Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:24][C:25](O)=[O:26])([CH:6]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[NH:28]1[CH2:42][CH2:41][CH2:40][C@H:29]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(#N)C>[CH2:1]([O:3][P:4]([CH2:24][C:25]([N:28]1[CH2:42][CH2:41][CH2:40][C@H:29]1[C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:26])([CH:6]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCOP(=O)(CC(=O)O)C(CCc1ccccc1)CC(=O)c1ccccc1
Solvent: CC#N
Product: CCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(CCc1ccccc1)CC(=O)c1ccccc1
Reaction time: 1.5 h
Yield: 74 %

Procedure:
A solution of the product from part (d) (834 mg., 2.15 mmole) in dry acetonitrile (8 ml.) is treated with N,N'-carbonyldiimidazole (375 mg., 2.31 mmole) and stirred at 0° (ice bath) under argon for 1.5 hours. The resulting solution is then treated with L-proline, benzyl ester (455 mg., 2.22 mmole) in acetonitrile and stirred at room temperature for 4 hours. The mixture is evaporated to dryness and the residue is taken up in ethyl acetate. The ethyl acetate solution is washed successively with 5% potassium bisulfate, saturated sodium bicarbonate and saturated sodium chloride, dried over Na2SO4 and evaporated. The residue (1.325 g.) is purified by flash chromatography on silica gel (75 g.) eluting with 1% methanol/dichloromethane to give (±)-1-[[ethoxy[3-oxo-3-phenyl-1-(2-phenylethyl)propyl]phosphinyl]acetyl]-L-proline, phenylmethyl ester (74%) as a colorless glass, Rf (methanol/dichloromethane; 5:95) 0.29.
Reaction SMILES: [I-].[Li+].[OH:3][CH:4]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:19]=1)[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]1[S:11][CH2:10][CH2:9][CH2:8][S:7]1.Cl>N1C=CC=CC=1>[OH:3][CH:4]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH:19]=1)[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]1[S:11][CH2:10][CH2:9][CH2:8][S:7]1
Reactant: COC(=O)COc1cccc(C(O)C(c2ccccc2)C2SCCCS2)c1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)COc1cccc(C(O)C(c2ccccc2)C2SCCCS2)c1
Temperature: 25 °C

Procedure:
A solution of anhydrous lithium iodide (2.68 g, 20 mmol, Aldrich) in 25 mL dry pyridine was brought to reflux under a nitrogen atmosphere and treated with (±)-1-hydroxy-1-(3-carbomethoxymethoxyphenyl)-2-phenyl-2-(1,3-dithian-2-yl)-ethane (1.95 g, 5 mmol). The reaction was refluxed for 6 h, then allowed to cool to room temperature under a stream of nitrogen. The solution was poured into 1 N HCl (300 mL), and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate layers were extracted with 5% sodium bicarbonate (4×50 mL). The aqueous phase was acidified to pH 2, and extracted with ethyl acetate (3×50 mL). The organic phase was dried with Mg2SO4, filtered through activated charcoal, evaporated, and triturated with hexanes to yield a white solid. Yield: 1.71 g (91%). mp 99-101° C. IR: 3448 (br), 1735, 1595, 1462, 1232, 719 cm-1. 1H NMR (CDCl3, TMS) d 7.656 (dd, J=8.00, 1.71 Hz, 2 H), 7.299-7.254 (m, 3 H), 7.036 (t, J=7.98 Hz, 1 H), 6.794-6.773 (m, 1 H), 6.573 (d, J=7.55 Hz, 1 H), 6.251 (s, 1 H), 4.955 (s, 1 H), 4.357 (s, 2 H), 2.728-2.620 (m, 4 H), 1.914-1.868 (m, 2 H). 13C NMR (CDCl3, TMS) d 173.47, 156.32, 139.01, 137.40, 130.50, 128.12, 128.07, 127.56, 122.02, 115.43, 113.66, 80.56, 66.13, 64.73, 27.26, 26.96, 24.67. Anal. Calcd. for C19H20O4S2 : C, 60.62; H, 5.35. Found: C, 60.36; H, 5.21.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[C:16]([O:19][CH3:20])[CH:15]=[C:14]([O:21][CH3:22])[C:13]=2[F:23])=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[C:24]([Cu])#[N:25]>CN1C(=O)CCC1.C(Cl)Cl>[F:23][C:13]1[C:14]([O:21][CH3:22])=[CH:15][C:16]([O:19][CH3:20])=[C:17]([F:18])[C:12]=1[C:9]1[C:8]2[N:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:2]([C:24]#[N:25])=[CH:11][CH:10]=1
Reactant: N#C[Cu]
Reactant: COc1cc(OC)c(F)c(-c2ccc(Br)c3nccnc23)c1F
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1cc(OC)c(F)c(-c2ccc(C#N)c3nccnc23)c1F
Temperature: 150 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A mixture of 5-bromo-8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline (Step 88.3) (1.1 g, 2.9 mmol) (Step 88.3) and CuCN (312 mg, 3.4 mmol, 1.2 equiv) in NMP (10 mL) was stirred for 4 h at 150° C., under an argon atmosphere. The reaction mixture was allowed to cool to rt, diluted with DCM/(10% aqueous solution of ethylenediamine) (100 mL) and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in EtOAc to provide 702 mg of the title compound as a beige solid: ESI-MS: 328.1 [M+H]+; tR=4.48 min (System 1).
