Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[N:19]=1)([OH:17])[CH2:13]2.[C:32]([NH:39][CH2:40][CH2:41][NH2:42])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]([C:18]1[N:19]=[C:20]([NH:42][CH2:41][CH2:40][NH:39][C:32](=[O:33])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:21]=[CH:22][CH:23]=1)([OH:17])[CH2:13]2
Reactant: OC1(c2cccc(Br)n2)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCNc1cccc(C2(O)CC3CCC(C2)N3C(c2ccccc2Cl)c2ccccc2Cl)n1
Temperature: 25 °C

Procedure:
Stir a solution of the product from Step 1 (64.5 mg, 0.128 mmol), N-Boc-ethylenediamine (123 mg, 0.77 mmol) and pyridine (12 mg, 0.154 mmol) at 110° C. in a sealed tube for 3.5 h. Cool to RT, add N-Boc-ethylenediamine (0.3 ml) and heat at 140° C. overnight. Cool to RT, quench the reaction with H2O, extract with EtOAc, dry and concentrate. Purify the residue by column chromatography to give the desired product.
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].[NH2:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:46]([NH:48][C@H:49]([C:55]([OH:57])=[O:56])[CH2:50][CH2:51][C:52](=[O:54])[NH2:53])=[O:47])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31].C(N(CC)CC)C>CN(C)C=O>[NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C@H:2]([C:7]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:46]([NH:48][C@H:49]([C:55]([OH:57])=[O:56])[CH2:50][CH2:51][C:52](=[O:54])[NH2:53])=[O:47])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.41 Grams of Z-Ile-OSu, the above-obtained H-Leu-Leu-Ala-Gln-OH and 0.36 ml of triethylamine were dissolved in 50 ml of dimethylformamide, then the mixture was stirred at a room temperature for 20 hours. After removal of dimethylformamide by distillation, 1N-citric acid was added to the residue, and crystals being precipitated were collected by filtration and washed with hot methanol to obtain 1.17 g of Z-Ile-Leu-Leu-Ala-Gln-OH.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:30]([O:29][C:27]([CH2:26][O:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[CH2:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[O:9][CH:7]([CH3:8])[C:6]([OH:37])=[O:5])=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-[2-(2-benzyloxycarbonylmethoxy-5-chloro-benzyl)-4-chloro-phenoxy]-propionic acid tert-butyl ester (1.736 g, 3.18 mmol) in DCM (10 mL) is treated with TFA (5 mL) and allowed to stir at RT for 1 hour. The solvent is removed in vacuo to yield the titled compound as an off-white solid.
Reaction SMILES: O[CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[SH:34]>ClCCl>[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[S:34][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1
Reactant: OCC1(CO)CCC1
Reactant: Cn1ccnc1S
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1ccnc1SCC1(CO)CCC1
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
To a solution of 1.0 g (8.6 mmol) of [1-(hydroxymethyl)cyclobutyl]methanol in 20 mL of dichloromethane was added 2.48 g (9.48 mmol) of triphenylphosphine and 2.18 g (9.48 mmol) of di-tertbutylazodicarboxylate. After 5 min of stirring, 1.03 g (9.05 mmol) of 1-methyl-2-mercaptoimidazole was added as a solid. After stirring for 2 h, the reaction was concentrated under vacuum and the residue was purified using silica gel chromatography eluting with ethyl acetate:hexane (3:7) to afford 1.3 g (71%) of (1-{[(1-methyl-1H-imidazol-2-yl)sulfanyl]methyl}cyclobutyl)methanol as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.95 (s, 1H), 6.87 (s, 1H), 6.54 (br s, 1H), 3.62 (s, 2H), 3.56 (s, 3H), 3.43 (s, 2H), 1.98-1.75 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1>>[C:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=3[F:19])=[CH:6][N:5]=2)[CH2:27][CH2:28]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2c(F)ccc(OC)c2F)c(N)n1
Product: COc1ccc(F)c(C(=O)c2cnc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2N)c1F

