Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCC([O:5][CH:6]([CH2:41][O:42]C(=O)CCl)[CH2:7][NH:8][C:9](=[O:40])[C:10]1[C:31]([I:32])=[C:30]([NH:33][C:34](=[O:37])[CH2:35][Cl:36])[C:29]([I:38])=[C:12]([C:13]([NH:15][CH2:16][CH:17]([O:24]C(=O)CCl)[CH2:18][O:19]C(=O)CCl)=[O:14])[C:11]=1[I:39])=O.[OH-].[Na+].O.Cl>CN(C)C(=O)C.C(#N)C>[OH:5][CH:6]([CH2:41][OH:42])[CH2:7][NH:8][C:9](=[O:40])[C:10]1[C:31]([I:32])=[C:30]([NH:33][C:34](=[O:37])[CH2:35][Cl:36])[C:29]([I:38])=[C:12]([C:13]([NH:15][CH2:16][CH:17]([OH:24])[CH2:18][OH:19])=[O:14])[C:11]=1[I:39]
Reactant: O=C(CCl)Nc1c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: O=C(CCl)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Yield: 92.2 %

Procedure:
N,N′-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide in N,N-dimethylacetamide and acetonitrile, from Example 3, was hydrolyzed by adding 130 mL of 10N sodium hydroxide solution (1.3 moles). Water (36 mL) was then added to the mixture to give a homogeneous solution. 1N Hydrochloric acid (100 mL, 0.1 moles) was added to precipitate the N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. The precipitate was collected and washed with water. The wet product was dried at 60° C. in a vacuum oven to give 71.6 g of product, 92.2% yield. The material was 100% pure by HPLC analysis.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=3[NH2:24])[CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].C(O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]4[NH:24][C:27](=[O:28])[NH:23][C:19]=4[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[O:7])=[CH:25][CH:26]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc(N2CCN(CCNC(=O)c3ccc(F)cc3)CC2)c1N
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCCN1CCN(c2cccc3[nH]c(=O)[nH]c23)CC1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
10 Mmol (3.57 g) of 4-fluoro-N-[2-{4-(2,3-diaminophenyl)-1-piperazinyl}ethyl]benzamide were dissolved in 35 ml of tetrahydrofuran (which had been distilled over LiAlH4), and the solution was cooled in an ice-bath to 0° C. under an atmosphere of nitrogen. 21 Mmol (3.4 g) of 1,1'-carbonyldiimidazole in 20 ml of tetrahydrofuran was added in one portion to this solution while vigorously stirring. The temperature raised to 10° C. Thereafter the mixture was stirred for 3 hours at room temperature. The reaction mixture was evaporated to dryness under reduced pressure, the residue was taken up into chloroform, and the solution was washed with water. The organic layer was evaporated to dryness, and the residue was chromatographed over silicagel with a mixture of methylene chloride, methanol and 25% of ammonia (92:7.5:0.5) as the eluent. The so obtained base was cyrstallized from ethanol, and the title compound was obtained having a melting-point of 240°-243.5° C.
Reaction SMILES: C[O:2][C:3](=[O:50])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](=[O:33])[CH:31]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:30]([C:41](=[O:43])[CH3:42])[CH:29]2[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[OH-].[Na+]>CCO.CC(O)=O>[C:41]([N:30]1[CH:31]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:32](=[O:33])[N:28]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][C@@H:4]([C:3]([OH:50])=[O:2])[NH:5][C:6]([C:8]3([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:7])=[CH:23][CH:24]=2)[CH:29]1[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)(=[O:43])[CH3:42]
Reactant: COC(=O)[C@H](Cc1ccc(N2C(=O)C(Cc3ccccc3)N(C(C)=O)C2c2ccccc2)cc1)NC(=O)C1(CCCCS(C)(=O)=O)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)N1C(Cc2ccccc2)C(=O)N(c2ccc(C[C@H](NC(=O)C3(CCCCS(C)(=O)=O)CCCC3)C(=O)O)cc2)C1c1ccccc1
Yield: 95 %

Procedure:
4-(3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl)-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester diastereomer 1 (90 mg, 0.128 mmol) in EtOH (3 mL) was treated with NaOH (1N, 0.3 mL) at room temperature for 30 min. The resulting solution was acidified with 1 drop of HOAc and was purified by HPLC (C-18, linear gradent from 5% acetonitrile to 95% in water over 30 min) to give 84 mg (95%, 0.122 mmol) of 4-(3-acetyl-5-oxo-2-phenyl-4-phenylmethyl-1-imidazolidinyl)-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]carbonyl]-L-phenylalanine diastereomer 1. LR MS: 688 (M+H).
Reaction SMILES: [O:1]1C2=NC=CC=C2C=C1.[CH:10]([C:13]1([CH3:31])[C:17](=[S:18])[NH:16][C:15]([C:19]2[N:24]=[C:23]3S[CH:26]=[CH:27][C:22]3=[CH:21][C:20]=2[C:28]([OH:30])=[O:29])=[N:14]1)([CH3:12])[CH3:11]>>[CH:10]([C:13]1([CH3:31])[C:17](=[S:18])[NH:16][C:15]([C:19]2[N:24]=[C:23]3[O:1][CH:26]=[CH:27][C:22]3=[CH:21][C:20]=2[C:28]([OH:30])=[O:29])=[N:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)C1(C)N=C(c2nc3sccc3cc2C(=O)O)NC1=S
Reactant: c1cnc2occc2c1
Product: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=S

