Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)(Cl)Cl.[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:20][CH2:19]1)#[N:17]>C(OCC)(=O)C>[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:9])=[O:26])[CH2:20][CH2:19]1)#[N:17]
Reactant: CC(C)(C)S(=O)NC1CCN(C#N)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)S(=O)(=O)NC1CCN(C#N)CC1
Reaction time: 16 h

Procedure:
Meta-chloroperbenzoic acid (60 mg) was added to the chloroform solution (0.5 mL) containing 1-cyano-4-(tert-butylsulfinyl-amino)piperidine at room temperature, followed by stirring at the same temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with aqueous saturated sodium hydrogencarbonate and aqueous saturated sodium chloride solutions successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (58 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH:21]([C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[O:26][CH2:27][C:28]([OH:30])=[O:29])=O>>[C:17]([C@H:11]1[C@H:12]2[CH2:16][C@H:15]([CH:14]=[CH:13]2)[C@H:10]1[NH:9][C:6]1[C:5]([Cl:20])=[CH:4][N:3]=[C:2]2[NH:1][C:21]([C:23]3[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=3)[O:26][CH2:27][C:28]([OH:30])=[O:29])=[N:8][C:7]=12)(=[O:18])[NH2:19]
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccc(OCC(=O)O)c1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cccc(OCC(=O)O)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 31 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (1 eq.) and 2-(3-Formylphenoxy)acetic acid (48) (1.1 eq) were reacted in an analogous manner as compound CCXXIII to yield the desired product (31%) as a brown solid. NMR: δ (1H, 400 MHz, DMSO-d6): 1.38 (1H, d, J=8.8 Hz), 2.23 (1H, d, J=8.4 Hz), 2.63 (1H, d, J=8 Hz), 2.78-2.88 (2H, m), 4.26 (2H, s), 5.20 (1H, t, J=8.4 Hz), 6.36-6.42 (2H, m), 6.90 (1H, d, J=8.8 Hz), 7.14 (1H, d, J=8.8 Hz), 7.21 (1H, bs), 7.36 (1H, t, J=7.2 Hz), 7.60-7.70 (2H, m), 7.78 (1H, s), 7.94 (1H, s).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9](C([O-])=O)[CH2:10]2.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[F:19][C:2]([F:1])([F:18])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][NH:9][CH2:10]2
Reactant: O=C([O-])N1CCc2c(cccc2OCC(F)(F)F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COc1cccc2c1CCNC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5-(2,2,2-Trifluoroethoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (120 mg) was dissolved in DCM (6 mL) followed by addition of TFA (2 mL). The reaction mixture was stirred at RT for 20 min. The reaction solvent was removed under reduced pressure and the residue was dried on high vacuum overnight to yield 5-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydroisoquinoline 2,2,2-trifluoroacetate (125 mg) as a colorless oil which was used without purification.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9][CH2:8]1)(=O)=O.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[CH2:15]([NH:22][CH2:6][CH:7]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9][CH2:8]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC1(C)OCC(COS(C)(=O)=O)CO1
Solvent: CCOC(C)=O
Product: CC1(C)OCC(CNCc2ccccc2)CO1
Yield: 84.7 %

Procedure:
A solution of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (1.70 g, 7.58 mmol) in benzylamine (10 mL, 92 mmol) was stirred at 80° C. and monitored by TLC. After 2 h the reaction was complete therefore concentrated in vacuo. The residue was diluted with toluene (containing a small amount of ethyl acetate) and washed with water, dried and concentrate in vacuo. Column chromatography on silica eluting with ethyl acetate afforded N-benzyl(2,2-dimethyl-1,3-dioxan-5-yl)methanamine (1.51 g, 85% yield) as a yellow oil. 13C NMR (CD3OD) δ 140.8, 129.4 (2XCH), 128.1, 99.3, 64.0 (2XCH2), 54.7, 33.7, 25.6, 23.0
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.Cl[C:22]([O:24][C@H:25]1[CH2:29][CH2:28][O:27][CH2:26]1)=[O:23]>C(Cl)Cl>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:22](=[O:23])[O:24][C@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=C(Cl)O[C@H]1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)O[C@H]2CCOC2)C1
Temperature: 25 °C

