Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:12][NH2:13])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].[OH-].[Li+].O>CO>[NH2:13][CH2:12][C:5]1([C:3]([OH:4])=[O:2])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1
Reactant: COC(=O)C1(CN)CC12CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NCC1(C(=O)O)CC12CCCC2
Yield: 38.8 %

Procedure:
To a solution of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid methyl ester (3.40 g, 18.6 mmol) was added methanol (75 mL) and lithium hydroxide-water (LiOH—H2O) (1.55 g, 37.1 mmol). The mixture was heated to reflux under nitrogen for 48 hours. The solvent was removed by evaporation under reduced pressure and the residue was dissolved in water (50 mL). With ice bath cooling, concentrated HCl (˜2.5 mL) was added until the pH was adjusted to 6. A white precipitate was isolated by filtration and dried under vacuum to yield 1.22 g (39%) of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid as an off-white solid: mp 231–235° C. (decomposition); 1H NMR (300 MHz, D2O) δ 0.78 (d, J=4.7 Hz, 1H), 1.32 (d, J=4.7 Hz, 1H), 1.40 (m, 1H), 1.54–1.77 (m, 7H), 2.86 (d, J=13.2 Hz, 1H), 3.43 (d, J=13.2 Hz, 1H); MS (APCI) m/z 170 [M+H]+. Anal. Calcd. For C9H15NO2 −1.1H2O: C, 57.18; H, 9.17; N, 7.41. Found: C, 57.38; H, 8.82; N, 7.09.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.O[CH2:26][CH2:27][CH2:28][O:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:40]=[C:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38](=[O:39])[N:30]1[O:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1OCCCO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCCCON2C(=O)c3ccccc3C2=O)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
To a solution of 100 mg (0.30 mmol) of methyl (2S)-3-(4-hydroxyphenyl)-2-[(phenylmethoxy)carbonylamino]propanoate, as prepared in the preceding step, 67 mg (0.30 mmol) of 2-(3-hydroxypropoxy)isoindoline-1,3-dione, as prepared in step 2, and 88 mg (0.34 mmol) of triphenylphosphine in 10 mL THF at water/ice mixture temperature was added 66 mL (0.34 mmol) of DIAD dropwise. The solution was stirred at the same temperature for additional 20 min. Then the solution was allowed to warm to room temperature and stirred overnight. The solvent was removed under reduced pressure. The mixture was chromatographed on a silica gel column using EtOAc/hexanes (3:7 to 2:3 v/v) as eluent to yield 89 mg (55%) of viscous liquid as product: 1H NMR (300 MH, CDCl3) δ7.85-7.80 (m, 2H), 7.77-7.71 (m, 2H), 7.38-7.27 (m, 5H), 6.98 (d, J=8.65 Hz, 2H), 6.82 (d, J=8.65 Hz, 2H), 5.19 (d, J=8.16 Hz, 1H), 5.09 (s, 2H), 4.61 (m, 1H), 4.40 (t,J=6.22, 2H), 4.19 (t, J=6.11 Hz, 2H), 3.71 (s, 3H), 3.08-2.96 (m, 2H), 2.23 (quintet, J=6.15 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[C:17](OC)(OC)(OC)[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO.C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:17]([CH3:18])[N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Temperature: 70 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (300 mg, 1.07 mmol) in a mixture of methanol (5 mL) and THF (20 mL) was added trimethyl orthoacetate (2.02 ml, 0.02 mol) and TsOH (0.02 ml, 0.11 mmol). The reaction mixture was stirred at 70° C. for 40 min then allowed to stand at RT for 3 days. A saturated aqueous solution of NaHCO3 was added. The product was extracted into DCM (×3) and the organic layers were washed with brine and then dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Isolute column, 1-2% MeOH in DCM) to give the title compound as a yellow solid; 1H NMR (500 MHz, DMSO) δ 2.67 (3H, s), 6.88 (1H, d, J=5.20 Hz), 7.13 (2H, br. s.), 7.41 (1H, dd, J=8.51, 1.89 Hz), 7.58 (1H, d, J=8.51 Hz), 7.86 (1H, d, J=1.89 Hz), 8.48 (1H, d, J=5.20 Hz); LC-MS: m/z=+303.9, 305.7 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([C:11]1([CH3:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1)(O)=[O:9]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2([CH3:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: CC1(C(=O)O)CCC(=O)O1
Product: CC1(C(=O)c2ccc(F)cc2)CCC(=O)O1

