Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:25][CH:26]([CH3:30])[C:27](Cl)=[O:28]>O>[Cl:25][CH:26]([CH3:30])[C:27]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:28]
Reactant: Cc1ccc(Cl)cc1NCC=O
Reactant: CC(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(Cl)cc1N(CC=O)C(=O)C(C)Cl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-chloroanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0°C and α-chloropropionyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochoric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloropropionyl-2-methyl-5-chloroanilino)-acetaldehyde.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]=[C:11](Cl)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29].O>ClCCl>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]=[C:11]([NH:28][NH2:29])[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: N#Cc1cc2c(cc1C(F)(F)F)nc(Cl)c(=O)n2OCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc2c(cc1C(F)(F)F)nc(NN)c(=O)n2OCc1ccccc1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 5.2 g (13.7 mmol) of 1-benzyloxy-3-chloro-7-cyano-6-trifluoromethylquinoxalin-2(1H)-one in 150 ml of dichloromethane was added 2.7 ml of hydrazine monohydrate (~55.7 mmol) at 0° C. Stirring was continued at 0° C. for 1 h. The evaporated reaction mixture was stirred with water to give the title compound (5.0 g; 97%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH3:32]>C(Cl)Cl>[CH3:27][O:28][CH2:29][CH2:30][N:31]([CH3:32])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CNCCOC
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(C)S(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (500 mg; 1.48 mmol; 1.00 eq) in DCM (30 ml). The solution is degassed with N2 and cooled down to 0° C. Triethylamine (1.0 ml; 7.42 mmol; 5.00 eq) followed by N-(2-methoxyethyl)methylamine (0.80 ml; 7.42 mmol; 5.00 eq) are added. After 45 minutes at 0° C., the reaction is complete. The reaction mixture is washed with NaHCO3 sat. (twice) and water (twice). The organic phase is dried over MgSO4, filtered and concentrated under vacuum, affording Compound (21) as a beige solid (478 mg; 83%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([NH2:60])=[CH:57][CH:58]=2)[CH:53]=[N:52]1>ClCCCl>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:60][C:56]1[CH:55]=[C:54]3[C:59](=[CH:58][CH:57]=1)[N:51]([CH2:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=1)[N:52]=[CH:53]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: C[C@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)N(C)C
Temperature: 45 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A mixture of (2S)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (200 mg, 0.77 mmol), triphenylphosphine (603 mg, 2.3 mmol) and carbon tetrachloride (2.2 ml, 23 mmol) in 1,2-dichloroethane (5 ml) was stirred at 45° C. for 2 hours. 1-(Pyridin-2-ylmethyl)-1H-indazol-5-amine (179 mg, 0.8 mmol) was added and the solvent was evaporated under vacuum. Acetonitrile (5 ml) was added. The mixture was stirred at 75° C. for 2 hours. After cooling, 6N methanolic ammonia (3 ml) was added. The solvents were evaporated under vacuum. The residue was purified by chromatography on silica gel (eluant: 3% to 5% methanol in DCM) to give the title compound as a white foam (208 mg, 58%); NMR Spectrum (CDCl3) 1.72 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.75 (s, 2H), 6.81 (m, 2H), 7.17 (m, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 7.62-7.53 (m, 2H), 7.81 (dd, 1H), 8.10 (s, 1H), 8.44 (d, 1H), 8.58 (d, 1H), 8.62 (s, 1H); Mass spectrum 468.
