Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[N:7]=[C:8]([CH3:21])[N:9](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[CH3:23][N:2]([CH3:1])[C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[N:7]=[C:8]([CH3:21])[NH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(/C=C/C(=O)N(C)C)nc2C)cc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1nc(/C=C/C(=O)N(C)C)c[nH]1
Reaction time: 1 h
Yield: 63.3 %

Procedure:
A solution of (E)-N,N-dimethyl-3-[2-methyl-1-(4-methylbenzenesulphonyl)-1H-imidazol-4-yl]-2-propenamide (1.0 g) in pyridine (5 ml) and acetic anhydride (10 ml) was stirred at room temperature for 16 h. The reaction mixture was evaporated in vacuo, methanol (15 ml) was added and stirring was continued for 1 h. The mixture was evaporated in vacuo and the resulting gum partitioned between potassium carbonate solution (ca. 25% saturated) (30 ml) and chloroform (4×25 ml). The combined organic layers were dried, evaporated in vacuo and the residue triturated with ether (30 ml) to give the title compound (340 mg) as a solid, t.l.c. (ether:methanol 9:1), Rf 0.07.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:38]=[C:37]([C:39]2([O:43][CH3:44])[CH2:42][O:41][CH2:40]2)[CH:36]=[C:35]([F:45])[C:34]=1B1OC(C)(C)C(C)(C)O1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:35]([F:45])=[CH:36][C:37]([C:39]4([O:43][CH3:44])[CH2:40][O:41][CH2:42]4)=[CH:38][C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: COC1(c2cc(F)c(B3OC(C)(C)C(C)(C)O3)c(F)c2)COC1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: COC1(c2cc(F)c(-c3nc(C(=O)Nc4cnn(C)c4[C@@H]4CC[C@@H](N)[C@H](F)CO4)cs3)c(F)c2)COC1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 2-(2,6-difluoro-4-(3-methoxyoxetan-3-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (US2012/225062) gave 339. 1H NMR (500 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.65 (s, 1H), 7.88 (s, 1H), 7.46-7.44 (m, 2H), 4.82-4.79 (m, 5H), 4.37-3.93 (m, 3H), 3.78 (s, 3H), 3.24-3.17 (m, 1H), 3.12 (s, 3H), 2.07-1.67 (m, 4H). LCMS (ES+) m/z 538 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[N:10]=[CH:11]OCC.C(NCCCC)CCC.C([N-]CCCC)CCC.[K+].[NH2-].[K+]>C(O)C>[CH2:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[NH:10][CH:11]=[CH:1]2)[CH3:9]
Reactant: CCOC=Nc1c(C)cccc1CC
Agent: CCCC[N-]CCCC
Agent: [K+]
Agent: [NH2-]
Solvent: CCCCNCCCC
Solvent: CCO
Product: CCc1cccc2cc[nH]c12
Temperature: 159 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Ethyl N-(2-methyl-6-ethylphenyl)formimidate (65.9 g.) in 50 ml. of di-n-butylamine was slowly added, over about 5 minutes, to the potassium di-n-butylamide reaction mixture at 20° C. The metallation and cyclization reactions were substantially instantaneous under these reaction conditions. The transient appearance of a deep red color characteristic of benzyl anion was developed and discharged immediately upon contact of ethyl N-(2-methyl-6-ethylphenyl)formimidate with the potassium amide reaction mixture near the neck of the reactor. All solids dissolved resulting in a light brownish solution. Stirring was continued for another half hour. Then 150 ml. of ethyl alcohol were added to destroy the excess amide and unreacted metal and also to convert potassium indole salt to indole. After the removal of the excess alcohol at reflux temperature (159° C.) through a distillating column packed with Fenske packing materials, a brown oily material separated and settled at the bottom of the flask. The top amine layer was decanted off. The brown oily layer was dissolved in 300 ml. of hexane, then washed with 500 ml. water which was extracted with two 300 ml. portions of hexane. The combined hexane extracts were dried over Na2SO4 and filtered. Evaporation of volatile components furnished 39.8 g. of 7-ethylindole (80.0 percent yield) of over 98.5 percent purity.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:3]([O:5]C(C)(C)C)=[O:4].C1(C)C=CC=CC=1.[ClH:27]>CC(O)C>[ClH:27].[NH2:1][C:2]([CH3:19])([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:3]([OH:5])=[O:4]
Reactant: COc1ccc(CC(C)(N)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: COc1ccc(CC(C)(N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 67 %