Reaction SMILES: [O:1]1[CH2:6]OOOO1.O=O.[C:9]([N:13]=[N:14][C:15]([O:21][OH:22])([CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:16])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([N:13]=[N:14][C:15]([O:21][OH:22])([CH2:17][C:18]([O:1][CH3:6])([CH3:19])[CH3:20])[CH3:16])([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)CC(C)(N=NC(C)(C)C)OO
Reactant: C1OOOOO1
Agent: O=O
Product: COC(C)(C)CC(C)(N=NC(C)(C)C)OO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 60 grams of the t-butylhydrazone of pentoxane (4-methoxy-4-methyl-pentanone-2) in 60 grams of odorless mineral spirits was oxidized by passing oxygen through the solution as in Example II. The oxidation was initiated at 30° C by adding 2 drops of a 50% solution of 2-t-butylazo-2-hydroperoxy-4-methylpentane. The oxidation was 1/2 complete after 50 minutes at 30° C. The temperature was lowered to 20° C. and an additional 1 hour was required before the oxidation was complete. It was then cooled to 0° C. by circulating ice water through the jacket and weighed into a cold poly bottle and stored at -30° C. or below. The yield was 126 g (97% of theory). The solution is not sensitive to shock.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH:27]([CH3:30])[CH2:28][CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH:27]([CH3:30])[CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCC(C)C(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)C(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 60 °C
Yield: 36.4 %

Procedure:
To a solution of methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methypentanoate (0.108 g; 0.256 mmol) in methanol (2.5 mL) was added a solution of sodium hydroxide 5 N (0.5 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. A purification by preparative TLC using a mixture ethyl acetate/heptane (1:1)+0.5% AcOH furnished 0.038 g (36%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:27])[CH:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11][O:12][C@@H]1CCCCO1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:1]([NH:8][C:9](=[O:27])[C@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(CO[C@@H]1CCCCO1)C(=O)NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Reaction time: 8 h
Yield: 65 %

Procedure:
A solution of 12.86 g of Intermediate 3 and 0.65 g of p-toluensulfonic acid in 100 mL of ethanol was heated at reflux temperature for 2 hours. The solvent was evaporated under vacuum and to the residue was added ethyl acetate (100 mL) which resulted in the precipitation of a white solid. The solvent was partially distilled and 150 mL of petroleum oil was added and stirred overnight. The solid was collected by filtration and dried yielding 6.5 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([SH:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[H-].[Na+].Br[C:25]([CH3:33])([CH2:31]C)[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[CH2:1]([S:21][C:25]([CH3:33])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCS
Reactant: CCOC(=O)C(C)(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(C)(C)C(=O)OCC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaene-1-thiol (305 mg, 1.00 mmol) in dry DMF (10 mL) at 0° C. under inert atmosphere was added NaH (60% in mineral oil, 44 mg, 1.1 mmol). After fifteen minutes ethyl 2-bromo-2-methylbutyrate (154 μL, 1.05 mmol) was added and the mixture was stirred for 1.5 hour at 0° C. The reaction mixture was quenched by addition of sat. aq. NH4Cl (20 mL). Water (20 mL) and heptane (50 mL) were added and the phases were separated. The water phase was extracted with heptane (2×25 mL). The combined organics were washed with water (25 mL) and brine (2×25 mL), dried (MgSO4), filtered and evaporated to give 377 mg of the title compound as a crude oil. Purification by flash chromatography on silica gel using isocratic elution (heptane:EtOAc 98:2) afforded 307 mg (77% yield) of the title compound as oil.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:10][C:9]([CH2:11][OH:12])=[CH:8][CH:7]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:20]([O:12][CH2:11][C:9]1[S:10][C:6]([CH2:5][O:4][CH3:3])=[CH:7][CH:8]=1)(=[O:22])=[O:21]
