethanesulfonic acid anhydride (16 mmol, 3 eq.) in pure pyridine yielded 1.49 g 2-pyridyl triflate (3.6 mmol, 68% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([F:18])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:19])[CH:3]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(N[C:42]([NH:44][C:45](=[O:54])[CH2:46][C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)=[O:43])=CC=3F)C=2)=CC=1>>[C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[C:16]([F:18])=[CH:17][C:2]([NH:1][C:42]([NH:44][C:45](=[O:54])[CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)=[O:43])=[CH:3][C:4]=2[F:19])[CH:12]=[CH:11][N:10]=1)(=[O:14])[NH2:15]
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Reactant: NC(=O)c1cc(Oc2c(F)cc(N)cc2F)ccn1
Product: NC(=O)c1cc(Oc2c(F)cc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Yield: 52 %

Procedure:
4-(4-Amino-2,6-difluorophenoxy)picolinamide (104 mg, 0.39 mmol) was converted to the title compound (91 mg, 52%) in a manner similar to the preparation of Compound D of Example 112. 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.50 (d, 1H, J=5.6 Hz), 8.11 (br s, 1H), 7.72 (br s, 1H), 7.61 (m, 2H), 7.36-7.37 (d, 1H, J=2.3 Hz), 7.23-7.31 (m, 3H), 7.11 (m, 2H), 3.69 (s, 2H); HRMS (ESI+), 445.1124 (M+H)+ calcd., 445.1117 (M+H)+ found.
Reaction SMILES: N[C:2]1[C:3]([CH3:15])=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.N(OCCC(C)C)=O.[I:24]CI>>[I:24][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: ICI
Reactant: Cc1cc(NC(=O)C(C)(C)C)ncc1N
Agent: CC(C)CCON=O
Product: Cc1cc(NC(=O)C(C)(C)C)ncc1I
Temperature: 85 °C

