Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([NH:5][S:6]([C:9]1[C:10]2[CH2:11][N:12]([CH3:18])[CH2:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:8])=[O:7])(C)C.B.[ClH:20]>CO>[ClH:20].[CH3:18][N:12]1[CH2:11][C:10]2[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13]1
Reactant: CN1Cc2cccc(S(=O)(=O)NC(C)(C)C)c2C1
Agent: B
Agent: Cl
Solvent: CO
Product: CN1Cc2cccc(S(N)(=O)=O)c2C1
Temperature: 25 °C

Procedure:
A suspension of 5.3 g of the compound prepared in Example 16 in 20 ml of methanol was cooled to 10° and 50 ml of concentrated hydrochloric acid was added dropwise at 10°-15° (gas evolution). The reaction mixture was allowed to warm to room temperature and then refluxed 3.75 hours. The reaction solution was cooled and concentrated in vacuo. The white solid was washed with ethanol followed by ethyl acetate then dried to give 4.1 g of 2,3-dihydro-2-methyl-1H-isoindole-4-sulfonamide hydrochloride, m.p. >250°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([N:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1
Reactant: COc1ccc(NC(c2cnc(Cl)nc2Cl)C(C)C)cc1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)Nc2ccccc2)C(c2cnc(Cl)nc2Cl)C(C)C)cc1
Temperature: 146 °C

Procedure:
(±)-[1-(2,4-Dichloro-pyrimidin-5-yl)-2-methyl-propyl]-(4-methoxy-phenyl)-amine (35.0 mg; 0.107 mmol) (from Example 11c supra) and phenyl isocyanate (12.8 μL; 0.12 mmol) (Aldrich) were combined in toluene (0.6 mL), sealed and heated in a microwave reactor (SmithCreator™, 160 seconds to a maximum of 146° C., then 800 seconds at 160° C., and finally 600 seconds at 180° C.). The reaction was incomplete, and the mixture was concentrated and purified by flash chromatography (Biotage 12M; 20:80 ethyl acetate-hexanes) to give the intermediate (±)-1-[1-(2,4-dichloro-pyrimidin-5-yl)-2-methyl-propyl]-1-(4-methoxy-phenyl)-3-phenyl-urea. (Yield 24.0 mg).
Reaction SMILES: C([O:5][C:6](=[O:49])[CH:7]([CH2:25][C:26]1([C:32](=[O:48])[NH:33][CH:34]([C:44](=[O:47])[NH:45][CH3:46])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])(C)(C)C.CCOCC>FC(F)(F)C(O)=O>[O:19]=[C:18]1[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11](=[O:24])[N:10]1[CH2:9][CH2:8][CH:7]([CH2:25][C:26]1([C:32](=[O:48])[NH:33][CH:34]([C:44](=[O:47])[NH:45][CH3:46])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:6]([OH:49])=[O:5]
Reactant: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCN2C(=O)c3cc4ccccc4cc3C2=O)C(=O)OC(C)(C)C)CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C1(CC(CCN2C(=O)c3cc4ccccc4cc3C2=O)C(=O)O)CCCCC1

Procedure:
A solution of 4-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl)ethylcarbamoyl]cyclohexylmethyl}butyricacidtert-butyl ester (diastereomer A) (50 mg, 0.075 mmol) in trifluoroacetic acid (1 mL) was stirred overnight at room temperature. The solvent was evaporated under vacuum leaving a white foam which was titrated with ether to afford 4-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)-2-{1-[2-(4-methoxyphenyl)-1-(methylcarbamoyl) ethylcarbamoyl]-cyclohexylmethyl}butyric acid (diastereomer A) as a white solid, 40 mg (87%). High Resolution Mass Spectrum M+ calculated for C35H39N3O7 : 613.2788; found: 613.2746.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:22])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C@H:11]2[CH3:22])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c2c(-c3ccc(C(C)C)cc3)c(C)oc2c1C
Solvent: CO
Product: Cc1cc(C)c2c(c1C)O[C@@H](C)[C@H]2c1ccc(C(C)C)cc1
Yield: 63 %