Procedure:
Intermediate tert-butyl 2-amino-3-(4-methoxyphenyl)-2-methylpropanoate (0.60 g, 2.26 mmol) was mixed with toluene (6 mL) and a 5-6 N HCl solution in IPA (2 mL). A clear yellow solution was heated to reflux and kept at that temperature for 7 h. The resulting slurry was cooled to ambient temperature and filtered. The solid was washed with toluene (3 mL) on a filter and air-dried to afford 2-amino-3-(4-methoxyphenyl)-2-methylpropanoic acid hydrochloride [0.37 g; 67%] as a white solid [HPLC 71.8% (AUC; tR=3.71]. 1H NMR (500 MHz, DMSO-d6): δ 13.96 (br. s, 1H, COOH), 8.44 (br. s, 3H, NH3), 7.16 (d, J=8.7 Hz, 2H, Ar), 6.90 (d, J=8.7 Hz, 2H, Ar), 3.74 (s, 3H, CH3), 3.08 (s, 2H, CH2), 1.48 (s, 3H, CH3). Optical rotation (α25D, DMSO, c=1.10)+7.27°.
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1[C:20]([C:21]([CH2:23]Br)=O)=[CH:19][CH:18]=[C:17]([Cl:25])[CH:16]=1>>[Cl:25][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:8]3[N:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH2:12]3)[CH:23]=2)=[CH:15][CH:16]=1
Reactant: CC1(C)CN=C(Cc2ccccc2)C1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Product: CC1(C)Cc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)cn2C1

Procedure:
The 2-benzyl-4,4-dimethyl-1-pyrroline of the formula III is then cyclized with ω-bromo-4-chloroacetophenone to give the 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine of the formula II. The reaction is known from the prior art mentioned at the outset. ω-Bromo-4-chloroacetophenone can be obtained, for example, as described in Bull. Soc. Chim. Fr. 21, 69 (1899).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([NH:9][C:10]([C:12]3[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=3)=[O:11])[S:7][CH:8]=2)[CH2:3][CH2:2]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=1>>[CH:1]1([C:4]2[N:5]=[C:6]([NH:9][C:10]([C:12]3[C:17]([NH:18][C:21]4[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=4)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=3)=[O:11])[S:7][CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(N)c(C(=O)Nc2nc(C3CC3)cs2)n1
Reactant: Fc1cncc(Br)c1
Product: Cc1ccc(Nc2cncc(F)c2)c(C(=O)Nc2nc(C3CC3)cs2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-cyclopropyl-thiazol-2-yl)-amide in accordance with the general method of example 20 using 3-Bromo-5-fluoropyridine instead of 3-bromopyridine to yield the final compound as a yellow solid, MS (ISP): m/e=370.1 (M+H+).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][CH2:6][C:7](=O)[CH2:8][C:9]#[N:10]>C(O)C>[CH3:4][O:5][CH2:6][C:7]1[CH:8]=[C:9]([NH2:10])[NH:2][N:3]=1
Reactant: NN
Reactant: COCC(=O)CC#N
Solvent: CCO
Solvent: O
Product: COCc1cc(N)[nH]n1
Temperature: 25 °C
Yield: 53 %