Procedure:
A mixture of 5-amino-4-methyl-2-(trimethylacetyl)aminopyridine (1.0 g, 4.82 mmol) in 34 mL of diiodomethane containing isoamyl nitrite (4.0 mL, 29.77 mmol) was heated at 85° C. for 0.5 h, cooled to room temperature and evaporated at 60° C. under high vacuum to give a red semi-solid. The crude material was purified by silica gel column chromatography using 10% ether/hexane as eluant to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]2=[O:16])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:17]([O-])=O.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C1COCC1.C(Cl)Cl>[NH2:17][C:3]1[C:2]([Cl:1])=[C:9]([N:10]2[CH2:15][CH2:14][N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:12][C:11]2=[O:16])[CH:8]=[C:5]([C:6]#[N:7])[CH:4]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N#Cc1cc(N2CCNCC2=O)c(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C#N)cc(N)c2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This amine was dissolved in THF (2.000 mL) and DCM (2.000 mL), then TEA (0.030 mL, 0.214 mmol) was added followed by BOC2O (0.033 mL, 0.143 mmol). After stirring at room temperature for 2 h, LC-MS indicated completion, it was concentrated and purification via flash chromatography (0-10% MeOH in DCM, 12 g) gave tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)-3-oxopiperazine-1-carboxylate (20 mg) as an off-white solid.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:34][C:20]1[N:21]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=2)[S:23][C:19]=1[CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:35])=[O:5]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2c1ccn2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2c1ccn2CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
To a solution of {4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester (50 mg, 99 μmol) in dichloromethane (4 ml) was added trifluoroacetic acid (1 ml). The reaction mixture was stirred for 2 h at ambient temperature. The solvent was removed under reduced pressure and the residue purified by preparative HPLC to give 5 mg (11 μmol, 11%) of the title compound as light yellow solid.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH3:36])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:31][C:32]2([CH3:36])[CH2:35][O:34][CH2:33]2)=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CC1(CBr)COC1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC2(C)COC2)c1OC(F)F
Temperature: 70 °C
Yield: 20 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and 3-bromomethyl-3-methyl-oxetane (122 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 20%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:40].[Na+]>CN(C=O)C>[CH:1]1([N:6]([C:7]2[C:8]([NH:9][CH3:16])=[CH:17][N:18]=[C:19]([NH:21][C:22]3[CH:37]=[CH:36][C:25]([C:26](=[O:27])[NH:28][CH:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[CH:24][C:23]=3[O:38][CH3:39])[N:20]=2)[CH2:12][C:11]([F:14])([F:13])[C:10]([OH:40])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: [OH-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2OC)nc1N(CC(F)(F)C(=O)O)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (543 mg, 1 mmol) in 10 ml of DMF, was added 1N NaOH (5 ml) dropwise. The reaction mixture was stirred at rt. for 1 h and then subjected to reverse phase HPLC purification using basic column. The final compound was obtained by lyophilization first and then dried in the vacuum oven at 60° C. for 3 d (380 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47-1.99 (m, 12 H) 2.54 (d, J=2.8 Hz, 2 H) 2.64-2.79 (m, 5 H) 3.00 (d, J=4.6 Hz, 2 H) 3.85-4.10 (m, 6 H) 4.20 (d, J=7.3 Hz, 1 H) 7.42 (s, 2 H) 7.48 (d, J=8.3 Hz, 1 H) 7.61-7.80 (m, 1 H) 8.23 (br. s., 1 H) 8.42 (d, J=8.3 Hz, 1 H). [M+H] calc'd for C27H37F2N7O4, 562; found 562.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8](N2[C@@H](C(C)C)COC2=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:27]O.[OH-].[Li+]>O1CCCC1.O>[CH:1]1([CH2:6][C@H:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]([OH:9])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one (1.88 g, 4.72 mmol) in tetrahydrofuran (73 mL) and water (22 mL) cooled to 0° C. was treated with a 30% aqueous hydrogen peroxide solution (2.1 mL) and lithium hydroxide (394 mg, 9.4 mmol). The reaction was stirred at 0° C. for 1 h. At this time, the reaction was quenched with a saturated aqueous sodium sulfite solution (16 mL) followed by the addition of a 0.5N aqueous sodium bicarbonate solution (50 mL). The tetrahydrofuran was then removed in vacuo. The residue was diluted with water (40 mL) and extracted with methylene chloride (3×20 mL). The aqueous layer was then acidified to pH=2 with a 5N aqueous hydrochloric acid solution and extracted with ethyl acetate (4×25 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (928 mg, 70%) as a white solid: mp 75.1-78.3° C.; [α]23589=−50.3° (c=0.100, chloroform); EI-HRMS m/e calcd for C14H16Cl2O2 (M+) 286.0527, found 286.0535.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].S(=O)(=O)(O)[OH:13].OO>C(O)(=O)C>[C:6]12[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:1][C:2](=[O:13])[O:3][C:4]2=[O:5]
Reactant: O=S(=O)(O)O
Reactant: O=C1Nc2ccccc2C1=O
Agent: OO
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c(=O)o1
Temperature: 25 °C

Procedure:
The isatin derivative (70 g) obtained in the above item (i), 200 ml of acetic acid and 0.8 ml of concentrated sulfuric acid were charged in a 500 ml two-neck flask and the mixture was stirred at room temperature. Then, 50 ml of 30% hydrogen peroxide was added dropwise to the mixture. After the completion of dropping, the mixture was stirred at 60° to 65° C. for one hour and a half and then cooled. The deposit was filtered, washed with water and dried under vacuum to give 35 g of a derivative of isatoic acid anhydride represented by the following formula (20): ##STR24##
Reaction SMILES: [CH3:1][CH:2]([N:8]([CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15]CC)[C:9](=[O:12])[CH2:10][Cl:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)CO.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][CH:2]([N:8]([CH2:13][CH:14]1[O:15][CH2:20][CH2:19][O:18]1)[C:9](=[O:12])[CH2:10][Cl:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(C)N(CC(OCC)OCC)C(=O)CCl
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CCO
Product: CCCCCC(C)N(CC1OCCO1)C(=O)CCl

Procedure:
N-(1-Methylhexyl)-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), ethylene glycol (2.0 grams) and trace amounts of toluenesulfonic acid were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux until no more ethanol was given off. After this time sodium carbonate (1 gram) was added to the mixture with stirring and the resulting mixture was distilled to yield the desired product N-(1-methylhexyl)-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide having a boiling point of 173° C. at 1 mm of Hg pressure.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40].C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[Cl:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=[C:2]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])[C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(OCC(F)(F)F)c(-c3ccccc3)c(Cl)c2c1
Temperature: 25 °C

