Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>C(OCC)C.Cl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(-c2cccnc2)n(COC(=O)C(C)(C)C)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask is charged with 5-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2, 1.0 g, 3.58 mmol) and THF (20 mL) and cooled to 0° C. KHMDS (0.5 M in toluene, 17.9 mL, 8.95 mmol) is added and the mixture is stirred at room temperature for 30 min, followed by addition of 2,2-dimethyl-propionic acid chloromethyl ester (2.58 mL, 8.95 mmol). The reaction mixture is stirred at room temperature for 3.5 h, then washed with water and extracted with ethyl acetate twice. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to afford an oil, which is taken up in diethyl ether. A few drops of concentrated HCl are added. Evaporation of the solvent and lyophilization give 2,2-dimethyl-propionic acid 5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl ester as a solid. 1H NMR (400 MHz, MeOD) δ ppm (HCl salt) 1.12 (s, 9H), 2.27 (s, 3H), 6.06 (s, 2H), 7.30 (dd, J=8.6, 2.0 Hz, 1H), 7.60 (s, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.74 (dd, J=7.8, 5.1 Hz, 1H), 8.01-8.16 (m, 1H), 8.64-8.79 (m, 2H). HRMS (ESI) m/z 357.1121 [(M+H)+ Calcd for C20H22ClN2O2: 357.1127].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31](OCC)=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12
Reactant: C1COCCN1
Reactant: CCOC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Product: Nc1ncnc2c1c(-c1ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c1)nn2CC(=O)N1CCOCC1

Procedure:
Ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate was treated with morpholine using the representative procedure for amide formation. Purification by preparative HPLC (25 to 100% CH3CN in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersi1HS C18, 250×21 mm column, Rt 9.3-9.8 min) afforded N1-{4-[4-amino-1-(2-morpholino-2-oxoethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-2,3-dichloro-1-benzenesulfonamide as a white solid (0.005 g, 0.009 mmol): RP-HP (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersi1HS C18, 250×4.6 mm column) Rt 8.22 min. 1H NMR (DMSO-d6, 400 MHz) δ 10.82 (s, 1H), 8.21 (s, 1H), 7.96 (d, 1H), 7.94 (m, 1H), 7.53 (t, 1H), 7.39 (m, 3H), 6.97 (br, 2H), 5.32 (s, 2H), 3.5 (m, 8H); MS: MH+ 580.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])C.S(Cl)(Cl)=O.Cl.[NH2:25][CH2:26][C:27]([NH2:29])=[O:28]>O>[C:27]([CH2:26][NH:25][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])(=[O:28])[NH2:29]
Reactant: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Reactant: NCC(N)=O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: NC(=O)CNC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 25 °C

Procedure:
A mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (100 mg, 0.43 mmol) (from Example 11) and thionyl chloride (0.2M in DCM, 10 mL) was heated to reflux for 2 hours. The reaction was concentrated, the residue was dissolved in DCM, to it was added glycinamide hydrochloride (242 mg, 2.19 mmol), followed by TEA. The mixture was then stirred at room temperature until the reaction was completed by TLC. The reaction was diluted with water and extracted with DCM. The combined DCM was concentrated and purified on a silica gel column to give the titled compound.
Reaction SMILES: [Na].[NH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)[NH2:3].[C:11](#[N:15])[C:12]([CH3:14])=[CH2:13]>C(O)C>[NH2:15][C:11]1[CH:12]([CH3:14])[CH2:13][N:2]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=2)[N:3]=1
Reactant: C=C(C)C#N
Reactant: Cc1cccc(NN)n1
Agent: [Na]
Solvent: CCO
Product: Cc1cccc(N2CC(C)C(N)=N2)n1

