Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.BrC1C=CC2C(=CC=CC=2)C=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:15]=1
Reactant: c1csc(-c2cccc3ccccc23)c1
Agent: Brc1ccc2ccccc2c1
Product: c1csc(-c2ccc3ccccc3c2)c1

Procedure:
The 2-(2-thienyl)-naphthalene was prepared in the same manner as for the 1-thienyl-naphthalene derivative, with the Grignard being added to 2-bromonaphthalene (2.07 g, 0.01 m). After workup, a brown solid (2.39 g) was isolated. Column chromatography yielded 2-bromonaphthalene (630 mg) and a white crystalline solid (1.13 g, 73% yield based on recovered starting material); m.p. 103°-104° C.; m/z 210 (M+); (Found: C, 79.75; H, 4,80; S, 15.09. C14H10S requires C, 80.0; H, 4.76; S, 15.24); H NMR (CDCl3); δ7.17 (dd, J=5.6, 3.5 Hz, 1H), δ7.30 (dd, J=<1, 5.6 Hz, 1H), δ7.42 (dd, J=<1, 5 Hz 1H), δ7.45 (dd, J=<1, 7 Hz, 1H), δ7.46 (dd, J=1, 4.0 Hz, 1H), δ 7.73 (dd, J=1, 8.0 Hz, 1H), δ7.79 (dd, J=1, 8 Hz, 1H), δ7.81 (s, 1H), δ7.83 (s, 1H), δ5.803 (d, <1, Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][C:6]=1[CH3:18])=O.[NH2:19][C:20]([NH2:22])=[S:21]>CCO>[CH:13]1([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:19]=[C:20]([NH2:22])[S:21][CH:2]=3)=[C:6]([CH3:18])[CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(N)=S
Reactant: Cc1cc(OC2CCCC2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(OC2CCCC2)cc(C)c1-c1csc(N)n1
Yield: 73.5 %

Procedure:
A mixture of 2-bromo-1-(4-(cyclopentyloxy)-2,6-dimethylphenyl)ethanone (6.16 g, 19.8 mmol) and thiourea (1.51 g, 19.8 mmol) in 95% EtOH (28.3 mL) was heated at reflux for 90 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-(cyclopentyloxy)-2,6-dimethylphenyl)thiazol-2-amine (4.2 g) as white solids in 73.7% yield: 1H NMR (500 MHz, CDCl3) δ 6.58 (s, 2H), 6.24 (s, 1H), 4.75 (m, 1H), 2.13 (s, 6H), 1.88-1.78 (m, 6H), 1.62-1.59 (m, 2H).
Reaction SMILES: COC1C=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[S:31]1C=CC(C=O)=C1>>[S:31]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:29]1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1ccsc1
Product: O=C(NCCNCc1ccsc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 3-thiophenecarboxaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 398 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.26 (1H, s) 7.98-8.08 (2H, m) 7.77 (1H, d, J=5.42 Hz) 7.46 (1H, d, J=5.42 Hz) 7.42 (1H, dd, J=4.93, 2.98 Hz) 7.30 (1H, dd, J=3.29, 2.66 Hz) 7.24 (1H, dd, J=2.78, 1.03 Hz) 7.05 (1H, dd, J=4.91, 1.20 Hz) 6.80 (1H, d, J=5.42 Hz) 6.43 (1H, dd, J=3.44, 1.93 Hz) 3.67 (2H, s) 3.34 (2H, d, J=5.76 Hz) 2.64 (2H, t, J=6.54 Hz)
Reaction SMILES: [OH-].[Na+].CC([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([C:16]1[C:17]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:26][C:18]=2[S:19][C:20]=1[C:21]([O:23]CC)=[O:22])=[O:15])=O.C(O)(=O)C>CO.O>[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([C:16]1[C:17]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:26][C:18]=2[S:19][C:20]=1[C:21]([OH:23])=[O:22])=[O:15]
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1S(=O)c1ccccc1COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C(O)c1sc2cc(OCc3cccnc3)ccc2c1S(=O)c1ccccc1CO
Yield: 16.5 %

Procedure:
Sodium hydroxide (3 ml of 1M in water) was added to a suspension of ethyl 3-(2-[(methylcarbonyloxy)methyl]phenylsulfinyl)-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Example 35--500 mg, 0.98 mmol) in methanol (15 ml). The mixture was heated to reflux for 30 minutes. The resultant solution was cooled, diluted with water and acidified by dropwise addition of acetic acid. The precipitate was isolated by filtration and washing with water. The solid was recrystallised twice by dissolving in hot methanol, and cooling, to give the title compound as a colourless solid (71 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:29]=[CH:28][C:22]4[N:23]([CH3:27])[C:24]([CH3:26])=[N:25][C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:29]=[CH:28][C:22]4[N:23]([CH3:27])[C:24]([CH3:26])=[N:25][C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)nc(C)n4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(c3)nc(C)n4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetate in MeOH (2 mL) and THF (2 mL) was added a sodium hydroxide solution (2 M aqueous, 500 μL). The reaction mixture was stirred at 50° C. for 4 h. The mixture was purified using reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C29H29ClN3O3S: 534.2 (M+H+); Found: 534.2 (M+H+); 1H NMR (400 MHz, CD3OD): δ 8.38 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.69 (m, 1H), 7.60 (m, 3H), 5.26 (s, 1H), 4.00 (s, 3H), 2.87 (s, 3H), 2.62 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])[C:11](=[O:32])[C@H:10]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40]C)[N:35]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I[Si](C)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])[C:11](=[O:32])[C@H:10]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[N:35]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@H](Cc2cccc(OC)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@H](Cc2cccc(O)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To the product of Example 420, Step C (0.05 g, 0.081 mmol) in chloroform (1.622 ml) was added iodotrimethylsilane (0.046 ml, 0.324 mmol). The reaction was warmed to 50° C. After 4 hours, the reaction was quenched with saturated bicarbonate (10 mL) and extracted with dichloromethane (2×15 mL) and 5% MeOH in CH2Cl2 (1×15 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (0.5 to 7.5% MeOH in dichloromethane) afforded the title compound.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:16](=[O:18])[CH3:17])[CH2:11][C:12]([O:14][CH3:15])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:17][C:16]1[O:18][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC(NC(=O)c1ccccc1)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
To β-methyl N-benzoyl-L-aspartate (compound [3]; 229.9 g) obtained in Example 1 were successively added toluene (1.2 L), acetic anhydride (346 mL), N-methylmorpholine (4.7 mL) and 4-dimethylaminopyridine (1.04 g) and the mixture was stirred at internal temperature of 55–0° C. for 4 hr to give a solution of methyl 3-benzoylamino-4-oxopentanoate (compound [4]) in toluene. Without isolating compound [4], p-toluenesulfonic acid monohydrate (31.8 g) was added to this solution of methyl 3-benzoylamino-4-oxopentanoate (compound [4]) in toluene. The mixture was stirred at 85–90° C. for 5 hr and cooled to room temperature. To the reaction mixture was added, with stirring, an aqueous solution of sodium carbonate (75.6 g) in water (303 mL), and the mixture was adjusted to pH 7–7.5. After standing still, the aqueous layer was removed and the organic layer was concentrated to give the title compound (compound [5]; 206.7 g, yield 97.7%).
