Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1C=C(S[C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])C=C(C(C)(C)C)C=1O)(C)C.C(OC1[O:43][C@H:42]([CH2:44][OH:45])[C@@H:41]([CH2:46]O)[O:40]1)C>>[C:32]([C:23]1[CH:22]=[C:21]([SH:20]([CH:17]([CH3:18])[CH3:19])[S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:33])([CH3:34])[CH3:35])[C:24]([OH:31])=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)[CH:26]=[C:25]([C:27]([CH3:30])([CH3:28])[CH3:29])[C:24]=1[O:31][CH2:46][C@@H:41]([OH:40])[C@H:42]([OH:43])[CH2:44][OH:45])([CH3:33])([CH3:35])[CH3:34]
Reactant: CCOC1O[C@H](CO)[C@@H](CO)O1
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CC(C)[SH](Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(OC[C@@H](O)[C@H](O)CO)c(C(C)(C)C)c1

Procedure:
The title compound was prepared using the same procedure as described in Ex-1 starting from probucol and 2-ethoxy-1,3-dioxolane-4(R),5(R)-dimethanol. White solid, mp 69–71° C. 1H-NMR (CDCl3) δ 7.56 (s, 2H, Ph-H), 7.45 (s, 2H, Ph-H), 5.38 (s, 1H, PhOH), 4.2{tilde over (5)}4.32 (m, 1H, PhOCH2CH), 3.96 (dd, J=9, 10, 1H, CH—O—), 3.7{tilde over (2)}3.86 (m, 4H, , CH—O—), 3.0{tilde over (0)}3.40 (m, 3H, OH), 1.46 (s, 6H, S,S′-isopropylidene), 1.45 (s, 18H, tert-butyls), 1.43 (s, 18H, tert-butyls). MS m/z: 643 ([M+Na]+, 100%). Anal. calcd. for C35H56O5S2.⅓H2O: C67.05, H9.11, S, 10.23; found: C67.03, H9.06, S10.01.
Reaction SMILES: CC1C=C(C)N([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[CH2:24]([C:26]1[O:30][C:29]([NH2:31])=[N:28][N:27]=1)[CH3:25].CC(C)=O>CN(C=O)C>[CH2:24]([C:26]1[O:30][C:29]([NH:31][C:8]([CH:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:9])=[N:28][N:27]=1)[CH3:25]
Reactant: CCc1nnc(N)o1
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCc1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.7 %

Procedure:
500.5 mg (1.64 mmol) (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)methanone and 186.8 mg (1.64 mmol) 5-ethyl-[1,3,4]oxadiazol-2-ylamine were suspended in 1.5 ml DMF and stirred for 6 h at 130°. The reaction mixture was allowed to cool to room temperature and 5 ml of acetone were added. After stirring for 5 min, the product was filtered, washed with acetone and dried in vaccuo to yield 219.5 mg of 9H-xanthene-9-carboxylic acid (5-ethyl-[1,3,4]oxadiazol-2-yl)amide as a white solid, m.p. 256-257° C. and MS: m/e=321.2 (M+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34]>>[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:38]4[CH:39]=[CH:40][C:35]([C:33]([OH:34])=[O:32])=[CH:36][CH:37]=4)[CH:16]=3)([OH:14])[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:37][CH:36]=1)=[O:34]
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccnc(-c4ccc(C(=O)O)cc4)c3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 49, trifluoromethanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester) (Example 26, step 1) was reacted with (4-methoxycarbonyl-phenyl) boronic acid 19 h at 70° C. to give the title compound as a white solid. MS (m/e)=584.2 [M+H+].
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:4]2=[N:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH:1]1[N:5]2[C:6]3[C:11]([N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:4]2=[N:3][C:2]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)N1Cc2nccn2-c2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(n1)CN(C(=O)OCC)c1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
A solution of 1.0 g of ethyl 4,5-dihydroimidazo[1,2-a]quinoxaline-5-carboxylate in 5 ml of dry dimethylformamide was treated with 0.5 g of ethyl chloroformate and the mixture was stirred at room temperature. After 2 hours, the mixture was set solid, was filtered and the residue was triturated with water and chromatographed over silica gel with ethyl acetate as eluant to obtain 0.98 g (76% yield) of diethyl 4,5-dihydroimidazo[1,2-a]quinoxaline-2,5-dicarboxylate melting at 151°-3° C.
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([OH:9])[CH2:2]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:9][CH:3]1[CH:4]2[CH:5]([O:6][CH2:7][CH2:8]2)[O:1][CH2:2]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: OC1COC2OCCC12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1COC2OCCC12
Temperature: 5 °C
Yield: 87.7 %