Reaction SMILES: [CH3:1][Li].[C:3]([CH2:6][N:7]1[C:11]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[N:8]1)([OH:5])=O>C(OCC)C.O1CCCC1>[C:3]([CH2:6][N:7]1[C:11]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[N:8]1)(=[O:5])[CH3:1]
Reactant: O=C(O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)Cn1nccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of methyllithium in diethyl ether (250 ml) was added to a solution of 1-carboxymethyl-5-triphenylmethylaminopyrazole (25.95 g) in tetrahydrofuran (400 ml) under ice-cooling and the mixture was stirred for 6 hours at ambient temperature. The reaction mixture was added to a mixture of ice-cold water (500 ml) and diethyl ether (500 ml). The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-acetylmethyl-5-triphenylmethylaminopyrazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([F:22])=[C:20]([F:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[F:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][C:19]=1[F:22]
Reactant: C#CCCn1nc2ccc(F)c(F)c2n1
Reactant: Brc1ccccn1
Product: Fc1ccc2nn(CCC#Cc3ccccn3)nc2c1F
Yield: 58.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (42 mg, 0.26 mmol) and 2-(but-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24 mmol); Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 41 mg (0.14 mmol, 60%) of 4,5-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[C:46]([F:48])=[CH:47][C:39]1=2)#[N:27]>C1COCC1.CCOC(C)=O>[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[CH:44]=[C:45]([S:49]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:51])=[O:50])[C:46]([F:48])=[CH:47][C:39]1=2)#[N:27]
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Cl)c(F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)c(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (2.83 g, 12.86 mmol) was added THF (38.2 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (14.03 ml, 14.03 mmol), faster than dropwise. After 15 min, a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (4.92 g, 11.69 mmol) in THF (30 ml) was added. The mixture was allowed to warm to rt over 1.5 h, providing a brown solution and product as the primary species according to LC-MS (m/z=605). The solution was added to ice, diluted with EtOAc and extracted with water (brine added to help resolve emulsion). The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. To the crude material was added DCM (70 ml) and the resulting light brown solution cooled in an ice water bath prior to the addition of TFA (20 ml) and the mixture stirred at 0° C. for 20 mins and at room temperature for 1 h affording a purplish solution. The mixture was concentrated under reduced pressure and the resulting brownish oil purified with a 330 g ISCO gold column ramping EtOAc in heptane (0-45%, then isocratic at 45% with 10% DCM isocratic throughout, sample loaded with DCM providing product (˜3.9 g) as a slightly off-white solid. The solid was triturated with MeOH to afford a white solid, 4-(2-cyano-4-(trifluoromethyl)phenyl)-6-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (3.208 g, 6.62 mmol, 56.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.80-3.88 (m, 2 H) 4.28-4.35 (m, 2 H) 6.64 (d, J=11.64 Hz, 1 H) 6.84 (d, J=4.69 Hz, 1 H) 7.23 (d, J=6.75 Hz, 1 H) 7.27 (d, J=4.60 Hz, 1 H) 7.77 (d, J=8.61 Hz, 1 H) 8.09 (dd, J=8.90, 1.96 Hz, 1 H) 8.41 (d, J=1.66 Hz, 1 H) 12.81 (s, 1 H). m/z (ESI) 485.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[C:6]([C:9]1[CH:40]=[CH:39][C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[C:22]3[CH:23]=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=3)C#N)=[CH:17][CH:16]=2)=[C:11]([CH2:41][CH2:42][CH3:43])[C:10]=1[OH:44])(=[O:8])[CH3:7]>>[OH:44][C:10]1[C:11]([CH2:41][CH2:42][CH3:43])=[C:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([C:22]3[CH:29]=[CH:26][C:25]([O:30][CH3:31])=[C:24]([C:5]4[N:1]=[N:2][NH:3][N:4]=4)[CH:23]=3)[O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)=[CH:19][CH:20]=2)[CH:39]=[CH:40][C:9]=1[C:6](=[O:8])[CH3:7]
Reactant: c1nnn[nH]1
Reactant: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3ccc(OC)c(C#N)c3)cc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3ccc(OC)c(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O

Procedure:
Using the method of tetrazole formation described in Example 1 with 5-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzonitrile (1.00 g, 1.89 mmol), the title compound is obtained (0.620 g, 1.10 mmol, 58%): MS (m/z): 571 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[Br:13]Br>C(OCC)C>[Br:13][CH:10]([CH3:11])[C:9]([C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])=[O:12]
