Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]([NH:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[NH:36][CH:35]=3)[CH2:30][CH2:29]2)=[O:23])[CH:6]=[C:7]([O:16][CH3:17])[C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:9][C:8]1[C:7]([O:16][CH3:17])=[CH:6][C:5](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[C:22]([NH:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][CH:31]([C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[NH:36][CH:35]=3)[CH2:32][CH2:33]2)=[O:23])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COCCOCOc1c(OC)cc(/C=C/C=C/C(=O)NCCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(/C=C/C=C/C(=O)NCCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1O
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of 1-[3-[5-[3,5-dimethoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(2E,4E)-2,4-pentadienoylamino]propyl]-4-(3-indolyl)piperidine (1.67 g) and p-toluenesulfonic acid monohydrate (0.64 g) in methanol (33 ml) was refluxed for 30 minutes under an inert atmosphere. Upon cooling to ambient temperature, the mixture was added dropwise to an aqueous sodium carbonate solution. The resulting powder was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The obtained residue was recrystallized from a mixture of ethanol and water (7:3 V/V) to give 1-[3-{5-(4-hydroxy-3,5-dimethoxyphenyl)-(2E,4E)-2,4-pentadienoylamino}propyl]-4-(3-indolyl)piperidine (0.51 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][Si](C(C)(C)C)(C)C)=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:20]([F:23])([F:22])[F:21])=[N:7]2.Cl.O>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:20]([F:21])([F:22])[F:23])=[N:7]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c2ccc(C(F)(F)F)nc12
Agent: Cl
Solvent: O
Solvent: CO
Product: Oc1ccc(Br)c2ccc(C(F)(F)F)nc12
Temperature: 45 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A solution of 5-bromo-8-(tert-butyldimethylsilanyloxy)-2-trifluoromethylquinoline (21 g) in methanol (150 ml) was treated with 37% hydrochloric acid solution (5 ml) and water (5 ml). The mixture was stirred for 12 h at room temperature and at 45° C. for 2 h. The methanol was removed in vacuo and the residue partitioned between 10% sodium hydroxide solution (100 ml) and dichloromethane (50 ml). The aqueous layer was neutralised with 37% hydrochloric acid solution to pH7.2 and extracted with dichloromethane (4×50 ml). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the product (12 g) as a cream solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f14) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].Cl.[CH3:18][C:19]([CH3:21])=O>>[C:19](=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][N:4]=1)([CH3:21])[CH3:18]
Reactant: COc1cc2c(cc1OC)C(NN)=NCC2
Reactant: CC(C)=O
Agent: Cl
Product: COc1cc2c(cc1OC)C(NN=C(C)C)=NCC2

Procedure:
In a manner similar to that of Example 25, condensation of 1-hydrazino-6,7-dimethoxy-3,4-dihydroisoquinoline (7.0 g.) and acetone (100 ml.) and treatment of the reaction mixture with hydrochloric acid afforded 1-(2-isopropylidenehydrazino)-6,7-dimethoxy-3,4-dihydroisoquinoline (I: X = X' = CH3, Y = Y' = H, Z = Z' = CH3O) hydrochloride (7.55 g., m.p. 211.5°-213° C. with decomposition).
Reaction SMILES: Br[CH:2](Br)[C:3]1[NH:4][C:5]2[C:10]([CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([O:24][CH:25]([CH3:27])[CH3:26])[N:8]=[CH:7][CH:6]=2.C([OH:31])C>O.[N+]([O-])([O-])=O.[Ag+]>[CH:2]([C:3]1[NH:4][C:5]2[C:10]([CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([O:24][CH:25]([CH3:27])[CH3:26])[N:8]=[CH:7][CH:6]=2)=[O:31]
Reactant: CCOC(=O)C1=C(C(Br)Br)Nc2ccnc(OC(C)C)c2C1c1ccccc1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CCOC(=O)C1=C(C=O)Nc2ccnc(OC(C)C)c2C1c1ccccc1

