Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[CH3:26][CH:27]([CH3:41])[CH2:28][C:29](=O)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl>[CH2:1]([O:3][C:4]([CH:6]=[C:29]([CH2:28][CH:27]([CH3:41])[CH3:26])[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)CC(=O)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=C(CC(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
Ethoxycarbonylmethylenetriphenylphosphorane (53.8 g., 0.155 mol.) was dissolved in dry dichloromethane (400 mls.) and the resulting solution was cooled to 0° C. To the cooled solution was added a solution of benzyl 4-methyl-2-oxopentanoate (34.0 g., 0.155 mol.) in dry dichloromethane (100 mls.) over a period of 25 minutes and the reaction mixture was then heated under reflux for 1 hour. The solvent was removed from the reaction mixture by evaporation in vacuo to yield an off-white solid. The solid was extracted with hexane (3×200 mls.) and the solvent was removed from the combined hexane extracts to yield a crude product as a yellow oil. The crude product was purified by distillation (0.6 mm Hg), to yield E and Z benzyl 3-(ethoxycarbonyl)-2-(2-methylpropyl)propenoate (41.0 g.) being collected at 137°-142° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:11](OC)[C:10]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].N.[Na].[Cl-].[NH4+]>>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[NH:11][C:10]1=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C1CCCCC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N[C@H]1C1CCCCC1
Reaction time: 0.08 h

Procedure:
(trans)-3-(t-Butoxycarbonylamino)-4-cyclohexyl-1-methoxy-2-azetidinone (1 g) is added to 50 ml of liquid ammonia with stirring. Sodium (0.154 g) is added in 5 to 6 portions within 5 minutes. After this time an additional amount of 0.025 g sodium is added and stirring is continued for 5 minutes. Ammonium chloride (0.89 g) is added and the ammonia is removed. The residue is extracted with warm ethyl acetate. The organic extract is evaporated to dryness and the remaining crystals of the title compound are filtered with petrol ether, yielding 0.5 g, melting point 130°-132° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]1[CH2:13][C@:14]3([CH2:24][C:8]=1[CH:7]=2)[C:22]1[C:17](=[N:18][CH:19]=[CH:20][CH:21]=1)[NH:16][C:15]3=[O:23].S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]1[CH2:13][C@:14]3([CH2:24][C:8]=1[CH:7]=2)[C:22]1[C:17](=[N:18][CH:19]=[CH:20][CH:21]=1)[NH:16][C:15]3=[O:23]
Reactant: O=S(Cl)Cl
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3cc(CO)cnc3cc1C2
Solvent: ClCCl
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3cc(CCl)cnc3cc1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (7S)-3-(hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (970 mg, 3.06 mmol) in CH2Cl2 (30 mL) was added thionyl chloride (2.23 mL, 30.1 mmol) and the resulting mixture was stirred at ambient temperature for 2 h, then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (30 mL) and CH2Cl2 (30 mL). The layers were separated and the aqueous layer was extracted further with CH2Cl2 (2×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title. MS: m/z=336 (M+1).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:16]=3)=[CH:12][CH:13]=2)[N:8]([CH3:27])[S:7]1(=[O:29])=[O:28].CN1C(=O)CCC1.CCN(C(C)C)C(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>CO>[F:30][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]4[CH2:26][CH2:25][N:24]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:23][CH2:22]4)[CH:16]=3)=[CH:12][CH:13]=2)[N:8]([CH3:27])[S:7]1(=[O:29])=[O:28]
Reactant: CN1c2nc(-c3cccc(C4CCNCC4)c3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN1c2nc(-c3cccc(C4CCN(S(C)(=O)=O)CC4)c3)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vial was added 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-(3-piperidin-4-ylphenyl)-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (31-3) (0.030 g, 0.064 mmol), NMP (1 mL), DIPEA (0.060 mL, 0.344 mmol), and finally methanesulfonyl chloride (0.0374 mL, 0.480 mmol). The reaction mixture was then permitted to stir at room temperature for 1 hour. The crude reaction mixture was then diluted with methanol, then filtered. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) to give 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-{3-[1-(methylsulfonyl)piperidin-4-yl]phenyl}-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (31-4) as a tan solid. HRMS (M+H)+: observed=513.1430, calculated=513.1436.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>C(Cl)Cl.Cl>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23]([O:1][CH2:2][C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])(=[O:24])=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: O=C(CO)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)OCC(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Benzyl 2-hydroxyacetate (211 mg, 1.268 mmol) was dissolved in DCM (10 ml). TEA (0.265 ml, 1.901 mmol) and 3,4-dimethoxybenzene-1-sulfonyl chloride (300 mg, 1.268 mmol) were added, and the reaction was stirred at RT for 3 hours to achieve completion. The reaction mixture was diluted with HCl 1N and extracted with DCM. The organic phase was washed with HCl 1N and Na2CO3 sat. sol., dried over Na2SO4 and concentrated under vacuum to give benzyl 2-(3,4-dimethoxyphenylsulfonyloxy)acetate (400 mg, 86% yield).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([NH:23][CH:24]([CH2:28]O)[CH:25]([CH3:27])[CH3:26])=[O:22])[C:17]=3[CH:30]=2)[C:3]1=[O:31].S(Cl)([Cl:34])=O>C(OCC)C>[Cl:34][CH2:28][CH:24]([NH:23][C:21]([C:18]1[C:17]2[CH:30]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[N:2]([CH3:1])[C:3]3=[O:31])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1)=[O:22])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C(CO)NC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: CC(C)C(CCl)NC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Yield: 89.8 %

