Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccncc1F
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNc2cnccc2C(=O)O)c(OC)c1
Yield: 61 %

Procedure:
The title compound was prepared in 61% yield from 2,4-dimethoxybenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.41 (br s, 1H), 8.20 (s, 1H), 7.80 (d, 1H, J=5.0 Hz), 7.54 (d, 1H, J=5.0 Hz), 7.18 (d, 1H, J=8.3 Hz), 6.59 (d, 1H, J=2.4 Hz), 6.48 (dd, 1H, J=8.3, 2.4 Hz), 4.40 (s, 2H), 382 (s, 3H), 3.74 (s, 3H). [M+H] calc'd for C15H16N2O4, 259. Found 259.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.ClC1C=CC=CC=1Cl.Cl>[N+](C)([O-])=O>[CH3:13][O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([S:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: COc1cccc2ccccc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: Clc1ccccc1Cl
Solvent: C[N+](=O)[O-]
Product: COc1ccc(S(=O)(=O)c2ccc(OC)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
p-Methoxybenzenesulfonyl chloride, 2.0 mol, anhydrous stannic chloride, 2.25 mol, 1-methoxynaphthalene, 2.25 mol, and 3 1 of o-dichlorobenzene were mixed at room temperature under nitrogen. The mixture was stirred at room temperature overnight (ca 7 hours needed) and decomposed with 3N hydrochloric acid. The organic layer was diluted with 1250 ml of nitromethane and washed with 2 portions of 1N hydrochloric acid followed by pure water. The organic layer was treated with magnesium sulfate, filtered, evaporated, extracted with hot toluene and dried at 120° C. for two hours to give 577 g, 88% yield, m.p. 160°-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N+:3]=1[O-].O=P(Cl)(Cl)[Cl:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:15])[N:3]=1
Reactant: [O-][n+]1cc(C(F)(F)F)ccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(Cl)nc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
2-Chloro-5-trifluoromethyl-pyridine-N-oxide (17, 4 mmol) was dissolved in freshly distilled POCl3 (4.5 mL). The reaction mixture was heated to 80° C. for 17 h. After cooling to room temperature, the solvent was removed under reduced pressure. Ice was added, and the mixture was allowed to stand for 4 h. The mixture was partition between CH2Cl2 (50 mL) and saturated aqueous NaHCO3. Column chromatography afforded compound 18 as yellow oil (yield: 50%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[CH:16][C:17]([F:27])=[C:18]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>O1CCCC1.C(OCC)(=O)C>[C:11]([C:10]1[C:4]2[S:3][C:2]([NH:1][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([F:27])=[C:18]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:23])[F:24])[CH:19]=1)#[N:12]
Reactant: N#Cc1c(Oc2ccc(F)c(NC(=O)C(F)(F)F)c2)ccc2nc(N)sc12
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)C(F)(F)F)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of N-{5-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]-2-fluorophenyl}-2,2,2-trifluoroacetamide (1.0 g, 2.52 mmol) in tetrahydrofuran (10 mL) were added pyridine (1.0 mL, 12.5 mmol) and cyclopropanecarbonyl chloride (395 μL, 4.35 mmol), and the mixture was stirred at room temperature for 10% hr. Pyridine (4.0 mL, 50 mmol) and cyclopropanecarbonyl chloride (100 μL, 1.10 mmol) were added, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed successively with 1N hydrochloric acid (20 mL×2), 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (410 mg, 38%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:36])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:36][C:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)=[O:14])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[CH:19][CH:18]=1
Reactant: NC(c1ccc(Cl)cc1)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CC(=O)NC(c2ccc(Cl)cc2)c2ccccc2N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5 gm (22.1 m mol) of 4-ethoxycarbonylphenylacetyl chloride in 20 ml of chloroform was added dropwise, under cooling with ice, to a solution of 6.02 gm (20 m mol) of α-(4-chloro-phenyl)-2-piperidino-benzylamine and 3.5 ml (25 m mol) of triethylamine in 50 ml of chloroform. The mixture was stirred for two hours at ambient temperature, added to water, and extracted with chloroform. The extracts were dried and concentrated by evaporation. The evaporation residue was chromatographed on silica gel by use of toluene/ethyl acetate (5:1) as eluant.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:43])C.[OH-].[Na+].Cl>C(O)C>[CH3:42][S:39]([C:36]1[CH:35]=[CH:34][C:33]([C:32]#[C:31][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:44])=[O:3])=[C:8]([CH3:43])[CH:9]=3)[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)=[CH:38][CH:37]=1)(=[O:40])=[O:41]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3ncccc3C(F)(F)F)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3ncccc3C(F)(F)F)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (197 mg; 0.31 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 150 mg (80%). HPLC-MS: m/z: 614.4 (M+H)+; Rt: 2.42 min.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O[N:24]1C(=O)CC[C:25]1=O.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:24][CH3:25])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.3 %