Procedure:
A solution of 3.1 g (6.1 mMole) ethyl (±)-2-dibromomethyl-1,4-dihydro-5-isopropoxy-4-phenyl-1,6-naphthyridine-3-carboxylate (Example 4) in 70 ml ethanol is heated to 60° C. and, at this temperature, a solution of 2.1 g (12.4 mMole) silver nitrate in 5 ml water/3 ml ethanol is added dropwise thereto. The reaction mixture is heated under reflux for ten minutes, cooled and the precipitate filtered off, whereafter the filtrate is evaporated. After dilution with dichloromethane, it is washed with water and the organic phase is dried over anhydrous magnesium sulphate and subsequently evaporated in a vacuum. The residue is chromatographed on silica gel with toluene/ethyl acetate (9:1 v/v). The fraction with the Rf of 0.3 is isolated and recrystallized from n-hexane/cyclohexane. There is obtained ethyl (±)-2-formyl-1,4-dihydro-5-isopropoxy-4-phenyl-1,6-naphthyridine-3-carboxylate in the form of yellow crystals; mp 132°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(N(CC)CC)C>[F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][O:23][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:18][CH:19]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(Cc1ccc(OCCO)cc1)Oc1ccc(F)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccc(F)cc1

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 2-(4-fluorophenoxy)-3-[4-(2-hydroxyethoxy)phenyl]propionate (2.68 g), which is the product of Reference example 37(d), triethylamine (1.61 ml) and methanesulfonyl chloride (0.65 ml) and the reaction mixture was treated to afford the desired compound (3.17 g) as a pale yellow oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH3:36])=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[CH:17][C:16]2=[O:37])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:37]=[C:16]1[CH:17]=[C:18]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH3:36])=[CH:30][N:29]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][N:15]1[C:12]1[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=1
Reactant: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(=O)(=O)NC(C)(C)C)cc4)c(=O)c3)CC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(N)(=O)=O)cc4)c(=O)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.2 %

Procedure:
To a stirring solution of N-tert-butyl-4-(2-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-1(2H)-yl)benzenesulfonamide (23 mg, 0.044 mmol) in CH2Cl2 (1 mL) was added trifluoroaceticacid (0.4 mL, 5 mmol, Aldrich). The reaction was stirred at room temperature for 2 days and then concentrated in vacuo to a yellow oil. The oil was purified by flash chromatography (SiO2, 0 to 5% MeOH in CH2Cl2) to yield 11 mg of the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (s, 2 H), 8.03 (d, J=8.53 Hz, 2 H), 7.54 (d, J=8.28 Hz, 2 H), 7.23 (d, J=7.78 Hz, 1 H), 6.07 (dd, J=7.65, 2.63 Hz, 1 H), 6.03 (d, J=2.51 Hz, 1 H), 4.56-4.65 (m, 1 H), 4.16-4.25 (m, 2 H), 3.60-3.71 (m, 2H), 2.42 (t, J=7.53 Hz, 2 H), 2.04-2.14 (m, 2 H), 1.80-1.90 (m, 2 H), 1.53-1.64 (m, 2 H), 0.95 (t, J=7.28 Hz, 3H). MS (ESI) 470 (M+H).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[C:13]([NH:17][OH:18])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([N+:17]([O-:18])=[CH:1][C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Reactant: CC(C)(C)NO
Agent: [Na]
Product: CC(C)(C)[N+]([O-])=Cc1ccc(S(=O)(=O)O)o1
Yield: 36 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-tert-butylhydroxylamine, the title compound was prepared in 36% yield as the sodium salt, m.p. 117-120° C. (dec.).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]1[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][CH2:26][C@@H:27]([CH3:31])[CH2:28][O:29][CH3:30])=[CH:20][CH:19]=2)[C@@H:15]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]3[O:42][CH2:41][CH2:40][N:39]([CH2:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]=3[CH:48]=2)[CH2:14][N:13]1[S:49]([C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=1)(=[O:51])=[O:50])C1C=CC=CC=1>CO>[CH3:30][O:29][CH2:28][C@H:27]([CH3:31])[CH2:26][O:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:16]2[C@@H:15]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][CH2:40][N:39]([CH2:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]=4[CH:48]=3)[CH2:14][N:13]([S:49]([C:52]3[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=3)(=[O:50])=[O:51])[C@@H:12]([CH2:11][NH2:10])[CH2:17]2)=[CH:19][CH:20]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CNC(=O)OCc4ccccc4)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Solvent: CO
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CN)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21