Procedure:
To 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-N-[1-(hydroxymethyl)-2-methylpropyl]-1,2-benzisothiazole-3-carboxamide(1.89 g, 4.14 mmol) at 0° C. is added thionyl chloride (5.00 ml). The resultant mixture is stirred one hour at 0° C. and two hours at room temperature. Anhydrous diethyl ether is added and the resultant suspension stirred vigorously for 1.75 hour. The suspension is filtered to afford the title compound as a cream-colored solid (1.77 g, 89.8%, mp>220° C.) which is identified by NMR spectral analysis.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[C:27]1([CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:49]([OH:51])=O)=[C:46]([CH3:48])[N:47]=3)[C:39]2=[O:52])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1.[NH2:53][CH2:54][C:55]1[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=1>>[C:27]1([CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:49]([NH:53][CH2:54][C:55]4[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=4)=[O:51])=[C:46]([CH3:48])[N:47]=3)[C:39]2=[O:52])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3nccc4ccccc34)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3nccc4ccccc34)C2=O)sc1C(=O)NCc1cccnc1
Yield: 43 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(isoquinolin-1-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)-pyridine, the title compound was obtained as a colorless solid in 43% yield: mp 151-153° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.53 (d, J=3.0 Hz, 1H), 8.45 (d, J=6.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 7.86 (d, J=6.0 Hz, 1H), 7.74-7.63 (m, 4H), 7.31-7.28 (m, 1H), 6.06 (br s, 1H), 5.12 (s, 2H), 4.59 (d, J=6.0 Hz, 2H), 4.08 (t, J=6.0 Hz, 2H), 3.61 (t, J=6.0 Hz, 2H), 2.61 (s, 3H); MS (ES+) m/z 459.3 (M+1).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[S:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: OB(O)c1ccc(S)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: OB(O)c1ccc(SC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 4-mercaptophenylboronic acid (20.7 mg, 0.135 mmol) in DCM (2.00 mL) was added dihydropyran (0.06140 mL, 0.6730 mmol) and pyridinium p-toluenesulfonate (3.38 mg, 0.0135 mmol) at 0° C. The resulting mixture was then stirred at rt overnight. Solvent was then removed under reduced pressure to give crude product which was used for next step without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([NH2:22])[S:21][C:17]=2[C:16]=1Br)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([NH2:22])[S:21][C:17]=2[C:16]=1[C:37]1[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc2nc(N)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 110 °C
Yield: 187.5 %