Procedure:
In the same manner as described above for the furo[2,3-b]pyridine compound, 6-(4-isopropyl-4-methyl-5-thioxo-2-imidazolin-2-yl)-thieno[2,3-b]pyridine-5-carboxylic acid is prepared in 37% yield having a mp 242° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[CH:28]=2)[NH3+:23])=[CH:18][CH:17]=1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[CH:28]=2)[NH:23][C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][CH:8]=2)=[CH:18][CH:17]=1
Reactant: Cn1cc([C@@H]([NH3+])c2ccc(Br)cc2)nn1
Reactant: O=C(O)Cc1ccc(C2CC2)cc1
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc([C@@H](NC(=O)Cc2ccc(C3CC3)cc2)c2ccc(Br)cc2)nn1
Reaction time: 24 h
Yield: 88.3 %

Procedure:
To a solution of 0.075 g (0.426 mmol) (4-cyclopropylphenyl)acetic acid in 0.850 ml DMF was added 0.194 g (0.638 mmol) (S)-(4-bromophenyl)(1-methyl-1H-1,2,3-triazol-4-yl)methanaminium chloride 0.063 g (0.468 mmol) HOAT, 0.090 g (0.468 mmol) EDC, and 0.186 mL (1.06 mmol) triethylamine. After 24 hr at room temperature, the reaction mixture was purified by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) to afford 0.160 g (88%) N-[(S)-(4-bromophenyl)(1-methyl-1H-1,2,3-triazol-4-yl)methyl]-2-(4-cyclopropylphenyl)acetamide. 1H NMR (CDCl3, 400 MHz) 7.43-7.40 (m, 2H); 7.39 (m, 1H); 7.14 (m, 4H); 7.03 (d, 2H, J=8.25 Hz); 6.73 (d, 1H, J=7.41 Hz); 6.20 (d, 1H, J=7.50 Hz); 4.04 (s, 3H); 3.56 (s, 2H); 1.91-1.84 (m, 1H); 0.98-0.94 (m, 2H); 0.70-0.66 (m, 2H). HRMS (ES) [M+1]+ calcd for C21H21BrN4O: 425.0977. Found: 425.0979.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:27][S:28]([N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:9])=[CH:6][N:5]=[C:4]([NH:37][CH:34]2[CH2:35][CH2:36][N:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:32][CH2:33]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2sccc2C)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccsc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(3-methyl-thiophen-2-yl)-methanone (Example 197) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C16H22N5O3S2 [(M+H)+] 396.1159, observed 396.1162.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][OH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CO[C:18](OC)([CH3:20])[CH3:19].C(=O)([O-])O.[Na+]>C1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:19][C:18]1([CH3:20])[N:5]([C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH:4]([C:3]([O:2][CH3:1])=[O:15])[CH2:13][O:14]1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Yield: 117.5 %