Procedure:
A 0.51 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 12.32 g. of 2-hydrazino-6-methylpyridine is added, followed by 6.7 g. of methacrylonitrile. The reaction mixture is refluxed on a steam bath for 16 hours then is evaporated in vacuo to an oil. Water is added to separate a solid. The solid is collected and recrystallized from ethyl acetate after treatment with activated charcoal to give 10.12 g. of the desired product as white crystals, m.p. 181°-185° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]([CH3:11])=[N:8]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-n2nc(C)cc2C(=O)O)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of 2-(4-methoxyphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.00 g, 3.84 mmol) in ethanol (20 mL) and water (20 mL) was added a sodium hydroxide solution (50% in water, 1 mL). The solution was stirred at 45° C. overnight. After the solution was allowed to cool to room temperature, 1 N HCl was added until the solution was acidic to pH paper. The solution was extracted with ethyl acetate (3×). The combined organic layers were dried (MgSO4) and concentrated to give 761 mg of the title compound, which was used in the next reaction without further purification. LC-MS (C12H12N2O3 calculated 232) m/z 233 (M+H).
Reaction SMILES: C([O:4][P:5]([CH2:11][P:12]([O:18]C(C)C)(=[O:17])[O:13]C(C)C)(=[O:10])[O:6]C(C)C)(C)C.Br[C:23]1[C:24](Br)=[C:25]([CH3:30])[C:26]([CH3:29])=[CH:27][CH:28]=1>>[CH2:29]1[C:26]2[C:25](=[CH:24][CH:23]=[CH:28][CH:27]=2)[CH2:30][C:11]1([P:5]([OH:6])(=[O:10])[OH:4])[P:12]([OH:13])(=[O:17])[OH:18]
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Reactant: Cc1ccc(Br)c(Br)c1C
Product: O=P(O)(O)C1(P(=O)(O)O)Cc2ccccc2C1
Yield: 70 %

Procedure:
Using the procedure described in Example I, tetraisopropylmethanediphosphonate MDP was converted to the desired ester in 70% yield by reaction with dibromo-o-xylene at 80° C. for 3 h: mp 55°-57° C.; 1H NMR (CDCl3) 7.15 (s, 4H, aromatic), 5.00-4.55 (m, 4H, CH), 3.60 (t, 4H, J=17.6 Hz, CH2), 1.26 (t, 24H, J=6 Hz, CH3); 31P NMR (CDCl3) 24.7 ppm; Cl mass spectrum m/e 447 (MH+). Anal. calcd for C21H36O6P2 : C, 56.49; H, 8.13; P, 13.88. Found: C, 56.71; H, 8.24; P, 14.18.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]([F:42])([F:41])[C:25]1[CH:26]=[C:27]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34]([NH2:36])=O)[CH:28]=[CH:29][CH:30]=1>O1CCCC1>[F:23][C:24]([F:42])([F:41])[C:25]1[CH:26]=[C:27]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34](=[S:10])[NH2:36])[CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: NC(=S)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Lawesson's Reagent (4.55 g, 11.26 mmoles) is added to a colorless solution of 2-[(3-trifluoromethylphenyl)amino]-benzamide (5.22 g, 18.64 mmoles) in 100 ml of tetrahydrofuran at room temperature. The resulting mixture is stirred under nitrogen for one hour, and then heated at reflux for 2.5 hours. The solution is concentrated in vacuo, and purified by flash chromatography with a gradient of 5:1 to 3:1 hexane/ethyl acetate as eluant, to provide 3.01 g (55%) of a bright yellow solid 2-[(3-trifluoromethylphenyl)amino]-benzene thioamide, mp 106°-108° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.[CH3:55][C:56]1[O:60][N:59]=[C:58]([C:61](Cl)=[O:62])[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][N:49]([C:61]([C:58]2[CH:57]=[C:56]([CH3:55])[O:60][N:59]=2)=[O:62])[CH2:48]1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC[C@@H](CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)no1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 60% yield. LCMS for C29H30ClN8O3 (M+H)+: m/z=573.0.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Reactant: Fc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(Cc2ccc(F)cc2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 mg (0.067 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of DMF. 3 mg (0.08 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 12 mg (0.08 mmol) of 4-fluorobenzyl chloride was added to the obtained mixture and they were stirred at 60° C. overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[CH2:22]([O:21][C:19]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCCN1CCCC1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCCC1=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
To a 0° C. solution of 1-(3-aminopropyl)-2-pyrrolidinone (25.0 g; 176 mmol) and triethylamine (26.7 g; 264 mmol) in CH2Cl2 (500 mL) was added benzyl chloroformate (33.1 g; 194 mmol) dropwise over a period of 15 minutes. The mixture was stirred for 1.5 hr. at 0° C. and then for 15 hr. at ambient temperature, before the mixture was diluted with CH2Cl2 and extracted with 5% aqueous HCl (200 mL), H2O (200 mL), and saturated aqueous NaHCO3. The organic phase was dried (MgSO4), filtered, and the solvents were removed under reduced pressure, then the oil which resulted was flash chromatographed (SiO2 ; 2-5% MeOH/Ch2Cl2) to give the title compound as a colorless oil (42.7 g; 88% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:8][CH2:7]1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 73.2 %