Procedure:
2 separate microwave tubes were each charged with (S)-2-(2-Amino-7-bromo-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (768 mg, 1.74 mmol), K2CO3 (960 mg, 6.96 mmol), 4-chlorophenylboronic acid (325 mg, 2.09 mmol), Pd(PPh3)4 (200 mg, 0.174 mmol), dioxane (8.0 mL), and H2O (2.0 mL). The two sealed vessels were separately heated at 110° C. for 3 h. The reactions were cooled to 23° C. and combined. H2O (50 mL) was added, and the system was extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated. The residue was treated with benzene and purified via chromatography on silica gel (80 g “gold” ISCO column; Hex/EtOAc) giving (S)-2-(2-Amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (1.55 g, 90% yield). LCMS-ESI+: calc'd for C25H31ClN2O3S: 475.2 and 477.2 (M+H+); found: 475.3 and 477.3 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: 7.49-7.41 (m, 2H), 7.36-7.32 (m, 2H), 7.22 (d, J=7.3 Hz, 1H), 5.19 (s, broad, 2H), 4.67 (dd, J=9.0, 2.7 Hz, 1H), 4.36 (dd, J=11.7, 9.0 Hz, 1H), 4.23 (dd, J=11.7, 2.7 Hz, 1H), 2.68 (s, 3H), 1.14 (s, 9H), 0.94 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)=O.C(OP([CH2:31][C:32]#[N:33])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)=[CH:31][C:32]#[N:33]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2cccc(OC)c2OC)c1
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2cccc(OC)c2OC)c1
Yield: 90.5 %

Procedure:
(2,3-Dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (1.19 g, 3.94 mmol), cyanomethylphosphonic acid diethyl ester (1.24 ml, 7.87 mmol) in anhydrous THF (20 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 7.9 ml, 7.87 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 20% EtOAc in hexane in about 40 min.) to give 3-(2,3-Dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile as a clear light pink oil (1.16 g, 91%): 1HNMR (DMSO-d6) δ 7.21-7.08 (m, 2H, Ar), 6.83-6.79 (m, 1H, Ar), 6.62-6.56 (m, 1H, Ar), 6.47-6.46 (m, 2H, Ar), 6.00 (s, 1H, double bond proton), 3.86-3.72 (multiple singlets, 12H, 4OCH3): 13C NMR (CDCl3) δ 161.0, 160.9, 160.7, 160.4, 153.2, 153.1, 147.3, 146.7, 140.5, 140.1, 133.9, 131.7, 124.3, 124.0, 122.5, 122.2, 117.7, 117.5, 114.1, 107.0, 105.7, 102.0, 101.9, 97.8, 97.2, 60.9, 60.7, 56.1, 56.0, 55.7, 55.6; Anal. Calcd. For C19H19NO4: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.10; H, 5.72; N, 4.68.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]3[CH:20]=[CH:21][C:22]([OH:29])=[C:23]([CH:28]=3)[C:24]([O:26]C)=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]3[CH:20]=[CH:21][C:22]([OH:29])=[C:23]([CH:28]=3)[C:24]([OH:26])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(O)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(O)c(C(=O)O)c1
Reaction time: 8 h