Procedure:
Using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran obtained in Reference Example 347, the title compound was synthesized in the same manner as in Reference Example 144. Yield 63%. Melting point: 79-80° C. (methanol).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1>CO>[CH3:1][S:2][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(SC)c([N+](=O)[O-])c1
Reaction time: 4 h
Yield: 63.5 %

Procedure:
Sodium thiomethoxide (9.1 g) in dry methanol (50 mL) is added dropwise to a stirred solution of methyl 6-chloro-5-nitronicotinoate (25.1 g) in dry methanol (400 mL) and the mixture stirred for 4 hours. The pasty mixture is evaporated to low volume, diluted with water and the product extracted into ethyl acetate. The extracts are washed with water and brine, and finally dried (MgSO4). Evaporation gave methyl 6-methylthio-5-nitronicotinoate (16.8 g) as a yellow solid. The solid can be recrystallised from cyclohexane to give a yellow solid m.p. 115-6° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[N:6]=[CH:5]1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[OH:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH:20]1[CH2:21][CH2:22][N:17]([CH2:2][CH2:3][N:4]2[C:12]3[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=3[N:6]=[CH:5]2)[CH2:18][CH2:19]1
Reactant: Oc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: Cn1c(=O)c2c(ncn2CCCl)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cn1c(=O)c2c(ncn2CCN2CCC(c3c[nH]c4ccc(O)cc34)CC2)n(C)c1=O
Yield: 43 %

Procedure:
A mixture of 3.65 parts of 7-(2-chloroethyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione, 3 parts of 3-(4-piperidinyl)-1H-indol-5-ol, 4.25 parts of sodium carbonate, 0.1 parts and potassium iodide and 200 parts of 4-methyl-2-pentanone was stirred and refluxed overnight. The whole was filtered while hot and the filtrate was evaporated. The residue was suspended in 45 parts of trichloromethane and 2.4 parts of methanol. The product was filtered off, washed with 16 parts of methanol and dried, yielding 2.5 parts (43%) of 3,7-dihydro-7-[2-[4-(5-hydroxy-1H-indol-3-yl)-1-piperidinyl]ethyl]-1,3-dimethyl-1H-purine-2,6-dione; mp. 232.5° C. (compound 2).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([O:28][CH3:29])[C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[CH:6][C:7]=1[NH2:8]
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(Br)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 93.6 %

Procedure:
N-(4-Bromo-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 145, 1.074 g, 2.36 mmol), iron (0.792 g, 14.19 mmol) and NH4Cl (95 mg, 1.77 mmol) were heated at reflux in ethanol (39 mL) and water (13 mL) for 1.5 h. The mixture was then cooled and concentrated in vacuo. The resulting residue was triturated in 10% CH3OH in CH2Cl2 (30 mL) for 15 minutes and the mixture was then filtered. The residues were triturated again with 10% CH3OH in CH2Cl2 (30 mL) and the mixture then filtered. The combined filtrates were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with CH2Cl2 gave the title compound (0.937 g, 93%) as a cream foam; 1H NMR: 3.79 (3H, s), 3.89 (3H, s), 4.86 (2H, s), 7.06 (1H, s), 7.18-7.30 (3H, m), 7.54 (1H, d), 7.83 (1H, s), 7.87 (1H, s), 8.33 (1H, d), 8.35 (1H, s), 8.43 (1H, d); m/z: ES+ MH+ 424/426.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]([CH3:34])([CH2:17][CH:18]([CH2:31][CH2:32][OH:33])[CH2:19][CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]([CH3:34])([CH2:17][CH:18]([CH2:31][CH:32]=[O:33])[CH2:19][CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:26])[CH3:25])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C)(C)CC(CCO)CCCCO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)CC(CC=O)CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3.4 mL (48 mmol) dimethyl sulfoxide in 140 mL dry methylene chloride at -78° C. is added dropwise 3.0 mL (35 mmol) oxalyl chloride. The solution is stirred for 15 minutes and a solution of 2.57 g (7.1 mmol) methyl 2,2-dimethyl-4-(2-hydroxyethyl)-8-(t-butyldimethylsiloxy)octanoate in 20 mL dry methylene chloride is added slowly. The solution is stirred at -60° C. for 15 minutes and 15 mL (0.11 mole) triethylamine is added. The reaction is allowed to warm to room temperature and diluted with methylene chloride. The organic layer is washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase is dried, filtered and concentrated to dryness. The oil is dissolved in ether and the solution is washed with water. The organic phase is dried, filtered and concentrated to give methyl 2,2-dimethyl-4-formylmethyl-8-(t-butyldimethylsiloxy)-octanoate; NMR (CDCl3) delta 9.8 (t,1H), 3.67 (s,3H), 1.2 (s,6H), 0.89 (s,9H).
Reaction SMILES: Br[CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[O:4][CH3:5].[NH3:18]>C(O)C>[NH2:18][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[O:4][CH3:5]
Reactant: N
Reactant: COC(CBr)c1ccc(-c2ccccc2)cc1
Solvent: CCO
Product: COC(CN)c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Yield: 61 %

