Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12])=[C:6]([CH:16]=[CH2:17])[CH:5]=1)[CH3:3].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:1][CH:2]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12])=[C:6]([CH:16]=[CH2:17])[CH:5]=2)[CH3:3])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: C=Cc1cc(C(C)N)ccc1NS(=O)(=O)C=C
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Product: C=Cc1cc(C(C)NC(=O)Nc2ccc(C(C)(C)C)cc2)ccc1NS(=O)(=O)C=C
Reaction time: 5 h
Yield: 200 %

Procedure:
Ethenesulfonic acid [4-(1-amino-ethyl)-2-vinyl-phenyl]-amide (15.6 mg, 0.04 mmol), 4-tert-butyl phenylisocyanate (1.2 eq, 0.053 mmol, 9.45 μl), and TEA (1.2 eq, 0.12 mmol, 16.73 μl) were added in MC. The reaction mixture was stirred for 5 hrs. The reaction mixture was extracted with methylene chloride. A combined organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified with column chromatography (n-Hx:EA=3:1->2:1) to yield title compound (34.2 mg, 40%).
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([OH:24])([CH3:23])[CH2:19][CH:20]([CH3:22])[CH3:21])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[O:24][C:18]([CH2:19][CH:20]([CH3:21])[CH3:22])([CH3:23])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1C(C)(O)CC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nn(C)c(F)c1C1=Nc2ccccc2C(C)(CC(C)C)O1
Reaction time: 2 h
Yield: 63 %

Procedure:
The above product from step 2 is boiled in 150 ml of toluene with 0.2 g of p-toluenesulphonic acid on a water separator for 2 h. The mixture is washed with aqueous sodium bicarbonate solution and the organic phase is concentrated under reduced pressure. By stirring with heptane, it is possible to precipitate and remove by filtration the N-(2-acetylphenyl)-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide still present from the previous step. Chromatography gives 7.2 g (purity 85.1%; 63% of theory) of 2-(5-fluoro-1,3-dimethyl-1H-pyrazol-4-yl)-4-isobutyl-4-methyl-4H-3,1-benzoxazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[C:14](/[CH:28]=[CH:29]/[CH2:30][CH2:31][OH:32])=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1>O=[Pt]=O.O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[C:14]([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: COc1cc2c(cc1/C=C/CCO)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1CCCCO)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reaction time: 0.5 h
Yield: 135 %

Procedure:
A mixture of (170) (0.15 g, 0.33 mmol) prepared as described in example 309 and PtO2 (20 mg) in 1:1 tetrahydrofuran/methanol (30 mL) was shaken under an atmosphere of hydrogen gas at 40 psi pressure for 30 min. The catalyst was removed by filtration through Celite, washing through with more solvent. The combined filtrates were worked up and chromatographed on silica. Elution with ethyl acetate/petroleum ether (1:1) gave (171) as an orange solid (0.20 g, 100%), mp 256–260° C. (dec). 1H NMR δ [(CD3)2SO] 11.90 (br, 1H), 11.10 (br, 1H), 8.34 (s, 1H), 7.64–7.40 (m, 6H), 4.37 (br, 1H), 3.93 (s, 3H), 3.43 (t, J=6.3 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 1.66 (m, 1H), 1.50 (m, 2H).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[CH3:32][C@H:33]1[CH2:38][NH:37][CH2:36][C@@H:35]([CH3:39])[NH:34]1>>[CH3:32][C@H:33]1[NH:34][C@@H:35]([CH3:39])[CH2:36][N:37]([C:27]([C@@H:11]2[CH2:10][C@H:9]([SH:8])[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])=[O:29])[CH2:38]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Product: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Yield: 50 %