Reactant: BrBr
Reactant: CCC(=O)c1cc(F)ccc1F
Solvent: CCOCC
Product: CC(Br)C(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2′,5′-difluoropropiophenone (2.12 g) in diethyl ether (20 ml) under ice-cooling was added bromine dropwise, and the mixture was stirred at room temperature overnight. To this reaction mixture was added ice and the diethyl ether layer was separated, followed by washing with water and saturated aqueous solution of sodium hydrogen carbonate in that order and dried over anhydrous magnesium sulfate (MgSO4). The ether layer was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25]([NH:27][NH:28][C:29](=[O:31])[CH3:30])=S.C(O)C>ClCCl.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH3:1][C@@H:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25]1[O:31][C:29]([CH3:30])=[N:28][N:27]=1
Reactant: CC(=O)NNC(=S)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C[C@H]1C)OCO3
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3C[C@H]2C)OCO4)o1
Yield: 51 %

Procedure:
A stirred mixture of 2.2 g (5.15 mmol) of (R)—N′-(8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-7-carbothioyl)-acetic hydrazide (an intermediate of method B of Example 28), 44 ml of ethanol and 1.72 g (5.39 mmol) of mercury (II) acetate was refluxed for 2 h. The residue obtained on concentration was dissolved in dichloromethane and filtered through a neutral aluminum oxide column. After washing the column the filtrate was concentrated and the residue was purified by column chromatography using silica gel (MN Kieselgel 60) as adsorbent and a mixture of n-hexane-ethyl acetate (1:2.5) as eluent to yield 1.07 g (51%) of the title compound. Mp.: 202-204° C. after recrystallization from ethanol. [α]: −249° (c=0.22; CHCl3).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)CCC>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[NH:4][N:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2cc(C#N)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 57.3 %

Procedure:
To a solution of 300 mg of tert-butyl 3-bromo-5-cyano-1H-1-indazolecarboxylate produced in Production Example I-14-b in 10 ml dimethylformamide were added 376 mg of tri-n-butyl (phenyl)tin and 54 mg of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 150° C. for 45 minutes. After removing the solvent by distillation, the residue was dissolved in 1.5 ml of ethyl acetate and the mixture was adsorbed by 1.5 g of silica gel. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=3:97 to 1:19) and the resulting amorphous powder was crystallized from diisopropyl ether, to give 117 mg of the title compound as pale yellow crystals.
Reaction SMILES: [N:1]12CCCN=[C:7]1CCCC[CH2:2]2.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[O:14].S(C[N+]#[C-])(C1C=CC(C)=CC=1)(=O)=O>ClCCl>[O:14]1[C:13]([C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][N:1]=[CH:2]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)C=O
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cnco1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.574 mL; 3.84 mmol) was added simultaneously with ethyl glyoxalate (50% in toluene, 0.659 mL; 3.33 mmol) to a mixture of tosylmethyl isocyanide (0.500 g; 2.560 mmol) in dichloromethane (10 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours, diluted in dichloromethane and washed with sodium hydrogen sulphate, sodium carbonate, dried over magnesium sulphate and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 5 to 60% ethyl acetate in heptane) to yield 0.194 g (54%) of ethyl oxazole-5-carboxylate as a colorless oil.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:15]2[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)[C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])=[C:24]([Cl:23])[CH:25]=2)=[CH:9][C:10]=1[C:15]1[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1
Reactant: O=C(c1ccc(B(O)O)cc1Cl)N1CCOCC1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1cc(-c2cc(-c3ccc(C(=O)N4CCOCC4)c(Cl)c3)cnc2N)nn1
Temperature: 120 °C
Yield: 22.8 %

Procedure:
