Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO.C1COCC1>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[N:22]=[CH:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
785 mg (1.5 mmol) of 2-[5-(1-trityl-1H-imidazol-4-yl)pent-4-enyl]isoindole-1,3-dione, 10 ml of a MeOH/THF mixture (6/4) and 392 mg of 10% Pd/C are introduced into a Parr bomb. The reaction medium is stirred at room temperature under a hydrogen pressure of 5 bar. After 4 hours, the reaction medium is filtered through Celite and concentrated. The crude product obtained is chromatographed on silica gel (eluent: heptane/EtOAc (5/5) and then CH2Cl2/MeOH (9/1)). 380 mg of 2-[5-(1-trityl-1H-imidazol-4-yl)pentyl]isoindole-1,3-dione in the form of a white powder are obtained in a yield of 48%.
Reaction SMILES: S(=O)(=O)(O)O.O[CH2:7][S:8]([CH2:11][CH2:12][Cl:13])(=[O:10])=[O:9].[Cl:14][C:15]1[C:23]([NH2:24])=[CH:22][C:21]([Br:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>C(#N)C>[Cl:14][C:15]1[C:23]([NH:24][CH2:7][S:8]([CH2:11][CH2:12][Cl:13])(=[O:10])=[O:9])=[CH:22][C:21]([Br:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: Nc1cc(Br)cc(C(=O)O)c1Cl
Reactant: O=S(=O)(CO)CCCl
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: O=C(O)c1cc(Br)cc(NCS(=O)(=O)CCCl)c1Cl
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 63.9 %

Procedure:
1 ml of concentrated sulfuric acid, followed by 9.6 g (60 mmoles) of hydroxymethyl-(β-chloroethyl)-sulfone were added at 60° C, whilst stirring, to a filtered solution of 12.6 g (50 moles) of 2-chloro-5-bromo-3-aminobenzoic acid in 150 ml of hot acetonitrile. The mixture was stirred for a further 2.5 hours at 50° C and was then cooled to 10° C, and the product which had precipitated was filtered off. It was rinsed with water and dried in air. 15 g (77% of theory) of 2-chloro-5-bromo-[(β-chloroethyl)-sulfonylmethylamino]-benzoic acid were obtained in the form of a yellow powder of melting point 164° C (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][CH:19]=CC=1.C1(N)CC1>C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:16][CH:21]1[CH2:19][CH2:20]1)=[O:6]
Reactant: O=C(O)c1ccc(I)cc1Cl
Reactant: c1ccncc1
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(I)cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-iodobenzoic acid (3.31 g, 11.7 mmol) was dissolved in ethyl acetate (23 ml), admixed with one drop of N,N-dimethylformamide and thionyl chloride (6.96 g, 59.0 mmol), and heated under reflux overnight. The cooled suspension was concentrated under reduced pressure and taken up in dichloromethane (60 ml). The solution was cooled to 0° C., and pyridine (925 mg, 11.7 mmol) and cyclopropylamine (668 mg, 11.7 mmol) were added dropwise. The reaction mixture was warmed up to room temperature and stirred overnight. Then it was washed with hydrochloric acid (1 M), dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N:11]1([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:26][S:23]([C:20]2[CH:19]=[CH:18][C:17]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:22][CH:21]=2)(=[O:24])=[O:25])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc(N2CCOCC2)cc1
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorophenylisocyanate (2.61 g, 17 moles) was dissolved in 16 ml of acetone and was then added dropwise to the sulfonamide solution. The mixture was then stirred overnight at room temperature, resulting in the formation of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:54])[CH2:24][NH:25][C:26](=[O:53])[CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:45]C(OC(C)(C)C)=O)=[N:37]C(OC(C)(C)C)=O)=[CH:31][CH:30]=2)[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:55])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.Cl>C(OCC)(=O)C.CO>[Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:54])[CH2:24][NH:25][C:26](=[O:53])[CH:27]=[CH:28][C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:36]([NH2:45])=[NH:37])=[CH:33][CH:34]=2)[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:55])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc4)c3Cl)c2n1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=N)N)cc4)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.5 %