Procedure:
4-Vinyl-biphenyl, 1.70 g (9.4 mmol), was dissolved in methanol (10 mL) and dichloromethane (15 mL). Bromine, 0.48 mL (9.4 mmol), dissolved in methanol (10 mL) was added over 30 minutes and TLC analysis showed complete reaction. The mixture was diluted with dichloromethane and added to an aqueous solution of sodium hydrogen sulphite and the mixture was shaken. The dichloromethane phase was washed with aqueous sodium hydrogen carbonate and water and evaporated to give 2.81 g product. The product was purified by silica gel chromatography silica gel (200 mL) with heptane/ethyl acetate (95+5) to give 1.00 g (39 %) of pure 4-(2-bromo-1-methoxy-ethyl)-biphenyl. 4-(2-Bromo-1-methoxyethyl)-biphenyl, 1.00 g (3.64 mmol), was dissolved in ethanol (20 mL) and added to a large excess of concentrated ammonia (20 mL). The mixture was heated to 100° C. in a sealed vessel for 16 hours and evaporated. Chromatography on silica gel (180 mL) with dichloromethane followed by dichloromethane/methanol/concentrated ammonia (90+10+1) gave 0.47 g (61%) of the sub-titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([CH:16]=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[BH4-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([CH2:16][OH:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=Cc1cnn2c(-c3cccnc3)ccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 2.0 g. of 7-(3-pyridyl)pyrazolo[1,5-a]-pyrimidine-3-carboxaldehyde and 0.35 g. of sodium borohydride in 100 ml. of methanol is stirred for 16 hours. The mixture is concentrated to dryness in vacuo and dichloromethane is added. The solution is washed with saturated sodium bicarbonate and passed through a column of hydrous magnesium silicate. The eluent is concentrated and diluted with hexane to give the product of the example.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=1)[NH2:25].C(=O)([O-])O.[Na+]>C(O)(C)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:17]2[C:18]3[N:10]([CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:39])([F:40])[F:38])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(Oc2cccc(OC(F)(F)F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(OC(F)(F)F)c4)c(Cl)c3)c21
Yield: 91 %

Procedure:
A solution of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (100 mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (153 mg) in isopropyl alcohol (1.5 mL) was stirred at 80° C. for 12 hrs. Aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→ethyl acetate) to give the title compound (173 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([OH:13])[C:2]([C@@H:4]([OH:12])[C@H:5]([OH:11])[C:6]([C:8]([OH:10])=[O:9])=[O:7])=[O:3].C(O)[C@H](O)[C@@H](O)[C@H](O)C(C(O)=O)=O>>[CH2:1]([OH:13])[C@@H:2]([OH:3])[C@@H:4]([OH:12])[C@H:5]([OH:11])[C:6]([C:8]([OH:10])=[O:9])=[O:7]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)C(=O)CO
Agent: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The 2,5-diketo-D-gluconic acid produced by cultivating the strain (I) is directly converted into 2-keto-L-gulonic acid by the strain (II) without being isolated from the medium. The undesired 2-keto-D-gluconic acid produced by the strain (II) is converted into 2,5-diketo-D-gluconic acid by the strain (I) which is again converted into 2-keto-L-gulonic acid by the strain (II).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[NH:9][C:10](=[O:14])[NH:11][C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1.[CH3:17][NH:18][CH3:19]>C(O)C>[CH3:17][N:18]([CH3:19])[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[NH:9][C:10](=[O:14])[NH:11][C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Solvent: CCO
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(N(C)C)cc1

