Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([NH:21][CH3:22])[CH:13]=1.[OH-].[Na+]>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=1[N:21]([CH3:22])[CH:8]=[O:10])(=[O:20])[CH3:19]
Reactant: O=CO
Reactant: CNc1cc(Cl)ccc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)c1ccc(Cl)cc1N(C)C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of acetic anhydride (12 ml) and formic acid (8 ml) was heated at 55° for 3 hours and then cooled to ambient temperature. 4'-Chloro-2'-(methylamino)acetophenone (9.7 g) was then added and the mixture stirred at ambient temperature overnight. Water (40 ml) was added and the mixture stirred in an ice/salt bath and neutralised by adding aqueous sodium hydroxide (specific gravity 1.5, 22 ml) whilst maintaining the temperature below 30°. The reaction mixture was extracted with dichloromethane (3×50 ml) and the combined extracts were dried over magnesium sulphate to give a solution of 2'-acetyl-5'-chloro-N-methylformanilide.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[O:18]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:3]([C:2]([NH:1][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:33][CH:32]=1)([CH3:17])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12]2)=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1cc2cc(Cl)cc(Cl)c2n1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: CC(C#N)(Cn1cc2cc(Cl)cc(Cl)c2n1)NC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5,7-dichloro-2H-indazol-2-yl)propionitrile (60 mg, described in Example 98) and 4-phenoxybenzoyl chloride, the title compound was isolated as a white solid (90 mg, 87%). MS (ES): M/Z [M+H]=465. 1H NMR: (400 MHz, DMSO-d6): 1.71 (s, 3H), 5.12 (d, 1H), 5.21 (d, 1H), 7.04-7.13 (m, 4H), 7.23 (t, J=7.4 Hz, 1H), 7.41-7.51 (m, 3H), 7.85-7.92 (m, 3H), 8.52 (s, 1H) and 8.80 (s, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:18]([CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22]CC)=[O:21].[O-]CC.[Na+].O>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:18]([CH2:25][CH2:26][CH3:27])=[C:19]([C:20]([OH:22])=[O:21])[N:3]=[N:2]2)=[CH:16][CH:15]=1)=[O:9])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CCCCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
4-Azido-N-butylbenzamide (2.3 g) obtained in Example 56a) and ethyl 3-oxohexanoate (1.06 ml, 6.33 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (479 mg, 6.33 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 14 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.62 g, 4.91 mmol, 97.1%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][C:50]([F:58])([F:57])[CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:54]3[CH2:55][CH2:56][CH:51]([C:50]([F:58])([F:57])[F:49])[CH2:52][CH2:53]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: FC(F)(F)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCC(C(F)(F)F)CC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-trifluoromethylpiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:38](COCC[Si](C)(C)C)[C:37](S(C)(=O)=O)=[N:36][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:26][CH2:25][C@@H:24]([O:27]COCC[Si](C)(C)C)[CH2:23]3)=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C1(C2[O:62][C@H:61]3[CH2:63][C@@H:64]([OH:67])[CH2:65][O:66][C@@H:60]3[CH2:59][O:58]2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:38][C:37]([O:67][C@@H:64]3[CH2:63][C@H:61]([OH:62])[C@@H:60]([CH2:59][OH:58])[O:66][CH2:65]3)=[N:36][C:5]2=[N:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[O:21])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)CCOCO[C@@H]1CCN(C(=O)c2ccc(-c3ccc(-c4nc5nc(S(C)(=O)=O)n(COCC[Si](C)(C)C)c5cc4Cl)cc3)cc2)C1
Reactant: O[C@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccc(-c3nc4nc(O[C@H]5CO[C@H](CO)[C@@H](O)C5)[nH]c4cc3Cl)cc2)cc1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-(4′-(6-chloro-2-(methylsulfonyl)-1-((2 (trimethylsilyl)ethoxy)-methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)(3-((2-(trimethylsilyl)-ethoxy)methoxy)pyrrolidin-1-yl)methanone (150 mg, 0.198 mmol) and (4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol (100 mg, 0.423 mmol) in DMF (2 mL), was added cesium carbonate (150 mg, 0.460 mmol). The reaction mixture was stirred at room temperature for 2 h, then partitioned between water and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The chromatography of the resulting residue over silica (preparative TLC) eluting with 25% EtOAc in Hexanes afforded the title compound (Rf:0.7) LC-MS: calculated for C48H61ClN4O8Si2 912.37, observed m/e: 913.6 (M+H)+ (Rt: 3.30/4 min)
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[BrH:20].S(=O)(=O)(O)O.C>C(O)(=O)C.C(Cl)Cl>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: Br
Agent: C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCCCCCCCCBr
Temperature: 0 °C

Procedure:
A mixture of 18 g. of 16-hydroxyhexadecanoic acid and 160 g. of 30-34% hydrogen bromide in acetic acid is treated with 32 ml. of concentrated sulfuric acid and stirred at ambient temperature for 18 hours. The solution is stirred under reflux for 7 hours and then poured into 500 ml. of ice-water and filtered.A methylene chloride solution of the product is Darco clarified, dried over magnesium sulfate, and evaporated. Crystallization of the residue from ether-petroleum ether and then acetonitrile affords 16-bromohexadecanoic acid as a white solid.