Procedure:
Hydrazine monohydrate (0.49 ml) was added to a solution of the thus obtained 4-methoxy-3-oxobutyronitrile (1.14 g) in ethanol (50 ml), and refluxed for 17 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 50:1) to give 5-methoxymethyl-2H-pyrazol-3-ylamine (684 mg, Y.:53%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>ClCCl>[CH3:26][C:23]([CH3:27])([NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:24][OH:25]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CO)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 67.1 g (0.322 mole) of 4-chloro-3-nitroquinoline in 800 mL of dichloromethane was added 54 mL (0.38 mole) of triethylamine and 96 mL (0.96 mole) of 2-amino-2-methyl-1-propanol. The mixture was heated at reflux for one hour, then stirred at about 20° C. for about 16 hours. The mixture was concentrated by evaporation in vacuo and the residue was slurred in 1.5 l of water. The product was separated by filtration and dried to provide solid 2,2-dimethyl-2-[(3-nitro-4-quinolinyl)amino]ethanol. The structural assignment was confirmed by comparison of the nuclear magnetic resonance spectrum to that of a sample which was previously used for elemental analysis. Analysis of earlier sample: Calculated for C13H15 N3O2 : % C, 59.8; % H, 5.8; % N, 16.1; Found % C, 59.9; % H, 5.8; % N, 16.1.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[H-].[Na+].[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>CN(C)C=O>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:14]=2[F:13])[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Fc1cccc(CBr)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(=O)[nH]c(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
4-Amino-6-hydroxy-2-mercaptopyrimidine monohydrate (7.1 g) was added portion wise to a stirred suspension of 60% sodium hydride (2.4 g) in dry N,N-dimethylformamide (70 ml). After 1 hour a solution of 2,3-Difluorobenzyl bromide (10 g) in dry N,N-dimethylformamide (10 ml) was added. Stirred over weekend at room temperature. Poured on to ice/water and the precipitate was collected by filtration to give 9.6 g of product. 81% yield.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:8])[C@H:3]1[CH2:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:13]1[C:12]2[CH:11]([CH2:10][O:9][C:7]([N:4]([CH3:5])[C@@H:3]([CH2:24][C:25]3[N:26]=[CH:27][S:28][CH:29]=3)[C:2]([OH:6])=[O:1])=[O:8])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C1OCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]1Cc1cscn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](Cc1cscn1)C(=O)O
Temperature: 35 °C
Reaction time: 48 h
Yield: 87.1 %

Procedure:
(S)-(9H-Fluoren-9-yl)methyl 5-oxo-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (Compound SP817) (40.0 g, 98.4 mmol), trifluoroacetic acid (245 ml, 3.18 mol) and triethylsilane (160 ml, 1.00 mol) were dissolved in dichloromethane (1 l) under a nitrogen atmosphere, and the mixture was stirred at 35° C. for two days. The reaction solution was concentrated under reduced pressure and then dissolved in diethyl ether, and the organic layer was washed with an aqueous sodium bicarbonate solution. The aqueous layer was adjusted to pH 3 with a aqueous potassium bisulfate solution and extracted with dichloromethane. All organic extracts obtained were washed with brine, dried over sodium sulfate and then concentrated under reduced pressure to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(thiazol-4-yl)propanoic acid (Compound SP811, Fmoc-MeAla(4-Thz)-OH) (35 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[NH:11][N:10]=1.[N:20]([Sn](CCCC)(CCCC)CCCC)=[N+:21]=[N-:22]>C1(C)C=CC=CC=1>[N:19]1[NH:20][N:21]=[N:22][C:18]=1[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1-c1n[nH]c2ccc(C#N)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1n[nH]c2ccc(-c3nn[nH]n3)cc12
Temperature: 0 °C

