Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH:10]C(=O)C>S(=O)(=O)(O)O.CO.O>[NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH2:10]
Reactant: CC(=O)Nc1nc2c([nH]1)CCCC2
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Nc1nc2c([nH]1)CCCC2
Yield: 101.2 %

Procedure:
N-(4,5,6,7-Tetrahydro-1H-benzo[d]imidazol-2-yl)acetamide (0.40 g) was heated at reflux in a stirred solution of 1:1 methanol/water (5 mL) containing 5 drops of concentrated sulfuric acid for 12 hours. The mixture was cooled and evaporated to dryness on the lyophilizer to give 0.31 g of 4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-amine. 1H-NMR (400 MHz, DMSO-d6) 13.4 (bs, 1H), 6.59 (bs, 2H), 2.55 (m, 2H), 2.49 (m, 2H), 1.67 (m, 2H), 1.62 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@H:4]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:5]#[C:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[CH:10][CH:9]=1.O.[OH-].[Li+].Cl>CO.C1COCC1.O>[NH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH2:5][C@@H:4]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:3]([OH:27])=[O:2])=[CH:9][CH:10]=1
Reactant: COC(=O)[C@@H](C#CCc1ccc(CCCCN)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(CCCCN)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
Compound 240 (0.40 g, 0.780 mmol) was dissolved in a mixture of methanol and THF (10 mL, 1/1, v/v). To the solution was added lithium hydroxide monohydrate (0.063 g, 1.561 mmol) dissolved in water (1 mL). The reaction mixture was stirred at room temperature for two hours, and then neutralized with 2N aqueous HCl solution to pH 5. The mixture was then concentrated under vacuum. The residue was taken into ethanol (3 mL) and the resulting solution was concentrated again under vacuum. The procedure was repeated two more times to ensure no aqueous solvent remained. The residue was chromatographed over silica gel, eluting with a mixture of concentrated ammonium hydroxide (0-10%), methanol (0-30%), and dichloromethane (100-60%), to afford the product 280 (0.29 g, 75%) as a white solid. 1H NMR (300 MHz, CD3OD): δ 1.46 (s, 9H), 1.58-1.78 (m, 8H), 2.54-2.68 (m, 4H), 2.85 (t, J=6.6 Hz, 2H), 3.98 (t, J=6.5 Hz, 1H), 7.08 (s, 4H), 8.50 (s, 1H). m/z (APCI) 365 [C20H32N2O4+H]+.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C([O-])(=O)C.[Na+].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>O.O1CCCC1.CCOCC>[CH3:3][O:2][N:4]=[CH:15][C:14]1[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=1
Reactant: CON
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CON=Cc1ccc(F)cc1
Temperature: 22 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
A solution of methoxylamine hydrochloride (13.4 g, 0.16 mol) in a mixture of water (150 ml) and tetrahydrofuran (50 ml) was treated with sodium acetate (11.2 g, 0.136 mol) followed by 4-fluorobenzaldehyde (11.57 g, 93.2 mmol) and the resulting mixture was stirred at 22° C. for 4 hours. The reaction mixture was then diluted with ether, washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave 14.3 g of the crude title material as a clear oil which was used as such for the next step. Distillation of an aliquot in vacuo gave a clear oil; bp 45-50° C./0.5 torr.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]2)[C:12]([CH2:18][S:19][C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)([C:14]([F:17])([F:16])[F:15])[OH:13].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[C:7]([OH:8])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]2)[C:12]([CH2:18][S:19][C:20]1[N:21]=[CH:22][CH:23]=[CH:24][N:25]=1)([C:14]([F:17])([F:16])[F:15])[OH:13]
Reactant: COc1c(F)ccc(C(Nc2cccc3nc(C)ccc23)C(O)(CSc2ncccn2)C(F)(F)F)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc2c(NC(c3ccc(F)c(O)c3F)C(O)(CSc3ncccn3)C(F)(F)F)cccc2n1
Reaction time: 22 h