Procedure:
Following a procedure similar to that described in Preparation 8, but using 3.3 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 1.4 g of N,N'-carbonyldiimidazole and 1.0 g of cis-2,6-dimethylpiperazine, 1.56 g of the title compound was obtained as an amorphous solid.
Reaction SMILES: BrC1N=C([Si](C)(C)C)SC=1.C([Li])CCC.C([Sn](Cl)(CCCC)CCCC)CCC.C[Si](C)(C)[C:32]1[S:33][CH:34]=[C:35]([Sn:37]([CH2:46][CH2:47][CH2:48][CH3:49])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[N:36]=1>CCOCC.C(Cl)(Cl)Cl.CO>[CH2:46]([Sn:37]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[C:35]1[N:36]=[CH:32][S:33][CH:34]=1)[CH2:47][CH2:48][CH3:49]
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc([Si](C)(C)C)n1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)c1nc(Br)cs1
Agent: [Li]CCCC
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cscn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.6M, 3.1 mL, 4.94 mmol) was added to a solution of 2,4-dibromothiazole (1 g, 4.12 mmol) in anhydrous ether (25 mL) stirred at −78° C. under nitrogen. After 15 min, chlorotrimethylsilane (493 mg, 4.53 mmol) was added, then the solution was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched, and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give a brown oily residue (905 mg). The residue was purified by the distillation to give 4-bromo-2-trimethylsilylthiazole (650 mg) as a light-brown oil. Under nitrogen, the 4-bromo-2-trimethylsilylthiazole (340 mg, 1.44 mmol) was then dissolved in anhydrous ether (15 mL), and the resulting solution was stirred at −78° C. n-Butyllithium (1.5M, 1.4 mL, 2.16 mmol) was added, and the resulting solution was stirred at −78° C. for 30 minutes. Tri-n-butylstannyl chloride (703 mg, 2.16 mmol) was added, then the solution was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give a brown oily residue. The residue of 2-trimethylsilyl-4-tri-n-butylstannylthiazole was passed through a column of neutral alumina eluting with a gradient of ammoniated methanol in chloroform to give the sub-title compound, 4-tri-n-butylstannylthiazole as a yellow oil (330 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[C:21]([C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([CH2:42][C:43](O)=[O:44])=[CH:38][C:37]=3[Cl:46])=[CH:32][CH:31]=2)[C:27]([CH3:47])=[N:26][C:25]=1[CH3:48])(=[O:23])[NH2:22].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[C:21]([C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([CH2:42][C:43]([N:1]4[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]4)=[O:44])=[CH:38][C:37]=3[Cl:46])=[CH:32][CH:31]=2)[C:27]([CH3:47])=[N:26][C:25]=1[CH3:48])(=[O:23])[NH2:22]
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Reactant: CCOC(=O)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(C(=O)Cc2ccc(-c3ccc(-c4nc(C(N)=O)c(C)nc4C)cc3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 104.6 %

Procedure:
A mixture of ethyl piperidine-4-carboxylate (90 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL), and washed with water (5 mL). The organic layer was evaporated to afford ethyl 1-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetyl)piperidine-4-carboxylate (291 mg, 105%) which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].[H-].[Na+].Cl[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>CN(C)C=O.O.[Cu]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Clc1ccc2ccccc2n1
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(-c2ccc3ccccc3n2)c1C
Temperature: 20 °C
Reaction time: 0.2 h

Procedure:
2.75 g (17.9 mmol) of 3-ethoxycarbonyl-2-methyl-1H-pyrrole are added at 20° C. under an argon atmosphere to 0.756 g (18.9 mmol) of sodium hydride, at 60% by weight in liquid petroleum jelly, suspended in 12 mL of dimethylformamide. After stirring at 20° C. for 0.2 hour, 0.114 g (1.79 mmol) of copper powder and 2.93 g (17.9 mmol) of. 2-chloroquinoline are added. After stirring at 140° C. for 48 hours, the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 100 mL of water and then extracted with 4 times 50 mL of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give 6 g of an oil, which oil is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 2.2 g of 3-ethoxycarbonyl-2-methyl-1-(quinol-2-yl)-1H-pyrrole are obtained in the form of a yellow oil. Mass spectrum (EI): m/e 280 (M+.), m/e 251, m/e 206.
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:19]=[CH:20][C:21]([OH:23])=[O:22].C(O)(=O)C>[Pd].O1CCOCC1>[CH3:3][O:4][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: [H][H]
Reactant: COc1c(C=CC(=O)O)cccc1Oc1ccccc1C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1c(CCC(=O)O)cccc1Oc1ccccc1C
Yield: 90 %

Procedure:
Hydrogen gas was introduced to a mixture of 3-[2-methoxy-3-(o-tolyloxy)phenyl]acrylic acid (17 g), palladium on carbon (5%, 3.4 g) and a small amount of glacial acetic acid in dioxane (200 ml) with stirring. The reaction mixture was filtered, and the filtrate was evaporated. The residue was pulverized with n-hexane to give 3-[2-methoxy-3-(o-tolyloxy)phenyl]propionic acid (15.4 g). mp 71°-75° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[N:13](OCCC(C)C)=[O:14].Cl>CO>[OH:14]/[N:13]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: CC(C)CCON=O
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)C(=O)/C(=N/O)C2
Temperature: 40 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
6-methoxy-2,3-dihydro-1H-inden-1-one (17.2 g, 106 mmol) was dissolved in methanol (700 mL). The mixture was heated to 40° C., then isoamyl nitrite (30 mL, 220 mmol) and concentrated hydrochloric acid (17 mL) were added. The reaction mixture was stirred at 40° C. for 2 hours. After cooled to room temperature, the precipitate was collected by filtration and dried under high vacuum to obtain product (10.0 g, yield 50%).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)=[O:12])[CH2:10][CH:5]2[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.[NH:33]1[CH2:38][CH:37]=[CH:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[N:33]1([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([C:11]([N:9]3[CH2:8][CH2:7][N:6]4[C:2](=[O:1])[O:3][C:4]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:5]4[CH2:10]3)=[O:12])=[CH:14][CH:15]=2)[CH2:34][CH:35]=[CH:36][CH2:37][CH2:38]1
Reactant: O=Cc1ccc(C(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)cc1
Reactant: C1=CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(CN2CC=CCC2)cc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 27 h
Yield: 40.5 %

