Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].IC.[C:12]([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:12])[C:7]=1[CH3:8]
Reactant: Cc1[nH]c(=O)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: Cc1c(Br)ccc(=O)n1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-6-methylpyridin-2(1H)-one (164 mg, 0.872 mmol) and iodomethane (0.065 mL, 1.047 mmol) in DMSO (3 mL) was added K2CO3 (145 mg, 1.047 mmol). The mixture was stirred at 60° C. overnight, filtered, and purified via preparative HPLC, eluting with a gradient of 20-70% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21](O)[CH3:22])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[CH3:20].CN(C)C=O.S(Cl)([Cl:31])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([Cl:31])[CH3:22])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(Cl)cc(C(C)O)c2c1CN(C(=O)OC(C)(C)C)CCO2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(Cl)cc(C(C)Cl)c2c1CN(C(=O)OC(C)(C)C)CCO2
Yield: 99.9 %

Procedure:
A mixture of tert-butyl 7-chloro-9-(1-hydroxyethyl)-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (280 mg, 0.82 mmol) and N,N-dimethylformamide (30 μL) in methylene chloride (6 mL) was stirred and thionyl chloride (120 μL, 1.7 mmol) was added dropwise. The mixture was stirred at room temperature for 20 minutes. The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the desired product (295 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][OH:11]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH:10][OH:11])=[NH:7])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(F)cc1
Solvent: CCO
Product: N=C(NO)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
In a 50 ml round bottom flask, 3.0 g (24.8 mmol) of 4-fluoro-benzonitrile are suspended in 50 ml of ethanol and 1.46 ml of aqueous hydroxylamine (50%, 24.8 mmol) are added. The mixture is heated to 90° C. and the resulting solution stirred at this temperature for 16 h. After cooling to room temperature, the solvent is removed in vacuo and the resulting residue recrystallised from 25 ml of ethanol/water (1:5) which yields a white solid. Mass spectrum: m/z (M+H)+: 155.0
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[C:19](Br)[C:12]2=[N:11][C:10]=1[C:27]1[O:28][C:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:30][N:31]=1)C1C=CC=CC=1.[Si]([I:44])(C)(C)C.CO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[F:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C:29]2[O:28][C:27]([C:10]3[N:11]=[C:12]4[C:19]([I:44])=[CH:18][C:17]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:16][N:13]4[C:14](=[O:15])[C:9]=3[OH:8])=[N:31][CH:30]=2)=[CH:34][CH:35]=1
Reactant: O=c1c(OCc2ccccc2)c(-c2ncc(Cc3ccc(F)cc3)o2)nc2c(Br)cc(N3CCOCC3)cn12
Reactant: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: O=c1c(O)c(-c2ncc(Cc3ccc(F)cc3)o2)nc2c(I)cc(N3CCOCC3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of the product of example 3 (25 mg, 0.042 mmol) in acetonitrile (1 ml) was added idodotrimethylsilane (TMSI) (0.05 ml, 0.338 mmol) at room temperature. The mixture was stirred at room temperature for 8 hours, after which methanol (0.1 ml) was added to quench the reaction. Then saturated solution of Na2S2O3 was added drop-wise till a yellow solid was precipitated. The resulting solids were collected by filtration, washed with ethyl acetate to give the titled compound (13 mg, 60% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([OH:23])[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].[CH3:26][CH:27]([CH3:31])[C:28](Cl)=[O:29].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:25])[C@@H:11]([O:23][C:28](=[O:29])[CH:27]([CH3:31])[CH3:26])[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6]
Reactant: CCOC(=O)OCCOC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCCl
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)OCCOC(=O)[C@H](OC(=O)C(C)C)C(C)(C)COS(=O)(=O)CCCCl
Yield: 98.8 %

