Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([O:16]C)=O)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=O)C.C(OCC)(=O)C.[OH-].[NH4+:25]>CO>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([NH2:25])=[O:16])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: [NH4+]
Reactant: COC(=O)Cc1ccc2c(ccn2C(C)=O)c1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)Cc1ccc2[nH]ccc2c1

Procedure:
A solution of 1-acetyl-1H-indole-5-acetic acid, methyl ester (1.46 g) in methanol (10 ml) and conc. ammonium hydroxide (20 ml) was stirred at ambient temperature for 48 h. The resulting solution was poured into ethyl acetate (100 ml). The layers were separated and the aqueous layer was washed with ethyl acetate (3×50 ml) and chloroform (3×50 ml). The organic layers were dried (MgSO4) and the solvent was evaporated to give a solid (0.72 g). Crystallisation from ethyl acetate gave the title compound as a white solid, (0.3 g) m.p. 146°-7°.
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH2:15][CH3:16])[CH:5]=1.[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:17])[S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([CH2:15][CH3:16])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(Br)ccc1NS(C)(=O)=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1N(C)S(C)(=O)=O
Reaction time: 24 h
Yield: 71.8 %

Procedure:
Methyl iodide (1.6 g, 0.0256M) was added to a mixture of N-(4-bromo-2-ethylphenyl)methanesulfonamide (4.77 g, 0.0171M) and potassium carbonate (3.5 g, 0.0256M) in dimethylformamide (50 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for a further 24 hrs after which time it was partitioned between diethylether (100 ml) and water (100 ml). The aqueous was extracted further with diethyl ether (2×100 ml). The combined organics were dried over magnesium sulfate, filtered and the solvent concentrated in vacuuo to afford the title compound as a brown oil (3.6 g).
Reaction SMILES: O=C1CCC(=O)N1[C:8](=[O:20])[C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10].[NH2:21][C@H:22]([C@@H:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:27])[C:23]([OH:25])=[O:24].O>C1COCC1>[CH2:29]([O:28][C@@H:26]([CH3:27])[C@@H:22]([NH:21][C:8](=[O:20])[C:9]([NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])([CH3:11])[CH3:10])[C:23]([OH:25])=[O:24])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1C(=O)CCC1=O
Reactant: C[C@H](OCc1ccccc1)[C@@H](N)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](OCc1ccccc1)[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture comprising of tert-butyl 1-(2,5-dioxopyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ylcarbamate (1 g, 3.33 mmol) (prepared according to the procedure described in EP1486498A1 page 20) and (2R,3S)-2-amino-3-(benzyloxy)butanoic acid (0.697 g, 3.33 mmol) in THF (40 ml)/water (10 ml) was treated with TEA (1.392 ml, 9.99 mmol) and stirred at 50° C. for 4 hours. The resulting mixture was concentrated in vacuo and EtOAc (20 ml) was added. The pH was adjusted to pH2 with 1M HCl. The organic portion was separated and the aqueous phase was back extracted with EtOAc (30 ml). The combined organic portions were washed with a saturated solution of brine (50 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DCM and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:26])=[CH:16][C:17](OS(C(F)(F)F)(=O)=O)=[C:12]3[C:11]([CH3:27])=[CH:10]2)=[C:4]([CH3:28])[CH:3]=1.[NH:29]1[CH2:39][CH2:38][CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30]1.C(N(CC)C(C)C)(C)C>O>[CH2:36]([O:35][C:33]([CH:32]1[CH2:38][CH2:39][N:29]([C:17]2[CH:16]=[C:15]([CH3:26])[N:14]=[C:13]3[N:9]([C:5]4[C:4]([CH3:28])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=4[CH3:8])[CH:10]=[C:11]([CH3:27])[C:12]=23)[CH2:30][CH2:31]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c2c(C)cn(-c3c(C)cc(Cl)cc3C)c2n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2cc(C)nc3c2c(C)cn3-c2c(C)cc(Cl)cc2C)CC1
Temperature: 160 °C
Yield: 79.7 %

Procedure:
A mixture of the crude trifluoromethanesulfonic acid 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl ester (20.5 g), ethyl isonipecotate (74.4 g) and N,N-diisopropylethylamine (12.2 g) was heated at 150-170° C. for 1 hour. To the reaction mixture, water was added and extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=5:1) to give 1-[1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidine-4-carboxylic acid ethyl ester (16.6 g) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:5][CH:4]=1)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl [7-cyano-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (30 mg, 0.07 mmol, cf. example 34d) were dissolved in methanol (3 mL). Raney nickel (10 mg) was added and the reaction mixture stirred at room temperature under an atmosphere of hydrogen for 4 h. The catalyst was removed by filtration and the methanol was evaporated in vacuo. Yield: 18 mg (0.041 mmol, 59%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[C:6]([F:10])[C:5]([N:11]=[N:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:4]([F:18])[CH:3]=1.C1(P(=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:42]([O:41][C:39](=[O:40])[CH:38]=[CH:8][C:7]1[C:2]([Br:1])=[CH:3][C:4]([F:18])=[C:5]([N:11]=[N:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:6]=1[F:10])[CH3:43]
Reactant: O=Cc1c(Br)cc(F)c(N=NN2CCCC2)c1F
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1c(Br)cc(F)c(N=NN2CCCC2)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 0.3 1 three necked flask fitted with a magnetical stirrer and dropping funnel under inert atmosphere, 6.62 g (20.8 mmol, 1 eq) of 6-bromo-2,4-difluoro-3-(pyrrolidin-1-ylazo)-benzaldehyde a9 are dissolved in THF (100 ml) and cooled down to 0° C. Ethyl (triphenylphosphoranylidene)acetate (9.43 g, 1.3 eq) is then added under efficient stirring, the temperature raising to 10° C. The mixture is kept under stirring one hour at 0° C., and then overnight at room temperature. The mixture is concentrated to dryness, the residue suspended in diethyl ether, the triphenylphospine oxide is filtered off and the filtrate concentrated to dryness. The residue is purified by PrepLC on silicagel (CH2Cl2/pentane: 50/50 (v/v)) to give 4.17 g of pure of 3-[6-bromo-2,4-difluoro-3-(pyrrolidin-1-ylazo)-phenyl]-acrylic acid ethyl ester a10 (47%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl.Cl[CH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH3:37]>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH:36]1[CH2:30][CH2:31][CH2:32][N:33]([CH3:37])[CH2:34][CH2:35]1)[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: CN1CCCC1CCCl
Agent: Cl
Product: CN1CCCC(Oc2cc3c4c(c2)c(=O)c(Cc2cccnc2)cn4-c2cc(Br)ccc2S3)CC1
Yield: 36.7 %

Procedure:
According to Example 34, the compound (100 mg) produced in Example 37 was reacted with 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (54 mg) to obtain the ring expanding title compound (46 mg; 37%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:20])=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH2:14][C:13](=[O:15])[NH:12][C:11]4[CH:16]=[C:17]([C:21]([F:22])([F:23])[F:24])[C:18]([CH3:20])=[CH:19][C:10]=4[N:9]=3)[CH:3]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c1)=N2

Procedure:
The title compound was prepared from 4-(3-bromo-phenyl)-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example B.1) (200 mg, 0.50 mmol) and commercially available 3-tert-butylsulfamoyl-benzeneboronic acid [CAS-no. 221290-14-8] (155 mg, 0.60 mmol) according to the general procedure II. Obtained as a light yellow solid (275 mg, 97%). MS (ISP) 530.1 [(M+H)+]; mp 133° C. (dec).
Reaction SMILES: [OH:1][C@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1.[Br:15]N1C(=O)CCC1=O>O1CCCC1>[Br:15][C:11]1[C:10]([OH:13])=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:3][C@H:2]([OH:1])[CH3:14])[N:5]=[CH:6]2
Reactant: C[C@@H](O)Cn1ncc2ccc(O)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1ncc2ccc(O)c(Br)c21
Temperature: 25 °C

Procedure:
A solution of 1-[(R)-2-hydroxypropyl]-1H-indazol-6-ol (4.76 g, 24.8 mmol) in tetrahydrofuran (50 mL), cooled in an ice bath, added small portions of N-bromosuccinimide (4.41 g, 24.8 mmol) and stirred while the reaction warmed to room temperature. The reaction was quenched with aqueous saturated sodium sulfite (100 mL) and extracted with ethyl acetate (100 mL). The combined extracts were dried (magnesium sulfate), filtered and evaporated to a yellow solid (7 g): mp 134–136° C.; LC/MS m/z 271/273.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[C:33](B(O)O)=[CH:32][C:31]([CH3:37])=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:33]5[C:28]([O:27][CH3:26])=[N:29][CH:30]=[C:31]([CH3:37])[CH:32]=5)[CH:3]=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Reactant: COc1ncc(C)cc1B(O)O
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: COCCOC
Product: COc1ncc(C)cc1-c1cc(C)cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)n1
Temperature: 120 °C
Yield: 99.2 %

Procedure:
To a mixture of N-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (60 mg, 0.16 mmol) and 2-methoxy-5-methylpyridin-3-ylboronic acid (41 mg, 0.25 mmol) in DME (2 mL) and Na2CO3 (2M, 0.165 mL, 0.32 mmol) was added Pd(PPh3)4 (9.5 mg, 0.008 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The reaction was re-partitioned between EtOAc and H2O and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (0-20% EtOAc-Hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (72 mg, 97%). 1H NMR (400 MHz, CDCl3) 7.98 (s, 1H), 7.96 (dd, J=0.7, 2.4 Hz, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.68 (s, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.23 (dd, J=1.7, 9.4 Hz, 2H), 7.10 (d, J=8.2 Hz, 1H), 3.96 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H), 1.77-1.70 (m, 2H), 1.19-1.11 (m, 2H). Retention time: 2.01 min; ESI-MS m/z calc. 453.4. found 454.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]([NH:14][C:15]2[NH:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[C:18]([CH3:20])[N:19]=2)=[O:13])[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].[NH4+].[Cl-]>C(Cl)Cl>[C:38]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]([NH:14][C:15]2[NH:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[C:18]([CH3:20])[N:19]=2)=[O:13])[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1)(=[O:40])[CH3:39]
Reactant: Cc1nc(NC(=O)c2cc(CN)cnc2C(F)F)[nH]c1-c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cnc(C(F)F)c(C(=O)Nc2nc(C)c(-c3ccc(C(F)(F)F)cc3)[nH]2)c1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Dissolve 5-(aminomethyl)-2-(difluoromethyl)-N-[4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]pyridine-3-carboxamide (0.047 g, 0.110 mmol) in DCM (3 mL). Add triethylamine (0.038 mL, 0.276 mmol) followed by acetyl chloride (9.830 μL, 0.138 mmol), and stir overnight. Pour the reaction into saturated aqueous NH4Cl (15 mL) solution, and extract with EtOAc (2×10 mL). Combine the organic extracts; dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to dryness to give the title compound (0.039 g, 75% yield) as a light yellow solid. LCMS (m/z) 468 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Br:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:14]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Br:12])=[C:10]([Cl:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(Br)ccc(N)c1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1c(C)c(N)cc(Cl)c1Br
Temperature: 60 °C
Reaction time: 15 h
Yield: 95.9 %

Procedure:
To a solution of methyl 3-amino-6-bromo-2-methylbenzoate (960 mg, 3.93 mmol) in acetonitrile (40 mL) was added N-chlorosuccinimide (525 mg, 3.93 mmol) under ice-cooling, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→30/70) to give the title compound (1.05 g, yield 96%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1.O[CH:39]1[CH:44]2[CH2:45][CH2:46][N:41]([CH2:42][CH2:43]2)[CH2:40]1>O1CCCC1>[N:41]12[CH2:46][CH2:45][CH:44]([CH2:43][CH2:42]1)[CH:39]([O:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1)[CH2:40]2
Reactant: OC1CN2CCC1CC2
Reactant: Oc1ccon1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OC2CN3CCC2CC3)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.2 %

Procedure:
A solution of 9.18 g of triphenylphosphine in 100 ml of tetrahydrofuran was cooled to 5° C. 6.10 g of diethyl azodicarboxylate were then added dropwise to the cooled solution, after which 2.98 g of 3-hydroxyisoxazole and 4.45 g of 3-hydroxyquinuclidine were added, and the resulting mixture was stirred at room temperature for 24 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to afford 5.18 g (yield 76.2%) of the title compound as a colorless powder, melting at 80°-81° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C1COCC1>[CH2:3]([O:5][C:6]([C:8]1[N:9]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 30 °C

Procedure:
To a stirred suspension of sodium hydride (3.7 g, 120 mmol, 80% in paraffin oil) in dry THF (75 mL), a solution of indol-2-carboxylic acid ethyl ester (18.9 g, 100 mmol) in dry THF (75 mL) was added in 1 hour with stirring while the inner temperature was maintained under 30° C. The reaction mixture was stirred for 30 minutes and then a solution of p-toluenesulphonyl chloride (22.9 g, 120 mmol) in dry THF (75 mL) was added dropwise to the stirring reactant. After 2 hours stirring at room temperature and 1 hour at 45° C. the solvent was evaporated in vacuo and the residue partitioned between water and ethyl ether. The organic phase was dried over MgSO4 and the solvent evaporated to leave a solid which was recrystallized from diisopropyl ether (26.8 g, 78%), mp 92°-950° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:23])=[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH:31]1([C:36](Cl)=O)[CH2:35][CH2:34][CH2:33][CH2:32]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:8][C:7]1[C:2]2[N:1]=[C:36]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:23][C:3]=2[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])=[C:5]([F:9])[CH:6]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(N)c2O)c1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(C4CCCC4)oc23)c1=O
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
0.48 g of 3-[3-amino-4-chloro-6-fluoro-2-hydroxyphenyl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (from intermediate 7) was initially charged with 0.14 g of triethylamine in 30 ml of absolute xylene, and the mixture was, at 0° C., admixed dropwise with 0.18 g of cyclopentanecarbonyl chloride. After 10 minutes, the mixture was warmed to 20° C., 0.1 g of pyridinium p-toluenesulfonate was added and the mixture was heated at reflux for six hours. After cooling, the xylene phase was washed three times with 30 ml of water each time, dried over sodium sulfate and freed from the solvent under reduced pressure. The crude product was purified by medium pressure liquid chromatography (MPLC); mobile phase: cyclohexane/ethyl acetate (9:1). Yield: 0.27 g;
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].C([O-])([O-])=O.[K+].[K+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[C:6]([O:8][CH3:9])=[O:7])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc[nH]1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccn1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 36 h
Yield: 86.5 %

Procedure:
Methyl 1H-pyrrole-2-carboxylate (330 mg, 2.64 mmol) was dissolved in anhydrous DMF (8 mL). Solid K2CO3 (547 mg, 3.96 mmol) was added, followed by the addition of 1-chloro-4-(chloromethyl)benzene (638 mg, 3.96 mmol). The reaction was permitted to stir at 60° C. for 36 h, at which time the reaction was allowed to cool to rt. Water was added and the resulting precipitate was isolated over a filter, and dried under high vacuum overnight to give 570 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].N1C=CC=CC=1.Cl[C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:22]>ClCCl>[OH:13][C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:10][CH:11]=[CH:12][C:2]=1[NH:1][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:22]
Reactant: O=C(Cl)C1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)c1cccc(N)c1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)C2CCCN2C(=O)OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a stirred solution of ethyl 3-amino-2-hydroxybenzoate (0.601 g, 3.6 mmol) and pyridine (0.633 g, 8 mmol) in anhydrous dichloromethane (20 mL) was added dropwise a solution of benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate (1.12 g, 4 mmol) in anhydrous dichloromethane (5 mL). After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water (30 mL×3), 1N hydrochloric acid (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give benzyl 2-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)pyrrolidine-1-carboxylate (1.43 g). LC-MS (ESI) m/z: 399 (M+1)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17](OCCCC)=[O:18])[O:14][C:13]3=[O:24])=[CH:11][C:6]=2[S:5][C:4]1=[O:25])[CH3:2].[NH3:26]>CO>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([NH2:26])=[O:18])[O:14][C:13]3=[O:24])=[CH:11][C:6]=2[S:5][C:4]1=[O:25])[CH3:2]
Reactant: N
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3CC)C(=O)O1
Solvent: CO
Product: CCn1c(=O)sc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The butyl (5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 3, 500 mg, 1.37 mmol) is treated with 7N ammonia in MeOH (14 mL) with vigorous stirring, and the mixture is diluted with additional MeOH (20 mL) and stirred at ambient temperature for 30 mins. The resulting slurry is filtered to give the title compound, mp 211-212.5° C.; MS (ESI+) for C13H13N3O4S m/z 308 (M+H)+; [α]25D−25 (c 0.92, DMSO).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[NH:10]([C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:32])[C:21]=2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH:10]([C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:32])[C:21]=2[C:20]([NH:5][C:4]2[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[CH:3]=2)=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(Nc3ccccc3)c3c2C(=O)c2ccccc2C3=O)cc1
Reactant: Cc1cc(C)cc(N)c1
Product: Cc1cc(C)cc(Nc2ccc(Nc3ccccc3)c3c2C(=O)c2ccccc2C3=O)c1
Yield: 56 %

Procedure:
1-anilino-4-(3,5-dimethylanilino)anthraquinone was prepared by reaction of 3,5-dimethylaniline with 1-(anilino)-4-tosyloxyanthraquinone. The isolated and purified reaction product has the structure illustrated below. ##STR15## The yield was 56% and m.p. 219.5°-220.5° C. Mass spectrum, m/e 418 (M+); 1H-NMR (CD2Cl2)δ12.20 (br s, 2H), 8.41-8.30 (m, 2H) 7.80-7.69 (m, 2H), 7.52-7.34 (m, 7H), 6.90 (br s, 3H), 2.32 (s, 6H); UV/VIS max (Xylenes) 404 nm (ε6 600), 600 (13 400), 641 (14 400).