Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[C:9]2[CH:10]=[CH:11][N:12]([C:13]([C:15]3[C:23]([Cl:24])=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=3[Cl:25])=[O:14])[C:8]=2[CH:7]=[CH:6][N:5]=1)(=O)C.[N:26]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[C:13]([NH:12][C:4]1[C:9]2[CH:10]=[CH:11][N:12]([C:13]([C:15]3[C:16]([Cl:25])=[CH:17][C:18]([C:19]([NH:35][CH2:34][CH2:33][CH2:32][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:21])=[CH:22][C:23]=3[Cl:24])=[O:14])[C:8]=2[CH:7]=[CH:6][N:5]=1)(=[O:14])[CH3:15]
Reactant: CC(=O)c1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Reactant: NCCCN1CCOCC1
Product: CC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)NCCCN2CCOCC2)cc1Cl

Procedure:
This was prepared analogously from 4-[(4-acetyl-1H-pyrrolo[3,2-c]pyridin-1-yl)carbonyl]-3,5-dichlorobenzoic acid and 3-(morpholin-4-yl)propylamine.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:14][CH2:13][CH2:12][N:10]3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:15][C:11]1[N:10]2[CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cn3c(n2)CCC3)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1c(-c2ccccc2)nc2n1CCC2
Yield: 73 %

Procedure:
To a solution of 2-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (3.38 g, 18.3 mmol) in dry CH2Cl2 (113 mL) slowly add bromine (1.0 mL, 20.2 mmol) and stir the mixture at room temperature for 1.5 hours. Add a saturated aqueous solution of NaHCO3 (100 mL) and extract with CH2Cl2 (3×100 mL). Wash the combined organic layers with NaHSO3 (40%, 30 mL), dry (MgSO4) and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, eluent: CH2Cl2 to CH2Cl2/MeOH 20:1) to yield a red solid, 3.54 g, 73% yield. MS(ES+): m/z=263.0 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[F:15])#[CH:2].[N:16]([CH:19]1[CH2:25][CH2:24][C:23]2[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:22]=2[N:21]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:20]1=[O:36])=[N+:17]=[N-:18]>>[F:30][C:26]1[C:23]2[CH2:24][CH2:25][CH:19]([N:16]3[CH:2]=[C:1]([C:3]4[CH:8]=[CH:7][C:6]([C:9]5[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=5)=[CH:5][C:4]=4[F:15])[N:18]=[N:17]3)[C:20](=[O:36])[N:21]([CH2:31][C:32]([F:33])([F:34])[F:35])[C:22]=2[CH:29]=[CH:28][CH:27]=1
Reactant: [N-]=[N+]=NC1CCc2c(F)cccc2N(CC(F)(F)F)C1=O
Reactant: C#Cc1ccc(-c2ccncc2)cc1F
Product: O=C1C(n2cc(-c3ccc(-c4ccncc4)cc3F)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Yield: 43.6 %

Procedure:
Following GP 3, the title compound (32 mg) was prepared using 4-(4-ethynyl-3-fluorophenyl)pyridine (29 mg) and 3-azido-6-fluoro-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (58 mg).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:16]=[C:15](F)[C:14]([F:18])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:15]2[C:14]([F:18])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([F:6])[CH:16]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc(F)c(F)cc1F
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(N2CCN(Cc3ccccc3)CC2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a 30 ml tetrahydrofuran solution of 4.25 g (22.35 mmol) of methyl 2,4,5-trifluorobenzoate, 3.89 ml (22.35 mmol) of N-benzylpiperazine was added with ice cooling. The mixture was stirred at 0° C. for 0.5 hour, and at room temperature for 2.5 hours. Then, the reaction mixture was diluted with ethyl acetate, and the dilution was washed with water and a saturated aqueous solution of sodium chloride in this order. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 2.61 g (34%) of the captioned compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[O:54])=[CH:48][CH:47]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(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:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:22])[CH3:23])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:47]=[CH:48][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[O:54])=[CH:50][CH:51]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CN(C)CCCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCCN(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, 3-(dimethylamino)propyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded 3-(dimethylamino)propyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].Br[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.O>CN(C)C=O>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([O:4][CH2:3][CH:2]([NH2:1])[CH3:5])=[CH:10][CH:11]=1)#[N:14]
Reactant: CC(N)CO
Reactant: N#Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N)COc1ccc(C#N)cc1
Yield: 40.9 %

