Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.[CH3:22][NH:23][C:24](=[O:31])[CH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.CO.[H-].[Na+]>CN(C)C=O.O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[CH:3]=[C:25]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[C:24](=[O:31])[N:23]([CH3:22])[C:5]=2[C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)=[CH:18][CH:17]=1
Reactant: CNC(=O)Cc1nccs1
Reactant: COc1ccc(C(=CN(C)C)C(=O)c2ccncc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(-c3nccs3)c(=O)n(C)c2-c2ccncc2)cc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A solution of 3-dimethylamino-2-(4-methoxyphenyl)-1-(pyridin-4-yl)propen-1-one (2.53 g), N-methyl thiazol-2-ylacetamide (1.70 g) and methanol (0.73 cm3) in dry dimethylformamide (20 cm3) was added via cannula at room temperature to a stirred suspension of sodium hydride (55% in oil; 0.80 g) in dry dimethylformamide (10 cm3) under nitrogen. The mixture was stirred at 40° C. for 18 hours, then poured into water (200 cm3). The resulting yellow precipitate was collected and recrystallised from ethyl acetate to give 3-(4-methoxyphenyl)-1-methyl-5-(thiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one as a yellow powder (2.18 g; 62%) m.p. 224-225° C. (EtOAc). Found: C, 66.9; H, 4.45; N, 11.2. C12H17N3O2S requires C, 67.2; H, 4.6; N, 11.2%. δH (360 MHz; CDCl3) 3.50 (3 H, s, NCH3), 3.74 (3 H, s, OCH3), 6.70 (2 H, d, J 9, methoxyphenyl H-2), 6.93 (2 H, d, J 9, methoxyphenyl H-3), 7.15 (2 H, d, J 6, pyridyl H-3), 7.50 (1 H, d, J 3, thiazolyl H-5), 7.96 (1 H, d, J 3, thiazolyl H-4), 8.64 (2 H, d, J 6, pyridyl H-2) and 8.72 (1 H, s, pyridone H-4); m/z (ESP+) 376 (MH+; 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([N+:31]([O-])=O)[CH:25]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:34].[CH:35](O)=O>[Pd]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]3[NH:30][CH:35]=[N:31][C:26]=3[CH:25]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:34]
Reactant: O=CO
Reactant: CC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Agent: [Pd]
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Temperature: 50 °C
Reaction time: 1.33 h

Procedure:
1.06 g (2 mMol) of 4-amino-N-[1-((4-amino-3-nitro-phenyl)methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide are suspended in 20 ml of formic acid and hydrogenated, with the addition of 0.1 g palladium/charcoal, in an autoclave under a hydrogen pressure of 5 bar at ambient temperature for 80 minutes. Then the catalyst is filtered off and the filtrate is heated to 50° C. for 2 hours. It is then concentrated by evaporation, mixed with 30 ml of water, made alkaline with concentrated ammonia and extracted twice with ethyl acetate. The organic phase is washed twice with water, dried over magnesium sulphate and evaporated down. The residue obtained is purified on a silica gel column (ethyl acetate/methanol/ammonia=95:5:0.5). After evaporation the residue is recrystallised from isopropanol.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[F:15][C:16]1([F:20])[CH2:19][NH:18][CH2:17]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH3:10])[C:11]([N:18]1[CH2:19][C:16]([F:20])([F:15])[CH2:17]1)=[O:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: FC1(F)CNC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.3 %