Procedure:
To a solution of methyl 5-[{4-[(4-butylphenyl)ethynyl]benzyl}(hexyl)amino]-2-hydroxybenzoate in MeOH (400 mL) and water (40 mL) was added an aqueous solution of NaOH (6.0 mL, 5N). The reaction mixture was sired at 60° C. overnight. Then an aqueous solution of HCl (10 mL, 5N) was added and the solvents were removed under reduced pressure. The residue was taken up in water and extracted with Et2O (3×). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure to give a yellow solid. Precipitation from a DCM/MeOH mixture gave 2.17 g (53%, stop e and f) of the title compound as a beige powder. HPLC, Rt: 4.8 min purity: 99.7%). LC/MS, M+(ESI): 484.4, M−(ESI): 482.2. 1H NMR (CDCl3/CD3OD (15/1)) δ: 7.39 (m, 4H), 7.18-7.09 (m, 5H), 6.87 (dd, J=9.0, 3.0 Hz, 11), 6.78 (d, J=9.0 Hz, 1H), 4.38 (s, 2H), 3.22 (t, J=7.5 Hz, 2H), 2.57 (t, J=7.8 Hz, 2H), 1.55 (m, 4H), 1.34-1.21 (m, 8H), 0.90-0.75 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:50][C:51]1[C:66]([F:67])=[CH:65][C:54]2[NH:55][C:56]([CH2:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][NH:60]3)=[N:57][C:53]=2[CH:52]=1>CN(C=O)C>[F:50][C:51]1[C:66]([F:67])=[CH:65][C:54]2[NH:55][C:56]([CH2:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][N:60]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:16])=[N:57][C:53]=2[CH:52]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: Fc1cc2nc(CC3CCCCN3)[nH]c2cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)c(-c2ccc(F)cc2)s1
Reaction time: 16 h
Yield: 97 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (700 mg, 3.0 mmol), HATU (1.12 g, 3.0 mmol) and N,N-diisopropylethylamine (1.54 ml, 9.0 mmol) in DMF (20 ml) was stirred at room temperature under argon for 2 min. The mixture was then treated with (RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D18 (742 mg, 3.0 mmol) and stirring was continued for 16 h. The solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-5% methanol-ethyl acetate) afforded the title compound as a pale yellow solid (1.35 g, 97%).
Reaction SMILES: C([O:3][C:4]([CH2:6][S:7][C:8]1[C:13]([F:14])=[CH:12][NH:11][C:10](=[O:15])[N:9]=1)=[O:5])C.Cl>[OH-].[K+]>[C:4]([CH2:6][S:7][C:8]1[C:13]([F:14])=[CH:12][NH:11][C:10](=[O:15])[N:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CSc1nc(=O)[nH]cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CSc1nc(=O)[nH]cc1F
Yield: 41 %

Procedure:
4-Ethoxycarbonylmethylthio-5-fluoropyrimid-2-one (0.0013 mol) in 2 M potassium hydroxide (4 ml) was heated on a waterbath for 5-6 min. The solution was allowed to cool before neutralisation with dilute hydrochloric acid. The precipitated solid was recrystallised from methanol: yield 41%, m.p. 255° C.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:41])=[C:11]([CH3:40])[C:12]=1[C:13]([C:15]1[CH:34]=[CH:33][C:18]([O:19][S:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([OH:32])[CH:24]=2)(=[O:22])=[O:21])=[C:17]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Mg+2].[I-].[C:45](OC(=O)C)(=[O:47])[CH3:46]>CCOCC>[C:45]([O:32][C:25]1[CH:24]=[C:23]([S:20]([O:19][C:18]2[CH:33]=[CH:34][C:15]([C:13]([C:12]3[C:11]([CH3:40])=[C:10]([CH3:41])[S:9][C:8]=3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:14])=[CH:16][C:17]=2[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:22])=[O:21])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1sc(Cc2ccccc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(C(=O)c3c(Cc4ccccc4)sc(C)c3C)cc2C2CCCC2)ccc1C(=O)O
Yield: 51 %

Procedure:
The title compound was prepared according to the procedure in Example 22 using 4-[4-(2-benzyl-4,5-dimethyl-thiophene-3-carbonyl)-2-cyclopentyl-phenoxysulfonyl]-2-hydroxy-benzoic acid (0.233 g, 0.394 mmol), magnesium iodide (0.110 g, 0.394 mmol) and acetic anhydride (3.3 mL) in ether. Purification on 2% H3PO4 /MeOH treated silica gel, eluting with 18% EtOAc/pet ether followed by a second chromatography on 2% H3PO4 /MeOH treated silica gel, eluting with 5% CH3CN/CH2Cl2 gave 0.128 g (51%) of the title compound as a white solid, mp 94-96° C. 1H NMR (DMSO-d6) δ 1.24-1.33 (m, 2 H), 1.52-1.57 (m, 2 H), 1.61-1.76 (m, 4 H), 1.79 (s, 3 H), 2.23 (s, 3 H), 2.26 (s, 3 H), 2.94 (quintet, 1 H), 3.85 (s, 2 H), 6.99-7.01 (m, 2 H), 7.13 (m, 4 H), 7.52 (dd, 1 H), 7.59 (d, 1 H), 7.84 (d, 1 H), 7.90 (dd, 1 H), 8.14 (d, 1 H), 13.8 (br s, 1 H). mass spectrum (-ESI) m/z 631 (M-H). Anal. Calcd. for C34H32O8S2.0.2H2O: C, 64.17; H, 5.13; N, 0.00. Found: C, 64.06; H, 4.98; N, 0.04.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[C:7]([F:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[OH:5])[CH2:3][CH2:2]1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH:1]1([C:4]([C:6]2[C:7]([F:12])=[N:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: OC(c1cccnc1F)C1CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=C(c1cccnc1F)C1CC1
Yield: 28.1 %

