Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:2]2[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[O:27])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C1NC2CCC1C2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C2CCC(C2)N1C(=O)c1ccc(OC)cc1
Yield: 73.6 %

Procedure:
To a solution of ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (181 mg, 1.07 mmol) obtained in Example 1 (b) in chloroform (2 ml) were added triethylamine (0.16 ml, 1.18 mmol) and 4-methoxybenzoyl chloride (201 mg, 1.18 mmol) while being cooled with ice. After a reaction at room temperature for 1 hour, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (25%–40% ethyl acetate/hexane), to give ethyl 2-(4-methoxybenzoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (239 mg, 74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[O:9][CH2:10][C:11]([F:33])([F:32])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:29]=[N:28][C:27](Cl)=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:31])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.CC([O-])(C)C.[K+].[CH2:46]([OH:49])[C:47]#[CH:48]>O>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[O:9][CH2:10][C:11]([F:33])([F:32])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:29]=[N:28][C:27]([O:49][CH2:46][C:47]#[CH:48])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:31])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(NC(=O)c3cnc(Cl)cn3)ccc2F)C(F)(F)CO1
Reactant: C#CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(NC(=O)OC(C)(C)C)OCC3(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
((R)-4-{5-[(5-Chloro-pyrazine-2-carbonyl)-amino]-2-fluoro-phenyl}-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl)-carbamic acid tert-butyl ester (400 mg, 800 μmol) was combined with DMF (1.2 ml) to give a colorless solution. KOtBu (180 mg, 1.6 mmol) and propargyl alcohol (449 mg, 477 μl, 8.00 mmol) were added and the reaction mixture was stirred 2 h at RT. Water was carefully added and the product was extracted with EtOAc. The organic layers were dried over Na2SO4 and concentrated under vacuum. The crude material was purified by flash chromatography (SiO2, 20 g, 0 to 50% EtOAc in heptane). Light yellow solid (350 mg, 84%). MS (ISP): m/z=520.2 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[C:25]1([CH2:31][C:32]([O:34][CH2:35]Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:35][O:34][C:32](=[O:33])[CH2:31][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:13])(=[O:6])=[O:7]
Reactant: O=C(Cc1ccccc1)OCCl
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCOC(=O)Cc1ccccc1
Yield: 64.2 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (0.5 g, 1.3 mmol) dissolved in 10 mL of anhydrous toluene was reacted with 1.1 g (4.0 mmol) of chloromethyl 2-phenylacetate in the presence of 0.44 g (1.6 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.44 g (64% yield) of the title compound (28a) as a colorless oil. Rf=0.47 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.97 (s, 3H), 0.99 (s, 3H), 2.24-2.30 (m, 2H), 3.20-3.24 (m, 2H), 3.62-3.65 (m, 2H), 3.68 (s, 2H), 3.84 (s, 1H), 3.91 (d, J=9.2 Hz, 1H), 4.15 (d, J=9.6 Hz, 1H), 4.28 (d, J=10.8 Hz, 1H), 4.53 (d, J=11.2 Hz, 1H), 5.78 (d, J=5.6 Hz, 1H), 5.87 (d, J=5.6 Hz, 1H), 7.25-7.38 (m, 10H) ppm. MS (ESI) m/z 548.99 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37](O)=[O:38])=[CH:31]2.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:37]([C:32]2[NH:33][C:34]3[C:30]([CH:31]=2)=[CH:29][C:28]([Cl:27])=[CH:36][CH:35]=3)=[O:38])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-({4-[2-(Heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (400 mg) obtained in Example 303-2 and 5-chloro-1H-indole-2-carboxylic acid (196 mg) were dissolved in N,N-dimethylformamide (5 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (211 mg) and hydroxybenzotriazole (HOBT) (168 mg) were successively added thereto, and the mixture was stirred at room temperature for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and ether was added to the residue to give the title compound as a white powder.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2].S(Cl)(Cl)=O.[CH3:16]O>C(Cl)Cl>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C=Cc1ccc(C(=O)OC)cc1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
4-Vinylbenzoic acid 69 (2.222 g, 15.00 mmol) was dissolved in 5 ml of methanol at room temperature. Thionyl chloride (1.094 ml, 15.00 mmol) was added dropwise and allowed to stir for 2 hours. The mixture was then heated to reflux for 20 minutes. Upon cooling the mixture was diluted with methylene chloride. The solvent was removed under a stream of nitrogen. The residue was purified by flash chromatography on silica eluted with 95:5 methylene chloride/methanol to give 2.370 g (97.4%) of methyl-4-vinylbenzoate 70 as a yellow oil.
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][C:6]1[S:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1>CO>[CH3:1][O:12][C:11]([C:9]1[S:10][C:6]([CH3:5])=[CH:7][CH:8]=1)=[O:13]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(C)s1
Temperature: 25 °C
Yield: 81 %