Procedure:
To a solution of 4-[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]benzaldehyde (0.15 g, 0.35 mmol) and 1,2,3,6-tetrahydropyridine (44 mg, 0.53 mmol) in tetrahydrofuran (4 mL) was added sodium triacetoxyborohydride (0.11 g, 0.52 mmol), and the mixture was stirred at room temperature for 27 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=4:1) and crystallized from diisopropyl ether to obtain the title compound (70 mg, yield 41%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.FS([C:22](C(O)=O)([F:24])[F:23])(=O)=O>[Cu]I.C(#N)C>[CH2:6]([CH:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8](=[O:11])[C:7]21[CH2:16][CH2:15][CH:14]([O:17][CH:22]([F:24])[F:23])[CH2:13][CH2:12]2)[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: O=C1c2cc(Br)ccc2CC12CCC(O)CC2
Agent: [Cu]I
Solvent: CC#N
Product: O=C1c2cc(Br)ccc2C(Cc2ccccc2)C12CCC(OC(F)F)CC2
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 63.6 %

Procedure:
In a 25 mL round bottom flask was placed 6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (368 mg, 1.252 mmol) and it was azeotroped twice with acetonitrile (2 mL/each). CuI (24 mg, 0.126 mmol) was added followed by acetonitrile (2.5 mL). This solution was purged under a stream of N2 for 30 seconds. The solution was heated to 60° C. under a nitrogen atmosphere. After being 5 minutes at 60° C., FSO2CF2CO2H (136 mL, 1.316 mmol) was added dropwise. After 1 hour, the reaction was quenched with H2O (10 mL) and diluted with diethyl ether (10 mL). The phases were separated and the aqueous phase was back-extracted with diethyl ether (5 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 40 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding benzyl 6′-bromo-4-(difluoromethoxy)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (137 mg, 0.398 mmol, 32% yield). M+H=344.9, 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, J=1.2 Hz, 1H), 7.69 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.26 (t, J=75.2 Hz, 1H), 4.20 (m, 1H), 2.98 (s, 2H), 2.14 (m, 2H), 1.80 (m, 2H), 1.65-1.52 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[NH:10])[NH:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[O:21]>C1C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:20]([NH:10][C:4](=[N:5][C:6]([O:8][CH3:9])=[O:7])[O:3][CH2:1][CH3:2])=[O:21]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=N)NC(=O)OC
Solvent: c1ccccc1
Product: CCOC(=NC(=O)OC)NC(=O)Nc1ccc(Cl)cc1Cl
Yield: 80.8 %

Procedure:
2 g of 2-ethyl-1-methoxycarbonylisourea [prepared as described in Japanese Patent Provisional Publication No. 49-25133 (1974)] and 1.88 g of 2,4-dichlorophenyl isocyanate were dissolved in 100 ml of benzene and the mixture was refluxed for 1 hour. The benzene was then removed by evaporation under reduced pressure and the residue was recrystallized from hexane, giving 2.7 g (yield 81%) of the desired compound as white needles melting at 92°-93° C.
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:20][CH3:21])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12](C(=O)C)=[CH:11][CH:10]=3)(=O)C.ClC1C=CC=[C:25]([C:29]([O:31]O)=[O:30])C=1>C(Cl)(Cl)Cl>[C:29]([O:31][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:20][CH3:21])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([O:31][C:29](=[O:30])[CH3:25])=[CH:11][CH:10]=3)(=[O:30])[CH3:25]
Reactant: CCn1c2ccc(C(C)=O)cc2c2cc(C(C)=O)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCn1c2ccc(OC(C)=O)cc2c2cc(OC(C)=O)ccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 104 g (0.37 mole) of 3,6-diacetyl-N-ethylcarbazole in 1700 ml of chloroform (hydrocarbon stabilized) previously cooled to 15°C was added 138 g (0.8 mole) of m-chloroperbenzoic acid. The reaction was stirred at room temperature for 4 days, then filtered. The filtrate was washed with saturated sodium bicarbonate solution and with water, then dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo leaving a solid which was recrystallized from acetone-water and then from acetone methanol to give the desired product. M.P. 138°-139°C, λmaxEtOH 237, E1cm1% 1330.
Reaction SMILES: [CH3:1][C:2]1(O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[Cl-].[NH4+]>C(Cl)Cl>[CH3:1][C:2]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6][CH2:5]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C)(O)c1ccccc12
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CC1=CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
tert-Butyl 1-methyl-1-hydroxyspiro[indane-3,4′-piperidine]-1′-carboxylate (0.140 g, 0.441 mmol) obtained in step 1 was dissolved in methylene chloride (2 mL), toluenesulfonic acid monohydrate (0.008 g, 0.044 mmol) was added, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous ammonium chloride solution was added dropwise to the reaction mixture, and the mixture was extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (0.108 g, 81%).
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]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)CO)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f3) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[CH:20]=[CH:19][CH:18]=[C:17]([C:22]#[N:23])[C:16]=4[C:15]([CH:24]=[O:25])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.[OH:26]O>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[C:16](=[C:17]([C:22]#[N:23])[CH:18]=[CH:19][CH:20]=4)[C:15]([C:24]([OH:26])=[O:25])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cccc2c1c(C=O)nn2Cc1cc(-c2ccc(Cl)s2)on1
Reactant: OO
Product: N#Cc1cccc2c1c(C(=O)O)nn2Cc1cc(-c2ccc(Cl)s2)on1