Procedure:
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (500 mg, 2.6 mmol) in 5 mL CH2Cl2 was added triethylamine (0.73 mL, 5.2 mmol), and the reaction was cooled to −20° C. (S)-tetrahydrofuran-3-yl chloroformate (525 mg, 3.48 mmol) was added in portions over a period of 10 minutes to the above reaction mixture. After allowing the reaction to warm to room temperature, it was quenched with water and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to afford (S)-tetrahydrofuran-3-yl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2 gave (S)-tetrahydrofuran-3-yl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate (490 mg, 63%). LC/MS: m/z 301.3 (M+H)+ at 2.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.[F:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH2:5].C(N(CC)CC)C.[N:15]([C@H:18]([C@H:28]1[CH2:30][O:29]1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[N+:16]=[N-:17]>CC(O)C>[N:15]([C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C@H:28]([OH:29])[CH2:30][NH:5][CH2:4][C:3]([F:2])([CH3:7])[CH3:6])=[N+:16]=[N-:17]
Reactant: COc1ccc(C[C@H](N=[N+]=[N-])[C@H]2CO2)cc1
Reactant: CC(C)(F)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1ccc(C[C@H](N=[N+]=[N-])[C@H](O)CNCC(C)(C)F)cc1
Temperature: 60 °C
Yield: 50 %

Procedure:
To a solution of 2-fluoro-2-methylpropan-1-amine-HCl (2.0 eq) and triethyl amine (4.0 eq) in iPrOH was added an iPrOH solution of (S)-2-((S)-1-azido-2-(4-methoxyphenyl)ethyl)oxirane. The mixture was heated at 60° C. for 6 h. Upon completion the reaction mixture was concentrated then dissolved in ethyl acetate and washed with H2O. The organic layer was combined washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography. 50% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.4 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 3.80 (s, 3H), 3.64-3.57 (m, 2H), 2.96-2.88 (m, 2H), 2.78-2.68 (m, 4H), 1.42 (d, J=3.1 Hz, 3H), 1.37 (d, J=3.1 Hz, 3H).
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]([OH:8])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[CH:2]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>O1CCCC1>[CH2:27]=[CH:26][C:25]([O:8][C:4]1[CH:5]=[C:6]([Cl:7])[CH:1]=[CH:2][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])=[O:28]
Reactant: C=CC(=O)Cl
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Irgasan® DP300 5-chloro-2-(2,4-dichlorophenol) (triclosan), 23.5 g (0.081 mol) was dissolved in 300 ml of dry tetrahydrofuran in a 1-I jacketed kettle with agitator, addition funnel and reflux condenser. Then 10.6 ml of triethylamine was added to the solution with agitation. To the resulting solution was added dropwise 6.68 (0.0738 mol) g of acryloyl chloride. The reaction temperature was maintained at 20° C. with a circulating cooling bath. After the addition of acryloyl chloride was completed, the agitation and temperature conditions were maintained for 5 hours. Then the reaction product was kept overnight at room temperature, filtered to remove solid triethylamine hydrochloride and the filtrate rotovapped at room temperature under 100-110 mm Hg to concentrate the product. The remaining solution was dissolved in 100 ml heptane and washed with 5% Na2CO3 solution in DI water until basic; then with DI water until neutral. The heptane solution of the product was dried with MgSO4 in a refrigerator overnight, and filtered. The filtrate contained 25.3% triclosan acrylate as determined by bromination. FTIR spectrum confirmed the presence of the unsaturated ester of a phenol (1753 cm−1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Br:19]C1C=C(C=CC=1)N.N1C=CC=CC=1C=O>>[Br:19][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: Nc1cccc(Br)c1
Agent: O=Cc1ccccn1
Product: Brc1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-bromoaniline (223 mg, 1.3 mmol) and pyridine-2-carboxaldehyde (135 mg, 1.3 mmol) were employed to obtain 2-[2-(3-bromophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([CH3:15])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C(O)COCCO.O>[CH3:16][O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[N:20]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH3:15])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1ccccc1N
Reactant: Cc1cccc2c1=NC(=O)C1CCOC=21
Solvent: OCCOCCO
Solvent: O
Product: COc1ccccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Temperature: 250 °C
Yield: 79 %