Procedure:
acylating fluorobenzene with gamma-carbonylhalide-gamma-valerolactone, gamma-carboxy-gamma-valerolactone or gamma-carboxy-gamma-valerolactone anhydride in the presence of gallium trihalide, aluminum trihalide, antimony trihalide, titanium tetrahalide, boron trihalide or iron trihalide to form gamma-(para-fluorobenzoyl)-gamma-valerolactone; or acylating fluorobenzene with gamma-methyl-glutaconic anhydride in the presence of aluminum chloride, polyphosphoric acid, hydrogen fluoride, sulfuric acid, fluoroboric acid, boron trifluoride, boron trichloride or boron tribromide at a temperature of from 0°-85° C to form 4-(para-fluorobenzoyl)-3-pentenoic acid;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[C@H:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C@H:10]2[C:31]([OH:33])=[O:32])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1.[CH2:38]1[CH2:48]CN2C(=NCCC2)C[CH2:39]1.C(Br)C=C>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[C@H:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C@H:10]2[C:31]([O:33][CH2:48][CH:38]=[CH2:39])=[O:32])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCOC)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Reactant: C1CCC2=NCCCN2CC1
Solvent: C=CCBr
Solvent: CC#N
Product: C=CCOC(=O)[C@H]1[C@H](c2ccc(OC)cc2OCOC)c2cc(OCCC)ccc2[C@@H]1c1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
(1S,2R,3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (4.8 g, 9.5 mmol) was dissolved in dry acetonitrile (30 ml) and DBU (1.7 ml, 11.4 mmol) was added followed by allyl bromide (3,4 g, 28. mmol). After stirring for 0.5 h. the product was partitioned between 3M aqueous HCl and ethyl acetate. The organic layer was washed with water and brine, then dried (MgSO4 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography to provide the title compound as a pale yellow oil (5.7 g, quantitative).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:31]1[CH:35]=[CH:34][CH:33]=[N:32]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C.[OH-].[Na+]>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22]([N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: c1cn[nH]c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(-n2cccn2)ccc1Br
Temperature: 180 °C
Yield: 82.7 %

Procedure:
To (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 32, 198 mg, 0.382 mmol) was added pyrazole (450 mg, 6.61 mmol) and p-toluenesulfonic acid (20 mg, 0.116 mmol). The mixture was heated by microwave irradiation to 180° C. for 30 minutes. The reaction was diluted with ethyl acetate and aqueous sodium hydroxide (1M). The organic was washed with water and brine and was dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by column chromatography to yield (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-bromo-6-(1H-pyrazol-1-yl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (173 mg, 0.316 mmol). LCMS calc.=549.0/551.0. found=549.0/551.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].N1C[CH2:26][O:25][CH2:24]C1.C(#N)C>Cl.CCOCC>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:18][CH2:26][O:25][CH2:24][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: CN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Reactant: C1COCCN1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCOCC3)C2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared using procedures analogous to the ones used for Intermediate 39, but using morpholine for Step 1, a saturated solution of hydrogen chloride in ether, and diethyl ether as a solvent for Step 2 and acetonitrile for Step 3. MS (ES+APCI) (M+H) 336.1; LCMS retention time: 4.033 min (Method I).
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][OH:14])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[C:4]1(=[O:27])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH2:10][C:11]([F:16])([F:15])[CH2:12][CH2:13][O:14][S:40]([CH3:39])(=[O:42])=[O:41])[C:1](=[O:32])[C:2]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:3]12
Reactant: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCOS(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
To a mixture of 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-hydroxy-4-aza-octane (6.75 g 14.5 mM), dry dichloromethane (25 mL) and dry pyridine (10 mL), a solution of methanesulfonyl chloride (1.7 g) in dichloromethane (25 mL) is slowly added with stirring. The reaction mixture is kept at room temperature overnight, additional dichloromethane is added, and the reaction mixture is washed with 1N HCl (twice) and then washed with brine (twice). The resulting solution is dried (Na2SO4) and the solvent evaporated to yield an oil. Upon scratching this oil with ether/petroleum ether, the compound 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-methanesulfonyloxy-4-aza-octane is obtained as white crystals: 7.64 g (97%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-1-propanol (4.0 g, 19 mmol), as prepared in the preceding step, N-hydroxyphthalimide (3.26 g, 20 mmol) and triphenylphosphine (5.25 g, 20 mmol) in tetrahydrofuran (80 mL) was added diethyl azodicaroxylate (3.5 g, 20 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, the solution washed with saturated NaHCO3 (2×100 mL) and brine (100 mL), and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography (methylene chloride to 4% ethyl acetate in methylene chloride) to give the title compound as a white solid (6.85 g, 100%). 1H-NMR (300 MHz, CDCl3) δ 7.83 (m, 2H), 7.77 (m, 2H), 7.36 (m, 5H), 5.67 (br s, 1H), 5.12 (s, 2H), 4.28 (t, J=5.8 Hz, 2H), 3.51 (q, J=6.1 Hz, 2H), 1.99 (pentet, J=6.0 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=O>C(OC(=O)C)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[N:8][C:9]2[C:10](=[CH:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(nc1C)CCCC2
Reactant: O=Cc1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(nc1C)C(=Cc1cccs1)CCC2