Reactant: COCc1ccc(CO)s1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1ccc(COS(C)(=O)=O)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-(methoxymethyl)thiophen-2-yl)methanol (900 mg, 5.69 mmol) in dry CH2Cl2 (20.0 mL) was treated at 0° C. with Et3N (1.19 mL, 8.53 mmol) followed by DMAP (70 mg, 0.57 mmol) and Ms-Cl (0.57 mL, 7.39 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (5 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 1.38 of crude (5-(methoxymethyl)thiophen-2-yl)methyl methanesulfonate as an orange oil. LC-MS-conditions 07: tR=0.51 min. A solution of this crude material in DMF (10.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (7.05 g of a 9.6% solution in DMF, 5.93 mmol) in DMF (15.0 mL) pre-treated for 30 min with DIPEA (1.96 mL, 11.9 mmol) and the reaction mixture was stirred overnight at 50° C. Water (10 mL), followed by EA (10 mL) was added. The aq. layer was extracted with EA (2×15 mL) and the combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (gradient from 95:5 hept-EA to 80:20 hept-EA) gave the title compound as a yellow oil. TLC: rf (8:2 hept-EA)=0.36. LC-MS-conditions 07: tR=0.80 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].Br[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[S:7](=[O:13])(=[O:12])[N:8]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH2:9][C:10]1=[O:11]
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Reactant: O=C(O)c1ccc(CBr)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)O)cc3)S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of the title B compound in Example 9, 2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (13.87 g, 48.4 mmol) and 4-bromomethylbenzoic acid (10.42 g, 48.4 mmol) in CH2Cl2 (150 mL) is added DBU (14.5 mL, 96.9 mmol) at once and the mixture is stirred at RT overnight. The reaction mixture is washed two times with 1N aqueous HCl, one time with brine, then dried over anhydrous MgSO4 and concentrated to a small volume to crystallize the product. The solid is collected by filtration, washed with ethyl ether and dried under high vacuum to afford 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid: mp=175-177° C.; [M−1]−=419.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][CH:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].N.[CH3:32]O>>[C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:11]3[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=3[N:19]=[CH:32]2)[CH2:8][CH:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])C(OC(C)=O)C1OC(C)=O
Reactant: CO
Agent: N
Product: CC(=O)OCC1CC(n2cnc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)(1R*, 2S*, 3R*, 5R*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (5.00 g, 10.8 mmol) was stirred in ammonia/methanol (ca. 2N, 100 mL) at ambient temperature for 18 hours. Evaporation of volatiles in vacuo left residual orange solid (±)-(1R*, 2S*, 3R*, 5R*)-5-(4,5-dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediol having an identical Rf on silica gel TLC plates to that of the chiral sample described in Example 54. This solid was reduced with Raney nickel/hydrogen(45 psi) in isopropanol (200 mL). Catalyst was filtered off with Celite. The filtrate-wash was evaporated to dryness in vacuo. The residue was refluxed in formic acid (96%, 50 mL) for one hour, as described in Example 2. The oil remaining on evaporation of the formic acid was dissolved in methanol. The pH was adjusted to 13 with aqueous 5N sodium hydroxide and the solution was stirred at ambient temperature for one hour to hydrolyze formate esters. The pH was adjusted to 7 with 1N hydrochloric acid and volatiles removed by evaporation in vacuo. Pyridine (100 mL) and acetic anhydride (4 mL) were added to the residue and the mixture stirred at ambient temperature overnight. Evaporation of volatiles in vacuo followed by chromatography on silica gel with 1% methanol-chloroform gave (±)(1R*, 2S*, 3R*, 5R*)-3-(acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate as white crystals from ethanol-water (2.6 g, 53%), 1H-NMR(DMSO-d6) consistent with structure.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](Cl)=[O:11].[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(=O)C1C=CC=CC=1>>[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:11]
Reactant: O=C(NCCCCO)c1ccccc1
Reactant: O=C(Cl)C1Cc2ccccc2C1
Product: O=C(NCCCCO)C1Cc2ccccc2C1
Yield: 62 %

Procedure:
Indane-2-carboxylic acid-(4-hydroxybutyl)amide (26B) is prepared from 26A as described for 1D.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]3OCC[O:19]3)[CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:1]([S:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[O:19])[CH:16]=2)[NH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1nc(SCc2ccccc2)c2cc(C3OCCO3)ccc21
Agent: Cl
Solvent: CCO
Product: O=Cc1ccc2[nH]nc(SCc3ccccc3)c2c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The product mixture obtained in Example 7A was dissolved in ethanol (4 ml), treated with 3 N hydrochloric acid (1 ml) and heated to 90° C. for 4 h. After this time, 3 N hydrochloric acid (0.2 ml) was again added, and heating was continued for 3 h. The mixture was evaporated to dryness, and the crude product thus obtained was used in the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7](=[O:21])[CH:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[NH:9][CH2:10][CH2:11][CH2:12]O>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7](=[O:21])[CH:8]([NH:9][CH2:10][CH2:11][CH2:12][Cl:3])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(NCCCO)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(NCCCCl)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