Procedure:
50.0 g of 2-amino-1-propanol was added drop by drop to a mixture containing 29.3 g of 60% sodium hydride and 300 ml of N,N-dimethylformamide, in an ice bath, and the resultant mixture was stirred for 30 minutes in an ice bath. A solution containing 121.2 g of 4-bromobenzonitrile dissolved in N,N-dimethylformamide was added slowly to the reaction mixture while being stirred in an ice bath, followed by stirring the reaction mixture for 20 hours at room temperature. After the completion of the reaction, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate, and the ethyl acetate was removed under reduced pressure. The obtained residue was distilled under reduced pressure to yield 48.0 g of the desired product (41%).
Reaction SMILES: C([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:17]1[CH:26]=[C:25]3[C:20]([C:21](=[O:32])[C:22]([C:29]([OH:31])=[O:30])=[CH:23][N:24]3[CH2:27][CH3:28])=[CH:19][C:18]=1[F:33])[CH2:12][CH2:13]2)C1C=CC=CC=1.Cl.[H][H].C(Cl)(Cl)Cl>CO.[Pd].CCOCC>[CH2:27]([N:24]1[C:25]2[C:20](=[CH:19][C:18]([F:33])=[C:17]([N:11]3[CH2:12][CH2:13][CH:14]4[NH:8][CH:9]([CH2:16][CH2:15]4)[CH2:10]3)[CH:26]=2)[C:21](=[O:32])[C:22]([C:29]([OH:31])=[O:30])=[CH:23]1)[CH3:28]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4CCC(C3)N4Cc3ccccc3)cc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4CCC(C3)N4)cc21
Temperature: 25 °C
Yield: 19.3 %

Procedure:
7-(9-benzyl-3,9-diazabicyclo[4,2,1]non-3-yl)-6-fluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (963 mg, 2.15 mmoles) was dissolved in 125 ml of methanol that was previously saturated with HCl. To this solution was added 1.25 g of 10% Pd/C and the mixture was treated with an atmosphere of 45 psi hydrogen on a Parr hydrogenation apparatus at 60° C. for 4.5 hours. The mixture was then cooled to room temperature and filtered of catalyst through a celite pad. The filtrate was stripped to dryness, taken up in water (50 ml) and the pH was adjusted to 7.0 with saturated sodium bicarbonate. This aqueous layer was extracted with three times 200 ml chloroform which was dried over sodium sulfate and evaporated to give a solid residue. This residue was taken up in a small amount of chloroform and ether from which crystallized an off-white material that was filtered and dried to give 149 mg (19.3%) of the title compound, m.p. 147°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Agent: [Fe]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2nc(Cl)ccc2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-chloro-6-nitro-quinoline (12.5 g, 59.9 mmol) and ammonium chloridel (9.78 g, 183 mmol) were suspended in ethanol (175 mL) and water (50 mL). The resulting mixture was heated to 60° C. and iron powder (15.06 g, 270 mmol) was added as a solid in portions. The reaction mixture was stirred at 60° C. for 2 hours. LC-MS at this point showed one major peak corresponding to desired product. The reaction mixture was then concentrated to remove the majority of ethanol, and the residue was diluted with ethyl acetate and filtered to remove brown solids. The filter cake was washed with ethyl acetate. The filtrate was then dried over MgSO4, filtered and concentrated to afford a brown solid. This material was adsorbed onto silica and purified via Biotage automated flash column chromatography, eluting with 10-100% ethyl acetate/heptane. Relevant fractions were pooled and concentrated to afford a creamy yellow soft fluffy solid, which was dried under high vacuum to provide 6.45 g (60% yield) of product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]([CH3:16])=[C:4]([CH3:17])[N:3]=1>[Pt].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]([CH3:16])=[C:4]([CH3:17])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCC(C)C)c1C
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c(N)c(NCC(C)C)c1C

