Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:16])=[C:7]([CH:15]=1)[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])=[CH2:2].I[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>[Pd].CC(N(C)C)=O>[OH:16][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH:2][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:15][C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[O:9]
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(I)cc1
Reactant: C=Cc1ccc(O)c(C(=O)OCC(C)C)c1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C=Cc2ccc(O)c(C(=O)OCC(C)C)c2)cc1
Yield: 51.4 %

Procedure:
10% Palladium on charcoal (0.5g) was added to a solution of isobutyl 5-ethenyl-2-hydroxybenzoate (6.6 g, 30mmol) and 4-iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide (11.2 g, 30 mmol) in dimethylacetamide (10 ml) and tributylamine (10 ml, 42 mmol) at 110° C. After 90 min. the solution was filtered and diluted with isopropanol (0.3 l) and chilled in a freezer. The product was filtered off, dried and dissolved in boiling formic acid (100 ml). The solution was filtered and water (65 ml) was added. After cooling to refrigerator temperature the product was filtered off and dried to yield 7.2 g (51%) product
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([NH2:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]1=2)(=[O:3])[CH3:2].[CH3:24][CH:25]([C:29]([NH:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[O:30])[C:26](O)=[O:27]>>[C:1]([N:4]1[CH2:10][C@H:9]([NH:11][C:26](=[O:27])[CH:25]([CH3:24])[C:29]([NH:31][CH2:32][C:33]([F:38])([F:39])[C:34]([F:35])([F:36])[F:37])=[O:30])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: CC(=O)N1C[C@H](N)C(=O)N(Cc2ccccc2)c2ccccc21
Product: CC(=O)N1C[C@H](NC(=O)C(C)C(=O)NCC(F)(F)C(F)(F)F)C(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-1-benzyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one and (2RS)-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25 b)] yielded the title compound as a white solid; MS: m/e=539 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: O=S(=O)(O)O
Product: O=C1Nc2c(cc(Br)cc2[N+](=O)[O-])C1=O
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a solution of 5-bromo-1H-indole-2,3-dione (5 g, 22.1 mmol) in conc. H2SO4 (22.5 mL) was added fuming nitric acid (1.45 mL) very slowly at −5 to 0° C. The reaction mixture was stirred at the same temperature for one hour. After completion of the reaction, the reaction mixture was poured on to crushed ice and the resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid (5.5 g, 91.8%) which was used for the next step directly.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([CH3:18])[N:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][C:5]1[CH:6]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:8]=[C:3]([C:1]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19](=[O:27])[N:2]=2)[N:4]=1
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)cc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Yield: 65.4 %

Procedure:
tert-Butyl 3-(2-cyano-6-methyl-4-pyridyl)propanoate (1.2 g, 4.8 mmol) and methyl thiosalicylate (1.6 g, 9.9 mmol) were dissolved in toluene (10 ml), and triethylamine (4.0 ml, 28.6 mmol) was added thereto. The mixture was refluxed for 24 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:2, v/v) were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (1.2 g, 66%)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]2[S:16][C:17]3[C:18]([NH:25][C:26]4[CH:31]=[C:30]([CH2:32][OH:33])[N:29]=[CH:28][N:27]=4)=[N:19][CH:20]=[C:21]([F:24])[C:22]=3[N:23]=2)=[C:10]([Cl:34])[CH:9]=1)(C)(C)C.C(Cl)[Cl:37]>Cl>[ClH:14].[ClH:37].[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]2[S:16][C:17]3[C:18]([NH:25][C:26]4[N:27]=[CH:28][N:29]=[C:30]([CH2:32][OH:33])[CH:31]=4)=[N:19][CH:20]=[C:21]([F:24])[C:22]=3[N:23]=2)=[C:10]([Cl:34])[CH:9]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(-c2nc3c(F)cnc(Nc4cc(CO)ncn4)c3s2)c(Cl)c1
Agent: Cl
Product: Nc1cc(Cl)c(-c2nc3c(F)cnc(Nc4cc(CO)ncn4)c3s2)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of {3,5-dichloro-4-[7-fluoro-4-(6-hydroxymethylpyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]phenyl}-carbamic acid tert-butyl ester (102 mg, 0.19 mmol) in HCl (4 N in dioxane, 3 mL) under a nitrogen atmosphere was heated at 50° C. for 5 hours. After cooling to room temperature, the precipitate was collected by filtration and then purified by column chromatography on silica gel eluting with 0-5% MeOH in EtOAc. To the resultant solid obtained was added DCM (1 mL) followed by HCl (4 N in dioxane, 1 mL) and the resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to afford the title compound as an off white solid (50 mg, 91% yield). 1H NMR (300 MHz, DMSO-d6): δ 11.75 (br s, 1H), 8.89 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 7.70 (s, 1H), 6.78 (s, 2H), 4.61 (s, 2H). LCMS (Method C): RT=3.11 min, m/z: 437 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Reaction time: 3 h