Procedure:
A mixture of 11.0 g (0.05 mole) of 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one, 100 ml of 30% aqueous solution of dimethylamine and 200 ml of ethanol is heated in a pressure bomb at 130°-135° C. for 22 hours. The mixture is cooled, the solid is collected and recrystallized from isopropanol-water to give the title compound. M.P. >310° C. λ(max)(methanol) 364 nm (ε=23,300).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:15][C:14]=1[N:28]([C:36]1[CH:41]=[C:40]([N:42]([CH3:64])[C:43]([N:45]([C:52]2[C:57]([Cl:58])=[C:56]([O:59][CH3:60])[CH:55]=[C:54]([O:61][CH3:62])[C:53]=2[Cl:63])C(C(C)(C)C)=O)=[O:44])[N:39]=[CH:38][N:37]=1)C(=O)OC(C)(C)C)(=[O:11])[CH:9]=[CH2:10]>C(Cl)Cl>[Cl:58][C:57]1[C:56]([O:59][CH3:60])=[CH:55][C:54]([O:61][CH3:62])=[C:53]([Cl:63])[C:52]=1[NH:45][C:43](=[O:44])[N:42]([C:40]1[N:39]=[CH:38][N:37]=[C:36]([NH:28][C:14]2[CH:15]=[CH:16][C:17]([C:19]([N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[O:20])=[CH:18][C:13]=2[NH:12][C:8](=[O:11])[CH:9]=[CH2:10])[CH:41]=1)[CH3:64]
Reactant: C=CC(=O)Nc1cc(C(=O)N2CCN(C)CC2)ccc1N(C(=O)OC(C)(C)C)c1cc(N(C)C(=O)N(C(=O)C(C)(C)C)c2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(C(=O)N2CCN(C)CC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 153 %

Procedure:
TFA (0.2 mL) was slowly added to a stirred solution of tert-butyl (2-acrylamido-4-(4-methylpiperazine-1-carbonyl)phenyl)(6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-3-tert-butylcarbonyl-1-methylureido)pyrimidin-4-yl)carbamate (0.060 g, 0.0711 mmol) in dry DCM (2 mL) under argon atmosphere at 0° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 18 h. Reaction progress was monitored by LCMS, after completion of the reaction, excess solvents were removed under reduced pressure. The resulting residue was diluted with DCM and quenched with a saturated aqueous solution of NaHCO3. The aqueous layer was separated and extracted with DCM (3×10 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to get a crude residue. The residue was purified by silica gel column chromatography to afford 70 mg of desired product with HPLC purity 35% which was then purified by preparative HPLC (Conditions: Column: Gemini NX C18 (21.2 mm×150 mm particle size 5 μm); (Mobile Phase: A; 0.1% Ammonium bicarbonate in Water, B; ACN) to afford the desired compound. The compound was then diluted with dichloromethane and water. The aqueous layer was separated and extracted with DCM (3×10 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound (0.005 g, yield: 11%) as a white solid. 1H-NMR (CD3OD, 400 MHz): δ 8.41 (s, 1H), 7.79-7.76 (m, 2H), 7.36 (dd, 1H), 6.82 (s, 1H), 6.47-6.42 (m, 3H), 5.82 (d, 1H), 3.96 (s, 6H), 3.81-3.55 (m, 8H), 2.54 (s, 3H), 2.37 (s, 3H); MS (ESI): 643.1 [M+H]+; HPLC: 97.26%, rt: 6.19 min.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[CH3:10])=[N:5][N:4]=[C:3]1[S:14][CH3:15].[CH3:16]I.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:11]1([CH:9]([C:6]2[C:7](=[O:8])[N:2]([NH:1][CH3:16])[C:3]([S:14][CH3:15])=[N:4][N:5]=2)[CH3:10])[CH2:12][CH2:13]1
Reactant: CSc1nnc(C(C)C2CC2)c(=O)n1N
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNn1c(SC)nnc(C(C)C2CC2)c1=O