Reaction SMILES: [CH3:1][O:2][C:3](=[CH2:6])[CH:4]=O.[CH3:7][N:8]([CH3:10])[NH2:9]>CCOCC>[CH3:1][O:2][C:3]([CH:4]=[N:9][N:8]([CH3:10])[CH3:7])=[CH2:6]
Reactant: C=C(C=O)OC
Reactant: CN(C)N
Solvent: CCOCC
Product: C=C(C=NN(C)C)OC
Yield: 66.1 %

Procedure:
6.4 g of 2-methoxyacrolein are stirred for 1 hour at 30°-35° C. with 4.4 g of N,N-dimethylhydrazine in 50 ml of ether, dried at 20° C. with Na2SO4 and then the solvent is removed. Distillation at 74°-76° C./13 mbar gives 6.2 g of pure 2-methoxy-4-dimethylamino-4-azabutadiene. (b) 10.8 g of 2-methoxy-4-dimethylamino-4-azabutadiene and 15 g of 2-tert.-butylisothiazolin-3-one-1,1-dioxide are stirred for 11/2 h at 80°-85° C. in 250 ml of toluene. The crude bicyclic compound of formula IVb is further processed in the crude state as described in Example 4. ##STR16## The compounds listed in Table 1 are obtained in an analogous manner.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.C(N(CC)CC)C.[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[C:27](=[S:28])[O:19][CH2:18]1)=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C1C(CO)COC(=S)N1CC2
Yield: 19 %

Procedure:
To a solution of 2.67 g (0.01 mole) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in 150 ml of absolute chloroform a solution of 2.0 g (0.02 mole) of triethyl amine in 10 ml of absolute chloroform is added, and to the mixture 1.15 g (0.01 mole) of thiophosgene are added dropwise with stirring, under cooling with ice. The reaction mixture is stirred for 10 minutes, then it is washed to neutral with 15 ml of a 5% hydrochloric acid solution and subsequently water. The chloroformic phase is dried over sodium sulfate and evaporated to dryness. The residue is taken up in 15 to 20 ml of ethanol, and ether is added to the mixture until slight turbidity. The desired compound is obtained in crystalline form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](O)=[N:16]2)=[CH:11][CH:10]=1.[N:19]1([CH2:25][CH2:26][N:27]2[C:35]3[C:30](=[CH:31][C:32]([NH2:36])=[CH:33][CH:34]=3)[CH:29]=[N:28]2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.N1(CCN2C3C(=CC=C(N)C=3)C=N2)CCOCC1.N1(CCN2C3C=CC(N)=CC=3N=C2)CCOCC1.N1(CCN2C3C=C(N)C=CC=3N=C2)CCOCC1.N1(CCN2C=C3C(C=C(N)C=C3)=N2)CCOCC1.N1(CCN2C=C3C(C=CC(N)=C3)=N2)CCOCC1.C(C1NC2C=C(N)C=CC=2N=1)(C)(C)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:36][C:32]3[CH:31]=[C:30]4[C:35](=[CH:34][CH:33]=3)[N:27]([CH2:26][CH2:25][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:28]=[CH:29]4)=[N:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc2cnc(O)nn12
Reactant: Nc1ccc2c(cnn2CCN2CCOCC2)c1
Agent: CC(C)(C)c1nc2ccc(N)cc2[nH]1
Agent: Nc1ccc2c(c1)ncn2CCN1CCOCC1
Agent: Nc1ccc2cn(CCN3CCOCC3)nc2c1
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(cnn4CCN4CCOCC4)c3)nn12

Procedure:
Following the procedure of Example 1315, 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (365 mg, 1.51 mmol)was coupled in parallel fashion to 1-(2-morpholin-4-yl-ethyl)-1H-indazol-5-ylamine (74 mg, 0.30 mmol), 1-(2-morpholin-4-yl-ethyl)-1H-indazol-6-ylamine (74 mg, 0.30 mmol), 1-(2-morpholin-4-yl-ethyl)-1H-benzimidazol-5-ylamine (74 mg, 0.30 mmol), 3-(2-morpholin-4-yl-ethyl)-3H-benzimidazol-5-ylamine (74 mg, 0.30 mmol), 2-(2-morpholin-4-yl-ethyl)-2H-indazol-6-ylamine (74 mg, 0.30 mmol), 2-(2-morpholin-4-yl-ethyl)-2H-indazol-5-ylamine (74 g, 30 mmol) and 2-tert-butyl-3H-benzimidazol-5-ylamine (57 mg, 0.30 mmol). Products were purified by RP pHPLC as described in Example 1291c. Yield of TFA salt: 103 mg (82%); LC/MS: 470 (M+H); HPLC: 97% pure, RT=2.51 min; 1H NMR: (DMSO, δ) 9.86 (s, 1H), 9.50 (s, 1H), 8.97 (s, 1H), 8.36 (s, 1H), 7.83 (d, J=7.5, 1H), 7.62 (m, 2H), 7.54 (t, J=7.7, 1H), 7.32 (d, J=8.3, 1H), 7.18 (t, J=7.5, 1H), 6.95 (d, J=4.8, 1H), 6.93 (d, J=4.8, 1H), 4.79 (t, J=6.3, 2H), 3.95 (m, 2H), 3.81 (s, 3H), 3.71 (m, 6H), 3.16 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:21][C:20](=[O:22])[CH2:19]1)=[O:17])[CH3:14].CN(C)P(N(C)C)(N(C)C)=O.[CH2:34]=[O:35]>O1CCCC1.C(OCC)C>[OH:35][CH2:34][C@H:21]1[C@H:18]([C:16]([O:15][CH2:13][CH3:14])=[O:17])[CH2:19][C:20]1=[O:22]