Procedure:
According to general procedure E, 1 mmol of [(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-ylmethyl]-carbamic acid benzyl ester is reacted in MeOH, to afford the title compound as a yellow oil. Rf=0.1 (CH2Cl2/MeOH/25% conc. NH3 200:10:1); Rt=4.62 (gradient I).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:31][CH3:32])=[C:7]([CH2:9][C:10]([CH:18]2[O:23][CH2:22][CH2:21][N:20](CC3C=CC=CC=3)[CH2:19]2)([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[OH:11])[CH:8]=1.O>C(O)(C)C>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:31][CH3:32])=[C:7]([CH2:9][C:10]([CH:18]2[O:23][CH2:22][CH2:21][NH:20][CH2:19]2)([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[OH:11])[CH:8]=1
Reactant: COc1ccc(F)cc1CC(O)(C1CCOCC1)C1CN(Cc2ccccc2)CCO1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(F)cc1CC(O)(C1CCOCC1)C1CNCCO1
Reaction time: 0.5 h

Procedure:
A 6 L Parr bottle is loaded with 51b (1021 g), i-propanol (3630 mL) and water (639 mL). After purging with N2, 5% Pd—C 52% wet is added (105.6 g) and the mixture is then pressurized with hydrogen (50 psi). The reaction mixture is shaken for 9 h 30 mins, then the mixture is filtered on a Hyflo Super Cel® pad (100 g) pre-imbibed with 80/20 i-propanol/water (500 mL). The catalyst is rinsed with a 80:20: i-propanol:water mixture (500 mL). The solvents are stripped off then i-propanol is added (2000 mL) to be partially removed again. Then i-propanol is re-added (1400 mL) and the heterogeneous mixture is concentrated to provide an off-white solid To this crude alcohol 52b is added i-propanol (4474 mL) and the mixture is heated to reflux until a homogeneous solution is formed. Then, the mixture is cooled slowly and the crystallization starts at 60° C. The powder is filtered at room temperature, rinsed with i-propanol (2×350 mL) and dried under reduced pressure at 40° C. to give highly pure compound 52b with 80% recovery yield (98.4% de, 99.2% ee).
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[C:10](=[O:17])[O:11][C:12]([CH3:16])=[CH:13][C:14]=2[OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:18]O>C(O)(=O)C>[CH:1]1([CH2:7][S:8]([C:9]2[C:10](=[O:17])[O:11][C:12]([CH3:16])=[CH:13][C:14]=2[OH:15])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(O)c(SCC2CCCCC2)c(=O)o1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc(O)c(S(=O)CC2CCCCC2)c(=O)o1
Temperature: 0 °C
Reaction time: 26 h

Procedure:
A solution, consisting of 6.00 g. (0.0236 mole) of 3-cyclohexylmethylthio-4-hydroxy-6-methyl-2-pyrone and 2.67 g. (0.0236 mole) of 30% hydrogen peroxide in 30 ml. of glacial acetic acid, was allowed to stand at room temperature for 26 hours, after which period of time it was poured into ice water, giving a white solid precipitate, which was collected on a filter and dried in vacuo over calcium chloride. The crude product weighed 5.8 g. (91 percent) and melted at 132.5°-133.5°C. Recrystallization from ethanol gave the pure 3-cyclohexylmethylsulfinyl-4-hydroxy-6-methyl-2-pyrone as white needles, m.p. 137°-138°C.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:24][NH:25][C:26]([C:28]2[C:29]([CH3:38])=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][N:32]=3)=[O:27])[CH:16]=[CH:17][C:18]=1[CH2:19][O:20][CH2:21][CH2:22][OH:23].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][C:7]1[CH:9]=[CH:10][C:4]([S:1]([O:23][CH2:22][CH2:21][O:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([CH2:24][NH:25][C:26]([C:28]3[C:29]([CH3:38])=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][N:32]=4)=[O:27])=[CH:14][C:13]=2[F:12])(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2ncccc2cc1C(=O)NCc1ccc(COCCO)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCc2ccc(CNC(=O)c3cc4cccnc4nc3C)cc2F)cc1
Reaction time: 2 h