Procedure:
2-Chloro-N-isobutyl-5,6-dimethyl-3-nitropyridin-4-amine (25.8 g, 100 mmol) was combined with 5% platinum on carbon (2.58 g) and ethyl acetate (200 mL) in a pressure vessel and hydrogenated at 50 psi (3.4×105 Pa) for 2.5 hours on a Parr apparatus. The reaction mixture was filtered through CELITE filter agent, which was rinsed with ethyl acetate and methanol afterwards. The filtrate was concentrated to give 2-chloro-N4-isobutyl-5,6-dimethylpyridine-3,4-diamine and was used directly in the next step.
Reaction SMILES: C(O[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([F:24])=[CH:19][CH:18]=3)=[O:14])[C@H:8]([NH:25][C:26]([C:28]2[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=2)=[O:27])[CH2:7]1)=[O:5])C.[ClH:38].[CH3:39][NH:40][CH3:41]>>[ClH:38].[F:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:13]([NH:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([C:4](=[O:5])[N:40]([CH3:41])[CH3:39])[CH2:7][C@H:8]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:14])=[CH:23]2
Reactant: CCOC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(F)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Reactant: CNC
Agent: Cl
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cc4cc(F)ccc4[nH]3)sc2C1

Procedure:
(1S,2R,4S)-4-Ethoxycarbonyl-N1-[(5-fluoroindol-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was hydrolyzed and then subjected to a condensation reaction with dimethylamine hydrochloride in a similar manner to Example 157 to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([CH3:17])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1)=[O:8])[CH3:2].C(O)(=O)C.Br>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([CH3:17])[C:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(OC)cc1
Agent: Br
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC(C)C(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of crude 4-(4-methoxy-phenyl)-3-methyl-4-oxo-butyric acid ethyl ester (44 g, 175.8 mmol), acetic acid (300 mL) and 48% aqueous HBr (150 mL) was stirred at reflux for 10 h. The reaction was cooled to rt, concentrated at reduced pressure then partitioned between methylene chloride and water and the aqueous layer was extracted three times with methylene chloride and concentrated to provide a crude material. The crude material was dissolved in ethanol (125 mL) and added amberlyst then heated at 85° C. for 15 h. The reaction mixture was filtered over celite at rt and the filtrate was concentrated at reduced pressure and then partitioned between water and methylene chloride. The aqueous layer was extracted twice with methylene chloride to furnish a crude product and the crude product was purified by ISCO (330 g silica gel column) chromatography using 20 to 30% EtOAc in hexane to obtain a mixture (19 g) of 4-(4-hydroxyphenyl)-3-methyl-4-oxo-butyric acid ethyl ester (MS m/z 235 (M−H) and p-hydroxypropiophenone. The mixture was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:6]=[C:5]([CH3:15])[N:4]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22]>C(Cl)Cl>[F:14][C:11]([F:12])([F:13])[CH2:10][O:9][C:7]1[CH:6]=[C:5]([CH3:15])[N:4]=[C:3]([N:2]([CH3:1])[C:25]([NH:24][S:21]([C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)(=[O:22])=[O:23])=[O:26])[N:8]=1
Reactant: CNc1nc(C)cc(OCC(F)(F)F)n1
Reactant: O=C=NS(=O)(=O)c1cccs1
Solvent: ClCCl
Product: Cc1cc(OCC(F)(F)F)nc(N(C)C(=O)NS(=O)(=O)c2cccs2)n1