Procedure:
Analogously to example 10 59 mg 2,4-Difluoro-α-{[(pyrimidin-2-yl)sulfanyl]methyl}-3-methoxy-β-[(2-methylquinolin-5-yl)amino]-α-(trifluoromethyl)-benzeneethanol in 5 ml dichloromethane are treated with 4.4 ml of a 1 M solution of boron tribromide in dichloromethane at −30° C. The typical work up after 22 hours at room temperature and chromatography on silica gel (acetone in hexane 10-50%) yields 44 mg of the desired product.
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]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]2.[H-].[Na+].Br[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([F:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28].[Cl-].[NH4+]>CN(C)C=O>[F:32][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Reactant: COC(=O)c1cc(CBr)ccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cn2c(-c3ccccc3)cc3cc(OC)ccc32)ccc1F
Reaction time: 0.25 h
Yield: 33.6 %

Procedure:
To a solution of 5-methoxy-2-phenylindole (90.9 mg) in N,N-dimethylformamide (1.8 mL) was added sodium hydride (dispersed in liquid paraffin, minimum 55%, 18 mg) under cooling with ice and an argon atmosphere, and the mixture was stirred under cooling with ice for 5 minutes and then at room temperature for 15 minutes. Methyl 5-(bromomethyl)-2-fluorobenzoate (101 mg) was added at room temperature, and the mixture was stirred at 80° C. for 13 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (53.2 mg).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]([CH3:13])[N:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:7](=[O:12])[CH:6]([CH3:13])[N:5]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1C(=O)Nc2cnc(Cl)nc2N1c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C(=O)N(c2ccccc2)c2cnc(Cl)nc2N1c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37 %

Procedure:
To a stirred solution of 2-chloro-7-methyl-8-phenyl-7,8-dihydropteridin-6(5H)-one (1.59 g, 5.78 mmol) in dichloromethane (75 mL) was added triethylamine (8.07 ml, 57.8 mmol), cupric acetate (2.09 g, 11.56 mmol) and phenylboronic acid (1.41 g, 11.56 mmol) followed by 4 Å molecular sieves (2 g). The resulting mixture was stirred for 48 h at rt with an air balloon on the top. The reaction mixture was then filtered over celite to give a clear solution. The solution was washed with aqueous saturated sodium bicarbonate (50 mL×2), dried over anhydrous sodium sulfate and evaporated to give a crude material, which was then purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (750 mg, 37%). 1HNMR (300 MHz, CDCl3): δ 1.65 (d, J=6.9 Hz, 3H), 4.82 (q, J=6.9 Hz, 1H) and 7.36-7.65 (m, 11H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[C:20]([F:28])[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-]>CN(C=O)C.CC(=O)OCC.C1COCC1.CO>[F:28][C:20]1[CH:19]=[C:18]([NH:17][C:10](=[O:12])[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:13]([F:16])([F:15])[F:14])[CH:27]=[CH:26][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: COc1ccc(CC(=O)O)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(N)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)O)c(F)c2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
Prepared using General Procedures 6 and 9. To a stirring solution of 2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (500 mg, 2.13 mmol) and methyl 4-amino-2-fluorobenzoate (361 mg, 2.13 mmol) in DMF (5 mL) were added HATU (852 mg, 2.24 mmol) and TEA (744 μl, 5.34 mmol). After stirring at room temperature for 18 h the reaction mixture was diluted with EA (20 mL) and washed with NaHCO3 (2×20 mL) and 1 M HCl (2×20 mL). The organic phase was concentrated in vacuo to afford an orange solid which was dissolved in THF (5 mL) and MeOH (2 mL) and 1 M LiOH (4.3 μL, 4.27 mmol) was added. After stirring at room temperature for 2 h the reaction mixture was concentrated in vacuo, the residue dissolved in water (10 mL) and acidified to pH 1 using 1 M HCl. A white precipitate was formed and the mixture was filtered under vacuum. The captured solid was washed with MeOH (5 mL) to afford a pale brown solid. The solid was triturated with MeOH (5 mL) to afford 198 mg (25%) of 2-fluoro-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-78 as a white solid. LCMS-ESI (m/z) calculated for C17H13F4NO4: 371; found 372 [M+H]+, tR=1.94 min (Method 10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.Cl[C:18]1[NH:22][C:21]2[C:23]([N+:31]([O-:33])=[O:32])=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:20]=2[N:19]=1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:18]2[NH:22][C:21]3[C:23]([N+:31]([O-:33])=[O:32])=[CH:24][C:25]([C:27]([F:29])([F:28])[F:30])=[CH:26][C:20]=3[N:19]=2)[C@H:10]([CH3:14])[CH2:9]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc2nc(Cl)[nH]c12
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Solvent: CCO
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc([N+](=O)[O-])c2[nH]1