Procedure:
A solution of 5,6,7,8-tetrahydro-2-methyl-3-quinolinecarboxylic acid ethyl ester as prepared in Preparation I (3.66 g) in acetic anhydride (10 ml) is treated with sodium acetate (1.37 g) and 2-thiophenecarboxaldehyde (2.24 g). The solution is heated at reflux temperature for 56 hours. The cooled mixture is diluted with toluene, filtered and the filtrate evaporated to a solid residue. The residue is triturated with hexane and filtered to yield a residue of 5,6,7,8-tetrahydro-2-methyl-8-(2-thienylmethylene)-3-quinoline carboxylic acid ethyl ester (1.91 g) m.p. 117° C.-118° C. The filtrate residue is purified on silica gel (70 g) with 9:1 Skelly B:ethyl acetate as eluent. Fractions 7-13, 20 ml each, provide additional 5,6,7,8-tetrahydro-2-methyl-8-(2-thienylmethylene)-3-quinoline carboxylic acid ethyl ester (0.73 g). An analytical sample, m.p. 117° C.-118° C. is obtained by hexane recrystallization.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:21](=O)[CH2:22][CH2:23][CH2:24][CH3:25])[C:17](OC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][CH:28]1[CH2:33][CH:32]([NH:34][C:35]2[NH:39][CH:38]=[N:37][N:36]=2)[CH2:31][CH2:30][O:29]1>>[CH2:22]([C:21]1[N:36]2[N:37]=[CH:38][N:39]=[C:35]2[N:34]([CH:32]2[CH2:31][CH2:30][O:29][CH:28]([CH3:27])[CH2:33]2)[C:17](=[O:18])[C:16]=1[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][CH:13]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CC1CC(Nc2nnc[nH]2)CCO1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOC(C)C2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h

Procedure:
A mixture of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (1.2 g) and N-(2-methyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.3 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a mixture of 4 kinds of isomers (0.49 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[C:7]([C:12]([OH:14])=[O:13])=[CH:6]2
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)n2c(C(=O)O)cc3cc(OC)ccc32)cc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of commercially available 5-methoxyindole-2-carboxylic acid (6.69 g, 35 mmol) and triethylamine (10 mL, 71.7 mmol) in anhydrous CH2Cl2 (70 mL) containing catalytic amount of DMAP was added dropwise a solution of 4-methoxybenzoyl chloride (6.20 g, 36.34 mmol) in CH2Cl2 (15 mL) at 0° C. The reaction mixture was stirred at this temperature for 15 min and then at room temperature for 4 hours. The reaction mixture was washed successively with 5% aqueous KHSO4 solution (2×20 mL), brine (25 mL), dried over Na2SO4, and evaporated under reduced pressure to dryness. The solid residue was recrystallized from methanol to yield 5-methoxy-1-(4′-methoxybenzoyl)-1H-indole-2-carboxylic acid as a white solid (7.4 g, 65%): mp 185-187° C.; 1H NMR (DMSO-d6) δ 3.80 and 3.85 (each 3H, s, 2×OMe), 7.02 (1H, dd, J=2.5 Hz and J=9.0 Hz, ArH), 7.07 (2H, d, J=8.9 Hz, 2×ArH), 7.28 (1H, d, J=2.5 Hz, ArH), 7.33 (1H, s, ArH), 7.38 (1H, d, J=9.0 Hz, ArH), 7.59 (2H, d, J=8.9 Hz, 2×ArH), 13.2 (1H, brs, exchangeable, OH). Anal. Calcd. for C18H15NO5.0.1H2O: C, 65.73; H, 4.65; N, 4.25. Found: C, 65.77; H, 4.61; N, 4.24.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:27]([SH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(C)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:27]([S:34][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:15][CH:16]=3)[NH:10][C:4]=12)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: SCc1ccccc1
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c2c1SCc1ccccc1
Temperature: 80 °C