Procedure:
The title compound was prepared analogously to example 1 (iii) with the difference that 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3-formyl-1H-indazole-4-carbonitrile was used instead of 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3-formyl-1H-indazole-5-carboxylic acid methyl ester and that a modified oxidation procedure described by E. Dalacanale et al. J. Org. Chem. (1986) 51, 567 employing H2O2 instead of 2-methylbutene was utilized.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:25]=[C:26]([C:31](=O)[CH2:32][NH:33][C:34](=O)[CH2:35][CH2:36][C:37]2[N:38](S(N(C)C)(=O)=O)[CH:39]=[C:40]([CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][CH3:45])[N:41]=2)[CH:27]=[CH:28][C:29]=1[F:30]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26]([C:31]2[S:10][C:34]([CH2:35][CH2:36][C:37]3[NH:41][C:40]([CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][CH3:45])=[CH:39][N:38]=3)=[N:33][CH:32]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(CCC(=O)NCC(=O)c2ccc(F)c(F)c2)n1
Solvent: Cc1ccccc1
Product: CCC(C)(C)Cc1cnc(CCc2ncc(-c3ccc(F)c(F)c3)s2)[nH]1

Procedure:
Lawesson's reagent (50 mg, 0.12 mmol) was added to a solution of N-[2-(3,4-difluorophenyl)-2-oxoethyl]-3-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H -imidazol-2-yl]propanamide (30 mg, 0.06 mmol) in dry toluene (4 mL) at rt. After stirring at reflux for 30 min, volatiles were removed. The resulting residue was dissolved in THF (0.5 mL), and 2M aqueous hydrochloric acid (1.5 mL) was added. After stirring at 80° C. overnight, the volatiles were removed. The aqueous phase was diluted with water and washed with 1:5 ethyl acetate/diethyl ether. The aqueous phase was basified with 1N sodium hydroxide and extracted with ethyl acetate. Combined extracts were washed with brine, dried (sodium sulfate) and concentrated to afford the title compound, which was dissolved in methylene chloride and acidified with 1M hydrogen chloride in diethyl ether. Additional diethyl ether and hexane were added, and concentration afforded the HCl salt of the title compound. LC-MS: m/e 376 (M+H).
Reaction SMILES: [OH-].[Na+:2].ClC1C=CC(S(C2C3C(=CC=C(C)C=3)N(CC(O)=O)C=2C)(=O)=O)=CC=1.[Cl:28][C:29]1[C:30](C#N)=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39]([O:41]C)=[O:40])[C:33]([CH3:43])=[C:32]2[S:44]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)(=[O:46])=[O:45]>C1COCC1>[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39]([O-:41])=[O:40])[C:33]([CH3:43])=[C:32]2[S:44]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)(=[O:45])=[O:46].[Na+:2]
Reactant: COC(=O)Cn1c(C)c(S(=O)(=O)c2ccc(Cl)cc2)c2c(C#N)c(Cl)ccc21
Agent: Cc1ccc2c(c1)c(S(=O)(=O)c1ccc(Cl)cc1)c(C)n2CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)c2cc(Cl)ccc2n1CC(=O)[O-]
Reaction time: 8 h

Procedure:
Sodium hydroxide (1M, 4.3 ml) was added to a solution of the product of example 1 part (c) (1.75 g) in THF (60 ml). The reaction mixture was stirred overnight and then concentrated in vacuo. The residue was recrystallised from water to give the title compound as a white solid.