Procedure:
A round-bottomed flask was charged with Boc-D-alanine (400 mg, 2.11 mmol), 3,3-difluoroazetidine hydrochloride (383 mg, 2.96 mmol), HOBT (356 mg, 2.33 mmol) and EDC (446 mg, 2.33 mmol). DMF (9 ml) was added followed by N,N-diisopropylethylamine (1.0 ml, 5.73 mmol). The reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to give 509 mg (91%) of [(R)-2-(3,3-difluoro-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 5.14 (d, J=7.2 Hz, 1H), 4.59-4.80 (m, 1H), 4.17-4.55 (m, 4H), 1.45 (s, 9H), 1.32 (d, J=7.2 Hz, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[C:15]([C:21](=[O:23])[NH2:22])[N:14]=2)=[CH:9][CH:8]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([CH:42]([CH3:47])[C:43]([O:45][CH3:46])=[O:44])[CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[C:21]([C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:32]3[CH:31]=[CH:30][C:29]([CH:42]([CH3:47])[C:43]([O:45][CH3:46])=[O:44])=[CH:28][C:27]=3[Cl:26])=[CH:8][CH:9]=2)[C:18]([CH3:19])=[N:17][C:16]=1[CH3:20])(=[O:23])[NH2:22]
Reactant: Cc1nc(C)c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)nc1C(N)=O
Reactant: COC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: COCCOC
Product: COC(=O)C(C)c1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Temperature: 90 °C
Yield: 59.6 %

Procedure:
A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl trifluoromethanesulfonate (Intermediate 7-4; 1.249 g, 3.33 mmol) and methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (Intermediate 8-2; 1.08 g, 3.33 mmol) and potassium phosphate, tri-basic (0.847 g, 3.99 mmol) in DME (16 mL), methanol (8.00 mL) and water (4.00 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (0.136 g, 0.17 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 90° C. for 4 hours in the microwave. The reaction mixture was allowed to cool to room temperature and then evaporated. The crude product was partitioned between EtOAc (75 mL), and saturated brine (75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)propanoate (0.841 g, 59.6%) as a beige solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:9][C:10]1[C:15]([CH:16]=O)=[C:14]([CH3:18])[N:13]=[C:12]([S:19][CH3:20])[N:11]=1)[CH3:8].[C:21](#[N:25])[CH2:22][C:23]#[N:24]>C(O)C>[CH2:7]([N:9]1[C:10]2[N:11]=[C:12]([S:19][CH3:20])[N:13]=[C:14]([CH3:18])[C:15]=2[CH:16]=[C:22]([C:23]#[N:24])[C:21]1=[NH:25])[CH3:8]
Reactant: CCNc1nc(SC)nc(C)c1C=O
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1c(=N)c(C#N)cc2c(C)nc(SC)nc21
Temperature: 70 °C

Procedure:
Potassium carbonate (0.539 g, 3.90 mmol) was added to a suspension of 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (0.413 g, 1.95 mmol) from above, and malononitrile (0.194 g, 2.93 mmol) in absolute ethanol (15.0 mL) and heated to 70° C. After one h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and washed with saturated NaHCO3 (50 mL), and brine. The organic phase was separated and concentrated in vacuo. The residue was precipitated with ethyl acetate and hexanes to give 8-ethyl-7-imino-4-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile as a brown solid that was used in the subsequent step without further purification.
Reaction SMILES: BrC1C=CC(S(N(C)CCN2CCOCC2)(=O)=O)=CC=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][C:23]=1[C:30]1[CH:59]=[C:58]([CH3:60])[C:33]2[N:34]=[C:35]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([S:45]([N:48]([CH3:57])[CH2:49][CH2:50][N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)(=[O:47])=[O:46])=[CH:41][CH:40]=3)[N:36]=[N:37][C:32]=2[CH:31]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=1[C:30]1[CH:59]=[C:58]([CH3:60])[C:33]2[N:34]=[C:35]([NH:38][C:39]3[CH:40]=[CH:41][C:42]([S:45]([N:48]([CH3:57])[CH2:49][CH2:50][N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)(=[O:46])=[O:47])=[CH:43][CH:44]=3)[N:36]=[N:37][C:32]=2[CH:31]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(S(=O)(=O)N(C)CCN5CCOCC5)cc4)nnc3c2)c1
Agent: CN(CCN1CCOCC1)S(=O)(=O)c1ccc(Br)cc1
Product: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)N(C)CCN4CCOCC4)cc3)nc12