Procedure:
The product from Example 2 Step (a) (2 g) was dissolved in dioxan (100 ml) and 6N HCl (100 ml) added. After 18 hrs at room temperature the solvent was evaporated and the resultant solid basified with NaOH (2M) to pH 11. The aqueous was extracted with ethyl acetate, the organic phase separated, dried, filtered and evaporated to leave the sub-title compound as an oil (1.1 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][S:16][CH:15]3[N:12]([C:13](=[O:27])[CH:14]3[NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:11]=2[C:28]([O:30]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:29])=[CH:8][N:9]=1)(=[O:3])[CH3:2]>C(O)=O>[C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][S:16][CH:15]3[N:12]([C:13](=[O:27])[CH:14]3[NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:11]=2[C:28]([OH:30])=[O:29])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1
Solvent: O=CO
Product: CC(=O)Nc1ncc(C2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
A solution of 3-(2-acetamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.85 g) in formic acid (20 cc) is stirred for 30 minutes at 50° C. and then concentrated to dryness under reduced pressure (10 mm Hg; 1.3 kPa). The residue is taken up in ethanol (50 cc), the mixture is stirred for 5 minutes at 50° C. and the solvent is then evaporated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up in ethanol (100 cc); the mixture is stirred for 10 minutes at 50° C. and the solid is then filtered off and washed with ethanol (3×15 cc) and ethyl ether (3×10 cc). After drying, 3-(2-acetamidothiazol-5-yl)-2-carboxy-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.53 g) is obtained in the form of a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]1[O:33][C:32]2[CH:31]=[CH:30][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[S:26](Cl)(=[O:28])=[O:27])=[CH:14][C:13]=2[O:12]1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[CH:31][C:32]2[O:33][CH2:11][O:12][C:13]=2[CH:14]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1c(Cc2ccc3c(c2)OCO3)sc2ccccc12
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc4c(c3)OCO4)sc3ccccc23)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 using 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride (1.1 mmoles, 0.40 g) and THF (7 ml). Flash chromatography (50% ethyl acetate/hexanes) followed by recrystallization from chloroform and hexanes provided 0.23 g (45%) of a tan crystalline solid, m.p. 164-165° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[I:24]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:24])=[CH:19][C:18]=1[F:23]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc2c(C)noc2c(F)c1Nc1ccccc1F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c(C)noc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a suspension of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylate (2.84 g, 8.93 mmol) in DMF (50 ml) were added N-iodosuccinimide (3.01 g, 13.4 mmol) and TFA (3 ml). After stirring at room temperature for 4 h, the reaction was quenched with saturated aqueous NH4Cl solution (100 ml) and extracted with EtOAc (2×100 ml). The combined organic solution was washed with brine (100 ml), dried over MgSO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yielded 3.77 g (95%) of methyl 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylate as a tan solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:17]=[C:18]2[C:23](=O)[O:22][C:20](=[O:21])[C:19]2=[CH:25][CH:26]=1>>[F:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:25][CH:26]=1)[C:20](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:23]2=[O:22]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Product: CCOC(=O)C(CN1C(=O)c2ccc(F)cc2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.77 g, 56%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.80 g, 3.94 mmol) and 4-fluorophthalic anhydride (0.78 g, 4.72 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[S:4][C:3]=1[C:12]([NH2:14])=[O:13].C[Si]([N:19]=[C:20]=[O:21])(C)C>>[NH2:19][C:20]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[S:4][C:3]=1[C:12]([NH2:14])=[O:13])=[O:21]
Reactant: NC(=O)c1sc(-c2ccsc2)cc1N
Reactant: C[Si](C)(C)N=C=O
Product: NC(=O)Nc1cc(-c2ccsc2)sc1C(N)=O