Reactant: C=O
Reactant: CCOC(=O)C1CC(=O)C1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC(=O)[C@H]1CO
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
Under ice cooling, diisopropylamine (0.296 g, 2.92 mmols) was added to a solution of n-butyl lithium (1.59 M/hexane solution, 2.79 mmols) in tetrahydrofuran (8 ml) and the mixture was stirred for 10 minutes. After cooling to −78° C., a solution of 3-ethoxycarbonyl-1-cyclobutanone (Compound e-1) (355.4 mg, 2.50 mmols) in tetrahydrofuran (3 ml) was dropwise added to the mixture, which was then stirred for 15 minutes. After the temperature was once elevated to 0° C., the mixture was stirred for 15 minutes and again cooled to −78° C. Hexamethylphosphoramide (535.8 mg, 2.99 mmols) was added to the system. After stirring for 5 minutes, a solution obtained by trapping formaldehyde subjected to cracking at 160° C. and trapped in diethyl ether of −78° C. was poured into the system through a needle. The reaction was terminated by adding hydrochloric acid and the insoluble matters were filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (50 ml, hexane:diethyl ether=1:1 to 1:2) to give Compound (e-2) (50.7 mg, yield: 12%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:37])=[C:21]([C@:23]23[CH2:31][O:30][C@H:29]([C:32]([F:35])([F:34])[F:33])[C@H:28]2[CH2:27][S:26][C:25]([NH2:36])=[N:24]3)[CH:22]=1.[OH-].[Na+]>CN1CCN(C)C1=O.C(O)CC.CCOC(C)=O.O>[NH2:36][C:25]1[S:26][CH2:27][C@@H:28]2[C@@H:29]([C:32]([F:35])([F:33])[F:34])[O:30][CH2:31][C@:23]2([C:21]2[CH:22]=[C:17]([NH:16][C:9]([C:6]3[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=3)=[O:11])[CH:18]=[CH:19][C:20]=2[F:37])[N:24]=1
Reactant: COc1cnc(C(=O)O)cn1
Reactant: NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN1CCN(C)C1=O
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A suspension of 5-methoxypyrazine-2-carboxylic acid (26.29 g, 0.17 mol) in N,N′-dimethylimidazoline-2-one (160 mL) was stirred at ambient temperature for 15 min, then cooled to 2.2° C. Thionyl chloride (14.7 mL, 0.202 mol) was added while maintaining temperature under 5° C. The resulting suspension was stirred at 0−10° C. for 2 h while it transitioned to a clear solution. In another vessel, (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (52.0 g, 0.155 mol) was dissolved into N,N′-dimethylimidazoline-2-one (160 mL). The resulting solution was added to the solution of acyl chloride while maintaining temperature below 10° C. The reaction mixture was stirred for 30 min. Water (780 mL) was charged while maintaining temperature below 30° C. The resulting mixture was stirred for 30 min, and then EtOAc (780 mL) was added. To this mixture was added, 50% aq. NaOH (84.8 g) until the pH of the aqueous layer reached 11. The aq. layer was extracted with EtOAc (260 mL). The organics were combined, washed with sat. aq. NaCl (260 mL) and water (260 mL). The organics were filtered over Celite pad (26 g) and rinsed with EtOAc (260 mL). The organics were concentrated under vacuum to afford a solid. To the solid was added 1-propanol (728 mL), and the suspension was heated to 75° C. until a clear solution formed. The solution was cooled to −10° C. and held for 1 h. The solid was filtered, rinsed with cold 1-propanol (104 mL) and dried under vacuum (35° C.) until constant weight to afford the title compound (62.1 g, 84.9%). 1H NMR (500 MHz, DMSO) δ ppm 10.56 (s, 2H), 8.88 (d, J=1.2 Hz, 1H), 8.39 (d, J=1.2 Hz, 1H), 7.95-7.83 (m, 2H), 7.18 (dd, J=12.0, 8.8 Hz, 1H), 6.25 (s, 2H), 4.76-4.60 (m, 1H), 4.36 (d, J=8.1 Hz, 1H), 4.01 (s, 3H), 3.88 (dd, J=7.9, 2.3 Hz, 1H), 3.23-3.11 (m, 2H), 2.91 (dd, J=13.8, 3.6 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 162.11, 161.93, 156.13 (d, JCF=242.9 Hz), 149.38, 142.01, 138.35, 135.09, 133.98, 128.53 (d, JCF=11.6 Hz), 126.06 (q, JCF=282.0 Hz), 123.32, 121.93 (d, JCF=8.6 Hz), 116.76 (d, JCF=25.1 Hz), 78.86 (d, JCF=6.9 Hz), 76.94 (q, JCF=30.5 Hz), 66.37, 54.75, 36.44, 23.53.