Procedure:
4-Oxo-6-methyl-2,3-dihydrofuro[3,2-c]quinoline (201 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol and 2-methoxyaniline (282 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 242 mg of desired compound as solid in 79% of yield.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[S:13][CH3:14])=[O:5].C(O)(=O)C.CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1>O>[F:12][C:10]1[CH:9]=[CH:8][C:7]([S:13][CH3:14])=[C:6]([C:4](=[O:5])[CH2:3][N:2]2[CH:21]=[CH:25][CH:24]=[CH:23]2)[CH:11]=1
Reactant: CSc1ccc(F)cc1C(=O)CN
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(F)cc1C(=O)Cn1cccc1
Temperature: 95 °C
Yield: 44.9 %

Procedure:
To a solution of 2-amino-1-[5-fluoro-2-(methylthio)phenyl]ethanone hydrochloride (4.54 g, 19.27 mmol) in water (29 ml), heated at 90° C., were added trihydrated sodium acetate (2.62 g, 19.27 mmol), glacial acetic acid (17 ml) and 2,5-dimethoxytetrahydrofuran (2.40 ml, 18.50 mmol). After 20 seconds at 90-100° C. the mixture was cooled and extracted with ethyl acetate. The organic layers were washed with a 20% solution of sodium bicarbonate and brine, dried and evaporated. The residue was chromatographed (50% petroleum ether 40-60° in dichloromethane) to afford 2.07 g of 22c as white crystals mp 133.2-134.0° C. (50% yield). 1H NMR (CDCl3) δ7.39-7.15 (m, 34); 6.66-6.65 (m, 2H); 6.22-6.20 (m, 2H); 5.20 (s, 2H); 2.42 (s, 3H). MS m/z 252 (M++H), 234, 202 (100), 183, 169, 154, 141, 126, 109, 80.
Reaction SMILES: [C:1]([O:17][CH:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]1)(=[O:16])[CH2:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)=[O:4].[C:28]([C:32]1[CH:33]=[C:34]([CH:39]=[C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:41]=1[OH:42])[CH2:35]N(C)C)([CH3:31])([CH3:30])[CH3:29].[NH2-].[Li+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:14][C:8]1([CH3:15])[CH2:7][CH:6]([O:5][C:3](=[O:4])[CH:2]([CH2:35][C:34]2[CH:33]=[C:32]([C:28]([CH3:29])([CH3:31])[CH3:30])[C:41]([OH:42])=[C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=2)[C:1]([O:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)=[O:16])[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9]1
Reactant: CC1(C)CC(OC(=O)CC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [NH2-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)CC(OC(=O)C(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1

Procedure:
26 g (0.068 mole) of bis-(2,2,6,6-tetramethyl-4-piperidinyl) malonate and 17.8 g (0.068 mole) of N-(3,5-di-tert.butyl-4-hydroxybenzyl)dimethylamine are dissolved in 200 ml of toluene. After the addition of 0.5 g of lithium amide, the mixture is refluxed for 3 hours. After cooling, the mixture is neutralised with 1.5 ml of 1% acetic acid, and the organic phase repeatedly washed with water. After drying over Na2SO4, the solution is concentrated in vacuo to obtain, as oily residue, 3,5-di-tert.butyl-4-hydroxybenzyl-malonic acid-bis(2,2,6,6-tetramethyl-4-piperidinyl)ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]3[CH:18]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[O:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:26](=[O:29])[CH:27]([OH:28])[C:18]1[N:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]2=[N:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:32]
Reactant: COc1ccc(-c2cn3cc(C)ccc3n2)cc1
Reactant: CCOC(=O)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(O)c1c(-c2ccc(OC)cc2)nc2ccc(C)cn12
Temperature: 25 °C
Yield: 19.8 %