Procedure:
To a dry stirred solution of 22.1 parts of 2-methylamino-4-(2,2,2-trifluorethoxy)-6-methylpyrimidine in 250 parts of methylene chloride at ambient temperature was added 18.9 parts of 2-thiophenesulfonyl isocyanate. That mixture was stirred and refluxed for 2 hours. The methylene chloride was removed under reduced pressure, and the resulting solid was triturated with toluene to yield 19 parts of N-[N-[4-(2,2,2-trifluoroethoxy)-6-methylpyrimidin-2-yl]-N-methylaminocarbonyl]-2-thiophenesulfonamide.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][NH:7][C@@H:8]([C:11](=[O:13])[NH2:12])[CH2:9][CH3:10]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[CH2:4][CH2:5][CH2:6][N:7]1[C@H:8]([CH2:9][CH3:10])[C:11]([NH2:12])=[O:13]
Reactant: CC[C@@H](NCCCC(=O)OC)C(N)=O
Solvent: Cc1ccccc1
Product: CC[C@H](C(N)=O)N1CCCC1=O
Temperature: 80 °C
Yield: 30 %

Procedure:
To the crude methyl-(R)-4-(1-carbamoylpropylamino)butyrate (VIf) in toluene (20 ml) is added 2-hydroxypyrridine (50 mg, 10 mol %). The mixture is heated to 80° C. until complete conversion. After 16 hours (GC: 100% conversion) the mixture is concentrated to dryness to yield (R)-2-(2-oxopyrrolidin-1-yl)butyramide (0.28 g, 1.6 mmol, 30%, yield determination by GC assay from pure standard).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:18])[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([NH:18][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([CH3:19])=[CH:21][CH:22]=3)[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2nc(-c3ccccc3)c(-c3ccccc3)s2)cc1

Procedure:
4,5-Diphenyl-thiazol-2-ylamine (50.5 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was subjected to microwave irradiation for 5 minutes at 200° C. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (18.6 mg, 0.0502 mmol, 25.1%). ESI-MS m/z calc. 370.1. found 371.2 (M+1)+ Retention time 4.13 minutes.
Reaction SMILES: [CH:1]1([C:4]2[C:23]([F:24])=[C:22](F)[C:7]([C:8]([C:10](=[CH:16][NH:17][CH:18]([CH3:21])[CH2:19][OH:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6]([F:26])[C:5]=2[F:27])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([C:4]2[C:23]([F:24])=[C:22]3[C:7]([C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:17]3[CH:18]([CH3:21])[CH2:19][OH:20])=[C:6]([F:26])[C:5]=2[F:27])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(=CNC(C)CO)C(=O)c1c(F)c(F)c(C2CC2)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(C(C)CO)c2c(F)c(C3CC3)c(F)c(F)c2c1=O
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
In 3 ml of N,N-dimethylformamide was dissolved 300 mg of ethyl 2-(4-cyclopropyl-2,3,5,6-tetrafluorobenzoyl)-3-(2-hydroxy-1-methylethylamino)acrylate. To the resulting solution was added 130 mg of potassium carbonate. The resulting mixture was stirred at 80°-90° C. for 30 minutes, and 20 ml of water was added to the reaction mixture. The resulting crystals were collected by filtration to obtain 240 mg (yield: 84.5%) of ethyl 7-cyclopropyl-5,6,8-trifluoro-1-(2-hydroxy-1-methylethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate.
Reaction SMILES: O[C:2]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[O:7][CH2:6][CH2:5][N:4]([CH3:8])[C:3]1=[O:9].[CH2:18]([Si](C)(C)C)[CH:19]=[CH2:20]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:20]([C:2]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[O:7][CH2:6][CH2:5][N:4]([CH3:8])[C:3]1=[O:9])[CH:19]=[CH2:18]
Reactant: COc1cccc(C2(O)OCCN(C)C2=O)c1
Reactant: C=CC[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCC1(c2cccc(OC)c2)OCCN(C)C1=O
Temperature: -23 °C