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:31]=[C:32]([CH2:36][C:37]([O:39]C)=[O:38])[CH:33]=[CH:34][CH:35]=4)([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:41])=[N:3]1.[OH-].[Na+].C(O)(=O)C>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:31]=[C:32]([CH2:36][C:37]([OH:39])=[O:38])[CH:33]=[CH:34][CH:35]=4)([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:41])=[N:3]1
Reactant: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4cccc(CC(=O)O)c4)c3)c2)n(C)n1
Yield: 68.2 %

Procedure:
A 50 ml THF solution of methyl {3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}acetate (216 mg, 0.38 mmol) and 0.5M NaOH (6.1 ml, 3.04 mmol) was stirred at room temperature for 2 hours. The reaction was quenched with acetic acid (0.174 ml, 3.04 mmol) and rotary evaporated to remove the THF solvent. Additional impure lots of product (22 mg) were combined and the aqueous mixture partitioned between EtOAc and NaHCO3 solution. The EtOAc layer was extracted with another portion of NaHCO3 solution. The combined basic aqueous layers were adjusted to pH 4 using 10% HCl and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried with anhydrous Na2SO4 and rotary evaporated. The off-white solid foam was chromatographed eluting with CHCl3/MeOH and then recrystallized from a mixture of CHCl3/EtOAc/MeCN to give white solid (144 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][N:14]([CH:47]2[CH2:49][CH2:48]2)[C:15](=[O:46])[CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]3[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=3[Cl:45])=[CH:29][CH:28]=2)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:55]>ClCCl>[Cl:1][C:2]1[C:3]([CH2:13][N:14]([CH:47]2[CH2:48][CH2:49]2)[C:15](=[O:46])[CH:16]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]3[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=3[Cl:45])=[CH:31][CH:32]=2)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N+:6]([O-:55])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c(Cl)cn1
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c(Cl)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (3-[{[5-chloro-2-(methoxypropyl)pyridin-4-yl]methyl}(cyclopropyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Experiment 94, Step 4 in dichloromethane (0.03 M) was added 3-chloroperoxybenzoic acid. The reaction mixture was stirred at RT for 16 h. The reaction was quenched with water and then extracted with EtOAc. The combined organic extracts were washed with 10% aq. HCl and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 1:1 (v/v) Hex:EtOAc 4 EtOAc) afforded the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([NH2:15])[CH:14]=1)=[O:8])[CH3:5].[N:23]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[CH:12]=[C:13]([NH:15][NH2:23])[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COCC(C)NC(=O)c1cc(NN)cc(-c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-Amino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (596 mg, 2 mmol) was dissolved in 6 mL of concentrated HCl and stirred for 15 minutes at 0° C. To the reaction mixture was added a solution of NaNO2 (138 mg, 2 mmol) in water (1.5 mL) dropwise at 0° C. The mixture was stirred for 30 minutes, and then a solution of SnCl2 (4.5 mmol, 189.6 mg) in 2 mL of concentrated HCl was added dropwise. A precipitate began to form immediately. After stirring for another 30 minutes, the resulting 5-hydrazino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide was isolated as a hydrochloride salt by filtration and immediately used in the next step.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c12
Reactant: Cc1ncc[nH]1
Product: Cc1csc2nc(-n3ccnc3C)nc(NCc3ccc4c(c3)OCCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.