Procedure:
Diisopropylamine (0.9 mL, 6.42 mmol) and lithium chloride (0.120 g, 2.83 mmol) were dissolved in dry tetrahydrofuran (1 mL) under nitrogen and cooled in a dry ice bath. A solution of butyllithium (2.5 M in hexanes, 2.6 mL, 6.50 mmol) was added slowly and the reaction stirred for 10 minutes. 2-Fluoropyridine (0.5 mL, 5.81 mmol) was added dropwise and the mixture stirred for 1 hour. Cyclopropanecarboxaldehyde (0.5 mL, 6.69 mmol) was added slowly. After 30 minutes, the mixture was quenched by addition of saturated ammonium chloride (5 mL). Water (200 mL) and ethyl acetate (300 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave cyclopropyl(2-fluoropyridin-3-yl)methanol (0.415 g, 2.482 mmol, 42.7% yield). The alcohol was dissolved in chloroform (150 mL) and treated with manganese (IV) oxide (3.0 g, 34.5 mmol). The suspension was heated at gentle reflux for 14 hours. The crude product was purified using silica chromatography (hexane to ethyl acetate gradient) to give cyclopropyl(2-fluoropyridin-3-yl)methanone (0.270 g, 1.635 mmol, 28.1% yield) as a clear oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9]>>[Cl:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Yield: 93.4 %

Procedure:
In accordance with Method I, halogenating agent thionyl chloride (800 g, 6.72 m) was added to 2-chloro-4-nitrobenzoic acid (500 g, 2.48 m) while the reaction mixture was warmed. After addition, the mixture was refluxed for approximately three hours. The excess of the low-boiling thionyl chloride was removed by distillation and the residue reaction mixture was vacuum-distilled to yield 2-chloro-4-nitrobenzoyl chloride (510 g, 93% bp. 143° C./4 mm).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH:8]2[CH:11]([CH3:22])[NH:12][CH:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH:7]2[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[CH:24](O)=O.C=O>[OH-].[Na+]>[CH2:1]([N:5]1[C:9](=[O:10])[CH:8]2[CH:11]([CH3:22])[N:12]([CH3:24])[CH:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=3)[CH:7]2[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: O=CO
Reactant: CCCCN1C(=O)C2C(C)NC(c3ccc(C#N)cc3)C2C1=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CCCCN1C(=O)C2C(C1=O)C(c1ccc(C#N)cc1)N(C)C2C
Temperature: 100 °C
Yield: 84.9 %

Procedure:
A mixture of 2.84 g of (1RS,3SR,3aRS,6aSR)-4-(5-butyl-3-methyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile, 85% formic acid (4.9 g, 90 mmol) and 35% formalin solution (2.6 g, 30 mmol) were heated to 100° C. for 5.5 hours. After cooling 1N NaOH (50 ml) was added and the mixture was extracted four times with dichloromethane. The organic phase was concentrated and the residue was separated chromatographically (hexane/ethyl acetate 3:1+1% triethylamine). 2.52 g of (1RS,3SR,3aRS,6aSR)-4-(5-butyl-2,3-dimethyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile (85%) were isolated as a colourless oil. EI-MS: 325 (M+, 8); 310 (95); 223 (10); 183 (24); 171 (40); 157 (10); 143 (9); 70 (15); 56 (17); 43 (100).