Procedure:
To a solution of 8-[2,6-dichloro-3-[N-[4-[2,3-bis(tert-butoxycarbonyl)guanidino]cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylquinoline (51 mg) in ethyl acetate and methanol was added 4N solution of hydrogen chloride in methanol (0.5 ml), and themixture was stirred for 2 days at ambient temperature. The mixture was concentrated in vacuo, and the residuewas dissolved in methaol. The solution was adjusted to pH 7 to 8 with aqueous ammonia and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol-aqueous ammonia) to give 8-[2,6-dichloro-3-[N-(4-guanidinocinnamoylglycyl)-N-methylamino]benzyloxy]-2-methylquinoline (12 mg) as amorphous powder.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([CH:13]=[O:14])[C:6]=1[Cl:15])(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>>[C:1]([O:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=[C:7]([CH:13]=[O:14])[C:6]=1[Cl:15])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C=O)c(Cl)c1OC(C)=O
Product: COc1c([N+](=O)[O-])cc(C=O)c(Cl)c1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
38 g of 2-chloro-3-formyl-6-methoxyphenyl acetate are introduced portionwise at -5° to -10° within 15 minutes into 150 ml of 98 percent nitric acid. After stirring at -5° for 30 minutes the reaction mixture is poured into 1.5 l of ice-water and extracted three times with 500 ml of methylene chloride. The combined organic phases are washed with ice-water, dried over sodium sulfate and evaporated. The residue is crystallized from ether. There is obtained 2-chloro-3-formyl-6-methoxy-5-nitrophenyl acetate of m.p. 84°-85°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH2:17])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH:17][C:30]([NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Br:22])=[O:31])(=[O:12])=[O:13])[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccccc1NS(=O)(=O)c1cccc2cccnc12
Product: O=C(Nc1ccccc1Br)Nc1ccccc1NS(=O)(=O)c1cccc2cccnc12
Yield: 46.2 %

Procedure:
The urea was synthesized from 2-((8-quinolinyl) sulfonyl amino) aniline(1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.23 g, 46%).EI-MS m/z 495(M−H)−.
Reaction SMILES: CCOCC.Cl[C:7]1[N:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1.[NH2:18][C:19]1[CH:20]=[N:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:23]=1.C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].ClCCCl.CC(O)(C)C>[Cl:13][C:11]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=[C:7]([NH:18][C:19]2[CH:20]=[N:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:23]=2)[N:12]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)n1cc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 1.0 M solution of zinc chloride in Et2O (4.0 mL, 4.0 mmol) was added to 2,4-dichloro-5-trifluoromethylpyrimidine (0.49 mL, 3.6 mmol) in a 1:1 mixture of DCE/t-BuOH (40 mL) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 1 hour before tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.606 g, 3.31 mmol) and triethylamine (0.51 mL, 3.7 mmol) in a 1:1 mixture of DCE/t-BuOH (30 mL) was added. The mixture was allowed to warm to room temperature and stirred for 20 hours before concentrating in vacuo and adding gradually to 100 mL water. The resulting precipitate was removed by vacuum filtration and washed with DCM. The filtrate was purified using silica gel column chromatography (0-30% EtOAc in DCM) to give the title compound A61 (0.170 g, 14%). LCMS-D: rt 3.622 min; m/z 362.1 [M−H]−.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:17])[C@:10]2([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:9]1)=[O:7])(C)(C)C.[CH2:31]([O:38][CH2:39][CH:40]([NH:44][C:45](=[O:57])[C:46]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])([CH3:48])[CH3:47])C(O)=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>>[C:53]([O:52][C:50](=[O:51])[NH:49][C:46]([C:45](=[O:57])[NH:44][C@H:40]([CH2:39][O:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:20])([F:21])[F:22])[C:16](=[O:17])[C@:10]2([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:9]1)=[O:7])([CH3:48])[CH3:47])([CH3:54])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)[C@]2(Cc2ccccn2)C1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)NC(COCc1ccccc1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)[C@]2(Cc2ccccn2)C1

Procedure:
reacting said 1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester with 3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionic acid in the presence of a tertiary amine and 1-propanephosphonic acid cyclic anhydride in a reaction inert solvent to form (1-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester, and
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:4]=1.C(N(CC)CC)C.[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1S>C(O)CCC>[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[N:20]1[CH2:21][CH2:22][N:17]([C:5]2[N:4]=[C:3]([NH2:2])[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=2)[CH2:18][CH2:19]1
Reactant: Sc1nc2ccccc2o1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4nc5ccccc5o4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.2 %