Procedure:
The same procedure was used as described in Example 90 starting from (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(2,6-difluoro-3-methoxy-phenyl)-methanone, Example 89, and 4-amino-1-Boc-piperidine (Astatech) to give 4-[4-amino-5-(2,6-difluoro-3-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester. MS (M+H)+, 464.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11](O)[CH2:10]2)=[C:4]([F:15])[CH:3]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])[CH2:10]2)=[C:4]([F:15])[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC1CCC(c2cc(F)c(Br)cc2F)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1CCC(c2cc(F)c(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
To a solution of 13.9 g (50 mmol) of 3-(4-bromo-2,5-difluorophenyl)cyclopentanol, 7.4 g (50 mmol) of phthalimide and 13.1 g (50 mmol) of triphenylphosphine in 50 ml of dry tetrahydrofuran was added dropwise at room temperature a solution of 8.7 g (50 mmol) of diethyl azodicarboxylate in 20 ml of dry tetrahydrofuran. The reaction was stirred at room temperature for 18 hours and the solvent was removed in vacuo. The residue was triturated with ether and the solid removed by filtration. The filtrate was evaporated in vacuo and the residue was chromatographed on silica gel (E. Merck -230-400 Mesh) eluting with chloroform-ethyl acetate (4:1) to give 15.6 g of the title compound; mp 47°-48°.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[NH2:2].C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[NH2:23][C:22]1[N:1]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([OH:8])=[O:7])[N:2]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: NNc1cccc(C(=O)O)c1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cccc(C(=O)O)c2)c1N
Yield: 66.3 %

Procedure:
The mixture of 3-hydrazinobenzoic acid (5.0 g) and ethyl 2-ethoxymethylene-2-cyanoacetate (5.6 g) in ethanol (50 ml) was heated under reflux for 2 hours under stirring, and then the mixture was evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate solution. The separated aqueous layer was adjusted to pH 4 with 6N-hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with a solution of ethyl acetate and diisopropyl ether and the precipitate was collected by filtration to give 3-(5-amino-4-ethoxycarbonylpyrazol-1-yl)benzoic acid (6.0 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[F:21])[O:7][C:8]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:9]=1[C:10]#[N:11].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>C1COCC1.CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[F:21])[O:7][C:8]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:23]2[CH:24]=[C:25]3[N:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][N:26]3[C:27](=[O:29])[N:28]=2)=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: CC(C)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)N1CCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (16.85 mg, 0.702 mmol) in THF (4 mL), 2-(3,4-difluorophenoxy)-5-(hydroxymethyl)benzonitrile (100 mg, 0.468 mmol) in DMF (2.00 mL) and 7-chloro-1-isopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:47]=[C:48]3[C:52](=[CH:53][CH:54]=2)[CH2:51][N:50]([CH3:55])[CH2:49]3)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:47]=[C:48]3[C:52](=[CH:53][CH:54]=2)[CH2:51][N:50]([CH3:55])[CH2:49]3)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1Cc2ccc(Nc3nc(Br)cn(C)c3=O)cc2C1
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CN(C)C4)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
Following the procedures as described for compound 148h and starting with 400 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d and 278 mg of 5-bromo-1-methyl-3-(2-methylisoindolin-5-ylamino)pyrazin-2(1H)-one 231f, compound 231g was obtained as a yellow solid (258 mg, 51%). MS: [M+H]+ 611.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]([F:17])([F:16])C(OC)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[F:16][CH:11]([F:17])[O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 53.2 %

Procedure:
4-Cyanophenol (0.12 G, 1.0 mmol, Aldrich), methyl chlorodifluoroacetate (0.29 g, 2.0 mmol, Aldrich) and potassium carbonate (0.29 g, 2.1 mmol) were combined in dry DMF (0.5 mL) under an argon atmosphere. After stirring at 75°-80° C. for 0.3 h, the mixture was cooled to RT, ethyl acetate (20 mL) was added and the organic layer was washed twice with 10% NaOH. The organic extract was dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 20% ether/hexanes) to provide the title compound as a colorless solid (0.09 g, 53%). mp 34°-35° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:23]#[N:24])[CH2:6][CH:7]1[C:12](=O)[CH2:11][CH2:10][CH:9]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:8]1)[CH3:2].Br.C(O)(=[O:29])C>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH:9]2[CH2:10][CH2:11][C:12]3[NH:24][C:23](=[O:29])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:25])[CH2:6][C:7]=3[CH2:8]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(C#N)CC1CC(Cc2ccc(OC)cc2)CCC1=O
Reactant: CC(=O)O
Agent: Br
Product: CCOC(=O)C1CC2=C(CCC(Cc3ccc(OC)cc3)C2)NC1=O
Reaction time: 0.5 h

