Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:23])=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12][C:11]=2[C:19]([O:21]C)=[O:20])[CH:5]=[CH:6][CH:7]=1.C1COCC1.CO.[OH-].[Li+]>O>[Br:1][C:2]1[C:3]([CH3:23])=[C:4]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]([CH3:17])([CH3:18])[CH3:16])[S:12][C:11]=2[C:19]([OH:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(C(C)(C)C)cc1CNc1cccc(Br)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(Br)cccc1NCc1cc(C(C)(C)C)sc1C(=O)O
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A 50-mL single-necked round-bottomed flask equipped with a magnetic stirrer was charged with 102d (1.30 g, 3.28 mmol), THF (5.0 mL), methanol (5.0 mL) and water (5.0 mL). Lithium hydroxide (1.38 g, 32.8 mmol) was added and the mixture was placed in a 40° C. oil bath. After 16 h the reaction mixture was cooled to room temperature and the volatiles removed under reduced pressure. The resulting aqueous solution was acidified with 2 N hydrochloric acid to pH of 4. The resulting solid was filtered off and dried in a vacuum oven at 40° C. affording a quantitative yield (1.25 g) of 102e as a white solid: mp 150-152° C.; 1H NMR (300 MHz, DMSO-d6) δ 6.85 (t, 1H, J=7.8 Hz), 6.75-6.67 (m, 3H), 4.35 (s, 2H), 2.18 (s, 3H), 1.26 (s, 9H); MS (APCI−) m/z 380.2 (M−H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH3:13][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 6-nitroindole (4.05 g 25 mmol) in DMF (50 mL) was added K2CO3 (8.63 g, 62.5 mmol) and MeI (5.33 g, 37.5 mmol). After stirring at room temperature overnight, the mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give the product 1-methyl-6-nitro-1H-indole (4.3 g, 98%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([OH:32])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:33]([NH:35][NH2:36])=[O:34]>C1COCC1.[Cl-].[Na+]>[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([NH:36][NH:35][CH:33]=[O:34])=[O:32])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 190.9 %

Procedure:
1,1′-Carbonyldiimidazole (5.8 g, 36.2 mmol) was added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (5.0 g, 18.1 mmol) in dry THF (200 mL). The reaction mixture was allowed to warm to rt then was stirred at rt for 3 hrs. Formohydrazide (5.4 g, 90.5 mmol) was added in one portion, and the reaction mixture was stirred for additional 3 hrs. The mixture was then diluted with saturated sodium chloride and extracted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated to afford crude (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (˜11 g), which was directly used in the next step. ESI-MS (EI+, m/z): 319.1 [M+H]+.
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:3](=O)[CH3:4].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:28][C:29]([NH2:31])=[S:30])[CH:19]=[CH:20][C:21]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:2]2[S:30][C:29]([NH:28][C:18]3[CH:19]=[CH:20][C:21]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:16]([O:15][CH3:14])[CH:17]=3)=[N:31][C:3]=2[CH3:4])=[CH:8][CH:9]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CC(=O)C(Cl)Cc1ccc(Cl)cc1
Product: COc1cc(Nc2nc(C)c(Cc3ccc(Cl)cc3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 72 mg (0.33 mmol) 3-chloro-4-(4-chlorophenyl)-2-butanone and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 78 mg (61%) [5-(4-chloro-benzyl)-4-methyl-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light brown solid. MS ISP (m/e): 425.1/427.1 (100/42) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.15 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.37 (d, 2H), 7.26 (d, 2H), 7.23 (s, 2H), 3.98 (s, 2H), 3.77 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:31][NH2:32].C1COCC1>CN1C(=O)CCC1.O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([NH:32][CH3:31])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OS(=O)(=O)C(F)(F)F)cc1OCC2
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCOC1
Product: CNc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 85 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
A solution of trifluoro-methanesulfonic acid 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl ester (100 mg, 0.23 mmol) in NMP was treated with 2M methylamine in THF (1.8 mL, 0.9 mmol) and heated at 85° C. for 20 h then diluted with water and stirred for 4 h. The precipitate was collected by filtration and dried in vacuo to give 416 as a white solid (19.5 mg, 28%). LCMS: RT=2.26 min, [M+H]+=326. 1H NMR 400 MHz (DMSO-d6) δ: 9.02 (1H, s), 7.88 (1H, s), 7.80 (1H, s), 6.70 (1H, br, m), 5.95 (1H, s), 5.91-5.90 (1H, m), 4.47 (4H, q, J=6.12 Hz), 2.78 (3H, d, J=4.86 Hz), 1.47 (6H, d, J=6.60 Hz)
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:18][O:19][CH:20]([O:39][CH3:40])[C:21]1[C:30]([CH2:31][N:32]2[CH2:36][CH2:35][C@H:34]([OH:37])[C:33]2=[O:38])=[CH:29][C:28]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]=2[N:22]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[Si:1]([O:37][C@H:34]1[CH2:35][CH2:36][N:32]([CH2:31][C:30]2[C:21]([CH:20]([O:39][CH3:40])[O:19][CH3:18])=[N:22][C:23]3[NH:24][CH2:25][CH2:26][CH2:27][C:28]=3[CH:29]=2)[C:33]1=[O:38])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(OC)c1nc2c(cc1CN1CC[C@H](O)C1=O)CCCN2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CN1CC[C@H](O[Si](C)(C)C(C)(C)C)C1=O)CCCN2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
tert-Butyldimethylsilyl chloride (3.77 g, 25.02 mmol), DIPEA (4.84 ml, 27.7 mmol) and DMAP (51 mg, 0.42 mmol) were added to a solution of (S)-1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-3-hydroxypyrrolidin-2-one (intermediate 103A, 6.7 g, 20.85 mmol) in DMF (15 ml) and DCM (60 ml) at 0° C. The reaction mixture was stirred for 2 days at room temperature, partitioned between water and DCM, the organic layers washed with saturated aqueous NaHCO3, dried over Na2SO4 and evaporated to give the title compound as a brown glass. (UPLC-MS 6) tR 0.94; ESI-MS 436.2 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7](O)=[O:8].C(N1C=CN=C1)([N:13]1C=CN=C1)=O.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([NH2:13])=[O:8]
Reactant: Cn1ncc(I)c1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc(I)c1C(N)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.9 %