Procedure:
To a solution of 21 g of 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester in 100 mL of ethyl acetate cooled to 0° C. was added 100 mL of saturated sodium carbonate and 17 g of benzyl chloroformate. The solution was stirred for 3 h, then separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave the product as an oil:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CCOCC>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])([OH:30])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1cc(Br)ccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,5-dibromobenzoic acid (27.8 g, 100 mmol, 1.00 equiv) in THF/Et2O (450/50 mL) under nitrogen at −78° C. was added dropwise n-BuLi (2.5M) (88 mL, 2.20 equiv). After 2 h at −78° C., was added 1-benzylpiperidin-4-one (26.5 g, 140 mmol, 1.40 equiv). The resulting solution was stirred for 0.5 h at −78° C. and then warmed to room temperature, and stiffed overnight. The reaction was quenched by carefully adding 200 mL of water. The pH of the mixture was adjusted to 2-3 with hydrogen chloride (aq., 2 M). The aqueous phase was extracted with 3×500 mL of ethyl acetate and 3×500 mL of tetrahydrofuran. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 38.9 g (crude) of the title compound as a yellow solid.
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13]([N:15]([C:23]1[C:28]([C:29]#[CH:30])=[N:27][C:26]([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:25][N:24]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl/[C:44](/[C:47]1[CH:52]=[CH:51][C:50]([C@@H:53]2[CH2:58][O:57][CH2:56][CH2:55][N:54]2[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[CH:49][CH:48]=1)=[N:45]\[OH:46]>C1COCC1>[C:8]([O:12][C:13]([N:15]([C:16]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:22])[C:23]1[C:28]([C:29]2[O:46][N:45]=[C:44]([C:47]3[CH:48]=[CH:49][C:50]([C@@H:53]4[CH2:58][O:57][CH2:56][CH2:55][N:54]4[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[CH:51][CH:52]=3)[CH:30]=2)=[N:27][C:26]([C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:35][CH:36]=2)=[CH:25][N:24]=1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(/C(Cl)=N/O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc([C@@H]5COCCN5C(=O)OC(C)(C)C)cc4)no3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
Et3N (54.34 mg, 74.85 μL, 0.5370 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-ethynyl-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate 4 (224.5 mg, 0.4475 mmol) and tert-butyl (3R)-3-[4-[(Z)—C-chloro-N-hydroxy-carbonimidoyl]phenyl]morpholine-4-carboxylate 13 (183 mg, 0.5370 mmol) in THF (4 mL) and the resulting solution stirred at rt for 30 min and then heated at 65° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica, using the ISCO column companion system, eluting with ethyl acetate/petroleum ether (0-50% EtOAc, 8 g column) Product began to elute at 33% EtOAc. Product fractions were combined and concentrated in vacuo to leave the product as a cream coloured solid (144 mg, 40% yield); 1.20 (6H, d), 1.30 (18H, s), 1.42 (9H, s), 3.07 (1H, m), 3.50-3.60 (3H, m), 3.73-3.85 (3H, m), 4.32 (1H, m), 5.06 (1H, s), 7.53 (2H, m), 8.07 (5H, m), 8.64 (2H, m) and 9.51 (1H, s) ppm
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]#[N:15])[CH2:9]1)C1C=CC=CC=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[C:14]([C:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:10]1[CH2:11][CH2:12][N:8]([C:35]([O:37][CH3:38])=[O:36])[CH2:9]1)#[N:15]
Reactant: COC(=O)Cl
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CCC(C(C#N)(c2ccccc2)c2ccccc2)C1
Reaction time: 5 h
Yield: 68.7 %

Procedure:
To a solution of 36.5 g (0.10 mole) of α-(1-benzyl-3-pyrrolidinyl)-α,α-diphenylacetonitrile and 8.7 g (0.11 mole) of pyridine in methylene chloride was added dropwise at 25° C., 10.4 g (0.11 mole) of methyl chloroformate. The solution was refluxed for 16 hr. To the refluxing solution was added 26.1 g (0.33 mole) of pyridine and 31.2 g (0.33 mole) additional methyl chloroformate. Heating at reflux was continued for 5 hr. The mixture was cooled and washed four times with water. The methylene chloride layer was dried and concentrated in vacuo. The residual oil was crystallized twice from a mix of petroleum ether (30°-60°) and isopropanol to give 22 g (68%) of title product, m.p. 133°-135° C.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12]CC)=[O:11])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].O.[OH-].[Li+].Cl>C(O)C>[CH2:1]([N:3]([C:8]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:16]=[CH:15][C:9]=1[C:10]([OH:12])=[O:11])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)cc1N(CC)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN(c1cc(S(C)(=O)=O)ccc1C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 90.4 %