Procedure:
2-Cyano-3-(3-(4-methoxyphenyl)methyl-6-oxocyclohexanyl)propanoic acid ethyl ester (2.43 g) was added to 15% w/v solution of HBr in acetic acid at 5° C. and stirred for 30 minutes. The reaction mixture was evaporated under reduced pressure and washed with saturated sodium carbonate solution. The mixture was extracted into ethyl acetate and the organic phase dried (MgSO4) and evaporated. The residue was diluted with diethyl ether and allowed to crystallise to give the title compound (0.5 g) mp. 143°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH3:11])=[CH:9][S:8][C:7]=2[CH:12]=1.[O:13]1CCOCC1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]=[O:13])=[CH:9][S:8][C:7]=2[CH:12]=1
Reactant: C1COCCO1
Reactant: COc1ccc2c(C)csc2c1
Product: COc1ccc2c(C=O)csc2c1
Yield: 80 %

Procedure:
A mixture of 6-methoxy-3-methylbenzo[b]thiophene (2.753 g, 15.5 mmol) and SeO2 (2.06 g, 18.55 mmol) in 1,4-dioxane (30 mL) was refluxed for 2 days and then filtered. The filtrate was concentrated in vacuo, and the residue was purified on a silica gel column eluting with EtOAc/hexane (1:10) to give 6-methoxybenzo[b]thiophene-3-carbaldehyde (2.3 g, 80%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:8][C:9]=1[N:10]([C:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])[C@H:11]1[CH2:16][CH2:15][C@H:14]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4].[OH-].[Li+]>>[CH3:34][C:33]([CH3:35])([CH3:36])[C:32]#[C:31][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C:22]([C@H:24]2[CH2:25][CH2:26][C@H:27]([CH3:30])[CH2:28][CH2:29]2)=[O:23])[C@H:11]2[CH2:12][CH2:13][C@H:14]([N:17]3[CH:21]=[CH:20][N:19]=[N:18]3)[CH2:15][CH2:16]2)[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](n2ccnn2)CC1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](n3ccnn3)CC2)c(C(=O)O)s1

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(trans-4-[1,2,3]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.27 g, 0.52 mmol) is hydrolysed with lithium hydroxide as previously described (example 1, step V1) to give after HPLC purification 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(trans-4-[1,2,3]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:48][CH3:49]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:26][CH2:27][N:28]([CH2:48][CH3:49])[CH2:29][CH2:30]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCNCC4)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(CC)CC4)c3)sc2c1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of crude (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(piperazin-1-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (˜0.144 mmol) in DMF (1.5 mL) was added cesium carbonate (0.094 g, 0.288 mmol), followed by iodoethane (12.6 μL, 0.158 mmol). Reaction mixture was stirred for 1 h, then more iodoethane (5 μL) was added and reaction mixture stirred for 2 h. LC/MS showed incomplete reaction, so more iodoethane (5 μL) was added and reaction mixture stirred overnight. Reaction mixture was diluted with ethyl acetate, washed with 5% lithium chloride solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 10% MeOH/CH2Cl2) to give product. LCMS-ESI+: calc'd for C33H40ClN4O3S: 607.2 (M+H+); Found: 607.3 (M+H+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[O:12][C:13]3[C:18]([C:19](=O)[C:20]=2[CH3:21])=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:2]=1.Cl.[NH2:24][OH:25].Cl>N1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[O:12][C:13]3[C:18]([C:19](=[N:24][OH:25])[C:20]=2[CH3:21])=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:2]=1
Reactant: NO
Reactant: Cc1c(-c2cc3ccccc3cn2)oc2ccccc2c1=O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(-c2cc3ccccc3cn2)oc2ccccc2c1=NO
Temperature: 130 °C