Procedure:
Acetyl chloride (5 mL) was added to a 0° C. solution of methanol (40 mL) and the solution was allowed to warm to room temperature. 5-Methyl-thiophene-2-carboxylic acid (Lancaster; 1.58 g, 11.1 mmol) was added and the solution was allowed to stir at room temperature over the weekend. The solvents were evaporated under reduced pressure and ethyl acetate was added. The solution was extracted with aqueous sodium hydrogen carbonate and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered, and evaporated to give 5-methyl-thiophene-2-carboxylic acid methyl ester (1.40 g, 81%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1.[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[Br:33].CC(C)([O-])C.[Na+].O>C1COCC1>[Br:33][C:26]1[CH:27]=[C:28]([C:29]#[N:30])[CH:31]=[CH:32][C:25]=1[NH:24][C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Reactant: N#Cc1ccc(N)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(c1cc(Nc2ccc(C#N)cc2Br)nc2c(C=O)cnn12)C1CC1
Reaction time: 1.5 h
Yield: 31.8 %

Procedure:
Tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (225 mg, 0.67 mmol) and 4-amino-3-bromobenzonitrile (197 mg, 1 mmol) were dissolved in anhydrous THF (4.5 mL). Sodium tert-butoxide (96 mg, 1 mmol) was added in one portion. After 1.5 h, the reaction was poured into H2O (25 mL) and extracted with EtOAc (3×30 mL). The organics were washed with brine (1×100 mL), dried over MgSO4, filtered and concentrated in vacuo. The tan solid was purified via flash column chromatography (30% EtOAc/hexanes) to provide tert-butyl 5-(2-bromo-4-cyanophenylamino)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (106 mg, 32%) as a pale yellow solid. LCMS (ES): >90% pure, m/z 497 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Li+].O>>[F:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)CCCCCCCNC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCCCCCCCC(=O)O

Procedure:
50 mg of methyl 8-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)-amino]octanoate Example 15 (0.11 mmol, 1 equivalent) were reacted with 0.5 ml of 1 M lithium hydroxide solution in water (0.53 mmol, 5 equivalents) analogously to Example 20 and worked up. This gave 25 mg (47% of theory; purity: 92%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:45][C@@H:46]1[CH2:51][CH2:50][C@H:49]([OH:52])[CH2:48][CH2:47]1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([C:17]([NH:45][C@H:46]2[CH2:51][CH2:50][C@@H:49]([OH:52])[CH2:48][CH2:47]2)=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1
Reactant: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@@H](O)CC1)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (50 mg, 0.17 mmol) in acetonitrile (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (85 mg, 0.22 mmol), followed by cis-4-aminocyclohexanol hydrochloride (26 mg, 0.17 mmol). Triethylamine (52 mg, 0.51 mmol) was added before heating in the microwave at 150° C. for 10 minutes. After 10 minutes, the solvent was removed in vacuo, and the residue was partitioned between water and dichloromethane. The aqueous layer was separated and extracted with dichloromethane (3×10 mL), the combined organic extracts were dried with MgSO4, filtered and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford the title compound: (26 mg, 0.067 mmol).
Reaction SMILES: C[C:2]1[C:3]([NH2:11])=[C:4]([C:8](O)=[O:9])[S:5][C:6]=1[CH3:7].[NH2:12][C:13](N)=[O:14].[OH-].[Na+]>C(O)(=O)C>[CH3:7][C:6]1[S:5][C:4]2[C:8]([OH:9])=[N:12][C:13]([OH:14])=[N:11][C:3]=2[CH:2]=1
Reactant: NC(N)=O
Reactant: Cc1sc(C(=O)O)c(N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc2nc(O)nc(O)c2s1
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 60.3 %