To a solution of thionyl chloride (8.79 g) in chloroform (20 mL) was added (4-fluoro-phenyl)-(3-hydroxy-propylamino)-acetic acid methyl ester (14.85 g, dissolved in 60 mL of chloroform) dropwise via syringe. The reaction mixture was then stirred for 1.5 hours at 50° C. and the volatiles were subsequently removed in vacuo to give a solid residue which was triturated with diethyl ether (30 mL) to give the desired HCl salt of (3-chloro-propylamino)-(4-fluoro-phenyl)-acetic acid methyl ester (14.88 g, MS (ES+): 260.1 (MH+)) as an off-white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH:15]([OH:18])CO)[CH:11]=[C:10]([C:19]([NH:21][CH2:22][C:23]4[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=4[CH3:29])=[O:20])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.O>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH:15]=[O:18])[CH:11]=[C:10]([C:19]([NH:21][CH2:22][C:23]4[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=4[CH3:29])=[O:20])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C(O)CO)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(C=O)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a stirred solution of 1-cyclopentyl-6-(1,2-dihydroxyethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.6 g, 1.4 mmol) in 50% THF/Water (16 mL), was added NaIO4 (0.9 g, 4.2 mmol) at 0° C. and stirred at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-formyl-1H-indazole-4-carboxamide (0.4 g, 72.1%).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[O:12][CH:11]=[C:10]([CH2:13][OH:14])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([C:21]([O:23][CH3:24])=[O:22])#[C:16][C:17]([O:19][CH3:20])=[O:18]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:17]([C:16]1[CH:11]2[O:12][C:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:15]=1[C:21]([O:23][CH3:24])=[O:22])[CH:9]=[C:10]2[CH2:13][OH:14])=[O:18]
Reactant: OCc1coc(Cc2ccccc2)c1
Reactant: COC(=O)C#CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C(=O)OC)C2(Cc3ccccc3)C=C(CO)C1O2
Yield: 100.9 %

Procedure:
A stirred solution of 5.6 grams (0.03 mole) of [5-(phenylmethyl)-3-furanyl]methanol and 4.3 grams (0.03 mole) of dimethyl acetylenedicarboxylate in 100 ml of toluene was heated under reflux for 3 hours. The solvent was removed under reduced pressure to give approximately 10 grams of 2,3-bis(methoxycarbonyl)-4-phenylmethyl-7-oxabicyclo[2.2.1]hepta-2,5-diene-6-methanol. The alcohol was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][C:19]1[C:20](B(O)O)=[CH:21][S:22][CH:23]=1>>[CH3:18][C:19]1[C:20]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:21][S:22][CH:23]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Cc1cscc1B(O)O
Product: Cc1cscc1-c1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-methyl-3-thiopheneboronic acid to give [1-(4-methyl-thiophen-3-yl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 307(MH+).
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:54]([OH:55])[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][O:47][C:48]7[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=7)[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:56]([CH3:58])[CH3:57])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[O:47]([CH2:46][CH2:45][CH2:44][O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:56]([CH3:58])[CH3:57])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:54]([OH:55])[CH:41]1[O:40]3)[O:36]2)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(OCCCOc6ccccc6)C5O2)C4O)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(OCCCOc6ccccc6)C5O2)C4O)C13C(=O)O
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
13.0 mg of compound (58) was dissolved in 2 ml of ethyl acetate and stirred together with a catalytic amount of 10% palladium-carbon under a hydrogen atmosphere at room temperature. After 30 minutes, the reaction solution was filtered and concentrated in vacuo. The reaction product was dissolved in 2 ml of methanol and washed with 2 ml of n-hexane twice, and the lower layer was concentrated in vacuo to give 6.6 mg of compound (59) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccn1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ncccn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(3-Chloro-phenylethynyl)-2-methyl-1H-imidazole (200 mg, 0.92 mmol) was dissolved in 5 mL dimethyl formamide. Potassium carbonate (255 mg, 1.85 mmol) and 2-chloro-pyrimidine (159 mg, 1.38 mmol) were added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was poured into 70 mL water and extracted three times with ethyl acetate (100 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from diisopropyl ether and the desired compound was obtained as an off-white solid (212 mg, 78%), MS:m/e=295.1 (M+H+).