Procedure:
A mixture of ethyl 2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylbenzoate (11.4 g) and lithium hydroxide monohydrate (1.37 g) in aqueous ethanol (50%) was stirred at room temperature for 19 hours. The mixture was then acidified with conc. hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulphate), filtered and evaporated to yield 2-(N-ethyl-N-methylsulphonylamino)-4-methylsulphonylbenzoic acid as a brown solid (9.48 g), NMR (acetone-d6); 1.15(t,3H), 2.98(s,3H), 3.22(s,3H), 3.85(q,2H), 8.0-8.25(m,3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]([CH3:15])[CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1.[C:16](OC(=O)C)(=[O:18])C>C(O)=O>[CH:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]([CH3:15])[CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:18]
Reactant: CC(C)ON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(C)ON=C(C(=O)O)c1csc(NC=O)n1
Yield: 83.5 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 4 g.), acetic anhydride (7.6 g.) and formic acid (3.4 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 3.75 g.), mp. B 168° to 169° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][CH:3]=1.CS(O[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([O:9][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)nc1F
Reactant: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2F)CC1
Yield: 67.5 %

Procedure:
1-Methylethyl 4-{[(6-bromo-2-fluoro-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.238 g, 68%) was prepared as a white solid from 6-bromo-2-fluoro-3-pyridinol (0.18 g, 0.94 mmol), 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 131, Step 4, 0.38 g, 1.22 mmol) and K2CO3 (0.26 g, 1.88 mmol) in DMF (10 mL) in a manner similar to Example 131, Step 5. The crude product was purified by flash chromatography on an ISCO silica gel column using 0 to 35% EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 7.27 (d, 1H, J=8.3 Hz), 7.20-7.10 (m, 1H), 4.91 (septet, 1H, J=6.2 Hz), 4.30-4.10 (m, 2H), 3.85 (d, 2H, J=6.3 Hz), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.75 (m, 2H), 1.45-1.20 (m, 8H); LRMS (ESI), m/z 375/377 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[CH:11][C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:20](Cl)(=[O:22])[CH3:21]>ClC(Cl)C>[C:20]([C:11]1[C:12]([CH3:14])=[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=1)[S:7][CH2:6][CH2:5][CH:4]2[CH2:3][O:2][CH3:1])(=[O:22])[CH3:21]
Reactant: COCC1CCSc2c(C)ccc(C)c21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COCC1CCSc2c(C)cc(C(C)=O)c(C)c21
Temperature: 0 °C
Yield: 30 %

Procedure:
To a solution of 0.84 g (3.78 mmol) of 4-methoxymethyl-5,8-dimethylthiochroman and 0.60 g (4.54 mmol) of aluminum chloride in dichloroethane was dropwise added 0.36 g (4.54 mmol) of acetyl chloride at 0° C., and the mixture was further allowed to react at 0° C. for 1 hour. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, and an organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure to give 0.30 g (yield 30%) of the titled compound as a crude product.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH:14]([C:22]1([CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]1=[O:34])[C:15]([O:17]C(C)(C)C)=[O:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH:14]([C:22]1([CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]1=[O:34])[C:15]([OH:17])=[O:16]
Reactant: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)O)CCN(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cold (0° C.) solution of tert-butyl α-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetate (500 mg, 0.964 mmol) in CH2Cl2 (2 ml) is treated with TFA (2 mL) and maintained at 0° C. for 1 hour, and then at room temperature for 1 hour. The solvent is removed in vacuo to give a quantitative yield of α-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetic acid as a gelatinous solid.
Reaction SMILES: O[Li].O.[Cl:4][C:5]1[CH:6]=[CH:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH:18]=[CH:17]4)[C:10](=[O:31])[C:9]=12>O.CO>[Cl:4][C:5]1[CH:6]=[CH:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]([OH:26])=[O:25])[CH:18]=[CH:17]4)[C:10](=[O:31])[C:9]=12
Reactant: CC(C)(C)OC(=O)Cn1ccc2cc(N3CCn4ccc(Cl)c4C3=O)ccc21
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)Cn1ccc2cc(N3CCn4ccc(Cl)c4C3=O)ccc21
Temperature: 50 °C
Yield: 78 %