Procedure:
A mixture of methyl 3-amino-5-methylthiophene-2-carboxylic acid (1.2 g) and urea (2.2 g) was stirred at 180° C. for 2.5 h. The mixture was left stand for cooling to room temperature, followed by 1 M aqueous sodium hydroxide (20 mL), the solids were dissolved, and the mixture was neutralized with acetic acid. The precipitated crystals were collected by filtration to obtain 6-methylthieno[3,2-d]pyrimidine-2,4-diol (0.77 g). (2) To a mixture of 6-methylthieno[3,2-d]pyrimidine-2,4-diol (0.77 g) and phosphorus oxychloride (8 mL) was added N,N-dimethylaniline (1.6 mL) at room temperature, and the mixture was stirred at 100° C. for 2 h. The reaction solution was added dropwise to water with ice cooling, and the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform) to obtain 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (0.50 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[I:13])[C:5]([N:7]=[C:8]=[O:9])=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])=[CH:17][C:16]=1[NH:28][NH:29]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])=[CH:17][C:16]=1[N:28]1[C:8](=[O:9])[NH:7][C:5]([C:4]2[CH:10]=[CH:11][C:12]([I:13])=[C:2]([F:1])[CH:3]=2)=[N:29]1
Reactant: O=C=NC(=O)c1ccc(I)c(F)c1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(NNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)c(F)c3)[nH]c2=O)c1
Yield: 74.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 3-fluoro-4-iodobenzoyl isocyanate (Intermediate-102, 1.0 g), tert-butyl 2-(2-chloro-5-{[(2-methylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-97, 0.800 g), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.900 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.30 (s, 6H), 2.43-2.45 (m, 1H), 4.26 (m, 2H), 7.01 (m, 1H), 7.46-7.49 (m, 1H), 7.63-7.66 (m, 1H), 7.84-7.91 (m, 1H), 8.01-8.06 (m, 1H), 8.22 (s, 1H), 8.36 (br s, 1H), 12.66 (m, 1H); MS (m/z): 515.21 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])[CH2:13][C@H:12]2[CH3:29])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH3:30][S:31]([NH:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])[CH2:13][C@H:12]2[CH3:29])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(N)c2)[C@@H](C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(NS(C)(=O)=O)c2)[C@@H](C)C1
Reaction time: 18 h

Procedure:
The title compound was prepared from the product of Example 57 and methane sulphonyl chloride by the method of Example 62. The solid obtained at the end of the reaction was suspended in ethanol (50 ml) to which a solution of K2CO3 (0.2 g) in water (10 ml) was added, and stirred for 18 hours, in order to hydrolyse any bis-sulphonamide. The ethanol was removed, water (50 ml) was added and the pH was adjusted to 5.0. The solid was filtered off, washed with water and ether and dried in vacuo to give the title compound as a white solid. Yield 0.13 g.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1.Cl>CN1C(=O)CCC1.O>[C:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:27][CH:26]=1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Nc1ccc(NC(=O)c2ccccc2)cc1
Reactant: COC(=O)c1ccc2c(c1)c(=O)[nH]c1nccc(Cl)c12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Temperature: 115 °C
Reaction time: 30 h
Yield: 86.4 %

Procedure:
266 (250 mg, 0.77 mol), N-(4-aminophenyl)benzamide (179 mg, 0.85 mmol), and HCl (19 μm, 0.77 mmol, 4.0 M in dioxane) were suspended in NMP (5 mL) and stirred for 30 h at 115° C. The reaction mixture was diluted with H2O. The resulting precipitate was filtered, washed with H2O and MeOH, and dried under vacuum to provide 267 (341 mg, 96% yield) as a white solid. LC-MS (M+H=465, obsd.=465).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:29][CH2:28][CH2:27][C@@:15]3([C:19](=[O:20])[N:18]([CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[CH2:14]2)=[N:11][CH:12]=1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[O:20]=[C:19]1[C@@:15]2([CH2:27][CH2:28][CH2:29][N:13]([C:10]3[N:11]=[CH:12][C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])=[CH:8][CH:9]=3)[CH2:14]2)[CH2:16][CH2:17][N:18]1[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Nc1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)nc1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)nc1
Reaction time: 1 h