Reaction SMILES: [C:1]([C:4]1[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[C:25]([CH3:28])[CH:24]=[C:23]4[N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)[C:10]=2[Cl:34])[CH:6]=[CH:7][CH:8]=1)(O)=[O:2].Cl.C([N:38]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.O>[C:1]([C:4]1[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[C:25]([CH3:28])[CH:24]=[C:23]4[N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)[C:10]=2[Cl:34])[CH:6]=[CH:7][CH:8]=1)(=[O:2])[NH2:38]
Reactant: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4C(=O)O)c3Cl)c2n1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-n2cccn2)c2cccc(OCc3c(Cl)ccc(-n4cccc4C(N)=O)c3Cl)c2n1
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
To a solution of 2-carboxy-1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]pyrrole (80 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.3 mg) and 1-hydroxybenzotriazole (30.7 mg) at ambient temperature, and the mixture was stirred for 1.5 hours at the same temperature. To the mixture was added conc. ammonia solution (12 mg) at ambient temperature, and the mixture was stirred for 2 days at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The separated organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=20:1, V/V) to give 2-carbamoyl-1-[2,4-dichloro-3-[2-methyl-4-(pyrazol-1-yl)quinolin-8-yloxymethyl]phenyl]pyrrole (31 mg) as amorphous powder.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[NH2:5][N:6]1[CH2:14][C:13]2[C:8](=[C:9]([CH3:16])[CH:10]=[CH:11][C:12]=2[CH3:15])[CH2:7]1>C(COC)OC>[CH3:1][NH:2][C:3]([NH:5][N:6]1[CH2:7][C:8]2[C:13](=[C:12]([CH3:15])[CH:11]=[CH:10][C:9]=2[CH3:16])[CH2:14]1)=[S:4]
Reactant: CN=C=S
Reactant: Cc1ccc(C)c2c1CN(N)C2
Solvent: COCCOC
Product: CNC(=S)NN1Cc2c(C)ccc(C)c2C1
Reaction time: 15 h
Yield: 61.2 %

Procedure:
3.7 g (0.05M) of methyl isothiocyanate in 10 ml of dimethoxyethane is dripped into 8.0 g (0.05M) of 2-amino-4,7-dimethylisoindoline in 50 ml of 1,2-dimethoxyethane. Conventional processing was conducted after 15 hours, yielding 7.1 g of 1-methyl-3-(4,7-dimethylisoindolin-2-yl)-thiourea.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[C:6](/[CH:9]=[C:10]1\[CH2:11][N:12]([CH:17](C2CC2)[C:18]2[CH:19]([F:26])[C:20](=C=O)[CH:21]=[CH:22][CH:23]=2)[CH2:13][CH2:14][CH:15]\1[OH:16])([OH:8])=[O:7].Cl>C1C=CC=CC=1>[CH2:1]([O:8][C:6](/[CH:9]=[C:10]1\[CH2:11][N:12]([CH:17]([C:1]([CH:2]2[CH2:4][CH2:3]2)=[O:5])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:26])[CH2:13][CH2:14][CH:15]\1[OH:16])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: O=C=C1C=CC=C(C(C2CC2)N2CCC(O)/C(=C/C(=O)O)C2)C1F
Agent: Cl
Solvent: c1ccccc1
Product: CCCCOC(=O)/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1O
Reaction time: 2 h
Yield: 73.7 %

Procedure:
150 ml of 1-butanol were added to 3.19 g (9.58 mmol) of (E)-3-carboxymethylidene-1-(α-cyclopropyl-carbonyl-2-fluorobenzyl)-4-hydroxypiperidine. Hydrogen chloride gas was blown through the resulting mixture until the solution became acidic. After standing at room temperature for 2 hours, 100 ml of benzene were added and the mixture was subjected to azeotropic dehydration for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Toluene and an aqueous solution of sodium bicarbonate were added to the residue. The toluene layer thus separated was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by purification by chromatography on a silica gel column (eluting solvent: toluene/ethyl acetate=4/1), whereby 2.75 g (yield: 73.7%) of the tile compound were obtained as a pale yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]1[CH:14]([C:15]([O:17]C(C)(C)C)=[O:16])[CH2:13][N:12]([CH3:22])[C:11]1=[O:23])[CH3:9]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:8]([N:10]1[CH:14]([C:15]([OH:17])=[O:16])[CH2:13][N:12]([CH3:22])[C:11]1=[O:23])[CH3:9]
Reactant: CCN1C(=O)N(C)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1C(=O)N(C)CC1C(=O)O

Procedure:
A stirred solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (0.501 g, 2.5 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml) was cooled to −10° C. under argon and treated with iodoethane (0.404 ml, 5.00 mmol). Sodium hydride (60% dispersion in oil) (0.100 g, 2.500 mmol) was added portion wise. The mixture was allowed stirred warm to room temperature over 3 hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (20 ml) and brine (10 ml). The aqueous layer was re-extracted with ethyl acetate (20 ml) and the organic extracts were combined, washed with saturated sodium hydrogen carbonate solution (20 ml), water (2×20 ml) and brine (20 ml), dried and evaporated. The residue was purified by silica gel chromatography eluting with 25-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylate (433 mg, 76%). LC/MS [M+H]+=229. (ii) A solution of 1,1-dimethylethyl 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylate (433 mg, 1.897 mmol) in TFA/DCM (1:2, 6 ml) was stirred at room temperature for 18 hours. The solution was evaporated and the residue was co-evaporated with dichloromethane and dried to give crude 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylic acid, (assume ˜1.9 mmol). LC/MS [M+H]+=173.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[NH:25]([C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[O:43][CH3:44])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:26]1([NH:25][C:32](=[O:33])[C:34]2[CH:39]=[CH:38][C:37]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:36][C:35]=2[O:43][CH3:44])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B(O)O)ccc1C(=O)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)Nc1ccccc1

Procedure:
trans-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (266 mg, 0.604 mmol), 4-(anilinocarbonyl)-3-methoxyphenylboronic acid (180 mg, 0.664 mmol), palladium tetrakistriphenyphosphine (42 mg, 0.036 mmol) and sodium carbonate (154 mg, 1.449 mmol) were mixed with ethylene glycol dimethyl ether (8 mL) and water (4 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give trans-N1-phenyl-4-{4-amino-1-[-4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (226 mg, 69%). 1H NMR (CDCl3) δ 1.58 (m, 4H), 2.17 (m, 7H), 2.32 (s, 3H), 2.52 (m, 2H), 2.69 (2.69, 3H), 4.16 (s, 3H), 4.78 (m, 1H), 5.49 (bs, 2H), 7.14 (m, 1H), 7.43 (m, 4H), 7.69 (m, 2H), 8.44 (m, 2H), 9.77 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+=541.2, Rt=2.61 min.
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=1)=[O:17])(=[O:14])=[O:13].Cl.[N-:29]=[N+:30]=[N-].[Na+]>O>[N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([CH3:27])[N:20]=1)=[O:17])(=[O:14])=[O:13])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2N)n1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2N=[N+]=[N-])n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
A solution of 1 g of sodium nitrite in 4 ml of water is slowly added dropwise at 0°-5° C. to a mixture of 3.4 g of N-(2-aminophenylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea, 10 g of ice and 4 ml of 36% hydrochloric acid. After the reaction mixture has been stirred for 2 hours at 0° C., a solution of 1 g of sodium azide in 4 ml of water is added dropwise and the temperature is allowed to rise to 20° C. The reaction mixture is extracted with three 20 ml portions of methylene chloride. The combined organic phases are dried and concentrated. Recrystallisation of the residue yields 1.0 g of N-(2-azidophenylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea which decomposes at 175° C.
Reaction SMILES: I(O)(=O)(=O)=[O:2].C(OC([N:13]1[C@@H:17]([CH2:18][OH:19])[CH2:16][C@@H:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)[C:14]1=[O:34])=O)(C)(C)C>C(#N)C.C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6].I(O)(=O)(=O)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH2:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([C@H:15]2[C:14](=[O:34])[NH:13][C@@H:17]([C:18]([OH:2])=[O:19])[CH2:16]2)=[CH:25][CH:24]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H](c2ccc(OCc3ccccc3)cc2)C[C@@H]1CO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1N[C@@H](C(=O)O)C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution containing 6.0 g of periodic acid and chromium trioxide (13 mg) in wet acetonitrile (60 mL; 0.75 volume % water) was prepared. A portion of this solution (15 mL) was added dropwise to a solution of (3S,5R)-3-(4-benzyloxyphenyl)-5-hydroxymethyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1.02 g, 2.57 mmol) in wet acetonitrile (15 mL; 0.75 volume % water) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. At this time, more of the periodic acid/chromium trioxide solution (5 mL) was added. Stirring at 0° C. was continued for an additional 1 hour. After quenching with a solution of dibasic sodium phosphate (720 mg) in water (12 mL), the mixture was extracted twice with diethyl ether. The combined organic extracts were washed with aqueous sodium bisulfite solution (440 mg in 10 mL water) and brine. After drying over MgSO4, the solvent was evaporated to provide a yellow solid that was taken up in methylene chloride (100 mL) and cooled in an ice bath. Hydrogen chloride gas was bubbled through the cold solution for 2 minutes and the resulting mixture was stirred at 0° C. for 1 hour. The solvent and HCl were evaporated to afford a solid from which the title compound, 226 mg (28%) was isolated by trituration with a mixture of methylene chloride, diethyl ether and ethyl acetate. The trituration filtrate was dissolved in aqueous saturated NaHCO3 solution and washed twice with diethyl ether. After careful acidification with aqueous 6M HCl solution, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to provide more of the title compound, 123 mg (15%).
Reaction SMILES: [C:1]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30].[ClH:33]>CN1CCCC1=O.O1CCOCC1>[ClH:33].[C:1]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(O)CN
Reactant: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NCC(C)(C)O)cc3)cc2s1
Temperature: 150 °C
Yield: 25 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester (intermediate 78) (135 mg, 0.34 mmol) and 1-amino-2-methylpropan-2-ol (153 mg, 1.718 mmol) in 3 ml of N-methylpyrrolidone in a 5 ml microwave vial, equipped with a magnetic bar, is heated for 20 minutes at 150° C. by microwave. The reaction medium is extracted with ethyl acetate (3×20 ml) and washed with water (4×25 ml). The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness. The residue obtained is purified by chromatography on silica, on an 8 g 15-35 μm AIT column, eluting with a 9/1 ethyl acetate/cyclohexane mixture. After evaporating off the solvent, 55 mg of a colorless solid are obtained. The product is dissolved in a minimum amount of dioxane, and 4 N hydrochloric acid dissolved in dioxane is added. The precipitate obtained is filtered off by suction, washed with dioxane and then dried under vacuum at 40° C. to give 42 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester hydrochloride, i.e. a yield of 25%.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>ClCCl.O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C=O)[nH]1
Yield: 82.2 %

Procedure:
A suspension of 2-butyl-4-chloro-1H-imidazole-5-methanol (22.0 g) in dichloromethane:1,4-dioxan (2:1) (690 ml) was treated with manganese dioxide (63.15 g) and the reaction mixture heated at reflux under nitrogen for 3.5 h. The reaction mixture was cooled, filtered and the filtrate evaporated to leave an off-white solid. The residue was triturated with petroleum ether, filtered and dried to give the title compound as a white solid (17.9 g) m.p. 98°-99° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[N+:24]([O-])=O)[CH3:2].CO>[C].[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[NH2:24])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3)c2)cc1N
Temperature: 40 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a solution of 4-(3-cyano-4-phenylpyrrole-1-yl)-2-nitro-benzoic acid ethyl ester (0.090 g) in a mixed solvent of methanol (2.5 mL) and ethyl acetate (2.5 mL) was added 10% palladium-carbon powder (0.016 g) under an argon atmosphere, and this mixture was stirred at 40° C. under a hydrogen atmosphere for 3 hours. After this reaction mixture was replaced under an argon atmosphere, the insoluble material was removed by suction through a Celite pad. This filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane=50/50) to give the title compound (0.070 g).