Procedure:
Commercially available N-tert-butoxycarbonyl-serine methyl ester (2.0 g, 9.122 mmol), 2,2-dimethoxypropane (1.9 g, 18.24 mmol), and pyridinium-p-toluene sulfonate (26 mg, 137 μmol) were dissolved in benzene (29 ml) and heated under reflux for 15 hours. A saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with diethylether; the organic layer was subsequently washed with a saturated sodium chloride solution. The washed product was then dried over anhydrous magnesium sulfate and filtered, and the filtrate was subsequently concentrated. The resulting concentrate was purified by silica gel column chromatography to produce 3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (2.78 g, 91% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][C:75]([NH2:79])([C:77]#[CH:78])[CH3:76]>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:79][C:75]([CH3:76])([C:77]#[CH:78])[CH3:74])=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: C#CC(C)(C)N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CC(C)(C)NC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added 2-methylbut-3-yn-2-amine (7.6 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 2-methylbut-3-yn-2-amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (20-45—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methylbut-3-yn-2-yl)acetamide. (22 mg, 0.046 mmol, 33%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])(=[O:10])=[O:9])[N:3]=1.[CH3:20][C:21](=O)[CH2:22][C:23](=O)[CH3:24]>C(O)(=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([CH3:24])[N:6]2[N:5]=[C:4]([NH:7][S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])(=[O:10])=[O:9])[N:3]=[C:2]2[N:1]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1nc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])n[nH]1
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])nc2n1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A mixture of 2.43 g (9.00 mmol) of N-(5-amino-1,2,4-triazol-3-yl)-2-nitrobenzenesulfonamide and 1.85 ml (1.80 g, 18.0 mmol) of 2,4 pentanedione in 25 ml of glacial acetic acid was heated at reflux for 19 hours. After cooling to room temperature, the solid which separated was collected by filtration, washed with acetic acid and dried in vacuo to yield 2.58 g (82 percent) of the desired product as an off-white crystalline solid, mp 255°-256° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1([CH3:22])[CH:17]=[C:16](B(O)O)[NH:15][C:14](=[O:21])[O:13]1>O>[CH3:11][C:12]1([CH3:22])[O:13][C:14](=[O:21])[NH:15][C:16]2[CH:3]=[CH:2][C:7]([C:2]3[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=3)=[CH:6][C:17]1=2
Reactant: CC1(C)C=C(B(O)O)NC(=O)O1
Reactant: N#CCc1cccc(Br)c1
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(CC#N)c3)cc21

Procedure:
Prepared from 3-bromophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-oxazin-6-yl)boronic acid. White solid: mp 188-190° C.; 1H-NMR (DMSO-d6) δ10.33 (s, 1H), 7.62 (m, 2H), 7.55 (m, 2H), 7.48 (d, 1H, J=8.00 Hz), 7.33 (d, 1H, J=7.57 Hz), 6.99 (d, 1H, J=8.81 Hz), 4.09 (s, 2H), 1.67 (s, 6H); MS m/z 291(M−H). Anal. Calc. For C18H16N2O2.0.3 H2O: C, 72.61; H, 5.62; N, 9.41. Found: C, 73.00; H, 5.43; N, 8.81
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([S:25][CH:26]2[CH2:31][O:30]C(C3C=CC=CC=3)[O:28][CH2:27]2)[N:12]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:22][CH2:23][CH2:24]2)(=[O:20])=[O:19])[CH:14]=[C:13]([S:25][CH:26]([CH2:27][OH:28])[CH2:31][OH:30])[N:12]=1
Reactant: O=S(=O)(Nc1cc(SC2COC(c3ccccc3)OC2)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: O=S(=O)(Nc1cc(SC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1

Procedure:
A solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-phenyl-1,3-dioxan-5-yl)thio]pyrimidin-4-yl]azetidine-1-sulfonamide (the product of step (0.11 g) and pyridinium para-toluenesulfonate (99 mg) in methanol (5 mL) and H2O (2 drops) was heated at 60° C. for 1 h. The solution was cooled and the solvent evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with H2O, dried (MgSO4) and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with EtOAc/iso-hexane (8:2) to give the subtitle product as a yellow gum. The gum was dissolved in DCM and methanol, filtered through charcoal and the filtrate evaporated under reduced pressure. The residual solid was dried under high vacuum at 40° C. to give the title product as a white solid. Yield: 50 mg
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]2[CH3:21])=[CH:4][CH:3]=1.Br[C:23]1[C:24](=[O:38])[N:25]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:26]=[C:27]([Cl:29])[CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:29][C:27]1[CH:28]=[C:23]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]3[CH3:21])=[CH:4][CH:3]=2)[C:24](=[O:38])[N:25]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[N:26]=1
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(Br)c1=O
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Cl)nn(COCC[Si](C)(C)C)c2=O)nc1
Temperature: 100 °C
Yield: 90.7 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with (S)-tert-butyl 4-(6-aminopyridin-3-yl)-3-methylpiperazine-1-carboxylate 191f (580 mg, 2.0 mmol), 253a (1.36 g, 4.0 mmol), Pd2(dba)3 (180 mg, 0.20 mmol), Xantphos (230 mg, 0.40 mmol), Cs2CO3 (1.3 g, 4.0 mmol), and dioxane (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 4:1 petroleum ether/ethyl acetate to afford 253b (1.0 g, 91%) as yellow solid. MS-ESI: [M+H]+ 551.2
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:13]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2)cc1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1ccc(OC)c(OC)c1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under ice-cooling, 296 mg of sodium hydride was added to an N,N-dimethylformamide solution (30 ml) of 1.99 g N-(3,4-dimethoxyphenyl)benzene sulfonamide and stirred at room temperature for 30 minutes, and then 0.75 ml of ethyl bromoacetate was added thereto and stirred for 2 hours. The reaction liquid was poured into ice water, acidified by adding 1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography using ethyl acetate:n-hexane (1:2) as the elution solvent, thereby obtaining 2.47 g of ethyl [(3,4-dimethoxyphenyl)(phenylsulfonyl)amino]acetate as a pale yellow oily substance.
Reaction SMILES: Cl.[C:2]([N:5]([CH2:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=1)[CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:8]2[CH:19]=[C:20]([N:23]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=[CH:22][C:7]1=2)(=[O:4])[CH3:3]>O1CCCC1.C(OCC)(=O)C>[C:2]([N:5]([CH2:37][C:38]1[CH:39]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:41]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:43]=1)[CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:8]2[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:7]1=2)(=[O:4])[CH3:3]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N=C(c3ccccc3)c3ccccc3)ccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(N)ccc21
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Add 2 N hydrochloric acid (0.19 mL) to a solution of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-(benzhydrylideneamino)-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.520 g, 0.747 mmol) in tetrahydrofuran (5 mL) at room temperature and stir for 3 h. Dilute the mixture with ethyl acetate (20 mL) and wash with saturated sodium bicarbonate solution and brine (10 mL each), then dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (1:1), to provide the title compound as an off-white solid (0.297 g, 75%): 530 (M−H).
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.[CH3:16]O>S(=O)(=O)(O)O.CCOC(C)=O>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:5][C:6]([O:8][CH3:16])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CC(c1ccc(O)cc1)C1CC1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)CC(c1ccc(O)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 21.3 (2.4 g, 12 mmol) in MeOH (25 mL) was added five drops of sulfuric acid. The mixture was stirred overnight at reflux, cooled to room temperature, diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude product was chromatographed on silica gel (0-25% EtOAc/hexane) to afford 21.4 (2.2 g, 84%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.CO[CH:17](OC)[CH2:18][C:19](=O)[CH3:20]>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[CH:17][CH:18]=[C:19]([CH3:20])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(CC(C)=O)OC
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Solvent: CC(=O)O
Product: Cc1ccnc2nc(SCc3ccccc3)nn12
Temperature: 100 °C
Yield: 43.9 %