Procedure:
A solution of LiOH.H2O (4.0 equiv.) in water (5 ml) was added at 0° C. to a solution of tert-butyl 2-(5-(8-chloro-1-oxo-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-1H-indol-1-yl)acetate (1.5 mmol, 1.0 equiv.) in MeOH (20 ml), and the mixture was heated for 16 h at 50° C. The methanol was concentrated under reduced pressure, and the aqueous residue was diluted with water (20 ml) and extracted with ethyl acetate (2×15 ml). The aqueous phase was adjusted to pH 4 with 1 M HCl, the desired product precipitating in the form of a white solid. The solid was filtered out and dried. Yield: 78%
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH2:40].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH:40][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: CN(C)CCCN
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 220 °C
Yield: 69.5 %

Procedure:
To a solution of 4-{5-[2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19, 68 mg, 0.14 mmol) in NMP (2.5 mL) was added N,N-dimethyl-propane-1,3-diamine (54 μL, 0.43 mmol) followed by triethylamine (39 μL, 0.28 mmol). The reaction mixture was heated to 220° C. for 5 hrs using microwave irradiation. The cooled reaction mixture was concentrated in vacuo then loaded onto a SCX-2 cartridge (2 g) in MeOH. After washing with DCM/MeOH, the crude product was eluted with 2 M NH3 in MeOH and following concentration in vacuo gave a brown oil (53 mg). The oil thus obtained was purified using preparative TLC (20×20 cm×1 mm) eluting with 20% MeOH in DCM to give the title compound as a pale yellow oil, which solidified on standing (14 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:6].[NH2:20][C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([Cl:28])[N:22]=1.Cl>C(OCCO)C.C(OCC)(=O)C>[ClH:28].[NH2:20][C:21]1[N:22]=[C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=2)[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[O:6])[CH:24]=[C:25]([CH3:27])[N:26]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Nc1cccc(C(=O)Nc2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCCO
Product: Cc1cc(Nc2cccc(C(=O)Nc3ccc([N+](=O)[O-])cc3)c2)nc(N)n1
Temperature: 20 °C
Yield: 98.2 %

Procedure:
3-Amino-N-(4-nitrophenyl)benzamide (B1) (1.0 g, 3.89 mmol) and 4-chloro-6-methyl-2-pyrimidinylamine (A8) (569 mg, 3.89 mmol) were dissolved in warm 2-ethoxyethanol. (20 mL). Two drops c.HCl was then added to the reaction mixture and refluxed for 1 h. by this time TLC and mass spec. showed completion of the reaction. The reaction mixture was diluted with ethyl acetate and cooled to 20° C. The resulting precipitate was filtered, washed with more EtOAc and recrystallized from MeOH/EtOAc/Charcoal/Celite to give B2 (1.531 g, 98%); m.p (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ 12.86 (br s, 1H, N+H), 10.90 (s, 1H, NH), 10.80 (br s, 1H, NH), 8.30-8.26 (m, 2H, ArH), 8.11-8.08 (m, 4H, ArH), 7.80-7.78 (br m, 3H, ArH & NH2), 7.56 (t, J=7.8 Hz, 1H, ArH), 2.30 (s, 3H, CH3); mass APCl+365.
Reaction SMILES: [CH:1]1([C:7]2([C:10]([NH:12][C:13]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][C:17](Cl)=[N:18]4)=[O:11])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(#N)C>[Cl:23][C:22]1[C:13]([NH:12][C:10]([C:7]2([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:8][CH2:9]2)=[O:11])=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH:16]=[CH:15]2
Reactant: C1CNCCN1
Reactant: O=C(Nc1c(Cl)ccc2nc(Cl)ccc12)C1(C2CCCCC2)CC1
Solvent: CC#N
Product: O=C(Nc1c(Cl)ccc2nc(N3CCNCC3)ccc12)C1(C2CCCCC2)CC1
Temperature: 110 °C
Yield: 33.8 %

Procedure:
To a 10 mL vial was added 1-cyclohexyl-N-(2,6-dichloro-5-quinolinyl)-cyclopropanecarboxamide (Example 26 (b)) (0.13 g), piperazine (0.091 g) and acetonitrile (3 mL). The vial was sealed and heated in a microwave at 110° C. for 40 minutes. The solvent was removed from the cooled reaction and the residue taken up in dichloromethane and purified (SiO2, ammonia:methanol:dichloromethane, 1:2:97 as eluant). The solvent was removed from the combined fractions and the product recrystallised from ethanol to afford the title compound (0.050 g).