Procedure:
A mixture of {5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-yl}-methanol (1.21 g, 5.0 mmol, Example 150a) and 2-chloro-7-nitro-5-trifluoromethyl-1H-benzoimidazole (1.33 g, 5.0 mmol, Example 57c) in EtOH (4 mL) reacted under the conditions of Example 3c to give the title compound as a yellow solid. MS (ESI, pos. ion) m/e: 471 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61][C:62]([F:73])([F:72])C1C=CC(N=C=O)=CC=1>>[CH3:33][CH:32]([CH3:34])[C@H:27]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([C:62]([F:73])([F:72])[F:61])=[CH:3][CH:4]=4)=[O:35])=[CH:16][CH:15]=3)[CH:18]=2)[C:22]1=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 244 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 4-trifluoromethyl phenyl isocyanate. The compound of example 244 was used directly without isolation for the preparation of compound of example 245.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:36])[CH2:35][CH2:34][S:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])=[CH:9][CH:8]=1.P([O-])(O)(O)=O.[Na+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:36])[CH2:31][CH2:32][S:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCSCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCSCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 87.6 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.1 mL, 0.1 mmol) was added to a solution of (4′-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran-4-ylethynyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 136-(6); 35 mg, 0.065 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature for 13 hours. A 30% sodium dihydrogenphosphate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane:methanol=20:1) to give the target compound as a colorless oil (30 mg, 88%).
Reaction SMILES: C(CCCCC1C=C(/[C:14](=[CH:47]\[CH:48]=[C:49]2\[N:50]([CH2:72][CH2:73][CH2:74][S:75]([O-:78])(=[O:77])=[O:76])[C:51]3[CH:52]=[CH:53][C:54]4[C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:62][C:61]([S:68]([O-:71])(=[O:70])=[O:69])=[CH:60][C:55]=4[C:56]=3[C:57]\2([CH3:59])[CH3:58])/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:38])=[O:37])[CH:30]=[C:31]([S:32]([O-:35])(=[O:34])=[O:33])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][S:43]([O-:46])(=[O:45])=[O:44])C=CC=1)(O)=O.[Na+:79].[Na+].[Na+].[Na+].[Na+].B([C:87]1[CH:88]=[C:89]([CH:97]=[C:98]([F:100])[CH:99]=1)[O:90][CH2:91][CH2:92][CH2:93][C:94]([OH:96])=[O:95])(O)O>>[C:94]([CH2:93][CH2:92][CH2:91][O:90][C:89]1[CH:88]=[C:87](/[C:14](=[CH:47]\[CH:48]=[C:49]2\[N:50]([CH2:72][CH2:73][CH2:74][S:75]([O-:78])(=[O:77])=[O:76])[C:51]3[CH:52]=[CH:53][C:54]4[C:63]([S:64]([O-:67])(=[O:66])=[O:65])=[CH:62][C:61]([S:68]([O-:71])(=[O:69])=[O:70])=[CH:60][C:55]=4[C:56]=3[C:57]\2([CH3:59])[CH3:58])/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:26])([CH3:27])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:37])=[O:38])[CH:30]=[C:31]([S:32]([O-:35])(=[O:33])=[O:34])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][S:43]([O-:46])(=[O:44])=[O:45])[CH:99]=[C:98]([F:100])[CH:97]=1)([OH:96])=[O:95].[Na+:79].[Na+:79].[Na+:79].[Na+:79].[Na+:79]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Reactant: O=C(O)CCCOc1cc(F)cc(B(O)O)c1
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cc(F)cc(OCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21