Procedure:
To synthesize the title compound (CLXXII), intermediate compounds 67 (4-bromo-N-methyl-benzenesulfonamide), 68 (4-bromo-N-methyl-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide) and 69 (4-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-methyl-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide) shown below were used.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[OH:28]>>[OH:28][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14]
Reactant: NC1CCCCC1O
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: O=C(NC1CCCCC1O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-cyclohexanol (CAN 6850-38-0) as starting materials, MS (EI): m/e=382.2 [M+H]+.
Reaction SMILES: N(C(OCCOC)=O)=NC(OCCOC)=O.[CH3:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([CH3:27])=[CH:20][C:19]=1[OH:28].[CH2:29]([CH:32]1[CH2:34][CH:33]1[CH2:35]O)[CH2:30][CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([CH3:27])=[CH:20][C:19]=1[O:28][CH2:35][CH:33]1[CH2:34][CH:32]1[CH2:29][CH2:30][CH3:31]
Reactant: CCCC1CC1CO
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCC1CC1COc1cc(C)c([N+](=O)[O-])cc1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
3.84 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 2.11 g of 2,5-dimethyl-4-nitrophenol, 1.44 g of (2-propylcyclopropyl)methanol, 3.97 g of triphenylphosphine and 100 mL of toluene at 0° C., and the mixture was stirred at 80° C. for 4 hours. After cooling, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 2.52 g of 2,5-dimethyl-4-nitro-1-[(2-propylcyclopropyl)methoxy]benzene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18]([S:25][CH3:26])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[CH:21]=[C:20]([N:22]([CH3:23])[CH3:24])[N:19]=[C:18]([S:25]([CH3:26])=[O:35])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nc(Nc2cccc(OCc3ccccc3)c2)cc(N(C)C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C)c1cc(Nc2cccc(OCc3ccccc3)c2)nc(S(C)=O)n1
Yield: 69 %

Procedure:
A solution of N4-[3-(benzyloxy)phenyl]-N6,N6-dimethyl-2-(methylsulfanyl)-4,6-pyrimidinediamine (5.5 g, 15 mmol) and m-chloroperbenzoic acid (5.19 g) in CH2Cl2 at 0° C. was stirred for 1 hour. The reaction mixture was slowly brought to room temperature and quenched with a solution of sodium sulfite. The organic layer was separated and washed with NaHCO3 solution (3×250 mL), dried over anhydrous MgSO4, concentrated, and purified by column chromatography [eluent: chloroform/methanol (94:6)], giving N4-[3-(benzyloxy)phenyl]-N6,N6-dimethyl-2-(methylsulfinyl)-4,6-pyrimidinediamine (3.98, 69%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:30][C:29]5[CH:32]=[CH:33][C:34]([N+:35]([O-:37])=[O:36])=[C:27]([F:26])[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)cccc3[nH]2)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(F)c5)CC4)cccc3[nH]2)cc1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a stirring solution of 2-(4-tert-Butyl-phenyl)-4-piperazin-1-yl-1H-benzoimidazole (0.857 g, 2.56 mMol) and 3-Fluoro-4-nitro-benzaldehyde (0.52 g, 3.07 mMol) in N-methylpyrrolidinone (20 mL) was added sodium triacetoxyborohydride (1.36 g, 6.40 mMol) and the solution stirred overnight. Upon arrival the solution was diluted with ethyl acetate (200 mL). The mixture was washed with saturated sodium bicarbonate solution (75 mL), water (75 mL), and brine (75 mL). The organic layer was then dried with magnesium sulfate, filtered, concentrated, and purified by flash column chromatography on silica gel using 40% ethyl acetate in hexane as the eluant to yield 850 mg (68% yield) of 2-(4-tert-Butyl-phenyl)-4-[4-(3-fluoro-4-nitro-benzyl)-piperazin-1-yl]-1H-benzoimidazole as a light yellow solid. 1H NMR (DMSO-d6): δ=12.69 (s, 1H), 8.16 (t, 1H, J=8.2 Hz), 8.04 (d, 2H, J=8.5 Hz), 7.59 (m, 1H), 7.55 (d, 2H, J=8.5 Hz), 7.47 (d, 1H, J=8.6 Hz), 7.03 (m, 2H), 6.50 (dd, 1H, J=7.0, 1.8 Hz), 3.71 (s, 2H), 3.60 (br s, 4H), 2.66 (br s, 4H), 1.33 (s, 9H). LC/MS (Method A), rt=1.24 mins., purity=100%, calculated mass=487, [M+H]+=488, [M−H]−=486.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([O:6][CH2:7][CH2:8][N:9]2[S:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:14])=[O:13])=[N:4][CH:3]=1.C(N(CC)CC)C.[C:31]([O:34][CH2:35][CH3:36])(=[O:33])C>C(O)C>[CH2:35]([O:34][C:31]([C:2]1[CH:11]=[C:10]2[C:5]([O:6][CH2:7][CH2:8][N:9]2[S:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:14])=[O:13])=[N:4][CH:3]=1)=[O:33])[CH3:36]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ncc(Br)cc21
Reactant: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2
Yield: 67 %