Procedure:
(Ethoxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-hydroxy-3,3-dimethylbutanoate (36b) (0.2 g, 0.49 mmol) was reacted with 0.16 mL (0.16 g, 1.5 mmol) of 2-methylpropanoyl chloride in 5 mL of anhydrous dichloromethane (DCM) in the presence of 0.11 mL (0.11 g, 1.3 mmol) of pyridine. After work-up and isolation, the crude material was purified by silica gel column chromatography using ethyl acetate (EtOAc) and hexane (Hxn) mixtures (EtOAc/Hxn=1:2) as eluent to provide 0.23 g (99% yield) of the title compound (36c) as a colorless oil. Rf=0.55 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.12-1.15 (2s, 3H), 1.21-1.26 (m, 12H), 1.50-1.58 (2d, J=5.2, 5.6 Hz, 3H), 2.30-2.36 (m, 2H), 2.64-2.71 (m, 1H), 3.31-3.36 (m, 2H), 3.69-3.72 (m, 2H), 3.99-4.02 (2d, J=9.2, 9.6 Hz, 1H), 4.16 (d, J=9.6 Hz, 1H), 4.21-4.28 (m, 2H), 4.75-4.79 (2s, 1H), 6.77-6.82 (m, 1H) ppm. MS (ESI) m/z: 496.99 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O-].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[N:6][CH:5]=1>CN(C=O)C.CO>[CH3:1][N:14]1[CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][N:4]=[CH:5][N:6]=2)[CH:11]=[CH:12][C:13]1=[O:16]
Reactant: O=c1ccc(-c2ccncn2)c[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccncn2)ccc1=O
Temperature: 60 °C

Procedure:
A solution of 4.8 g of sodium methoxide in 300 ml of dry DMF and 15 ml of methanol is added to a suspension of 5-(4-pyrimidinyl)-2(1H)-pyridone (2 g) in 200 ml DMF. The reaction mixture is filtered and 5.5 ml of methyl iodide added to the filtrate. The reaction mixture is heated to 60° C. for 2 hours, cooled to RT, and the solvent evaporated in vacuo leaving a liquid residue that crystallizes upon the addition of distilled H2O. The crystalline solid is stirred with 400 ml of distilled H2O, filtered, washed with H2O, isopropyl alcohol, and ether and then air dried to yield the desired 1-methyl-5-(4-pyrimidyl)-2-pyridone, M.P. 147°-149° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:24]>O1CCOCC1.ClCCl>[NH2:24][C:2]1[C:11]([C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(OC)c1C(=O)c1cc2ccccc2nc1Cl
Reactant: N
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cccc(OC)c1C(=O)c1cc2ccccc2nc1N
Temperature: 150 °C

Procedure:
(2-Chloroquinolin-3-yl)(2,6-dimethoxyphenyl)methanone (2.0 g, 6.1 mmol) was dissolved in dioxane (15 mL), mixed with 25% aqueous ammonia solution (10 mL) and heated to 150° C. under its own pressure for 24 hours in a pressurized reactor. The reaction mixture was diluted with dichloromethane and washed several times with water. The organic phase was dried (sodium sulfate) and concentrated. The crude product was purified by chromatography (silica gel, dichloromethane, methanol). Yield: 1.15 g (3.73 mmol, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.C(OP([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:46]/[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carbaldehyde (1.00 g), ethyl diethylphosphonoacetate (0.50 g) and N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 100 mg) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)-2-propenoate (1.08 g, yield 95%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 194-195° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:14]3[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=3[Cl:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Product: FC(F)(F)c1ccc(Cl)c(-c2cccn3nc(Cl)nc23)c1

Procedure:
2-Chloro-8-(2-chloro-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.50 g, 2.15 mmol) and 2-chloro-5-trifluoromethylphenylboronic acid (0.72 g, 3.23 mmol) in a manner analogous to Example 2c (0.115 g, 16%). MP=156-158° C. MS=332 (MH)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]=[C:1]=[O:2])=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(Oc2cccc(Cl)n2)cc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Oc2cccc(Cl)n2)cc1
Reaction time: 0.33 h

Procedure:
A stream of phosgene was passed into 120 ml. of dry toluene maintained at a temperature of about 0° to about 5°C. until a weight of 13.4 grams (0.135 mole) had been absorbed. 4-((6-Chloro-2-pyridinyl)oxy)benzenamine (10.0 grams; 0.045 mole) in 100 ml. of dry toluene was then added to the stirred phosgene solution over a period of about 15 minutes while maintaining the reaction temperature within a range of about 2° to about 5°C. Following the completion of the addition, the reaction mixture was stirred for about 20 minutes and the reaction temperature then gradually raised as excess phosgene was purged with a stream of nitrogen. When a reaction temperature of about 85°C. was attained, the reaction mixture became clear. The toluene solvent was then substantially removed under reduced pressure and hexane added to the residue to give the desired 4-((6-chloro-2-pyridinyl)oxy)phenyl isocyanate product as a white crystalline product having a melting point of 96°-97° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2].[CH3:21][S:22]([NH:25][C:26]1[CH:41]=[CH:40][C:29]2[NH:30][C:31]([CH2:36][C:37](O)=[O:38])=[N:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1)(=[O:24])=[O:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[C:37](=[O:38])[CH2:36][C:31]2[NH:30][C:29]3[CH:40]=[CH:41][C:26]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:27][C:28]=3[S:33](=[O:34])(=[O:35])[N:32]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CC=CCC1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC=CCC1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.6 %