Procedure:
Prepared by the method of Example 1 from 3-amino-5-(3-thienyl)-2-thiophenecarboxamide and trimethylsilylisocyanate.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH3:45])[N:43]=[CH:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH3:45])[N:43]=[CH:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ncnn4C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ncnn4C)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(1-methyl-1H-1,2,4-triazol-5-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (565 mg) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.32 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the reaction solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:19→1:9) and further recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(1-methyl-1H-1,2,4-triazol-5-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 124) (515 mg) as yellow crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:14]([F:16])[F:15])=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10].C(N(CC)CC)C.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26].[OH-].[Na+]>ClCCl>[F:15][CH:14]([F:16])[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1cc(CN)ccc1C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCc1ccc(C(F)F)c(C(=O)O)c1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a mixture of methyl 5-(aminomethyl)-2-(difluoromethyl)benzoate hydrochloride (1.30 g, 5.17 mmol, 1.0 equiv) and triethylamine (1.51 mL, 10.85 mmol, 2.1 equiv) in dichloromethane (50 mL) at room temperature, add isobutyryl chloride (0.571 mL, 5.42 mmol, 1.05 equiv) and stir for one hour. Dilute the mixture with dichloromethane and wash with water then saturated aqueous NaCl. Separate the organic layer and dry over sodium sulfate, filter, and concentrate under reduced pressure. Dissolve the resulting crude material in 1,4-dioxane (10 mL), and add sodium hydroxide (5 N aqueous, 2 mL, 10 mmol, 1.93 equiv). Stir the resulting suspension at 40° C. overnight. Concentrate the mixture under reduced pressure, and treat the resulting residue with 1 N aqueous hydrochloric acid until the pH reaches 3. Extract the resulting suspension with EtOAc (2×30 mL). Wash the combined organic layers with saturated aqueous NaCl (50 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound as a white solid (1.32 g, 94%). MS (m/z) 272 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[C:20]([O:24]C(C)(C)C)(=[O:23])[CH:21]=[CH2:22]>CN(C)C=O>[CH3:13][O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]2[O:1][CH2:22][C:21]([C:20]([OH:24])=[O:23])=[CH:4][C:3]=2[CH:6]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1cc(O)c(C=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)OCC(C(=O)O)=C2
Reaction time: 0.17 h

Procedure:
A well stirred mixture of 81.7 g of 2-hydroxy-4,5-dimethoxybenzaldehyde, 62 g of potassium carbonate, 100 ml of t-butyl acrylate and 320 ml of dimethyl formamide is heated at 140° for 5 hours. Most of the solvent is removed, the reaction mixture is diluted with water and the product is extracted with ethyl acetate/ether. After washing with 1N aqueous sodium hydroxide solution and drying over magnesium sulfate, the solvent is removed and the residue dissolved in 130 ml of trifluoroacetic acid. After 10 minutes, the solid mass is diluted with ice water and 70 ml of 20% aqueous sodium hydroxide solution. The precipitated product is collected by filtration and air-dried to yield 6,7-dimethoxy-2H-[1]-benzopyran-3-carboxylic acid, melting at 225°-228°.