Procedure:
25 mg tosylchloride (0.13 mmol) was added to a solution of 40 mg N-[[3-fluoro-4-(2-hydroxyethoxymethyl)phenyl]methyl]-2-methyl-1,8-naphthyridine-3-carboxamide (0.11 mmol), 23 μl diisopropylethylamine (6.13 mmol) and 13 mg DMAP (0.11 mmol) in 1.0 ml CH2Cl2 at room temperature. The solution was stirred for 2 h. The reaction mixture was placed directly on a SiO2 column and purified by flash chromatography (CH2Cl2/MeOH 50:1). Gave 52 mg (90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11](O)(=[O:15])/[CH:12]=[CH:13]/[CH3:14].O>CS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:9][CH3:10])[O:8][CH:13]([CH3:14])[CH2:12][C:11]2=[O:15]
Reactant: C/C=C/C(=O)O
Reactant: COc1cc(O)ccc1Cl
Agent: CS(=O)(=O)O
Solvent: O
Product: COc1cc2c(cc1Cl)C(=O)CC(C)O2
Temperature: 23 °C

Procedure:
A solution of 1.0 g (6.3 mmol) 4-chloro-3-methoxyphenol and 5.4 g (6.3 mmol) crotonic acid in 15 ml methane sulfonic acid was heated at 95° C. under nitrogen for 20 hours. The reaction was cooled to 23° C., poured onto 150 ml ice and water and extracted with 100 ml ethyl acetate. The ethyl acetate extract was successively washed with 100 ml water, 2×100 ml 1N sodium hydroxide and 100 ml brine, dried over magnesium sulfate and concentrated in vacuo to a purple crystalline solid. This was purified by flash chromatography on 150 cc silica gel using chloroform as eluant to give the product as a yellow crystalline solid, 1.1 g (78%); m.p. 96°-100° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([C:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH:32]=2)[C:24]([N+:34]([O-:36])=[O:35])=[CH:23][C:21]=1[NH2:22].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CO>C1COCC1>[Cl:17][C:5]1[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:7][C:2]([NH:22][C:21]2[CH:23]=[C:24]([N+:34]([O-:36])=[O:35])[C:25]([C:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH:28]=3)=[CH:26][C:20]=2[O:19][CH3:18])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A mixture of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 21, 575 mg, 1.86 mmol) and 2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 490 mg, 1.86 mmol) was stirred in THF (30 mL) and cooled in an ice/water bath. Lithium bis(trimethylsilyl)amide (4.10 mL, 4.10 mmol, 1M in THF) was then added dropwise and the mixture was stirred for 1 h. CH3OH was added and the mixture was concentrated in vacuo. The crude material was suspended in CH3OH and the mixture was filtered. The collected solid was washed with CH3OH and diethyl ether and dried on the filter to give the title compound (660 mg, 72%) as a yellow powder; 1H NMR: 2.29 (3H, s), 2.30-2.38 (2H, m), 2.58 (2H, t), 2.97 (2H, dd), 3.96 (3H, s), 5.60-5.68 (1H, m), 7.00 (1H, s), 7.16 (1H, td), 7.36-7.45 (1H, m), 8.49-8.56 (3H, m), 8.87 (1H, d), 8.90 (1H, s), 8.97 (1H, s); m/z: ES+ MH+ 492.4.
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:24])[CH:6]([NH:9][C:10](=[O:23])[CH2:11][C:12]1[S:13][C:14]([C:17]2([CH3:22])[O:21][CH2:20][CH2:19][O:18]2)=[CH:15][CH:16]=1)[CH2:7]O.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[CH3:3][O:4][C:5]([CH:6]1[CH2:7][O:23][C:10]([CH2:11][C:12]2[S:13][C:14]([C:17]3([CH3:22])[O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:16]=2)=[N:9]1)=[O:24]
Reactant: COC(=O)C(CO)NC(=O)Cc1ccc(C2(C)OCCO2)s1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: N#N
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)C1COC(Cc2ccc(C3(C)OCCO3)s2)=N1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 3-hydroxy-2-{2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-acetylamino}-propionic acid methyl ester (470 mg, 1.43 mmol) in dry THF (5 mL) was added at 0° C. to solution of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (455 mg, 1.83 mmol) in dry THF (10 mL) and the resulting suspension was stirred at 0° C. for 20 min, followed by 15 min at rt. The reaction mixture was then stirred at reflux for 1 h. The mixture was then allowed to cool down to rt and filtered. The filter cake was rinsed with ether and EA and the filtrate was concentrated under reduced pressure. Purification of the residue by FC (1:1→1:0 EA-Hept) gave the title compound as a yellow oil. TLC: rf (EA)=0.6. LC-MS-conditions 02: tR=0.70 min, [M+H2O+H]+=329.90.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[Cl:26][C:27]1[CH:28]=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
Reaction of 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-chloro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=433.2 (M+H)+
Reaction SMILES: [CH2:1]([S:4]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:24]I>>[CH2:1]([S:4]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20](=[O:23])[N:21]([CH3:24])[N:22]=3)[CH:14]=2)[CH2:9]1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CI
Reactant: CCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Product: CCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)n(C)n3)cc2C1