Procedure:
Hexahydrofuro[2,3-b]furan-3-ol (25 g) was dissolved in dichloromethane (250 ml) and added triethylamine (23.3 g). N,N-dimethylaminopyridine (0.46 g) was added to the reaction mass. Reaction mass was cooled to 0-10° C. Acetic anhydride (21.5 g) was diluted with dichloromethane (50 ml) & added slowly drop-wise to the reaction mass. Reaction mass was stirred at 0-5° C. till completion. Reaction mass was washed with water (2×100 ml) & 10% Sodium chloride solution (100 ml). Reaction mass was concentrated under vacuum at <40° C. to get residue of Hexahydrofuro[2,3-b]furan-3-yl acetate (yield 29 g). Further, the product was purified by distillation (20 g) under vacuum using fractional distillation at 88-102° C. to get main fraction 17 g having purity 92.6%
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:3]=1[O:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=[O:7].[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33](O)[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:39]2)=[CH:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33]([O:7][C:6](=[O:8])[CH:5]([O:4][C:3]2[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:2]=2[CH3:1])[CH2:9][CH3:10])[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH2:39]2)=[CH:26]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1c(C)cc(C)cc1C)C(=O)O
Product: CCC(Oc1c(C)cc(C)cc1C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 800 mg of (2RS)-2-(2,4,6-trimethylphenoxy)butyric acid and 1.0 gof (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl)ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.44 g of the title compound as a colorless foam.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[S:31](Cl)(=[O:33])=[O:32].CCN(CC)CC>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[S:31]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)(=[O:32])=[O:33]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
A mixture of 37.7 mg (0.12 mmol) 2-(4-Trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, 29.7 mg (example 251, step A), 0.132 mmol), 2-chloro-6-methylbenzene-1-sulfonyl chloride and 36.4 mg (0.36 mmol) NEt3 in 2 mL DCM was stirred for 16 h at room temperature. The mixture was evaporated to dryness and the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 14.7 mg (24%) of the title compound. MS (ESI): 503.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1>C(O)C.[Pd]>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[OH:8]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(F)cc1O
Temperature: 25 °C
Yield: 100 %

Procedure:
To 5-fluoro-2-nitrophenol (26.63 g, 170 mmol) in ethanol under N2 atmosphere was added palladium on carbon (10 wt %, 250 mg, 0.235 mmol). The mixture was flushed with H2 and stirred at RT under H2 (balloon) until complete conversion according to thin layer chromatography (TLC) analysis. Pd/C was removed by filtration and the filtrate was concentrated to yield 21.6 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4](O)([C:22]([F:25])([F:24])[F:23])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[NH:7][C:6]=1[CH3:21].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[N:7]=[C:6]1[CH3:21])[C:22]([F:25])([F:24])[F:23]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(C(F)(F)F)cc2)c1=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(=C1C(=O)N(c2ccc(C(F)(F)F)cc2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1-(4-trifluoromethylphenyl)-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (171 mg).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O.O>[C:32]([O:31][C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:36])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[CH:22][N:21]=1)=[O:30])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(OCCCNC(=O)OC(C)(C)C)n3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ccnc(OCCCNC(=O)OC(C)(C)C)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Yield: 71.2 %