Procedure:
A solution of 7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene (200 mg, 0.476 mmol), triethylamine (120 mg, 1.19 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (19 mg, 29 μmol) in ethanol (2 mL) and ethyl acetate (2 mL) was heated at 110° C. under a carbon monoxide atmosphere (70 bar) for 20 h. The reaction mixture was evaporated and the residue chromatographed (SiO2, toluene-acetonitrile gradient) to produce 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylic acid ethyl ester (132 mg, 67%). Off-white solid, MS (ISP)=413.2 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:9]=1[NH:25][C:26](=[O:41])[CH2:27][C:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:9]2[NH:25][C:26](=[O:41])[CH2:27][C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N:35]4[CH:39]=[CH:38][N:37]=[N:36]4)[CH:30]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C#Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C#Cc1ccccc1)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example M5) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (76 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:13])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:14])[C:3]=1[N:15]1[C:23](=[O:24])[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]1=[O:25].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](Cl)=[O:37]>O1CCOCC1>[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36]([NH:1][C:2]1[C:7]2[N:8]([CH3:13])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:14])[C:3]=1[N:15]1[C:16](=[O:25])[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[C:23]1=[O:24])=[O:37]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)c(N)c21
Solvent: C1COCCO1
Product: CN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)c(NC(=O)c3ccc4ccccc4c3)c21
Yield: 34.6 %