Procedure:
The crude 6-(4-fluoro-benzylamino)-cyclohex-3-enecarboxylic acid ethyl ester (113.7 mg, 0.41 mmol) was mixed with (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 150 mg, 0.45 mmol) and dissolved in N,N-dimethylformamide (3.4 mL). N-methylmorpholine (100 μL, 0.9 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol). The reaction mixture was stirred at 25° C. for 16 h. LC-MS analysis indicated that the reaction was incomplete and thus additional (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (30 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17 mg) were added and the resulted mixture was stirred at 25° C. for 1.5 h. A 1.0 M aqueous hydrochloric acid solution (6.7 mL) was added. The product was extracted with ethyl acetate (3×15 mL) and the combined organic layers were washed with water (10 mL) and saturated aqueous brine solution (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and further dried under high vacuum for 16 h to afford the crude product, 6-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohex-3-enecarboxylic acid ethyl ester (295.4 mg). LC-MS (ESI) calcd for C26H29FN4O7S2 592.15, found 593.4 [M+H+]. This crude product was directly used in next step without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([CH3:21])[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].CC(O)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)=[C:14]([CH3:21])[CH:13]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: O=C(O)c1cccc(I)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(Cl)ccc1-c1cccc(C(=O)O)c1
Temperature: 80 °C

Procedure:
To a mixture of 3-iodobenzoic acid (11.9 g, 48 mmol), 4-chloro-2-methylphenylboronic acid (9.8 g, 57.7 mmol) and sodium carbonate (6.1 g, 57.7 mmol) under nitrogen atmosphere, was added i-PrOH-water (1/1, 180 mL) followed by 10% Pd—C (2 g, 19.2 mmol) with caution. The reaction mixture was heated at 80° C. under nitrogen overnight. The catalyst was removed by filtration, and the filtered catalyst was washed with EtOH (60 mL). Most of organic solvent was removed under reduced pressure. The resulting aqueous residue was treated with 2N HCl (aq) to bring the pH <2. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water and saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 9.7 was obtained as white solid (12 g), which was used directly in the next step. MS ESI (neg.) m/e: 245 (M−H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([NH:36][C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc(OCCN3CCC(N)CC3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 14 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (60 mg, 0.26 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamine (80 mg, 0.26 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by 1-hydroxybenzotriazole (38 mg, 0.29 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (57 mg, 0.30 mmol, 1.15 eq) and N,N-diisopropylethylamine (100 μL, 0.58 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as an off-white solid (18 mg, 13% yield).
Reaction SMILES: [Na].Cl.Cl[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.Cl.[CH:12]([OH:15])([CH3:14])[CH3:13]>>[CH:12]([O:15][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)([CH3:14])[CH3:13]
Reactant: ClCc1ccncc1
Reactant: CC(C)O
Agent: Cl
Agent: [Na]
Product: CC(C)OCc1ccncc1