Procedure:
Methyl chloroformate (4.4 μL, 0.000057 mol) was added to a solution of (5S)-7-(5-aminopyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one (15.8 mg, 0.0000478 mol), N,N-diisopropylethylamine (27 μL, 0.00016 mol) and methylene chloride (1.0 mL, 0.016 mol); and the mixture was stirred for 1 h. The volatiles were removed in-vacuo and the crude product was purified by prep-HPLC. LC-MS: 389.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)=[C:22]=[O:23].Cl>C(#N)C>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([NH:21][C:22]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[N:7]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:6]3)=[O:23])[CH:29]=[CH:28][C:27]=1[O:30][CH3:31]
Reactant: COc1ccc(N=C=O)cc1OC
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: COc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 4-isocyanato-1,2-dimethoxy-benzene (0.15 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding the 1-(3,4-Dimethoxy-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (400 mg, 91%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 30/70 CH3CN 0.1% H3PO4 in H2O: tR=2.43 min (97%); mp. 216-218° C. 1H NMR (DMSO-d6) δ 1.79-2.12 (m, 1H, CHH), 2.25-2.47 (m, 1H, CHH), 2.62 (br. s., 1H, CHH), 2.81-3.01 (m, 1H, CHH), 3.69 (d, J=6.0 Hz, 6H, OCH3+OCH3), 4.24-4.53 (m, 4H, CH2+CH2), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CHN), 6.64 (t, J=5.9 Hz, 1H, Ar), 6.82 (s, 2H, Ar), 7.18 (s, 1H, Ar), 7.44 (d, J=7.7 Hz, 1H, Ar), 7.51 (s, 1H, NH), 7.69 (d, J=7.9 Hz, 1H, Ar), 8.46 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.77, 47.12, 51.56, 55.28, 55.88, 103.55, 109.60, 112.56, 121.83, 122.91, 126.85, 130.25, 134.15, 142.36, 143.51, 145.03, 148.73, 155.35, 167.95, 170.99, 172.85. LCMS MH=453. Anal Calcd for: C23H24N4O6: C, 61.06; H, 5.35; N, 12.38. found: C, 59.84; H, 4.87; N, 12.13.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH3:11])=[CH:4][C:3]=1[N:12]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[N:13]1.S(Cl)([Cl:22])(=O)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH3:11])=[CH:4][C:3]=1[N:12]1[C:16]([CH3:17])=[C:15]([Cl:22])[C:14]([CH3:18])=[N:13]1
Reactant: CCOc1cc(-n2nc(C)cc2C)c(F)cc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOc1cc(-n2nc(C)c(Cl)c2C)c(F)cc1Cl
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of 1-(2-fluoro-4-chloro-5-ethoxyphenyl)-3,5-dimethylpyrazole (26.9 g) in chloroform (200 ml) was added dropwise sulfuryl chloride (13.5 g) for 10 minutes under water-cooling, and the reaction mixture was stirred for further 30 minutes to effect the chlorination reaction. Removal of the solvent from the reaction solution by distillation in vacuo gave the titled compound (30.0 g) as a pale yellow crystalline solid. After recrystallization of the solid from a mixture of n-hexane/ethyl acetate, the resulting white crystalline product showed the melting point of 106°-107.5° C.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.[Sn].[C:17]([C:21]1[CH:26]=[C:25](C)[CH:24]=[C:23](C(C)(C)C)[C:22]=1O)(C)(C)[CH3:18]>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:21]1([C:17]#[C:18][C:2]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=2[C:9]=34)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: [Sn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCc2c(C#Cc3ccccc3)[nH]c3cccc1c23
Temperature: 60 °C
Yield: 55 %

Procedure:
Tricyclic bromide 11 (58.6 mg, 0.22 mmol) in DMF (1 mL) was degassed and treated with tributylephenylethynyl)tin (95.2 mg, 0.24 mmol) and tetrakis(triphenylphosphine) palladium(0) (13 mg, 2 mol %). One crystal of 2,6-di-t-butyl-4-methyl phenol was added, and the solution was heated at 60° C. for 10 h. Starting material was still present, so the solution was heated at 100° C. for an additional 2 h. The reaction mixture was cooled to ambient temperature and diluted with water (2 mL) and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by radial chromatography (2 mm SiO2; 3% MeOH in CH2Cl2) to yield 17 as a white solid (34.8 mg, 55%). mp 255-256° C. (dec); 1H NMR (DMSO-d6) δ11.86 (s, 1H), 8.17 (m, 1H), 7.75 (d, 1H, J=7.6 Hz), 7.63 (m, 3H), 7.51 (m, 3H), 7.33 (t, 1H, J=7.6 Hz), 3.50 (m, 2H), 3.09 (m, 2H); HRMS (FAB, M+H) Calcd for C19H14N2O+H: 287.1184, Found: 287.1192; Anal. (C19H14N2O.0.6 H2O) C, H, N.