Procedure:
To a solution of {6-[2-(3-tert-butoxycarbonylamino-propoxy)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester (0.45 g, 0.89 mmol) in THF:H2O (1:1, 6 mL) at 0° C. was added a solution of LiOH (0.043 g, 1.79 mmol) in water (1 mL). The solution was allowed to warm to room temperature over 3 hours then acidified to pH 4 with 1N HCl and extracted with EtOAc (2×10 mL). The organic extracts were dried and concentrated in vacuo to give crude {6-[2-(3-tert-Butoxycarbonylamino-propoxy)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid (0.3 g) which was used without further purification. MS (ESI) m/z=472 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22](O)=[O:23])=[CH:18]2)(=[O:11])=[O:10].C[N:27](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]([NH2:27])=[O:23])=[CH:18]2)(=[O:11])=[O:10]
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(=O)O)[nH]c12
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(N)=O)[nH]c12
Temperature: 25 °C

Procedure:
To a mixture of 7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indole-2-carboxylic acid (3.0 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (1.65 g) and N,N-dimethylformamide (30 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.1 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (2.82 g, crude yield 94%) as pale-pink crystals. MS: 360 (MH+).
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[OH-].[K+].[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O.O>C(O)C>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:18][C:14]1[N:13]([CH3:12])[CH:17]=[CH:16][CH:15]=1
Reactant: CC1N(C)C=C[NH+]1C
Reactant: Cn1cccc1C=O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1C=C[NH+](C)C1C=Cc1cccn1C
Yield: 74.3 %

Procedure:
A mixture of 12.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 2g of potassium hydroxide and 12.0 g of N-methylpyrrole-2-carboxaldehyde in 60 ml of absolute ethanol is refluxed for 15 minutes during which time a precipitate is formed. The mixture is cooled and 10 ml of water is added. The solid is filtered off and crystallized from absolute ethanol to yield 12.3 g of the title compound, melting point 289°-291° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8].[C:9](OC)(OC)([O:11][CH3:12])[CH3:10]>CN(C=O)C>[C:7]([C:6]1[NH:5][CH:4]=[N:3][C:2]=1[N:1]=[C:9]([O:11][CH3:12])[CH3:10])#[N:8]
Reactant: N#Cc1[nH]cnc1N
Reactant: COC(C)(OC)OC
Solvent: CN(C)C=O
Product: COC(C)=Nc1nc[nH]c1C#N
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
5 g of 4-amino-5-cyanoimidazole was suspended in 10 mL of DMF and 10 mL of trimethyl orthoacetate was added, followed by stirring at 90° C. for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was dilute with ethyl acetate, and then 4.2 g of desired compound deposited as a crystal was collected by filtration. The solution was concentrated and the residue was purified by silica gel column chromatograpy (eluent: ethyl acetate) and then recrystallized from ethyl acetate-n-hexane to obtain 2.9 g of a desired compound as a crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([OH:20])=[O:19])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1ccccc1C(=O)O
Product: O=C(O)c1ccccc1N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 20.9 %

Procedure:
3-nitrophthalic anhydride (1.0 g, 0.0052 mol) and o-aminobenzoic acid (0.71 g, 0.0052 mol) were refluxed as above for four days. The clear solution was purified as per 120 to yield 0.34 g (21%) 127 as pale orange grains: mp=190-192° C.; Rf0.74 (A): Rf0.87 (C): Rf0.62 (E): IR (cm−1): 2700-3300 (OH), 3093 (C═CH), 2620 (C—H), 1718 (C═O), 1681 (bs, C═O), 1609 (C═C), 1592 (C═O), 1534 (N═O), 1482 (C═C), 1451 (C═C), 1360 (N═O), 1316 (C—O), 1257 (C—O), 771 (C═CH); MS m/z (rel intensity) 311 (50), 285 (100), 241 (55), 122 (45).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([O:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:18])([F:19])[F:20])=[O:14])=[CH:27][CH:28]=1
Reactant: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(OC(=O)c1ccc(O)cc1)C(F)(F)F