Procedure:
To a suspension of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride (3.26 g) in 250 ml of butanol, 1.01 g of triethylamine was added. The mixture was stirred at room temperature for 2 hr and 1.51 g of benzoxazole-2-thiol was added. The mixture was refluxed for 72 hr and evaporated. The solids were triturated with water and filtered to give 2.7 g of crude product. This was chromatographed over silica gel using 7% methanolmethylene chloride as eluent. Appropriate fractions were mixed together to give 0.25 g of the title compound, which was crystallized from hexanemethylene chloride; mp >250° C.; ir (nujol mull) 3420, 3320 and 3200 cm-1 ; uv max (MeOH) 341 (ε=6,650), 282 (ε=28,900), 278 (ε 29,300) and 252 nm (ε=73,000); and Anal. Calcd for C21H22N6O3 : C, 62.06% H, 5.45% N, 20.68% and Found: C, 61.38% H, 5.59% N, 20.78%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([O:20]CC)=[O:19])[NH:6]2>[OH-].[Na+]>[Cl:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([OH:20])=[O:19])[NH:6]2
Reactant: CCOC(=O)c1cc2c(Cl)c(Oc3ccccc3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2c(Cl)c(Oc3ccccc3)ccc2[nH]1

Procedure:
Ethyl 4-chloro-5-phenoxyindole-2-carboxylate (0.302 g, 0.956 mmol) was hydrolysed in methanolic NaOH (3.2M, 1.7 mL) at reflux, for 1.5 hr After work-up, the product: 4-chloro-5-phenoxyindole-2-carboxylic acid was obtained as an almost white solid, 0.275 g (ca 100%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br)#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19])#[N:22]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: N#Cc1cccc(CBr)c1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cccc(C#N)c2)c(=O)[nH]c1=O
Yield: 53.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (207 mg, yield: 53.4%).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:5]([O:22][C:23]2[CH:24]=[C:25]([CH:34]=[CH:35][C:36]=2[Cl:37])[C:26]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[O:27])=[CH:6][C:7]([NH:10][C:11]2[S:15][N:14]=[C:13]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]=2)=[N:8][CH:9]=1.CCN(C(C)C)C(C)C.[C:47](Cl)(=[O:49])[CH3:48]>CN(C=O)C>[C:47]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[N:12]=[C:11]([NH:10][C:7]3[CH:6]=[C:5]([O:22][C:23]4[CH:24]=[C:25]([CH:34]=[CH:35][C:36]=4[Cl:37])[C:26]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[O:27])[C:4]([Br:3])=[CH:9][N:8]=3)[S:15][N:14]=2)[CH2:17][CH2:18]1)(=[O:49])[CH3:48]
Reactant: CN(C)CCNC(=O)c1ccc(Cl)c(Oc2cc(Nc3nc(C4CCNCC4)ns3)ncc2Br)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2nsc(Nc3cc(Oc4cc(C(=O)NCCN(C)C)ccc4Cl)c(Br)cn3)n2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 5.9 %

Procedure:
3-(5-Bromo-2-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)pyridin-4-yloxy)-4-chloro-N-(2-(dimethylamino)ethyl)benzamide dihydrochloride (0.12 g, 0.18 mmol) was dissolved in DMF (2 mL) and the solution was cooled to 0° C. DIEA (0.13 mL, 0.73 mmol) was added followed by acetyl chloride (0.017 mL, 0.24 mmol). The solution was warmed to ambient temperature. After 15 minutes, the solution was quenched with water, extracted with EtOAc, dried, and concentrated. HPLC purification gave the title compound (0.0066 g, 6%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.69-1.76 (m, 1H), 1.81-1.88 (m, 1H), 1.86-2.12 (m, 2H), 2.04 (s, 3H), 2.26 (s, 6H) 2.60 (t, 2H), 2.78-2.85 (m, 1H), 2.95-3.04 (m, 1H), 3.13-3.21 (m, 1H), 3.54-3.60 (m, 2H), 3.78-3.84 (m, 1H), 4.41-4.46 (m, 1H), 6.15 (s, 1H), 7.40 (s, 1H), 7.53 (d, 1H), 7.59-7.64 (m, 3H), 8.49 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[CH3:28])[CH:15]=[C:16]([O:19]C)[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:29].ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(O)C=2)CCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[CH3:28])[CH:15]=[C:16]([OH:19])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:29]
Reactant: COc1cc(-c2ccc(F)cc2C)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Product: Cc1cc(F)ccc1-c1cc(O)cc2c1CCC(=O)N2c1c(Cl)cccc1Cl