Procedure:
A round-bottom flash was charged with 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid (297 g, 1.18 mol), DCM (2.97 L), and 1,1′-carbonyldiimidazole (CDI) (207 g, 97% by mass, 1.24 mol). The reaction mixture was stirred at room temperature for 45 min. Ammonium chloride (189 g, 3.53 mol) and triethylamine (498 mL, 3.53 mol) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was suspended in H2O (˜3 L) and granulated at room temperature for 1 h. The solid was collected via filtration, washed with H2O, and dried in a vacuum oven to afford 4-iodo-1-methyl-1H-pyrazole-5-carboxamide as a colorless solid (222 g, 75% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C(OC(=O)[C:16]1C=CC=[C:18]([F:22])[CH:17]=1)C.Cl.[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1>C(OCC)(=O)C.O>[F:22][C:18]1[CH:17]=[CH:16][CH:29]=[CH:25][C:26]=1[C:27]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:28]
Reactant: CCOC(=O)c1cccc(F)c1
Reactant: O=C1CCc2sccc21
Reactant: C1CCOC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccccc1F)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 14 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL of THF was treated with NaH (60 percent, 1.5 g, 36 mmol). After the addition of 3-Fluoro-benzoic acid ethyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (70 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(2-Fluoro-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.56 g, 2.1 mmol) as brown solid in 14% yield.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH3:26])=[C:6]([C:23]([OH:25])=O)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[CH:9]=1)[CH3:2].[NH2:27][CH2:28][C:29]1[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=1[CH3:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[CH3:35][C:34]1[CH:33]=[C:32]([CH3:36])[NH:31][C:30](=[O:37])[C:29]=1[CH2:28][NH:27][C:23]([C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[CH:9]=[C:4]([NH:3][CH2:1][CH3:2])[C:5]=1[CH3:26])=[O:25]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCNc1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)O)c1C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Product: CCNc1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
5-(Ethylamino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxylic acid (300 mg, 0.84 mmol) was dissolved in DMSO (2 mL) and 3-(amino methyl)-4,6-dimethylpyridin-2(1H)-one (257 mg, 1.69 mmol) was added to it. After 15 minutes stirring at room temperature PyBOP (660 mg, 1.26 mmol) was added to the reaction mixture and stirring was continued for overnight. After completion, the reaction mass was poured into ice, extracted with 10% MeOH/DCM (5 times). Combined organic layer was washed with water and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by solvent washings afforded the title compound (100 mg, 24%). LCMS: 489.20 (M+1)+; HPLC: 96.41% (@ 254 nm) (Rt; 4.060; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 9.90 (s, 1H), 8.06 (t, 1H), 7.73 (d, 2H, J=7.6 Hz), 7.55 (d, 2H, J=7.2 Hz), 6.80 (d, 2H, J=7.6 Hz), 5.86 (s, 1H), 4.38 (s, 2H), 4.27 (d, 2H, J=4 Hz), 3.95 (m, 2H), 3.62-3.65 (m, 2H), 3.28-3.31 (m, 2H), 3.20-3.24 (m, 2H), 3.14-3.19 (m, 2H), 2.20 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 1.21 (t, 3H, J=6.8 Hz).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26](Cl)=[O:27]>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2)=[O:27]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc(Cl)c(Cl)c4)ccc3C2=O)C(=O)N1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 58 %