Procedure:
To a magnetically stirred solution of 2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridine 13a (2.55 g, 10.71 mmol) and ethyl glyoxylate toluene solution (11.79 mL, 54.62 mmol) in toluene (130 mL) under Ar atmosphere was added p-toluenesulfonic acid monohydrate (60.9 mg, 0.32 mmol). The reaction mixture was equipped with a dean-stark trap and refluxed for 4 h. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (40:60 EtOAc/hexane, then 100% EtOAc as eluent), which gave the title compound (0.72 g, 20%) as an off white solid. 1H NMR (400 MHz, CDCl3) 1.15 (t, J=7.0 Hz, 3H), 2.31 (s, 3H), 3.83 (s, 3H), 4.13 (m, 1H), 4.24 (m, 1H), 5.75 (s, 1H), 6.91 (d, J=8.8 Hz, 2H), 7.04 (dd, J=1.4, 9.1 Hz, 1H), 7.47 (d, J=9.1 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.99 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[CH:21]=[CH:22][O:23][CH2:24][CH3:25])CCC>C1(C)C=CC=CC=1.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>[CH2:24]([O:23]/[CH:22]=[CH:21]/[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1)[CH3:25]
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCO/C=C/c1ccc2ncc(C(=O)OCC)n2c1
Temperature: 25 °C

Procedure:
To a stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (24s) (1 g, 3.72 mmol) and tetrakis(triphenylphosphine)palladium(0) (215 mg, 0.19 mmol) in anhydrous toluene (10 mL) under argon was added tributyl[2-ethoxyethenyl]stannane (1.7 g, 4.65 mmol). The reaction mixture was heated in a microwave sealed tube overnight at 90° C. The reaction was cooled to room temperature and was filtered through celite. The solvent was concentrated and the crude product was purified by silica chromatography to afford (E)-ethyl 6-(2-ethoxyvinyl)imidazo[1,2-a]pyridine-3-carboxylate (111). MS m/z 261.3 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:27]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][NH:28]1>>[O:32]=[S:27]1(=[O:33])[CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C#N)CC2)nc1C
Yield: 84.5 %

Procedure:
Using 5-bromo-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (413 mg) described in Preparation Example 172 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (383 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[CH3:12][CH:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14]>CN(C=O)C>[CH:13]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:12]
Reactant: CC(C)N1CCNCC1
Reactant: CC(=O)Nc1ccnc(Cl)c1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccnc(N2CCN(C(C)C)CC2)c1
Temperature: 150 °C