Procedure:
Following the procedure described by S. Pansare et al., J. Org. Chem. 1998, 63, 4120-4124, 2-hydroxy-2-(3-methoxy-phenyl)-4-methyl-morpholin-3-one, as described in Step C above, (0.133 g, 0.56 mmol) was dissolved in anhydrous CH2Cl2 (10 mL) under Ar, treated with allyltrimethylsilane (0.534 mL, 3.36 mmol), the mixture cooled to −23° C., then treated with TiCl4 (0.37 mL, 3.36 mmol). After 15 min the reaction mixture was quenched slowly with saturated aqueous NH4Cl solution, left to warm to room temperature, and partitioned between CH2Cl2 and H2O. The aqueous layer was washed with CH2Cl2, the organic layers combined, dried (Na2SO4), filtered and concentrated to dryness to give the title compound after chromatography (SiO2, 0-1% MeOH in CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>CN(C)C=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:23])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(Cl)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 10 g of ethyl 2-aminothiazol-4-ylglyoxylate, 8.6 g of p-chlorophenyl isocyanate and 100 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: COC1C=CC(C[N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=CC=1.Br[C:30]1[C:31]([O:40][CH3:41])=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:41][O:40][C:31]1[C:30]([N:20]2[CH2:19][CH2:18][O:17][C:16]3[CH:21]=[C:12]([S:9]([NH:8][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]2=3)=[CH:35][CH:34]=[C:33]([C:36]([F:39])([F:37])[F:38])[N:32]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: COc1nc(C(F)(F)F)ccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1nc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
To a 10-20 ml microwave vial charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE M) (0.05 g, 0.120 mmol), 3-bromo-2-methoxy-6-(trifluoromethyl)pyridine (Anichem) (0.046 g, 0.180 mmol), sodium t-butoxide (0.029 ml, 0.240 mmol), xantphos (0.014 g, 0.024 mmol), and Pd2(dba)3 (10.97 mg, 0.012 mmol) was added toluene (1.198 ml). The mixture was purged with argon and the vessel was sealed and irradiated at 130° C. for 30 mins. LC-MS indicated complete conversion to desired product (PMB protected, m/z=593). To the mixture was added TFA (200 μl) and the resulting mixture stirred at room temperature for 2 hrs. The mixture was filtered through celite and the filtrate dried under reduced pressure. The crude material was purified with a 25 g HP spherical silica column (15 μm, Interchim) ramping EtOAc in heptane (0-50%, then isocratic at 50%, 10% DCM isocratic throughout) providing product as a film which was lyophilized yielding an off-white solid. The material was further purified with preparative RP-HPLC ramping ACN in H2O (10-90%, 0.1% TFA) affording 4-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (10 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.67-3.72 (m, 2 H) 3.92 (s, 3 H) 4.29-4.33 (m, 2 H) 6.44 (d, J=8.51 Hz, 1 H) 6.79 (d, J=4.60 Hz, 1 H) 7.13 (dd, J=8.51, 2.15 Hz, 1 H) 7.16 (d, J=2.05 Hz, 1 H) 7.22 (d, J=4.60 Hz, 1 H) 7.56 (d, J=7.92 Hz, 1 H) 7.90-7.97 (m, 1 H). m/z (ESI) 473.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH2:4].[OH:10]O>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[N:4]=[O:10]
Reactant: OO
Reactant: Nc1c(Br)cccc1Br
Solvent: CC(=O)O
Product: O=Nc1c(Br)cccc1Br
Reaction time: 48 h

Procedure:
To a solution of 2,6-dibromoaniline (10 g, 40 mmol) in glacial acetic acid (160 mL) was added 30% hydrogen peroxide (30 mL). The mixture was left for 48 h at which point crystals had precipitated. The crystals were collected by filtration, washed with acetic acid and water then dried under high vacuum to give 2,6-dibromonitrosobenzene (6.24 g). This material (2.6 g, 10 mmol) was dissolved in DMSO (25 mL) along with sodium azide (650 mg, 10 mmol). The mixture was heated to 100° C. for 1 h then cooled to rt and diluted with ethyl acetate and water. The layers were separated and the organic phase was washed with water and brine, then dried over sodium sulfate and concentrated. FC (75 g silica, 10/1 hexane/ethyl acetate) afforded the title compound (1.7 g).