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.10 g, 0.25 mmol), benzyl mercaptan (0.036 ml, 0.3 mmol) and potassum tert-butanolate (0.071 g, 0.63 mmol) were dissolved in DMF (1 ml) and heated to 80° C. for 48 h. The reaction mixture was diluted with EtOAc and extracted with 2M HCl. The aqueous phase was basified with 10M NaOH and extracted with EtOAc. The organic phase was dried (Na2SO4) and evaporated in vacuo and the residue was dissolved in CH3CN (3 ml) and purified by HPLC-C18, giving the title product as a bis(trifluoroacetate) (37%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:6][C:5]=1[OH:22].[H-].[Na+].IC.[C:28](O)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:6][C:5]=1[O:22][CH3:28]
Reactant: COC(=O)c1ccc(OCCCNC(=O)OC(C)(C)C)cc1O
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(OCCCNC(=O)OC(C)(C)C)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 4-(3-(t-butyloxycarbonylamino)propyloxy)-2-hydroxybenzoic acid methyl ester (3.0 g, 9.2 mmol) from Step 1 in dry DMF (25 mL) was added sodium hydride (0.39 g of a 60% suspension in mineral oil, 9.7 mmol). The reaction was stirred at 0° C. for 1 h, when iodomethane (1.0 mL, 16 mmol) was added. The reaction was then warmed to ambient temperature. After 24 h, acetic acid (1 mL) was added and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (150 mL) and washed with saturated aqueous NaHCO3 (3×100 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 3:7 EtOAc:hexanes as eluant. 4-(3-(t-Butyloxycarbonylamino)propyloxy)-2-methoxybenzoic acid methyl ester was obtained as an oil (85% yield).
Reaction SMILES: [Na].ClC1N=NN=C(Cl)C=1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([N:18]([CH3:20])[CH3:19])[N:12]=1.[CH2:21]([OH:23])[CH3:22]>>[Cl:10][C:11]1[N:16]=[C:15]([O:23][CH2:21][CH3:22])[N:14]=[C:13]([N:18]([CH3:20])[CH3:19])[N:12]=1
Reactant: CN(C)c1nc(Cl)nc(Cl)n1
Reactant: CCO
Agent: Clc1cc(Cl)nnn1
Agent: [Na]
Product: CCOc1nc(Cl)nc(N(C)C)n1
Temperature: 0 °C

Procedure:
A solution of sodium (0.46 g.) in ethanol (50 ml.) was added with stirring and waterbath cooling (25° C.) to a solution of the dichlorotriazine (3.86 g.) from (a) in ethanol (50 ml.). Following the addition the solution was poured into ice water (250 ml.) and the product collected, dried and crystallised from petroleum as needles (2.5 g.) having a melting point of 124° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH2:25](I)[CH3:26].[H-].[Na+].O>CN(C=O)C>[C:21]([O:20][C:18]([N:17]([CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)[CH2:25][CH3:26])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)C1CCNCC1
Reaction time: 16 h
Yield: 126.1 %

Procedure:
To a solution of 476 mg (1.42 mmol) of 1-benzyloxycarbonyl-4-(t-butoxycarbonylamino)piperidine from Step B and 0.24 mL (2.8 mmol) of ethyl iodide in 10 mL of DMF was added 85 mg (2.1 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred for 16 h and was then poured into water and extracted three times with ether. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 15% ethyl acetate in hexanes to afford 409 mg of title compound.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][C:7]1[CH:8]=[C:9]([S:21](Cl)(=[O:23])=[O:22])[CH:10]=[CH:11][C:12]=1[NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15]>O1CCCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[S:21]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])=[C:7]([CH3:6])[CH:8]=1)(=[O:23])=[O:22])[CH3:2]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1ccc(NS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A solution of diethylamine (1 g) and 3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) in tetrahydrofuran (20 ml) was allowed to stand overnight. The resultant mixture was concentrated and shaken with chloroform and 5% aqueous hydrochloric acid. The chloroform extract was concentrated and recrystallized from a mixture of ethanol and water to give 0.97 g of N,N-diethyl-3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide. M.P., 128°-128.5° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1.C(Cl)Cl>O>[Br:7][C:8]1[N:13]=[CH:12][C:11]([O:14][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Product: CNc1nccc(-c2cccnc2Oc2ccc(Br)nc2)n1
Temperature: 125 °C

Procedure:
To a slurry of cesium carbonate (8.9 g, 27 mmol) and 6-bromopyridin-3-ol (2.6 g, 15 mmol) was added 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine (3.0 g, 14 mmol). The reaction mixture was sealed and heated to 125° C. for 16 h. The mixture was cooled and diluted with water and the aqueous solution was extracted with DCM (3×75 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a brown oil, which was taken up in a little DCM and purified on an ISCO 120 g column, eluting with a gradient of 0-100% EtOAc/DCM, to afford 4-(2-(6-bromopyridin-3-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine as an off-white solid. MS m/z=295 [M+H]+. Calc'd for C15H12BrN5O: 358.2.