Procedure:
Compound 35 is prepared analogously to compound 8 (Example 8), except that 4-(3-borono-5-fluorophenoxy)butanoic acid is used as a starting material.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[F:26][C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:28]=1[NH2:29]>>[F:26][C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:28]=1[NH:29][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Reactant: Nc1c(F)cccc1F
Product: CCc1cc2c(C(=O)Nc3c(F)cccc3F)cnc(OC)c2o1

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.10 g) and 2,6-difluoroaniline (0.093 ml). Purification by column chromatography on silica with 30% ethyl acetate in hexane plus 1% ammonia solution, followed by trituration with ether gave the title compound (0.040 g) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.C(N(CC)CC)C.Cl.[NH2:25][C@H:26]([CH2:31][OH:32])[C:27]([O:29][CH3:30])=[O:28]>>[OH:32][CH2:31][C@@H:26]([N:25]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[C:27]([O:29][CH3:30])=[O:28]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: COC(=O)[C@H](N)CO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 70 °C

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (10 g, 0.05 mol), methanol (200 mL, 5 mol), triethylamine (18 mL, 0.13 mol) and (R)-methyl 2-amino-3-hydroxypropanoate hydrochloride (9.8 g, 0.063 mol) where by the reaction became homogeneous. The reaction was then heated at 70° C. overnight. The solvent was removed and the residue purified by flash chromatography (120 g silica gel, 0-10% MeOH/DCM) to obtain the product as a yellow solid. MS m/z=293.5 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(NC(=NC(C)C)O[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(C)C>C(#N)C>[CH2:19]([O:8][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)N=C(NC(C)C)OCc1ccccc1
Reactant: Cc1sc(C(=O)O)cc1[N+](=O)[O-]
Solvent: CC#N
Product: Cc1sc(C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 81.7 %

Procedure:
A mixture of 5-methyl-4-nitro-thiophene-2-carboxylic acid (1.0 g, 5.3 mmol) and 1,3-diisopropyl-2-benzylisourea (1.54 g, 6.4 mmol) in acetonitrile (25 mL) was stirred under an inert atmosphere and heated to reflux. After 48 hours the mixture was cooled, the solvent was removed under reduced pressure, and the residue was triturated in diethyl ether and cooled. The precipitate was filtered off and rinsed with cold ether. The filtrate and washings were combined, and rotary evaporated under reduced pressure. The resulting residue was dissolved in a minimum of ethyl acetate, and the solution was filtered through a column of silica gel, eluting with more ethyl acetate. The filtrate was rotary evaporated to dryness under reduced pressure to afford 1.2 g of 5-methyl-4-nitro-thiophene-2-carboxylic acid benzyl ester. A sample was chromatographed on silica gel in ether/petroleum ether 1:1, then recrystallized from ethanol to give product with a mp 57-58° C.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([OH:16])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:19])[CH3:18].C(=O)(O)[O-].[Na+]>ClCCl.N1C=CC=CC=1>[C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([O:16][C:17](=[O:19])[CH3:18])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@@H]1O[C@@H](O)CS1)c1ccccc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CS[C@H](COC(=O)c2ccccc2)O1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 29.76 g (0.132 mol) of cis and trans 2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane (as prepared in Example 1) in dichloromethane (65 mL) and pyridine (32 mL) was added dropwise 28.1 mL (0.395 mol) of acetyl chloride at 0-5° C. over 1.5 to 2 hours. The reaction mixture was stirred at 0-5° C. for 30 minutes then it was poured carefully onto a cold (0° C.) solution of saturated sodium bicarbonate. The organic layer was separated and the water layer was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with saturated sodium bicarbonate (3×20 mL) and brine (20 mL), and was dried over sodium sulfate. Following filtration, the solvents were removed in vacuo to give 32.1 g of crude product which was purified by Kugelrohr distillation or filtration through a short silica gel column (eluent hexanes: EtOAc 3:1). The purified product consisted of a 3:1 mixture of trans:cis isomers.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH:8]=[N:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:5]1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:2][CH2:3][N:4]1[CH:8]=[N:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:5]1
Reactant: OCCn1cnc(-c2cccnc2)n1
Reactant: O=S(Cl)Cl
Product: ClCCn1cnc(-c2cccnc2)n1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
122 g (6.4 mmol) 1-(2-hydroxyethyl)-3-(3-pyridinyl)-1H-1,2,4-triazole were suspended in 15 ml thionyl chloride and heated at 70° C. for 45 minutes. Excess thionyl chloride was removed in vacuo and the residue was dissolved in water (100 ml). The aqueous solution was basified with NaHCO3 solution (10%) and the resulting slurry was stirred for 15 minutes. The product was isolated by filtration, washed with water and dried to give the desired product as a brownish solid. MS (EI): 208.1 (M+). 1H-NMR (DMSO-d6): 3.97 (t, 2H), 4.54 (t, 2H), 7.38 (m, 1H), 8.21 (s, 1H), 8.36 (m, 1H), 8.65 (m, 1H), 9.34 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20].[CH3:21][O:22][CH:23](OC)[CH2:24]OC>>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][CH2:24][CH2:23][O:22][CH3:21])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: COCC(OC)OC
Reactant: Nc1ccc2ncnc(Nc3ccc(F)cc3F)c2c1
Product: COCCNc1ccc2ncnc(Nc3ccc(F)cc3F)c2c1
Yield: 28 %