Procedure:
To a solution of 3-(2-methoxyphenyl)-1H-indazole-5-carbonitrile in toluene (20 mL) was added azidotributyl tin (0.716 g, 0.591 mL, 2.156 mmol). The reaction mixture was heated to reflux temperature for 18 hours. The solvent was removed under reduced pressure with no heat. The resulting oil was dissolved in tetrahydrofuran (2 mL) and toluene was added (20 mL). Hydrogen chloride was bubbled through the solution for 15 min, which resulted in the precipitation of a white solid. The product was collected by filtration after cooling to 0° C. and was washed with 5 mL portions of toluene. The impure solid was dissolved in 5 mL of aqueous sodium hydroxide (2.0 N) and the aqueous phase was washed with ethyl acetate. The product was precipitated out of the aqueous phase by bubbling hydrogen chloride gas. The solid was collected by filtration and washed with small portions of water. The product was isolated as an off-white solid after drying in a vacuum oven (0.110 g, 0.377 mmol, 20% over 2 steps): 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 8.4 (s, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 7.4 (t, 1H), 7.2 (d, 1H), 7.1 (t, 1H), 3.8 (s, 3H); ES-MS (m/z) 293 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20](Cl)[C:19]([CH3:26])=[C:18]([CH3:27])[N:17]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[C:19]([CH3:26])=[C:18]([CH3:27])[N:17]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: CC(C)(C)OC(=O)NCCOCCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCNC(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (2 3.1 g, 113 mmol) in N,N-dimethylformamide (100 mL) was added over a 1 hour period to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (25.02 g, 113 mmol) in N,N-dimethylformamide (400 mL) containing triethylamine (24 mL, 175 mmol). The reaction mixture was allowed to stir at ambient temperature overnight. The N,N-dimethylformamide was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), washed with water (3×100 ml), dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (450 g of silica gel eluting sequentially with 3/1 hexanes/ethyl acetate (1.2 L), 2/1 hexanes/ethyl acetate (1.2 L), and 1/1 hexanes/ethyl acetate (1 L)) to provide 20.67 g of tert-butyl 2-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethoxy}ethylcarbamate.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@@H:20]4[CH2:24][C@@H:23]([CH2:25][OH:26])[CH:22]=[CH:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[S:34]([NH2:37])(=[O:36])=[O:35]>C(C#N)(C)=O>[S:34](=[O:36])(=[O:35])([O:26][CH2:25][C@@H:23]1[CH2:24][C@@H:20]([N:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][C@@H:1]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:3][CH2:2]4)[C:12]=3[CH:19]=[CH:18]2)[CH:21]=[CH:22]1)[NH2:37]
Reactant: OC[C@H]1C=C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Reactant: NS(=O)(=O)Cl
Agent: CC(=O)C#N
Solvent: c1ccncc1
Product: NS(=O)(=O)OC[C@H]1C=C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of ((1R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopent-2-en-1-yl)methanol (35.7 mg, 0.103 mmol) and pyridine (0.0417 mL, 0.515 mmol) in AcCN (1.00 mL) at 0° C. under an atmosphere of nitrogen was added dropwise a 2.00 M solution of chlorosulfonamide in AcCN (0.260 mL, 0.520 mmol, as prepared in 1j). The solution was stirred for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate solution and partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 5% MeOH in DCM to afford the title compound as a solid (28.9 mg, 66%). 1H NMR (400 MHz, CDCl3, δ): 8.36 (s, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.30-7.18 (m, 3H), 6.89 (d, J=3.6 Hz, 1H), 6.32 (d, J=3.5 Hz, 1H), 6.14-6.12 (m, 1H), 6.04-5.97 (m, 2H), 5.89 (br s, 1H), 4.19 (dd, J=1.2, 6.0 Hz, 2H), 3.43-3.37 (m, 1H), 3.09-3.01 (m, 1H), 2.98-2.90 (m, 1H), 2.77-2.69 (m, 1H), 2.46-2.39 (m, 1H), 2.07-1.93 (m, 3H) ppm. LC/MS: Rt=1.24 min, ES+ 426 (FA standard).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:16][CH3:17])[CH:8]=2)=[O:5])[CH2:3][CH2:2]1.[N+:18]([O-])([OH:20])=[O:19]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH:1]1([C:4]([NH:6][C:7]2[C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:16][CH3:17])[CH:8]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: COc1cc(NC(=O)C2CC2)ccc1C(=O)O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(NC(=O)C2CC2)c([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 780 mg portion of 4-cyclopropylcarbonylamino-2-methoxybenzoic acid was dissolved in 10 ml of acetic anhydride and 0.5 ml of acetic acid, and 790 μl of concentrated nitric acid was slowly added to the above solution under ice-cooling, followed by 2 hours of stirring. The reaction solution was poured into ice water, and the thus formed precipitate was collected by filtration and dried under a reduced pressure to give 713 mg of 4-cyclopropylcarbonylamino-2-methoxy-5-nitrobenzoic acid.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]([F:21])([F:20])[C:10]1[C:11]([C:15]([O:17]CC)=[O:16])=[CH:12][NH:13][CH:14]=1.I[CH2:23][CH3:24]>O>[CH2:23]([N:13]1[CH:14]=[C:10]([C:9]([F:8])([F:20])[F:21])[C:11]([C:15]([OH:17])=[O:16])=[CH:12]1)[CH3:24]
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a mixture of 60% sodium hydride (212 mg, 5.31 mmol) and N,N-dimethylformamide (25 mL) was added with stirring at 0° C. ethyl 4-(trifluoromethyl)-1H-pyrrole-3-carboxylate (1.00 g, 4.83 mmol), and the mixture was stirred at room temperature for 30 min. Iodoethane (581 μL, 7.24 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, ethanol (4 mL) and 8N aqueous sodium hydroxide solution (2 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hr and at 60° C. for 15 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give the title compound (710 mg, 71%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N+:4]([O-:33])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=2[N:12]=1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3Br)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)c(Br)c1
Temperature: 50 °C
Yield: 70.7 %