Procedure:
100 ml of toluene and 56.5 g (0.25 mol) of 4-amino-6-(1-cyclopropylethyl)-3-methylthio-1,2,4-triazin-5(4H)-one, and then 89.5 g (0.63 mol) of methyl iodide and 8.5 g (0.025 mol) of tetrabutylammonium bromide are added to 100 ml of 50% strength aqueous sodium hydroxide solution with vigorous stirring. The emulsion is stirred vigorously until the exothermic reaction abates (temperature rise to 50° C.). The mixture is filtered with suction through a glass frit at 20° C., the phases are separated and the organic phase is evaporated. The residue is recrystallized from methyl tert.-butyl ether. 32.9 g of the above compound of melting point 66°-68° C., identical with a product prepared according to process A (cf. Example 5), are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26]OC)[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.ClC1C=CC(C2C3C(C)=C(C)SC=3NC(=O)C3(CCC3)N=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]3([CH2:25][CH2:26][CH2:24]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Agent: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CCC1)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CCC1)c1nnc(C)n1-2

Procedure:
A procedure analogous to that set forth in the synthesis of Compound 202 (Step 6) was followed, with the exception that 5′-(4-chlorophenyl)-6′,7′-dimethylspiro[cyclobutane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one 2,2,2-trifluoroacetate was used as starting material. LRMS (M+H)+: 383 m/z. 1H NMR (400 MHz, DMSO-d6) δ7.50 (s, 4H), 3.28-3.39 (m, 1H), 2.73-2.87 (m, 1H), 2.60 (s, 3H), 2.39 (s, 3H), 1.89-1.98 (m, 1H), 1.78-1.88 (m, 1H), 1.64-1.74 (m, 2H), 1.61 (s, 3H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[S:17](=[O:32])(=[O:31])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=O)(C)(C)C.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C.CCOCC>[ClH:33].[N:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][S:17]([C:9]3[NH:8][C:16]4[C:11]([CH:10]=3)=[CH:12][CH:13]=[CH:14][CH:15]=4)(=[O:32])=[O:31])=[CH:24][CH:23]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)n1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2)cc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=S(=O)(Nc1ccc(-c2ccncc2)cc1)c1cc2ccccc2[nH]1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-pyridin-4-yl-phenylsulfamoyl)-indole-1-carboxylic acid tert-butyl ester (0.030 g) in ethyl acetate (1.0 ml) was added 3.5 N HCl/ethyl acetate (2.0 ml). The reaction mixture was stirred at 45° C. for 8 h, then diluted with ether (40 ml). The precipitate was collected, washed with ether and dried under high vacuum over P2O5 to obtain the title compound (0.025 g) as a colorless amorphous powder. MS (ISP): 350.4 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:13]([C:12]2[C:8]([C:7]3[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:16])=[O:15])[CH2:29]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2cccnc2Cl)c1C(=O)O
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2cccnc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
Combine 3-(2-chloro-pyridin-3-yl)-5-methyl-isoxazole-4-carboxylic acid (0.50 g, 0.0021 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.63 g, 0.0021 mol), 1-[3-(dimethyl-amino)propyl]-3-ethylcarbodiimide hydrochloride (0.40, 0.0021 mol), 1-hydroxy-7-azabenzo-triazole (0.29 g, 0.0021 mol), and N,N-diisopropylethyl amine (1.10 mL, 0.0063 mol), in N,N-dimethylformamide (10 mL). Stir over a weekend at ambient temperature. Concentrate in vacuo and take up in water and extract with ethyl acetate. Wash the combined extracts with water, dry over sodium sulfate, and concentrate in vacuo. Elute over silica gel using ethanol/dichloromethane allowing for the isolation of 0.87 g (86%) of the desired amide as a white solid. MS(ES): (M+1)+ 483.1, 485.1 m/z.