Procedure:
A mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol), 3,4-dichlorobenzoyl chloride (0.34 g, 1.6 mmol) and TEA (0.32 g, 3.2 mmol) in THF (25 mL) was heated to 40° C. with stirring under N2, for 2.5 hours. The mixture was filtered, and the filtered solid was loaded onto a silica gel column, which was run using with a methylene chloride-methanol gradient. The product eluted at 93:7 methylene chloride-methanol, 0.42 g, in 58% yield; mp 260-262° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.36 (99.65%); 1H NMR (DMSO-d6) δ 1.96-2.03 (m, 1H), 2.31-2.43 (m, 1H), 2.56-2.62 (m, 1H), 2.85-2.97 (m, 1H), 4.30 (d, J=17.4 Hz, 1H), 4.44 (d, J=17.4 Hz, 1H), 4.59 (d, J=6.0 Hz, 2H), 5.11 (dd, J=13.4 Hz, J=5.0 Hz, 1H), 7.45-7.55 (m, 2H), 7.70 (d, J=7.8, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.88 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H), 9.33 (t, J=6.0 Hz, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.9, 47.1, 51.6, 122.2, 123.0, 127.2, 127.6, 129.2, 130.4, 130.7, 131.3, 134.1, 134.4, 142.4, 143.4, 164.0, 167.9, 171.0, 172.8; Anal. Calcd for C21H17Cl2N3O4+0.25H2O: C, 55.95; H, 3.91; N, 9.32. Found: C, 55.98; H, 3.55; N, 9.32.
Reaction SMILES: C1(C2C=CC(C(O[C@@H:14]3[CH2:27][C@@H]4[O:18][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH2:25][C@@H:16]4[C@H:15]3/[CH:28]=[CH:29]/[C:30]([F:40])([F:39])[CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=O)=CC=2)C=CC=CC=1.[OH-:43].[Na+].Cl.[CH3:46][OH:47]>C1COCC1>[F:39][C:30]([F:40])([CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)/[CH:29]=[CH:28]/[C@H:15]1[C@H:14]([OH:43])[CH2:27][C@H:46]([OH:47])[C@@H:16]1[CH2:25]/[CH:24]=[CH:23]\[CH2:22][CH2:21][CH2:20][C:19]([OH:26])=[O:18]
Reactant: [OH-]
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Reactant: CO
Agent: Cl
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/C(F)(F)COc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (6Z,8aR,9R,10R,11aS)-9-((E)-3,3-difluoro-4-phenoxybut-1-enyl)-2,3,4,5,8,8a,9,10,11,11a-decahydro-2-oxocyclopenta[b]oxecin-10-yl 4-phenylbenzoate (10.0 g from Example 35) in methanol (60 mL) and THF (160 mL) was treated with 3N sodium hydroxide aqueous solution (80 mL). This mixture was stirred at room temperature under an atmosphere of nitrogen for 2 hr. The reaction mixture was further adjusted to a pH of 8.5±0.2 with 3N hydrochloric acid aqueous solution and most of solvent was removed under reduced pressure. The residue was diluted with saturated aqueous solution of sodium bicarbonate (200 mL) and ethyl acetate (200 mL). The mixture was stirred at room temperatures for 5 minutes. The organic phase and the aqueous phase were separately collected. The aqueous layer was adjusted to a pH of 3.0±0.2 with 3N hydrochloric acid aqueous solution at room temperature and extracted with ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 12 g of crude Tafluprost acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CS(C)=O>[C:11]([C:7]1[CH:8]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
8.40 g (40.7 mmol) 2,6-di-tert-butylphenol was dissolved in 100 ml dried DMSO. 2.32 g (58 mmol) sodium-hydroxide and 8.5 g (54 mmol) p-chloronitrobenzene were added into the DMSO solution. The DMSO solution was heated to 100˜120° C. for 12 hrs with stirring. Then the reaction mixture was allowed to cool to room temperature and poured into distilled water. The aqueous solution was acidified to pH 2˜4 and yellow precipitate was collected by filtration. The yellow precipitate was washed with water and dried. The crude yield was 85%. The yellow precipitate was purified by recrystallizing in cyanomethane, mp 157˜160° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][NH:23][CH:24]2[CH3:29]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:23]3[CH2:22][CH2:21][C:20]4[C:25](=[CH:26][CH:27]=[CH:28][C:19]=4[C:15]4[O:14][CH:18]=[CH:17][CH:16]=4)[CH:24]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(-c3ccco3)cccc21
Product: CC1c2cccc(-c3ccco3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Furan-2-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[C:16]([C:18]([OH:25])([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])#[CH:17]>>[F:9][C:8]([F:11])([F:10])[C:7]([NH:6][CH2:5][C:4]1[CH:13]=[CH:14][CH:15]=[C:2]([C:17]#[C:16][C:18]([OH:25])([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH:3]=1)=[O:12]
Reactant: C#CC(O)(CCC)CCC
Reactant: O=C(NCc1cccc(Br)c1)C(F)(F)F
Product: CCCC(O)(C#Cc1cccc(CNC(=O)C(F)(F)F)c1)CCC