Procedure:
To a suspension of 2-Isoquinolin-3-yl-3-methyl-chromen-4-one (example 71A) (200 mg, 0.69 mmol) in anhydrous pyridine (5 ml) was added hydroxylamine hydrochloride (96 mg, 1.39 mmol). The mixture was heated to 130° C. under microwave irradiation for 30 min. The reaction mixture was poured into a 1N aqueous solution of hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with a 1N aqueous solution of hydrochloric acid, brine and dried over sodium sulfate and concentrated. The title compound was isolated as a white solid after Preparative HPLC purification (gradient 45-30% Water/Methanol+0.05% trifluoroacetic acid) (9 mg, 4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[C:14](Cl)(=O)[CH3:15]>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)Cl
Reactant: O=C(O)CCc1ccc(F)c(F)c1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of 3-(3,4-difluorophenyl)propionic acid (1.0 g, 5.4 mmol) in EtOH (10 mL) is added dropwise acetyl chloride (1.0 mL, 14.1 mmol), and the solution is stirred at RT for 2 h. The solvent is rotary evaporated, and the residue purified by chromatography on silica gel; elution with heptane:EtOAc (4:1) gives 0.99 g of the product 249. 1H NMR (CDCl3) δ 7.10-6.85 (m, 3H), 4.13 (q, 2H), 2.90 (t, 2H), 3.35-2.59 (t, 2H), 1.23 (t, 2H); MS: m/z 215 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCN(c3ccc([N+](=O)[O-])c(Nc4ccccc4)c3)CC2)cc1
Yield: 39 %

Procedure:
A solution of 2-nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (0.5 g, 1.7 mmol), 4-methylbenzene-1-sulfonyl chloride (0.32 g, 1.7 mmol) and triethylamine (0.60 ml, 4.2 mmol) in 20 ml dichloromethane was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. N-(2-nitro-5-(4-tosylpiperazin-1-yl)phenyl)benzenamine (0.30 g, 40%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.46 (s, 3H), 3.24 (t, J=4.5 Hz, 4H), 3.42 (t, J=4.5 Hz, 4H), 6.42 (d, J=9.6 Hz, 1H), 6.64 (s, 1H), 7.28-7.65 (m, 9H), 8.14 (d, J=9.5 Hz, 1H), 9.90 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 22.0, 45.5, 48.4, 48.5, 99.5, 99.6, 125.0, 106.8, 126.4, 128.2, 129.6, 130.3, 130.4, 132.7, 138.9, 144.8, 145.6.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:8]=1[CH3:9])#[N:2].[CH3:14][N:15](C=O)C.C([O-])(=O)C.[NH4+].N>O.C(O)C>[NH2:2][C:1]1[C:3]2[C:8](=[CH:7][C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][CH:4]=2)[CH:9]=[CH:14][N:15]=1
Reactant: Cc1cc(C(C)(C)C)ncc1C#N
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: N
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc2ccnc(N)c2cn1

Procedure:
Procedure analogous to A. Zhang et al., J. Combi. Chem. 2007, 9, 6, 916: A mixture of 17.4 g (100 mmol) of 3-cyano-4-methyl-6-tert-butylpyridine [942938-45-6], 14.0 ml (105 mmol) of N,N-dimethylformamind dimethyl acetal [4637-24-5] and 150 ml of DMF is heated under reflux for 16 h. The DMF is then removed at 70° C. in vacuo. 46.3 g (600 mmol) of anhydrous ammonium acetate are added to the oily residue, the mixture is homogenised, heated to melt ing in an oil bath (temperature about 135° C.) and stirred for 3 h. After cooling, the melt is taken up in a mixture of 200 ml of water and 100 ml of ethanol, rendered alkaline (pH about 9) by addition of conc. ammonia solution and extracted three times with 300 ml of dichloromethane each time. The combined org. phases are washed twice with 300 ml of water each time and dried over sodium sulfat e. Aft er evaporation of the org. phase in vacuo, the residue remaining is subjected to sublimation (p about 1×10−2 mbar, T=150° C.). Yield: 13.7 g (68 mmol), 68%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [N+]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-])=O.[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([CH3:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:13]1([CH3:18])[CH:12]=[CH:11][C:16]([O:17][C:4]2[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(O)cc1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(C#N)s2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
To a dimethyl sulfoxide (100 mL) solution of 5-nitro-2-thiophenecarbonitrile (6.30 g, 40.9 mmol) were added p-cresol (8.85 g, 81.8 mmol) and potassium carbonate (11.3 g, 81.8 mmol) under nitrogen atmosphere, which was stirred for 5 hours at 60° C. The reaction solution was cooled to room temperature, and extracted with ethyl acetate after addition of water. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3→2:1) to obtain the title compound (6.95 g, 78.9%).