Procedure:
(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl) [6-(trifluoromethyl) pyridin-3-yl]methanol (200 mg, 0.378 mmol, Example 66), 2,2,2-trifluoroethanol (14.0 μL, 0.19 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 19 mg, 0.47 mmol) were combined in a round bottom flask under an N2 atmosphere. The reaction solution was heated to reflux and refluxed overnight. Analysis showed the reaction had only progressed a moderate amount, so additional reagents were added, 2,2,2-trifluoroethanol (14.0 μL, 0.19 mmol) and sodium hydride (60% dispersion in mineral oil, 6 mg, 0.19 mmol) and contents were heated at reflux for an additional 48 hours. The contents were cooled to room temperature then transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C28H19ClF6N4O2, 592.1; m/z found, 593.2 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.80 (d, J=2.1 Hz, 1H), 8.28 (d, J=1.9 Hz, 1H), 8.17 (s, 1H), 8.05 (dd, J=8.2, 2.0 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.86 (dd, J=8.3, 0.4 Hz, 1H), 7.75 (dd, J=8.8, 2.2 Hz, 1H), 7.51-7.42 (m, 3H), 7.37-7.34 (m, 2H), 6.60 (s, 1H), 5.00 (q, J=8.6 Hz, 2H), 3.56 (s, 3H).
Reaction SMILES: [Cl-].[NH3+:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[NH:12][C:11](=[O:16])[C:10](=[O:17])[NH:9][C:8]=3[C:7]=2[CH:18]=1.CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1>>[N:2]1([C:3]2[CH:4]=[CH:5][C:6]3[CH:15]=[CH:14][C:13]4[NH:12][C:11](=[O:16])[C:10](=[O:17])[NH:9][C:8]=4[C:7]=3[CH:18]=2)[CH:21]=[CH:25][CH:24]=[CH:23]1
Reactant: [NH3+]c1ccc2ccc3[nH]c(=O)c(=O)[nH]c3c2c1
Reactant: COC1CCC(OC)O1
Agent: [Cl-]
Product: O=c1[nH]c2ccc3ccc(-n4cccc4)cc3c2[nH]c1=O

Procedure:
8.8 mmol of 9-ammoniobenzo[f]quinoxaline-2,3(1H,4H)-dione chloride were reacted with 8.8 mmol of 2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[C:18]3[N:17]=[C:16]([CH3:19])[N:15]=[C:14]([NH:20][CH2:21]CCC(N)=O)[C:13]=3[N:12]([CH3:27])[CH:11]=2)=[C:5]([CH3:28])[CH:4]=1.B.CSC>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:10][CH2:11][NH:12][CH2:13][CH2:21][NH:20][C:14]2[C:13]3[N:12]([CH3:27])[CH:11]=[C:10]([C:6]4[C:5]([CH3:28])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])[C:18]=3[N:17]=[C:16]([CH3:19])[N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1cc(C)c(-c2cn(C)c3c(NCCCC(N)=O)nc(C)nc23)c(C)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COc1ccc(CCNCCNc2nc(C)nc3c(-c4c(C)cc(OC)cc4C)cn(C)c23)cc1

Procedure:
Dissolve 2-(4-methoxyphenyl)-N-(2-{[7-(4-methoxy-2,6-dimethylphenyl)-2,5-dimethylpyrrolo[2,3-e]pyrimidin-4-yl]aminoethyl)acetamide in anhydrous THF (5 mL) and stir under N2. Add borane-dimethylsulfide complex (0.2 mL, 10.0 M in THF) and heat to reflux for 14 h. Quench by addition of N,N′-dimethyl-1,2-ethylenediamine (0.21 mL) in MeOH (5 mL) and stir for 1 h at ambient temperature. Concentrate under reduced pressure and purify the residue by preparative TLC, eluting with 10% MeOH in CH2Cl2. Dissolve the residue in a minimum amount of MeOH then add HCl in EtOAc (2 mL) and triturate with Et2O to obtain the title compound as a solid (HCl salt).