Procedure:
1-(2,6-Dichlorophenyl)-3,4-dihydro-5-(4-fluoro-2-methylphenyl)-7-hydroxy-2(1H)-quinolinone was prepared from 1-(2,6-dichlorophenyl)-3,4-dihydro-5-(4-fluoro-2-methylphenyl)-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 12) by a procedure analogous to that described in INTERMEDIATE 3. Mass spectrum (ESI) 416.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.56 (m, 3H); 7.44 (m, 1H); 7.37 (m, 1H); 7.02 (m, 2H); 6.76 (s, 1H); 6.58 (d, J=10 Hz, 1H); 6.01 (s, 1H); 3.73 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>CCOC(C)=O.O.C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: OC1CCCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCCCCC2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
Add 6-chloro-pyridin-3-ol (2 g, 15.4 mmol), cycloheptanol (1.93 g, 17 mmol), tri-n-butylphosphine (4.67 mL, 19.3 mmol), and ADDP (4.87 g, 19.3 mmol) to THF (60 mL) at 0° C. under a nitrogen atmosphere. Stir the mixture at 0° C. for 1 h and at room temperature for 12 h. Dilute with EtOAc (50 mL), add water (50 mL) and separate the layers. Extract the aqueous layer with EtOAc (4×30 mL). Wash the combined organic extracts with water (30 mL) and brine (20 mL). Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (120 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 1.25 h, 80 mL/min) to obtain the desired intermediate as a colorless oil (2.36 g, 68%). MS (APCI+) m/z: 226 (M H)+.
Reaction SMILES: [C:1]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCBr
Reactant: OCc1cccc2ccccc12
Product: BrCCCCCOCc1cccc2ccccc12

Procedure:
1-Naphthalenemethanol (6.00 g) and 1,5-dibromopentane (11.5 ml) were treated according to the method of Intermediate 1. FCC eluting with ether-cyclohexane (1:49→2:48) gave the title compound as a colourless oil (8.41 g), t.l.c. (Cyclohexane-ether 19:1) Rf 0.22;
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH:13]=2)[N:8]([C:23]2[CH:28]=[CH:27][C:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:25][CH:24]=2)[C:7]=1[CH2:34][C:35]([O:37]CC)=[O:36])=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[C:35]([CH2:34][C:7]1[N:8]([C:23]2[CH:24]=[CH:25][C:26]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[CH:27][CH:28]=2)[C:9]2[C:14]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:13][C:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)=[CH:11][CH:10]=2)([OH:37])=[O:36]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(Cl)c3)ccc2n1-c1ccc(N(CC)CC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(-n2c(CC(=O)O)c(C(=O)O)c3cc(Oc4cccc(Cl)c4)ccc32)cc1

Procedure:
A mixture of 5-(3-chlorophenoxy)-1-(4-diethylaminophenyl)-2-ethoxycarbonylmethyl-indole-3-carboxylic acid ethyl ester (100 mg, 0.18 mmol, see step (a) above), NaOH (1 M in methanol, 2 mL, 2.0 mmol), NaOH (aq, 1 M, 2 mL, 2.0 mmol) and dioxane (2 mL) was stirred at reflux for 4 h, cooled, acidified to pH 4 with HCl (aq, 1 M) and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography. Yield 50 mg (56%), mp 186-191° C.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:32][NH2:33]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[CH:30]=[CH:29][N:28]=[C:27]([NH:32][NH2:33])[N:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccnc(Cl)n4)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccnc(NN)n4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 433, Step A, starting from 2-[(S)-1-Phenylethylamino]-4-[5-(2-chloropyrimidin-4-yl)benzimidazol-1-yl]pyrimidine and hydrazine. Mass spectrum (ESI) 424.3 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:5]([CH3:25])[CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[CH3:25][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[S:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:11])=[O:10])[C:1]#[N:2]
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCNCC1
Yield: 107.2 %

Procedure:
A solution of 1,1-dimethylethyl 4-[(4-cyano-2-methylphenyl)sulfonyl]-1-piperazinecarboxylate (may be prepared as described in Intermediate 8; 3.33 g, 9.11 mmol) and TFA (10 ml, 130 mmol) in dry dichloromethane (10 ml) was stirred at rt for 1 h, then concentrated in vacuo, azeotroping with toluene (25 ml) to give a brown oil. This was partitioned between DCM (50 ml) and sat. aq NaHCO3 (50 ml), then the aqueos layer extracted with DCM:EtOH (3:1, 40 ml). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to give the title compound (2.59 g) as a yellow oil. The product became a pale yellow solid on standing.