Procedure:
2-n-Propylsulfonylamino-5-[pyridazin-3(2H)-on-6-yl]indane and methyl iodide were reacted in the same manner as in Example 91 to obtain 2-n-propylsulfonylamino-5-[2-methylpyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:11])[C:4]([C:7]([O:9]C)=[O:8])=[CH:5][N:6]=1.[OH-].[Li+]>O1CCCC1.O>[Br:1][C:2]1[N:3]([CH3:11])[C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: COC(=O)c1cnc(Br)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(=O)O)cnc1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
To a suspension of methyl 2-bromo-1-methyl-1H-imidazole-5-carboxylate (2.18 g, 10 mmol) in tetrahydrofuran (60 mL) and water (6 mL) was added lithium hydroxide (0.72 mg, 30 mmol) and the reaction mixture was allowed to stir at room temperature for 2.5 h. The solvent was removed under reduced pressure and water was added followed by formic acid, the resulting precipitate was filtered, washed with water and dried under vacuum overnight to afford the 2-bromo-1-methyl-1H-imidazole-5-carboxylic acid (82%). 1H-NMR (300 MHz, CDCl3): 7.79 (s, 1H), 3.91 (s, 3H). LCMS (ESI+) 205.0 (MH+). To a solution of the carboxylic acid (1.68 g, 8.2 mmol) in anhydrous tetrahydrofuran (24 mL) was added EDC (1.53 g, 9.9 mmol) followed by HOBt (1.22 g, 9.1 mmol) and the reaction mixture was allowed to stir for 1 h at room temperature. A solution of pyrrolidine (1.03 ml, 12.4 mmol) in tetrahydrofuran (8 mL) was added and the reaction mixture was allowed to stir overnight at room temperature. The solvent was removed under reduced pressure and residue partitioned between ethyl acetate and 1 M aqueous potassium carbonate. The organic layer was dried (Na2SO4) and solvent evaporated under reduced pressure. Purification by flash column chromatography (silica, EtOAc/MeOH 9:1) afforded the title compound (95%). 1H NMR (300 MHz, CDCl3): 7.79 (s, 1H), 3.92 (s, 3H), δ 3.35 (bs, 4H), δ 1.97 (bs, 4H). LCMS (ESI+) 257.0 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH:15]([CH2:16][OH:17])[NH:14][C:13](=[O:18])[C@H:12]([N:19](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[NH2:19][C@@H:12]1[CH2:11][CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH:15]([CH2:16][OH:17])[NH:14][C:13]1=[O:18].[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@@H](c2cccc(F)c2F)C(CO)NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)C(CO)NC1=O
Reaction time: 2 h

Procedure:
Di-tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-7-(hydroxymethyl)-2-oxoazepan-3-yl]imidodicarbonate (100 mg, 0.213 mmol) was diluted DCM (30 mL) and TFA (8 mL) was added. After 2 h, the reaction was concentrated to give the title compound as its TFA salt (57 mg). MS 271.0 (M+1).