Procedure:
To a mixture of 0.50 g of 2-(3-bromopyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 5 ml of chloroform, 0.58 g of 65% m-chloroperbenzoic acid was added. The reaction mixture was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and a saturated sodium chloride solution, sequentially. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.37 g of 3-bromo-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 28”).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.CCN(CC)CC.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:3][CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1csc(N)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1csc(NC(=O)Oc2ccccc2)n1
Yield: 51.2 %

Procedure:
A solution of 2-amino-4-methylthiazole (11.42 g, 0.10 mol) in CH2Cl2 was cooled to 0° C. in an ice bath and treated with Et3N (12.1 g, 0.12 mol). While stirring, the mixture was treated with phenyl chloroformate (15.6 g, 0.10 mol) drop-wise from an addition funnel. After the addition was complete the mixture was stirred for 10 minutes. The reaction mixture was washed with saturated NaHCO3, water, brine and then dried over MgSO4. The solution was filtered and the solvent removed under vacuum in a rotary evaporator and the resulting solid was chromatographed on silica gel (eluting with 40% ethyl acetate/hexane) to give 12 g of the desired carbamate as a white solid. 1H NMR (300 MHz, CDCl3) δ δ 12.38 (bs, 1H), 7.47-7.40 (m, 2H), 7.30-7.19 (m, 3H), 6.52 (d, J=1.1 Hz, 1H), 2.41 (d, J=0.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[NH2:10])=[O:4].[CH3:12][C:13]1([CH3:20])[O:18][CH2:17][C:16](=O)[CH2:15][O:14]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[NH:10][CH:16]1[CH2:17][O:18][C:13]([CH3:20])([CH3:12])[O:14][CH2:15]1)=[O:4]
Reactant: CC1(C)OCC(=O)CO1
Reactant: COC(=O)c1sc(Br)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(Br)cc1NC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.6 %

Procedure:
A suspension of 3-amino-5-bromo-thiophene-2-carboxylic acid methyl ester (0.5 g, 2.12 mmol) in dry THF (0.6 mL) was treated with 2,2-dimethyl-[1,3]dioxan-5-one (253 μl, 2.12 mmol), followed by dibutyltin dichloride (32 mg, 0.11 mmol). After 5 min phenyl silane (280 μl, 2.27 mmol) was added and the reaction was stirred at room temperature for 3 days. It was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution and brine. The organic layer was separated, dried over MgSO4, evaporated and left on vacuum pump overnight. The residue was triturated with hexane-ether (4:1) mixture (2×100 mL). The soluble portion was evaporated and purified by chromatography over silica gel (hexane:ethyl acetate-95:5) yielding pure 5-bromo-3-(2,2-dimethyl-[1,3]dioxan-5-ylamino)-thiophene-2-carboxylic acid methyl ester (220 mg, 29%).