Procedure:
The resulting ester compound and 0.07 g of 10% palladium-on-carbon were added to ethanol to conduct debenzylation in a hydrogen atmosphere to obtain 0.48 g of 1,1,1-trifluoro-2-octyl 4-hydroxybenzoate.
Reaction SMILES: C([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:6]1)(C)(C)C.O>FC(F)(F)C(O)=O>[CH3:15][O:14][C:9]1[C:8]2[C:7]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][CH:21]=3)=[N:6][NH:5][C:13]=2[CH:12]=[CH:11][N:10]=1
Reactant: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1nccc2[nH]nc(-c3ccc(N4CCOCC4)cc3)c12
Temperature: 130 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
To a solution of 1-tert-butyl-4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (2.2 g) in trifluoroacetic acid (50 mL) was added water (5 mL), and the mixture was stirred overnight at 130° C. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.332 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]#N.CC(C[AlH]CC(C)C)C.C(O)(=[O:26])C.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[CH:13]=[O:26]
Reactant: COc1cccc2c(C#N)cccc12
Reactant: CC(=O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c(C=O)cccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-methoxynaphthalene-1-carbonitrile (Preparation 11) (1.1 g, 6.00 mmol) in DCM (40 mL) at −78° C. under nitrogen was added DIBAL (1.0M in toluene, 18 mL) dropwise over 10 minutes. The reaction mixture was stirred at −78° C. for 1 h, warmed to rt for 1 h and then cooled to 0° C. Acetic acid (1 mL) followed by water (1 mL) were added. The mixture was partitioned between EtOAc (100 mL) and water (100 mL), the organic phase was separated and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (EtOAc:isohexane 2:8) to give the title compound: RT=3.54 min; m/z (ES+)=187.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)[C:5]#[N:6].[OH-:13].[K+]>CO.O>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)[C:5]([NH2:6])=[O:13]
Reactant: [OH-]
Reactant: CON=C(C#N)c1cnccn1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CON=C(C(N)=O)c1cnccn1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
α-Methoxyiminopyrazineacetonitrile Z-isomer (6.0 g) was dissolved in 35 ml of methanol. A solution of potassium hydroxide (4 g) in 10 ml of water was added and the dark reaction mixture was stirred for 1 hour at a temperature of 40° C. The greater part of the methanol was evaporated under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:25]4[CH:26]=[C:21]([C:18](=[O:20])[CH3:19])[CH:22]=[CH:23][CH:24]=4)=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(=O)c1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1
Yield: 95.2 %

Procedure:
This compound was prepared according to a process similar to that described in stage 6.3, by reacting 5 g (16.26 mmol) of 6-bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridine, prepared according to the protocol described in stage 6.1, with 3.46 g (21.13 mmol) of 3-acetylphenylboronic acid, in the presence of a 2M aqueous solution of sodium carbonate (90 ml) and of 0.94 g (0.81 mmol) of tetrakis(triphenylphosphine)palladium in 180 ml of a mixture of acetonitrile and toluene (v/v). 5.37 g of expected product are obtained
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH3:24])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2].[CH2:25](Br)C=C>>[CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH:24]=[CH2:25])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)C1(CC)CCCN(CC2COc3ccccc3O2)C1
Product: C=CCC1(C(=O)OCC)CCCN(CC2COc3ccccc3O2)C1

Procedure:
The procedure described above for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine-3-carboxylic acid ethyl ester was repeated except that allyl bromide was used instead of methyl iodide.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([F:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[C:19]([OH:21])[CH:20]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[C:19]([O:21][C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=2[F:13])[CH:20]=1
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)cc(CC(=O)O)c2)c(F)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of example 10 step (ii) and the product of example 18 step (iv).
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)[CH:3]([CH3:5])[CH3:4].[Cl:19]CCl.CS(Cl)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(N(CC)CC)C>[Cl:19][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1ccc(C(O)C(C)C)cc1[N+](=O)[O-]
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1ccc(C(Cl)C(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a stirred solution of 36 parts of intermediate 15, namely N-[4-(1-hydroxy-2-methylpropyl)-2-nitrophenyl]acetamide and 390 parts of dichloromethane were added 35.0 parts of N,N-diethylethanamine. After cooling to 0° C., 20.0 parts of methane-sulfonyl chloride were added dropwise to the previous mixture. Upon completion, stirring was continued for 12 hours at room temperature. The whole was poured into water and sodium carbonate was added while stirring. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 39 parts (100%) of N-[4-(1-chloro-2-methylpropyl)-2-nitrophenyl]acetamide (interm. 16).