Procedure:
N-(3-bromobenzyl)-2,2,2-trifluoroacetamide was coupled with alkynol 20 following the procedure described in Example 10 to give 2,2,2-trifluoro-N-(3-(3-hydroxy-3-propylhex-1-ynyl)benzyl)acetamide as a yellow oil. Yield (0.462 g, 38%): 1H NMR (400 MHz, DMSO-d6) δ 9.97 (t, J=5.6 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.27-7.22 (m, 3H), 5.15 (bs, 1H), 4.35 (d, J=6.0 Hz, 2H), 1.60-1.41 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]=[O:28].CN1CCOCC1>ClCCCl>[CH:10]1([N:9]2[C:4]3([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH2:3][O:28][C:27]2=[N:26][C:18]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=2[CH3:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCC1(NC2CCCCC2)CCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1OCC2(CCCC2)N1C1CCCCC1
Temperature: 50 °C
Yield: 1.4 %

Procedure:
To a solution of 1-(chloromethyl)-1-(cyclohexylamino)cyclopentane HCl salt (Method B7b; 1.06 g, 4.2 mmol) and 2-methyl-4-nitrophenyl isocyanate (0.75 g, 4.2 mmol) in 1,2-dichloroethane (10 mL) was added N-methylmorpholine (0.92 mL, 8.4 mmol). The resulting mixture was heated to 50° C. for 18 h, then cooled to 20° C. and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from hexane to 10% EtOAc/hex) to yield 1-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane (0.021 g, 1.4%): CI-MS m/z 358 ((M+H)+).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[N:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:27][CH2:28][N:29]([C:44]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:45])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Reactant: O=C(Cl)N1CCOCC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)N5CCOCC5)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with morpholine-4-carbonyl chloride to give the title compound. LC/MS (M+H)+: 648. Ret. time: 1.48 min. (Condition G); analytical HPLC Ret. time: 7.35 min (Condition H).
Reaction SMILES: [N+:1]([C:4]([CH3:9])([CH3:8])[CH:5]=[N:6][OH:7])([O-:3])=[O:2].[CH3:10][N:11]([S:15][C:16]([CH3:23])([C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH3:17])[C:12](F)=[O:13].C(N(CC)CC)C>O1CCOCC1>[CH3:10][N:11]([S:15][C:16]([CH3:17])([C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH3:23])[C:12]([O:7][N:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])([CH3:9])[CH3:8])=[O:13]
Reactant: CC(C)C(=O)C(C)(C)SN(C)C(=O)F
Reactant: CC(C)(C=NO)[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)C(C)(C)SN(C)C(=O)ON=CC(C)(C)[N+](=O)[O-]
Yield: 7.8 %

Procedure:
Prepared as in Example 1 by reacting 2.78 g (0.021 m) of 2-nitro-2-methylpropionaldoxime, 5.0 g (0.21 m) of N-methyl-N-(2,4-dimethyl-3-oxo-2-pentanesulfenyl)carbamoyl fluoride and 2.13 g (0.021 m) of triethylamine in 50 ml of dioxane. The product was purified by column chromatography to yield 0.55 g of an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[C:14](O)(=[O:17])[C:15]#[CH:16].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:14]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:17])[C:15]#[CH:16]
Reactant: C#CC(=O)O
Reactant: Cc1ccc(OCCCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C#CC(=O)OCCCCOc1ccc(C)cc1
Yield: 89.2 %

Procedure:
A mixture of 1 g of 4-(4-methylphenoxy)butanol, 1.1 g of propiolic acid, 0.005 g of p-toluenesulfonic acid and 25 ml of benzene was refluxed with stirring for six hours while water formed was removed by a Dean-Stark water separator. After the reaction was completed, the reaction solution was washed successively with a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 1.15 g of 4-(4-methylphenoxy)butyl propiolate (compound 11).