Procedure:
3.4 g of sodium are dissolved in 120 ml of isopropanol and 11 g (0.067 mol) of 4-chloromethylpyridine-hydrochloride are added. The reaction mixture is refluxed for 10 hours under nitrogen, with stirring, then after cooling it is made weakly acidic with dilute hydrochloric acid and concentrated by evaporation under reduced pressure. The residue is made alkaline with 40% potassium carbonate solution and extracted with ether. After drying with anhydrous sodium sulphate the organic phase is concentrated by evaporation. The crude product is then distilled.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[C:15]([C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH:14]=[CH:13][N:12]=2)[CH:4]=1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCc1cc(-c2cc(C(=O)O)ccn2)c(C)[nH]c1=O
Product: CCc1cc(-c2cc(C(=O)N3CCCC3)ccn2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-4-carboxylic acid and pyrrolidine to afford the title compound. MS: m/e=312 (M+H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[N:7]([CH3:13])[N:6]=1)[NH2:4].[CH3:14]OC(OC)OC.FC(F)(F)C(O)=O>CO>[CH3:13][N:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:5]([C:3]2[N:4]=[CH:14][O:1][N:2]=2)=[N:6]1
Reactant: COC(OC)OC
Reactant: Cn1nc(C(N)=NO)cc1[N+](=O)[O-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2ncon2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of N′-hydroxy-1-methyl-5-nitro-1H-pyrazole-3-carboximidamide (1.66 g, 8.97 mmol) and trimethoxymethane (17.6 mL, 161 mmol) in MeOH (2.8 mL) was added 2,2,2-trifluoroacetic acid (0.35 mL, 4.48 mmol) and the mixture was refluxed for about 1 h. The reaction was cooled to ambient temperature and continued to stir for about 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM (25 mL) and saturated NaHCO3 (10 mL). The aqueous layer was back extracted with DCM (25 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford 3-(1-methyl-5-nitro-1H-pyrazol-3-yl)-1,2,4-oxadiazole (1.75 g, 8.97 mmol, 100%, which was used without further purification). LC-MS (Table 1, Method g) Rt=1.56 min, m/z 196 (M+H)+. 1H-NMR (DMSO-d6, Bruker 400 MHz) 9.79 (s, 1H), 7.72 (s, 1H), 4.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:4]([Cl:15])[CH:3]=1.Cl.C(O)C.O=[C:21]([C:27](OCC)=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CO.[C].[Pd]>[NH2:14][S:11]([C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[Cl:15])[N:1]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27](=[O:28])[NH:8]2)(=[O:13])=[O:12]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.9 %

Procedure:
To a solution of 4-amino-2-chloro-5-nitrobenzenesulfonamide (2.00 g, 7.95 mmol) in methanol (40 ml) were added 10% palladium-carbon (400 mg) and successively 10% hydrochloric acid (6 ml) at room temperature, and catalytic hydrogenation was conducted for 2 hours at ambient temperature under ambient pressure. Catalyst was filtered off using celite and the filtrate was distilled off under reduced pressure. After dissolved this into ethanol (16 ml), diethyl ketomalonate (1.21 ml, 7.95 mmol) was added, which was stirred for 5 hours at room temperature. The precipitate was collected by filtration, washed with ethanol and then purified by means of silica gel column chromatography [hexane-ethyl acetate=1:2] to obtain 288 mg of the title compound. Yield 11%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[Cl:19][C:20]1[N:24]=[C:23](Cl)[S:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:23]3[S:22][N:21]=[C:20]([Cl:19])[N:24]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: Clc1nsc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nc(Cl)ns3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.0 g, 4.0 mmol) and 3,5-dichloro-1,2,4 thiadiazole (0.45 mL, 4.8 mmol) in DMF (24 mL) was added cesium carbonate (2.61 g, 8 mmol). The mixture was stirred at room temperature overnight. The reaction was diluted with H2O, acidified to pH 3 with aqueous HCl (1N). The mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (silica, Ethyl acetate) affording the title compound (1.25 g, 85%) as a white solid: 1H NMR (CDCl3) δ7.48 (d, 1H), 7.19 (d, 1H), 5.68 (dd, 1H), 5.18 (s, 1H), 4.18 (q, 2H), 3.10 (dd, 1H), 2.45 (dd, 1H), 2.39 (s, 3H), 1.25 (t, 3H). MS found: (M+H)+=369.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[C:16](OCC)(OCC)([O:19][CH2:20][CH3:21])[CH2:17][CH3:18]>>[CH2:20]([O:19][C:16]1([CH2:17][CH3:18])[NH:1][C:2]2[N:3]=[C:4]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:5][C:6]=2[C:7](=[O:8])[NH:9]1)[CH3:21]
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Reactant: CCOC(CC)(OCC)OCC
Product: CCOC1(CC)NC(=O)c2sc(N3CCOCC3)nc2N1

Procedure:
The title compound was prepared from 4-amino-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide and triethyl orthopropionate according to Method G and was isolated as a white solid (39%) after purification by preparative HPLC. δH (DMSO-d6) 7.26 (1H, br. s), 7.06 (1H, br. s), 4.19 (2H, q, J 7.0 Hz), 3.74-3.66 (4H, m), 3.46-3.36 (4H, m), 2.55-2.47 (2H, m), 1.29 (3H, t, J 7.0 Hz), 1.10 (3H, t, J 7.5 Hz). LCMS (ES+) 313.0 (M+H)+.