Procedure:
2-[5-Amino-7-fluoro-4-methyl-2H-1,4-benzoxazine-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.3 g) and 2-naphthoyl chloride (0.19 g) were dissolved in anhydrous dioxane (10 ml) and the solution refluxed for 2 hr. Solvent was evaporated and the residue subjected to column chromatography on silica gel in hexane-ethyl acetate (6:4) to furnish the title compound (0.15 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:13]=[C:14]([F:22])[CH:15]=[C:16]2[C:20]=1[NH:19][C:18](=[O:21])[CH2:17]2.N1CCCCC1>O1CCCC1>[F:22][C:14]1[CH:13]=[C:12]([NH:11][CH:1]=[O:3])[C:20]2[C:16](=[CH:17][C:18](=[O:21])[N:19]=2)[CH:15]=1
Reactant: Nc1cc(F)cc2c1NC(=O)C2
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: O=CO
Product: O=CNc1cc(F)cc2c1=NC(=O)C=2
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
A mixture of acetic anhydride (0.8 ml) and formic acid (0.6 ml) was stirred for 1 hour at room temperature, and added with 7-amino-5-fluoro-1,3-dihydro-indol-2-one 20b (2.0 g, 12 mmol) in 30 ml of tetrahydrofuran to the above mixture, followed by piperidine (0.02 ml). The resulting mixture was stirred for 3 hours until precipitates were formed, filtered to provide the crude product (1.95 g), and recrystallized from methanol to obtain the title compound 5-fluoro-7-formamido-indol-2-one 20c (700 mg, yield 30.4%) as a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:20]([O:24][C:25](=[O:45])[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[CH2:35][NH:36][C:37]([C@@H:39]1[CH2:44][CH2:43][CH2:42][CH2:41][NH:40]1)=[O:38])([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[C:1]([O:4][C@H:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([N:40]1[CH2:41][CH2:42][CH2:43][CH2:44][C@H:39]1[C:37](=[O:38])[NH:36][CH2:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[CH2:27][NH:26][C:25]([O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:45])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCCN1
Reactant: CC(=O)O[C@@H](C(=O)Cl)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H](C(=O)N1CCCC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a cooled (−10° C.) solution of (2R)-1-chloro-3,3-dimethyl-1-oxobutan-2-yl acetate (0.15 g, 0.82 mmol) in THF (5 mL) was added triethylamine (0.54 mL, 3.90 mmol) and a solution of (S)-tert-Butyl-4-chloro-2-{(piperidine-2-carboxamido)methyl}benzylcarbamate (0.3 g, 0.78 mmol) in THF (2 mL) at −10° C. The reaction mixture was stirred at room temperature for 1 h then quenched with water (50 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase combiflash column chromatography (C18, eluent: 0-10% acetonitrile water) to afford the title compound (0.27 g) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:17][C:18]1[C:19]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1>>[F:27][C:25]1[CH:24]=[CH:23][C:20]2[S:21][CH:22]=[C:18]([CH2:17][N:6]3[C:7]4[C:12](=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][CH:8]=4)[CH:13]=[C:5]3[C:3]([OH:2])=[O:4])[C:19]=2[CH:26]=1
Reactant: Fc1ccc2scc(CBr)c2c1
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Product: COc1cccc2c1cc(C(=O)O)n2Cc1csc2ccc(F)cc12

Procedure:
Using general procedure B, 4-methoxy-1H-indole-2-carboxylic acid methyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) and the product obtained was hydrolyzed to give the title compound as yellow solid. MS: 354.0 ([M−H]−).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C@@H:19]([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH2:18][O:17]C1(C)C)=O)(C)(C)C.[OH-].[Na+]>O.C(#N)C.C(OCC)(=O)C>[NH2:15][C@@H:19]([CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][N:24]=1)[CH2:18][OH:17]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCOc2ccc(C(F)(F)F)cn2)COC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N[C@H](CO)CCOc1ccc(C(F)(F)F)cn1
Temperature: 80 °C
Yield: 113.6 %

Procedure:
To a solution of trifluoroacetic acid (0.23 ml) in water (9 ml) was added dropwise a solution of (S)-2,2-dimethyl-4-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethyl]-oxazolidine-3-carboxylic acid tert-butyl ester (390 mg) in acetonitrile (1.5 ml). The mixture was heated for 90 min at 80° C. with stirring. The mixture was then cooled to room temperature and made basic by addition of 2 M aq. sodium hydroxide solution, then diluted with ethyl acetate and washed sequentially with water and with saturated brine. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo to give (S)-2-amino-4-(5-trifluoromethyl-pyridin-2-yloxy)-butan-1-ol (284 mg, quant.) as a yellow oil. MS (ISP): 251.2 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.C(O[CH:13]=[C:14]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][CH:13]=[C:14]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:8]=1
Reactant: COc1ccc(N)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(C)C
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)C(C)C

Procedure:
Ethyl 2-(((6-methoxypyridin-3-yl)amino)methylene)-4-methyl-3-oxopentanoate was prepared with conditions described in Example 99 using 2-methoxy-5-aminopyridine and ethyl 2-(ethoxymethylene)-4-methyl-3-oxopentanoate.