Procedure:
A mixture of 4.6 g (27 mmol) N-(2-chloropyridin-4-yl)acetamide (commercially available) and 5.2 g (41 mmol) 1-(2-propyl-)-piperazine in 2 ml DMF was heated to 150° C. for 4 h. Purification of the crude mixture with flash column chromatography on silica eluting with a gradient formed from DCM (1% NEt3) and methanol yielded after evaporation of the product fractions 3.38 g (47%) of the title compound as white solid. MS: (m/e): 263.4 (MH+).
Reaction SMILES: [C:1]1(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[O:8])[CH2:2]1.[Br:10]Br>C(Cl)Cl>[Br:10][CH:2]1[C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH2:7][C:1]1=[O:9]
Reactant: O=C1CCCCC(=O)C1
Reactant: BrBr
Solvent: ClCCl
Product: O=C1CCCCC(=O)C1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
Into the solution of 1,3-cycloheptanedione (252 mg, 2.0 mmol) in 5 mL of CH2Cl2 was added a solution of Br2 (320 mg, 2.0 mmol) in 2 mL of CH2Cl2. The mixture was stirred at room temperature for 15 minutes. The white solid was collected, washed with CH2Cl2, and dried to give 2-bromo-1,3-cycloheptanedione (330 mg), which was used for next step with no further purification. Into the solution of 2-bromo-1,3-cycloheptanedione (205 mg, 1 mmol) in 5 mL of MeOH was added thiourea (152 mg, 2 mmol) and K2CO3 (276 mg, 2 mmol). The mixture was stirred at 70° C. for 1 hour, cooled down to room temperature. The solution was concentrated, and the residue was partitioned between EtOAc and H2O. The aqueous layer was washed with EtOAc. The combined organic phases were dried (Na2SO4) and concentrated to give the crude thiazole 22a as a yellow solid.
Reaction SMILES: C[Si](C)(C)[O:3][NH2:4].C(=O)([O-])O.[Na+].[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]2[S:25][C@@H:24]([CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:23](=[O:37])[N:22]([CH2:38][C:39](O)=[O:40])[C:21]=2[CH:42]=1)=[O:16])[CH3:13]>C1COCC1.ClC(OCC(C)C)=O.CN1CCOCC1>[OH:3][NH:4][C:39](=[O:40])[CH2:38][N:22]1[C:21]2[CH:42]=[C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH:18]=[CH:19][C:20]=2[S:25][CH:24]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:23]1=[O:37]
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)O)C(=O)[C@H](CCCc1ccc(OC)cc1)S2
Reactant: C[Si](C)(C)ON
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc2c(c1)N(CC(=O)NO)C(=O)C(CCCc1ccc(OC)cc1)S2
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
In THF (40 ml) was dissolved {(2S)-6-(ethoxycarbonyl)-2-[3-(4-methoxyphenyl)propyl]-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl}acetic acid (the compound of Reference Example 11) (2.06 g), and isobutyl chloroformate (0.72 ml) and N-methylmorpholine (0.51 ml) were added thereto at −20° C. and stirred at −10 to −20° C. for 30 minutes. After O-(trimethylsilyl)hydroxylamine(0.87 ml) was added thereto, the resulting mixture was warmed up to room temperature and stirred for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogencabonate solution and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to obtain (−)-ethyl 4-[2-(hydroxyamino)-2-oxoethyl]-2-[3-(4-methoxyphenyl)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (1.69 g, 99.9% e.e.). The optical purity analysis conditions are as follows. [Column: AD-H(CHIRALCEL, DAICEL Chemical Industries Ltd.); detecting wavelength (UV): 254 nm; flow rate: 1.0 ml/min; mobile phase: n-hexane/isopropyl alcohol/TFA=80/20/0.1]
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>CN(C=O)C>[F:18][C:2]([F:1])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:16][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C(N1CCc2ccc(O)cc2CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
Add 2,2,2-trifluoro-1-(7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)ethanone (0.750 g, 2.89 mmol), 6-chloronicotinamide (0.377 g, 2.41 mmol) and K2CO3 (0.833 g, 6.03 mmol) to a round bottom equipped with a Dean-Stark trap. Add toluene (6 mL) and DMF (18 mL). Heat at reflux for two hours. Cool the reaction mixture to 100° C. and stir overnight. Remove the toluene and DMF as an azeotrope with xylenes. Suspend the solid in 5% methanol/ethyl acetate (100 mL) and filter. Wash the filter cake with ethyl acetate. Concentrate the filtrate, then purify by flash chromatography, eluting with 40% ethyl acetate in dichloromethane to give the title compound (0.312 g, 34.0%):
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClC(Cl)(Cl)Cl>O>[Br:13][CH2:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]([CH3:12])[C:2]=1[Cl:1]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(CBr)c1Cl
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A mixture of 129 g of 2-chloro-1,3-dimethyl-5-nitrobenzene, 125 g of 1-bromo-2,5-pyrrolidinedione, 12 g of dibenzoyl peroxide and 1200 ml of tetrachloromethane was stirred for 2 hours at reflux temperature using a water separator. Twice there was added an extra portion of 20 g of dibenzoyl peroxide during a refluxing period of 29 hours. After cooling, the reaction mixture was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /hexane 50:50). The eluent of the desired fraction was evaporated, yielding 130 g (70.2%) of 1-(bromomethyl)-2-chloro-3-methyl-5-nitrobenzene (interm. 5).