Procedure:
Using an analogous reductive amination procedure to that described in Example 1, 6-amino-4-(2',4'-difluoroanilino)quinazoline was reacted with 2-methoxyacetaldehyde dimethyl acetal to give 4-(2',4'-difluoroanilino)-6-(2-methoxyethylamino)quinazoline in 28% yield, m.p. 175-176° C.; NMR Spectrum: 3.31 (s, 3H), 3.38 (t, 2H), 3.61 (t, 2H), 6.19 (t, 1H), 7.07-7.18 (m, 2H), 7.27-7.38 (m, 2H), 7.48-7.6 (m, 2H), 8.2 (s, 1H), 9.3 (broad s, 1H); Elemental Analysis: Found C, 61.7; H, 4.9; N, 16.9; C17H16F2N4O requires C, 61.8; H, 4.9; N, 17.0%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[C@@H:13]([CH3:15])[OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:45])[C@H:22]([CH:25]([O:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[NH:23][CH3:24].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>ClCCl>[CH3:19][O:20][C:21](=[O:45])[C@H:22]([CH:25]([O:36][C:37](=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[N:23]([C:16](=[O:18])[C@H:12]([C@@H:13]([CH3:15])[OH:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:24]
Reactant: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN[C@H](C(=O)OC)C(OC(=O)c1ccccc1)c1ccc(OCOC)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: COCOc1ccc(C(OC(=O)c2ccccc2)[C@@H](C(=O)OC)N(C)C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H](C)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.2 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-threonine (3.7 g) and O-methoxymethyl-N-methyl-β-benzoyloxytyrosine methyl ester (threo isomer) (3.11 g) in dichloromethane (50 ml) was added ethyl 1,2-dihydro-2-ethoxy-1-quinolinecarboxylate (2.9 g). After stirring for 20 hours at room temperature, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with dil. hydrochloric acid, sodium bicarbonate aqueous solution and water. After evaporation, the residue was put on a column of silica gel (MERCK 7734, 100 g) and eluted with n-hexane-ethyl acetate (1:1, V/V) to give N-(N-benzyloxycarbonyl-L-threonyl)-O-methoxymethyl-N-methyl-β-benzoyloxytyrosine methyl ester (threo isomer) (2.04 g).