Procedure:
A mixture of 1.00 g of Cbz-Phe-OH (Sigma Chemical Company), 0.385 g of N-hydroxysuccinimide and 0.541 g of 1,3-dicyclohexylcarbodiimide in 5 mL of dry THF was kept at 4° C. under N2 overnight. The resulting precipitate was removed by filtration, and to the filtrate was added excess 40% aqueous methylamine at room temperature. The mixture was stirred at room temperature for 30 min. The solid was removed by filtration and the filtrate was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give 1.12 g of the crude Cbz-Phe-NHMe.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.F[C:14](F)(F)S(OC)(=O)=O>CN(C=O)C>[CH3:14][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cn1ccc2cc(C(=O)O)ccc21

Procedure:
0.1 g of indol-5-carboxylic acid was mixed with 2 equivalents of methyl trifluoromethane sulfonate in 1 ml DMF at room temperature. After 5 h the solvent was evaporated and 1H-NMR was recorded:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.O[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][C:31]1=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:26])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][C:31]5=[O:36])=[C:19]([O:24][CH3:25])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: O=C1COCCN1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN1CCOCC1=O
Temperature: 80 °C
Yield: 42.9 %

Procedure:
Combine 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (0.70 g, 1.82 mmol), 4-(2-hydroxy-ethyl)-morpholin-3-one (0.50 g, 3.45 mmol) and triphenylphosphine (0.50 g, 1.90 mmol) in THF (10.0 mL), stir for 10 min and add DIAD (0.77 g, 3.81 mmol). Heat to 80° C. for 2 days, cool the reaction mixture, and dilute with water. Extract with CH2Cl2 (2×), combine the organics, dry, and concentrate under vacuum. Purify the product by flash chromatography using 0-10% MeOH in CH2Cl2 to give the title compound (0.40 g, 43%). MS (ES+) 512.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 8.01 (d, 2H, J=8.6 Hz), 7.47 (d, 2H, J=8.6 Hz), 7.40 (d, 1H, J=7.5 Hz), 6.98-6.95 (m, 3H), 6.91 (dd, 1H, J=8.6, 2.4 Hz), 4.27 (t, 2H, J=5.2 Hz), 4.17 (s, 2H), 3.89-3.81 (m, 7H), 3.68 (t, 2H, J=5.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[C:22](=[O:25])(O)[O-:23].[Na+]>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH:20][C:22](=[O:25])[O:23][C:4]([CH3:15])([CH3:5])[CH3:3])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=NC2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (770 g, 1.624 mmol) was dissolved in dioxane (8 mL). 8 mL of saturated sodium bicarbonate solution was added, followed by boc-anhydride (3.77 mL, 16.24 mmol). The reaction was stirred overnight at RT. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (gradient elution 0-25% EtOAc:Hex) to afford tert-butyl 3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate as a yellow solid. MS m/z=576.0. Calc'd for C19H17BrIN3O3S: 574.23.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)[CH2:4][O:3]1.C(O)C.Cl[CH:21]([CH:27]=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:16])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][N:15]=[C:11]3[CH:10]=2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(COc2ccnc(N)c2)O1
Reactant: CCOC(=O)C(Cl)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(OCC3COC(C)(C)O3)ccn12
Temperature: 60 °C

Procedure:
4-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine (5.6 g, 0.025 mol) was mixed with ethanol (60 mL) in a reaction flask under an atmosphere of dry nitrogen. A solution of ethyl 2-chloro-3-oxopropanoate (5% in benzene; 93 mL; Commercial solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60° C. under nitrogen for 2 hours. After allowing the mixture to cool the solvent was removed under vacuum to give a brown solid. The solid was mixed with ethyl acetate (200 mL) and sodium bicarbonate solution (100 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted further with ethyl acetate (50 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give a solid. The crude material was dissolved in ethyl acetate and passed through a short column of silica gel, eluting with ethyl acetate to give ethyl 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylate as a pale yellow solid (5.76 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[CH2:34][CH3:35])[CH2:6][CH:7]([CH2:11][C:12](=[O:30])[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:15][CH2:14]1)[C:8](O)=[O:9])[CH3:2].[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[CH2:34][CH3:35])[CH2:6][CH:7]([CH2:11][C:12]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:15][CH2:14]1)=[O:30])[C:8]([N:46]1[CH2:45][CH2:44][CH:43]([N:40]2[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]2)[CH2:48][CH2:47]1)=[O:9])[CH3:2]
Reactant: CCc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: CN1CCN(C2CCNCC2)CC1
Product: CCc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-diethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-methyl-4-piperidin-4-yl-piperazine
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:47]=[CH:46][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[CH:23]=[CH:24]/[CH:25]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[CH2:26][CH2:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:48][NH:49][C:50]([NH2:52])=[S:51]>C1COCC1.CN(C=O)C>[C:7]([C:11]1[CH:47]=[CH:46][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[CH:23]=[CH:24]/[CH:25]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:48][NH:49][C:50](=[S:51])[NH2:52])=[O:33])=[CH:35][CH:36]=2)=[CH:13][CH:12]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C(=O)O)cc2)Cc2ccc(C#N)cc2)cc1
Reactant: NNC(N)=S
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C(=O)NNC(N)=S)cc2)Cc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.9 mg (0.05 mmol) of oxalyl chloride are slowly added dropwise to a solution of 12.7 mg (0.02 mmol) of 4-[(4E)-5-{2-[(4-tert-butylbenzyl)oxy]phenyl}-3-(4-cyanobenzyl)pent-4-en-1-yl]-benzoic acid from Example 100A in 0.2 ml of dry THF with 1 drop of DMF while cooling in ice. The reaction mixture is stirred at RT for 30 minutes and then concentrated in vacuo, and the residue is coevaporated twice with dichloromethane and then taken up in 0.2 ml of THF. This solution is added dropwise to a solution of 4.2 mg (0.05 mmol) of thiosemicarbazide in 0.25 ml of THF at 0° C. The mixture is stirred at RT for 1 hour and then concentrated, and the residue is reacted without further purification in the next stage.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[C:9]([CH3:21])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:9]([CH3:21])[CH:8]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)/C=C/C=C/c1ccc(C(=O)OC(C)(C)C)cc1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCc1ccc(C(=O)OC(C)(C)C)cc1C
Yield: 92 %