Procedure:
A solution of 50 g (0.24 mol) of 3-amino-5-benzylthio-1,2,4-triazole in 500 ml of glacial acetic acid was added dropwise over 3-4 hours to a solution of 34.0 g (0.25 mol) of acetylacetaldehyde dimethyl acetal in 500 ml of glacial acetic acid heated at 100° C. After the addition was complete the reaction mixture was heated at reflux overnight, cooled to room temperature and poured into an ice-water mixture. The solid which separated was collected by filtration and recrystallized from ethanol to yield 27 g (41%) of the desired product as a solid, m.p. 102°-104° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]([CH3:29])[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([Cl:22])=[CH:17]3)=[O:12])OCC[O:3]1.O1CCOCC1.Cl>O>[O:3]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]([CH3:29])[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]2[C:21]=1[CH:20]=[CH:19][C:18]([Cl:22])=[CH:17]2)=[O:12]
Reactant: Cn1c(C(=O)NCCCC2(C)OCCO2)c2ccc(Cl)cc2c1-c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)CCCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C

Procedure:
A suspension of 8.3 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid [3-(2-methyl-1,3-dioxolan-2-yl)propyl]amide in a mixture of 40 ml. of dioxane and 10 ml. of water is treated with 2 ml. of concentrated hydrochloric acid and then boiled at reflux for 3 hours. The solution obtained is concentrated to dryness under reduced pressure and the residue triturated with diethyl ether, and there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid (4-oxopentyl)amide having a melting point of 128°-131° C. which can be used in the process without further purification. An analytical sample is obtained by recrystallization from ethanol and has a melting point of 136°-138° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:4]1.Cl[C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)C>[CH3:15][O:14][C:12]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:3]([NH:2][C:17]1[C:18]3[C:25]([CH3:26])=[CH:24][S:23][C:19]=3[N:20]=[CH:21][N:22]=1)[CH2:4]2)=[O:13]
Reactant: COC(=O)c1cccc2c1CC(N)C2
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1cccc2c1CC(Nc1ncnc3scc(C)c13)C2

Procedure:
Using 2-(tert-butoxycarbonylamino)-4-methoxycarbonylindan (45 mg, 0.15 mmol) synthesized in the above Preparation Example 7, 4N hydrochloric acid-dioxane (0.7 ml) and acetic acid (2.1 ml), a similar procedure to Example 24 was carried out to obtain 2-amino-4-methoxycarbonylindan hydrochloride. Then, using the 2-amino-4-methoxycarbonylindan hydrochloride, 4-chloro-5-methylthieno[2,3-d]pyrimidine (28 mg, 0.15 mmol), triethylamine (63 μl, 0.45 mmol), and ethanol (1 ml), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (15 mg, 0.044 mmol) having the following physical properties: