Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[N:2]1C(=O)CCC1=O.[Br:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([F:20])[C:11]=1[CH:12]=[N:13][OH:14].[NH4+].[OH-].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[Br:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([F:20])[C:11]=1[C:12]([NH:13][OH:14])=[NH:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1c(F)cc(Cl)cc1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N=C(NO)c1c(F)cc(Cl)cc1Br
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of N-chlorosuccinimide (8.34 g, 62.49 mmol) in DMF (25 ml) was added slowly to a solution of 2-bromo-4-chloro-6-fluoro-benzaldehyde oxime (15 g, 59.52 mmol) in DMF (50 ml) at 50° C. After completion of the addition, the reaction mixture was allowed to stir for 30 min at 50° C. The reaction mixture was then cooled to 3-5° C. and NH4OH (4.6 ml, 119 mmol) was added dropwise. During addition the temperature was maintained between 0-10° C. and the reaction mixture was stirred for another 15 minutes at the same temperature. EtOAc and brine were then added and the mixture was agitated vigorously for 10 minutes before the phases were allowed to settle. The aqueous layer was separated and extracted two times with EtOAc. The combined organic layers were dried with Na2SO4 and evaporated to obtain the title compound as off white solid (13 g, 82%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:31]1[S:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>CN1C(=O)CCC1>[S:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[NH:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: Clc1nc2ccccc2s1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(CNc2nc3ccccc3s2)cn(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (40 mg, 0.140 mmol), N,N-diisopropylethylamine (74.0 mg, 100 μL, 0.567 mmol) and 2-chlorobenzothiazole (31 mg, 0.181 mmol) in NMP (0.5 mL) was heated at 115° C. in a sealed tube. After 2 hr., LCMS indicated the desired product to be present with some remaining starting material and minor impurities. Heating continued overnight. In the morning, more 2-chlorobenzothiazole (12 mg, 0.070 mmol) was added. Heating continued for another 24 hr. The reaction mixture was concentrated under a stream of nitrogen, and the crude product was purified by preparative reverse phase HPLC. The desired product 3-(benzothiazol-2-ylaminomethyl)-7-chloro-1-phenyl-1H-quinolin-4-one (13 mg, 22%) was obtained an off-white solid. MS calcd. for C23H16ClN3OS [(M+H)+] 418.1, obsd. 418.
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23]C)=[CH:20][CH:21]=3)[C:16]3[C:25](=[O:30])[C:26](=[O:29])[O:27][CH2:28][C:15]2=3)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>C(Cl)Cl>[C:5]([C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[C:16]3[C:25](=[O:30])[C:26](=[O:29])[O:27][CH2:28][C:15]2=3)=[CH:11][CH:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: COc1ccc2c(c1)c1c(n2Cc2ccc(C(C)(C)C)cc2)COC(=O)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)c1ccc(Cn2c3c(c4cc(O)ccc42)C(=O)C(=O)OC3)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 36.4 %

Procedure:
Boron tribromide (2.2 mL, 23.3 mmol) was added dropwise to a stirring suspension of 9-(4-tert-Butylbenzyl)-6-methoxy-1,9-dihydropyrano[3,4-b]indole-3,4-dione (4.92 g, 13.0 mmol) in methylene chloride (25 mL) at −78° C. under a nitrogen atmosphere over a period of 20 minutes. The mixture was then warmed up to room temperature. After stirring at room temperature for 6.5 hours, the reaction mixture was carefully quenched with a small amount of water and the evaporated to dryness. The residue was stirred in ether and filtered to afford a brown solid. Crystallization from aqueous methanol afforded the title compound as a brown solid (1.72 g). Mass spectrum (ESI, [M−H]−) m/z 362. 1HNMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 7.44 (d, 1H, J=8.85 Hz), 7.40 (d, 1H, J=2.29 Hz), 7.34 (d, 2H, J=8.25 Hz), 6.80 (dd, 1H, J=8.86 and 2.29 Hz), 5.84 (s, 2H), 5.37 (s, 2H), 1.22 ppm (s, 9H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].OS(O)(=O)=O.[CH3:18]O>>[CH3:18][O:11][C:10]([CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:12]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1Cc2ccccc2C1
Yield: 95 %

Procedure:
Indan-2-carboxylic acid (2.0 g, 12.34 mmol) was dissolved in MeOH (50 mL) and was then treated with H2SO4 (1 mL). The reaction mixture was refluxed overnight. MeOH was evaporated and the residue was diluted with water and ether. Layers were separated and the aqueous layer was extracted with ether (2×30 mL). The combined organics were dried with MgSO4 and condensed to afford the product (2.01 g, 95%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:36]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([CH2:28][CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:36][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:7][CH:8]=1)[C:14]([N:16]([CH2:28][CH:29]([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CCOC(CN(Cc1ccnc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: C1CCNCC1
Product: CCOC(CN(Cc1ccnc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Yield: 97.6 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (S)-(9H-fluoren-9-yl)methyl 3-(4-tert-butoxyphenyl)-1-((2,2-diethoxyethyl)(quinolin-4-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-4) (358 mg, 0.5 mmol) was treated with piperidine and the obtained residue was purified on silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (241 mg, 95%).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H].[N-]=C=O>O1CCOCC1.C(N(CC)CC)C>[CH:1]1([NH:7][CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C=NC1CCCCC1
Agent: [N-]=C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=CNC1CCCCC1
Temperature: -15 °C
Yield: 83.5 %

Procedure:
A solution of cyclohexyl isocyanate (1.25 g.; 0.01 mole) in 100 ml. anhydrous 1,4-dioxane containing two drops of anhydrous triethylamine was mixed with 0.5 gram 10% Pd-on-carbon and shaken at a pressure of 50 p.s.i. of hydrogen on a Parr low pressure hydrogenator. The uptake of hydrogen was complete in two hours. Work up, as in Example 1, gave 1.15 g. of colorless oil containing a trace of isocyanate. The product was purified by slurrying the oil with Skellysolve B, chilling at -15° C. and decanting the supernatant from the crystalline formamide. After drying under high vacuum, the weight of title product was 1.06 g. (83.5% yield). The ir, nmr and glc were identical to an authentic sample.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:47])[CH2:34][CH2:35][NH:36]C(OCC1C=CC=CC=1)=O)=[O:25])C1C=CC=CC=1.[C:48]([OH:51])(=[O:50])[CH3:49].[H][H].CCOCC>C(O)C.[C].[Pd]>[C:48]([OH:51])(=[O:50])[CH3:49].[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:47])[CH2:34][CH2:35][NH2:36])=[O:25]
Reactant: O=C(CCNC(=O)OCc1ccccc1)NCCCCCNC(=O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: NCCC(=O)NCCCCCNC(=O)Cc1ccc(O)cc1O
Reaction time: 4 h

Procedure:
To a solution (20 ml) of 1-(2,4-dibenzyloxyphenylacetyl)amino-5-(3-benzyloxycarbonylaminopropionyl)aminopentane (440 mg) in ethanol are added 10 % palladiumcarbon (70 mg) and acetic acid (0.01 ml) and catalytic reduction is conducted in a hydrogen stream at room temperature under atmospheric pressure. After four hours, the catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. To the glass-like product obtained is added ether to digest into powder. The resulting product is filtered and dried to yield 1-(2,4-dihydroxyphenylacetyl)amino-5-(3-aminopropionyl)aminopentane acetate (209 mg).
Reaction SMILES: COCCOCCOC.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]([CH3:19])[CH3:18].[OH:21][C:22]1[CH:31]=[C:30]([OH:32])[CH:29]=[C:28]2[C:23]=1[C:24](=[O:35])[CH2:25][C:26]([CH3:34])([CH3:33])[O:27]2>[I-].[K+]>[OH:21][C:22]1[CH:31]=[C:30]([O:32][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:29]=[C:28]2[C:23]=1[C:24](=[O:35])[CH2:25][C:26]([CH3:33])([CH3:34])[O:27]2
Reactant: CC1(C)CC(=O)c2c(O)cc(O)cc2O1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CC(C)COc1cc(O)c2c(c1)OC(C)(C)CC2=O
Temperature: 100 °C
Yield: 79 %

Procedure:
In 50 ml of diethylene glycol dimethylether (DIGLIM) 4.2 g (20 millimoles) of 5,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 3.0 g (22 millimoles) of potassium carbonate and 0.2 g of potassium iodide and thereafter 3.3 g (2.6 ml, 24 millimoles) of isobutyl bromide are added. The reaction mixture is heated at 100° C. for 10 hours and worked up according to Example 19. Thus 4.1 g of the desired compound are obtained, yield 79%. Mp.: 77°-79° C.
Reaction SMILES: [ClH:1].[CH2:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH2:6]1)[CH2:3][CH3:4].[CH2:18](Br)[CH:19]=[CH2:20].[OH-].[Na+].Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[ClH:1].[CH2:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:20][CH:19]=[CH2:18])[CH:12]=2)[CH2:6]1)[CH2:3][CH3:4]
Reactant: C=CCBr
Reactant: CCCN1CCCC(c2cccc(O)c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: C=CCOc1cccc(C2CCCN(CCC)C2)c1
Temperature: 25 °C

Procedure:
(-)N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrochloride (0.255 g, 1 mmol) and tetrabutylammonium hydrogen sulphate (0.340 g, 1 mmol) were suspended in dichloromethane (2 ml) and allylbromide (0.133 g, 1.1 mmol). 2-M NaOH (2 ml) was added during two minutes and the mixture was stirred at room temperature for half an hour. The layers were separated and the organic layer was dried over Na2SO4. After removal of the solvent by distillation, the residual oil was dissolved in ether (50 ml). A theoretical quantity of tetrabutylammonium iodide was precipitated. The precipitate was filtered off and to the filtrate was added one equivalent HCl-saturated ether. White crystals of the desired compound was obtained. The crystals were filtered, washed on the filters with ether and dried. Yield 190 mg (65%). Mp. 136°-138° C. [α]20D (C=1.5 MeOH) (-)7.6° .
Reaction SMILES: [Cl:1]C1SC(C2C=CC=CC=2)=NN=1.N[C:14]1[S:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=1>>[Cl:1][C:14]1[S:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]=1
Reactant: Clc1nnc(-c2ccccc2)s1
Reactant: Nc1nc(-c2ccccc2)ns1
Product: Clc1nc(-c2ccccc2)ns1

Procedure:
Was prepare in the same manner as 2-Chloro-5-phenyl-1,3,4-thiadiazole, from 5-amino-3-phenyl-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]([F:27])=[CH:20][C:21]=3F)[N:16]=2)[CH:12]=[C:11]([CH3:28])[N:10]=1.O>CN(C=O)C.C(O)(=O)C>[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]([F:27])=[CH:20][C:21]=3[O:5][CH2:4][CH2:3][O:2][CH3:1])[N:16]=2)[CH:12]=[C:11]([CH3:28])[N:10]=1
Reactant: COCCO
Reactant: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COCCOc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxyethanol (2.65 g, 34.8 mmol) in DMF (38 mL) was added sodium hydride (60% suspension in mineral oil, 0.70 g, 17.4 mmol) in portions and the reaction mixture was stirred at room temperature for 0.5 hours. To this mixture was added 2-(2,6-dimethylpyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (0.50 g, 1.74 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water (1.5 mL) was added, the mixture was neutralized to pH approximately 6-7 with acetic acid, concentrated, dissolved in ethyl acetate (200 mL), washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was washed with hexanes to give 2-(2,6-dimethylpyridin-4-yl)-7-fluoro-5-(2-methoxyethoxy)-3H-quinazolin-4-one) as a pale solid. Yield: 0.52 g (87%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].[CH2:28]([S:32](Cl)(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31]>C1COCC1.C(OCC)(=O)C>[CH2:28]([S:32]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)(=[O:24])=[O:23])(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reactant: CCCCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCS(=O)(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Reaction time: 0.17 h

Procedure:
Crude 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (prepared according to the procedure described in Example 10(c) above) was dissolved in THF (3 mL) under N2 (g). NaOH (1.0 mL, 1M, 1.0 mmol) was added to the mixture, which was then stirred for 10 min. Butanesulfonyl chloride (45 μL, 0.35 mmol) was then added, and the mixture was stirred for 24 h at room temperature. The reaction mixture was then diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried over MgSO4 and the solvent was removed in vacuo. The crude product was recrystallised from acetone to yield the title compound (31.7 mg, 0.064 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:20][N:21]([CH3:23])[CH3:22])[N:3]=1.[C:24]([Cu])#[N:25]>CS(C)=O>[CH3:22][N:21]([CH2:20][C:4]1[N:3]=[C:2]([C:24]#[N:25])[C:11]2[C:6]([C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH3:23]
Reactant: COc1ccc2c(Cl)nc(CN(C)C)c(-c3ccccc3)c2c1
Reactant: N#C[Cu]
Solvent: CS(C)=O
Product: COc1ccc2c(C#N)nc(CN(C)C)c(-c3ccccc3)c2c1
Reaction time: 3 h

Procedure:
A mixture of 1-(1-chloro-6-methoxy-4-phenylisoquinolin-3-yl)-N,N-dimethylmethanamine (31 mg), 1 mL DMSO, and 16 mg CuCN was stirred at 140 C for 3 h. The solution was cooled and purified directly by reverse-phase HPLC to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:25]C(=O)OC(C)(C)C)[CH:20]=[C:21]([F:24])[CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([OH:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][N:15]2[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH2:13][CH3:14])[C:9]([CH3:11])([OH:12])[CH3:10]
Reactant: CCC(c1ccc(Cl)cc1)(n1ccc2c(NC(=O)OC(C)(C)C)cc(F)cc21)C(C)(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(c1ccc(Cl)cc1)(n1ccc2c(N)cc(F)cc21)C(C)(C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 1-(3-(4-chlorophenyl)-2-hydroxy-2-methylpentan-3-yl)-6-fluoro-1H-indol-4-ylcarbamate (250 mg, 0.543 mmol) and TFA/DCM (V/V=¼, 10 mL) was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in ethyl acetate (20 mL), pH value adjusted to 9˜10 with a saturated sodium bicarbonate solution, dried over sodium sulfate, then filtered. After removing the organic solvent, a crude compound was obtained without purification. LC/MS m/z=361.2 [M+H]+.
Reaction SMILES: C(OC([N:6]=[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:28][CH:29]([CH3:31])[CH3:30])=[N:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:32][CH3:33])[CH:11]=1)([CH3:9])=[O:8])=O)C.C(O)C.[O-]CC.[Na+]>ClCCl.CO>[CH:29]([NH:28][C:22]1[C:21]2[C:26](=[CH:27][C:18]([O:17][CH2:16][C:12]3[CH:11]=[C:10]([S:7]([CH3:9])(=[NH:6])=[O:8])[CH:15]=[CH:14][CH:13]=3)=[C:19]([O:32][CH3:33])[CH:20]=2)[N:25]=[CH:24][N:23]=1)([CH3:30])[CH3:31]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC(C)C)c3cc2OC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: COc1cc2c(NC(C)C)ncnc2cc1OCc1cccc(S(C)(=N)=O)c1
Temperature: 80 °C
Yield: 36 %