Cs2CO3 (682 mg, 2.10 mmol) was added to a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and (3-chloro-4-(morpholine-4-carbonyl)phenyl)boronic acid (229 mg, 0.85 mmol) in dioxane: water (7 mL: 3 mL) degassed the reaction mixture for 10 min with nitrogen. Then added Pd(PPh3)4 (40 mg, 0.035 mmol), degassed the reaction mixture for additional 10 min with nitrogen, the reaction mixture was heated to 120° C. in microwave for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 70-80% ethyl acetate in pet-ether to afford 68 mg (Yield: 22.5%) of the title compound as a pale yellow solid. Product was converted to its HCl salt by using HCl in ether (2M) to afford 60 mg of the HCl salt of the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1([F:18])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][NH:14][C:13](=[O:17])[N:12]=3)[C:4]=2[O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].O>CN(C=O)C>[Cl:26][CH2:25][CH2:24][CH2:23][CH2:22][N:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:4]3[O:3][C:2]([F:1])([F:18])[O:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)=[N:12][C:13]1=[O:17]
Reactant: ClCCCCBr
Reactant: O=c1nc(-c2cccc3c2OC(F)(F)O3)cc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2cccc3c2OC(F)(F)O3)ccn1CCCCCl
Temperature: 100 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of 4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-1H-pyrimidin-2-one (232 mg, 0.92 mmol) in dry DMF (18 ml), 60% NaH (47 mg, 1.19 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (137 μl 1.19 mmol) was added and the mixture was stirred overnight at room temperature. Water was added and the mixture extracted with diethyl ether. The organic layer was dried (Na2SO4) and evaporated. The residue purified by flash chromatography with hexane-ethyl acetate (8-2) to give 123 mg of the title compound (39% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:16]#[C:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][C:9]=1[NH:10][C@@H:11]([CH3:15])[CH2:12][CH2:13][OH:14])=[O:4].[CH3:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:16]#[C:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:8][C:9]=1[N:10]([C:29]([C@H:26]1[CH2:27][CH2:28][C@H:23]([CH3:22])[CH2:24][CH2:25]1)=[O:30])[C@@H:11]([CH3:15])[CH2:12][CH2:13][O:14][C:29]([C@H:26]1[CH2:27][CH2:28][C@H:23]([CH3:22])[CH2:24][CH2:25]1)=[O:30])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N[C@@H](C)CCO
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: c1ccncc1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@@H](C)CCOC(=O)[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)3-(3-hydroxy-1-(S)-methyl-propylamino)-thiophene-2-carboxylic acid methyl ester (4.0 g, 12.94 mmol) was taken up in pyridine (100 mL). Trans-4-methyl-cyclohexanecarbonyl chloride (12.40 g, 77.66 mmol) was added and the reaction was placed in a 100° C. preheated oil bath and stirred for 16 h. After cooling to rt the solvent was removed under reduced pressure. The residue was partitioned between EtOAc and 2N HCl(aq), the organics dried over Na2SO4, and the solids filtered. Solvent was removed under reduced pressure and 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methylcyclohexanecarbonyl)-[1-(S)-methyl-3-(trans-4-methyl-cyclohexanecarbonyloxy)-propyl]-amino]-thiophene-2-carboxylic acid methyl ester (4.15 g, 58%) was isolated by silica gel chromatography as a yellow solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([NH:19][C:20]1[CH:30]=[C:29]2[C:23]([C:24]([Cl:35])=[C:25]([O:31][CH2:32][CH2:33][CH3:34])[O:26][C:27]2=[O:28])=[CH:22][CH:21]=1)=[O:18])CC1C=CC=CC=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:36](N[C@H](C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCCC)OC2=O)=CC=1)=O)C)=O)C)(=O)[C:37]1C=CC=C[CH:38]=1.C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCC)OC2=O)=CC=1)=O)C(C)C)(OC(C)(C)C)=O.C(N[C@H](C(NC1C=C2C(C(Cl)=C(OCC)OC2=O)=CC=1)=O)C)(OC(C)(C)C)=O>>[C:1]([NH:8][C@H:9]([C:17]([NH:19][C:20]1[CH:30]=[C:29]2[C:23]([C:24]([Cl:35])=[C:25]([O:31][CH2:32][CH2:33][CH3:34])[O:26][C:27]2=[O:28])=[CH:22][CH:21]=1)=[O:18])[CH:37]([CH3:38])[CH3:36])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CCCOc1oc(=O)c2cc(NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)c3ccccc3)ccc2c1Cl
Reactant: CCCOc1oc(=O)c2cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)ccc2c1Cl
Agent: CCOc1oc(=O)c2cc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc2c1Cl
Agent: CCOc1oc(=O)c2cc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)ccc2c1Cl
Product: CCCOc1oc(=O)c2cc(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc2c1Cl

Procedure:
7-(Boc-phenylalanyl)amino-4-chloro-3-propyloxyisocoumarin, 7-(benzoylalanylalanyl)amino-4-chloro-3-propyloxyisocoumarin, 7-(Boc-valyl)amino-4-chloro-3-ethoxyisocoumarin and 7-(Boc-alanyl)amino-4-chloro-3-ethoxyisocoumarin can be prepared by the same procedure.