Procedure:
4-((1E,3E)-4-Methoxycarbonyl-buta-1,3-dienyl) 3-methyl-benzoic acid tert-butyl ester from Example E31.2 (1.54 g, 5.1 mmol) was dissolved in methanol (40 ml) and hydrogenated over 10% Pd/C catalyst (200 mg) for 5 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to yield the title compound (1.43 g, 92%).
Reaction SMILES: [OH:1][C@H:2]([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[C:17]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=2)=[CH:11][CH:12]=1)=O)[CH3:4].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:34][O:33][CH2:32][C@@H:31]([O:30][C:15]1[CH:14]=[C:13]([C:10]2[NH:9][C:8]([C:6]3[O:1][C@@H:2]([CH3:36])[C@@H:3]([CH3:4])[N:5]=3)=[CH:12][CH:11]=2)[CH:18]=[C:17]([O:19][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:27]([CH3:29])[CH3:28])[CH:16]=1)[CH3:35]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](C)[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H](C)[C@H](C)O3)[nH]2)c1
Reaction time: 8 h
Yield: 100.6 %

Procedure:
N-[(2R,3R)-3-Hydroxybutan-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (722 mg, 1.39 mmol) synthesized in Example (109a) was dissolved in tetrahydrofuran (30 mL), and anhydrous methanesulfonic acid (430 mg, 2.47 mmol) and triethylamine (1.20 mL, 8.61 mmol) were added, and stirring was carried out at 50° C. overnight under nitrogen atmosphere. The reaction solution was brought back to room temperature, and a saturated aqueous ammonium chloride solution (50 mL) was added, followed by extraction with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=40%-70%) to afford the desired compound (700 mg, yield 100%) as a yellow liquid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:5][C@@H:4]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:6]1[CH2:7][C@H:2]([CH3:1])[CH2:3][C@H:4]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:5]1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2[N+](=O)[O-])C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Yield: 100.1 %

Procedure:
A mixture of tert-butyl [(3S,5R)-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate (1.14 g, 3.39 mmol) in MeOH was hydrogenated in the presence of 10% Pd on carbon (0.14 g) under 45 psi of hydrogen overnight. The mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the sub-title compound (1.04 g, 100%). LCMS calc. for C16H27N4O2 (M+H)+: m/z=307.2. found: 307.3.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Cl:14][S:15]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[C:1]2[C:11]([OH:13])=[O:12])(=[O:17])=[O:16]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1cccc2ccccc12
Product: O=C(O)c1cccc2c(S(=O)(=O)Cl)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
The titled compound was prepared using a modified procedure of Reefschlager et al. (see Reefschlager, J., et al., (2000) EP1038868A2). Naphthalene-1-carboxylic acid (6.56 g, 38.1 mmol) was added in small portions to chlorosulfonic acid (22 g, 12.6 mL, 190 mmol) that was cooled in an ice bath. The reaction was stirred overnight at room temperature. The reaction mixture was poured slowly over ice-water (250 mL) and filtered to afford 45 (8.3 g, 80%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 14.0 (s, 1H), 9.11 (d, 1H), 8.80 (d, 1H), 8.08 (d, 1H), 8.00 (d, 1H), 7.56 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]3[C:18]([C:19]=2I)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:28].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]3[C:18]([C:19]=2[C:32]#[C:31][CH2:30][CH2:29][OH:33])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:28]
Reactant: C#CCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)c(I)c2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)c(C#CCCO)c2ccccc21
Yield: 86.9 %

Procedure:
In a similar manner to Step 2 of Example 161, 4-chloro-7-[1-(tert-butoxycarbonyl)-3-iodoindol-2-yl]isoindolinone (148 mg, 0.291 mmol) was dissolved in diethylamine (7.4 mL), and the Solution was treated with bis(triphenylphosphine)dichloropalladium (16.3 mg, 0.0233 mmol), copper iodide (11.1 mg, 0.0582 mmol) and 3-butyn-1-ol (0.220 mL, 2.91 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-3-(4-hydroxy-1-butynyl)indol-2-yl]isoindolinone (114 mg, yield 87%).