Procedure:
(RS)-N-(Ethoxycarbonyl)-S-[3-({[4-(isopropylamino)-6-methoxyquinazolin-7-yl]oxy}-methyl)phenyl]-S-methylsulphoximide (105 mg, 0.22 mmol) is introduced into 2.5 ml of ethanol. 1.0 ml of a 1-molar ethanolic sodium ethoxide solution is added and the mixture is heated to 80° C., until starting material is no longer present according to TLC checking (eluent dichloromethane/methanol 10:1). The reaction solution is concentrated in vacuo, and the residue is taken up in ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is dried over sodium sulphate and concentrated. The crude product is purified by preparative HPLC and the desired product is obtained in 36% yield (32 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:15]2[CH:16]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:18]=[C:13]([F:12])[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C#N
Reactant: OB(O)c1cc(F)cc(Oc2ccc(F)cc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(Oc3ccc(F)cc3)c2)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4,using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 3.0 grams (0.012 mole) of 3-fluoro-5-(4-fluorophenoxy)-phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(O) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-[3-fluoro-5-(4-fluorophenoxy)phenyl]-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)(=[O:23])=[O:22].Cl[C:33]1C=C(S(Cl)(=O)=O)C=C[C:38]=1Cl>>[CH2:33]([O:14][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)(=[O:22])=[O:23])[CH:4]=2)=[CH:17][CH:16]=1)[CH3:38]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)c2)cc1

Procedure:
4-[4-Chloro-3-(3,4-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=499.0 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(3,4-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][C:29](=[O:33])[NH:30]3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH3:16]>N1CCCCC1.C(O)C>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28](=[CH:12][C:9]4[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=4[CH3:11])[C:29](=[O:33])[NH:30]3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH3:16]
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(CCC(=O)O)c2C)c1
Yield: 105.5 %

Procedure:
3-(2-carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.6 mg), 127 mg 6-(3-ethoxyphenyl)-2-oxindole, and 2 drops piperidine in 2 mL ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 227 mg of the title compound (˜100%) as a brown solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36]1([CH2:42][N:41]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40]1)[O:35][CH2:34]2.C(N(CC)CC)C.[CH:57]([O:59]CCCC)=[CH2:58].Cl.C([O-])(O)=O.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[C:57]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36]1([CH2:42][N:41]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40]1)[O:35][CH2:34]2)(=[O:59])[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(Br)ccc12
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc2c(c1)COC21CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
In a scintillation vial containing 15 mL of ethanol was added Pd(OAc)2 (8.3 mg, 0.037 mmol) and DPPP (31 mg, 0.073 mmol). The reaction vessel was purged with argon, capped, and heated to 60° C. for 18 hours. To this was added tert-butyl 5′-bromo-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (250 mg, 0.74 mmol) and triethyl amine(0.21 mL, 1.5 mmol) and the mixture was heated to 90° C. for 5 minutes. Butyl vinyl ether (0.2 mL, 1.5 mmol) was added and the reaction mixture was heated to 90° C. for 4 hours under argon. The reaction mixture was cooled to room temperature and 1.0 N HCl (21 mL) was added and stirred for 2 h at RT. The reaction was neutralized with sat-NaHCO3 and extracted with EtOAc. The organic phase was concentrated and the residue was purified using 40 g Redi-Sep column, eluting with 0 to 40% ethyl acetate in heptanes, to yield 0.17 g of tert-butyl 5′-acetyl-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate. H-NMR (400 MHz, CDCl3) δ ppm 7.99 (d, 1H, J=8.0 Hz), 7.82 (s, 1H), 7.57 (d, 1H, J=8.0 Hz), 5.16 (s, 2H), 4.34 (d, 2H, J=9.5 Hz), 4.15 (d, 2H, J=9.5 Hz), 2.63 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1nnc(Br)c(-c2ccc(F)cc2)n1
Reactant: OB(O)c1cccc(Cl)c1
Product: Nc1nnc(-c2cccc(Cl)c2)c(-c2ccc(F)cc2)n1
Yield: 19.5 %

Procedure:
6-(3-Chlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (65.0 mg, 19%) was prepared from 6-bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.30 g, 1.11 mmol) and 3-chlorophenylboronic acid (0.19 g, 1.23 mmol) according to the general procedure of Example 1.