Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O([C:8]([NH:10][C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][N:12]=1)=[O:9])C1C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.CN(C)C=O>O>[CH2:18]([NH:17][C:15]1[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][N:12]=[C:11]([NH:10][C:8]([NH:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[O:9])[N:16]=1)[CH2:19][CH3:20]
Reactant: Nc1ccncc1
Reactant: CCCNc1nc(NC(=O)Oc2ccccc2)ncc1C(=O)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCNc1nc(NC(=O)Nc2ccncc2)ncc1C(=O)OCC
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 28.7 %

Procedure:
To ethyl 2-((phenoxycarbonyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (E7, 2.89 g) and 4-aminopyridine (3.16 g), N,N-dimethylformamide (30 mL) was added at room temperature, and the mixture was stirred at 70° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then the reaction mixture was poured into water (300 mL). The solid matter was taken by filtration, and purified by silica gel column chromatography (eluent, ethyl acetate) to obtain ethyl 4-(propylamino)-2-(3-(pyridin-4-yl)ureido)pyrimidine-5-carboxylate (E8, 830 mg) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH:10]([CH2:21][CH2:22]Br)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:10]2([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:22][CH2:21]2)[CH:6]=1
Reactant: Fc1cn[nH]c1
Reactant: O=C(OCc1ccccc1)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1(n2cc(F)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
To a solution of 4-fluoropyrazole (125 mg, 1.45 mmol) in tetrahydrofuran (4 mL) at 0° C. was added sodium hydride (60% suspension in mineral oil, 116 mg, 2.90 mmol). The mixture was stirred at 0° C. for 40 min before benzyl 2,4-dibromobutyrate (0.30 mL, 1.50 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography to afford benzyl 1-(4-fluoro-1H-pyrazol-1-yl)cyclopropanecarboxylate as a clear oil (115 mg, 30.4%). 1H NMR (400 MHz, CDCl3) δ 1.64-1.70 (m, 2H), 1.81-1.86 (m, 2H), 5.14 (s, 2H), 7.22-7.26 (m, 2H), 7.31-7.36 (m, 3H), 7.40 (td, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1.FC(F)(F)C(O)=[O:37].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:37])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6,6′-trimethyl-[2,2′]bipyridine (compound 446) (75 mg) was dissolved in methylene chloride (2 ml) to prepare a solution. The solution was brought to 0° C., trifluoroacetic acid (1 ml) was added thereto, and the mixture was stirred at 0° C. for 30 min and then at room temperature for 4 hr. The reaction solution was brought to 0° C., was stirred and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (48 mg, yield 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][CH:19]=3)[C:11](=[O:24])[N:10]([CH2:25][C:26]([O:28]C)=O)[N:9]=2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][CH:19]=3)[C:11](=[O:24])[N:10]([CH2:25][C:26]([NH:31][NH2:32])=[O:28])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(C(=O)OC)c2)c1=O
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)NN)c2=O)c1
Reaction time: 18 h

Procedure:
172 mg (0.41 mmol) of the compound from Example 15A were suspended in 1 ml of ethanol, and 40 μl (0.83 mmol) of hydrazine hydrate were added. The mixture was heated under reflux for 4 h and then allowed to stand at room temperature for 18 h. The reaction was concentrated under reduced pressure on a rotary evaporator and the residue was dried under high vacuum. This gave 161 mg (94% of theory) of the target compound as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[OH-].[K+].Cl[CH2:21][C:22]1[CH:34]=[CH:33][C:25]2[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[CH:23]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:23]1[C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][C:25]=2[CH:33]=[CH:34][C:22]=1[CH2:21][C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=1[OH:17]
Reactant: ClCc1ccc2oc3ccccc3c2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1nc(O)c(Cc2ccc3oc4ccccc4c3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 11 %

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (50 mg, 214 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.11 mL, 0.22 mmol) at RT followed by 2-(chloromethyl)dibenzo[b,d]furan CCH 34116-2 (47 mg, 217 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with a mixture CH2Cl2:MeOH=9:1 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 96:4) gave 4-(dibenzo[b,d]furan-2-ylmethyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol (10 mg, 11%). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.2 M HCl solution in MeOH (0.25 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(dibenzo[b,d]furan-2-ylmethyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol hydrochloride 6 as a pale brown solid (11 mg, 11% yield).
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][OH:13])(=[O:9])[O:4][CH2:5][CH2:6]CC)[CH3:2].C(O)C[OH:16]>C([O-])(C([O-])=O)=O.C([O-])(C([O-])=O)=O.O=[Ti+2].[K+].[K+]>[CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][OH:13])(=[O:9])[O:4][CH2:5][CH2:6][OH:16])[CH3:2]
Reactant: CCCCOP(=O)(CC)CCCO
Reactant: OCCO
Agent: O=[Ti+2]
Agent: O=C([O-])C(=O)[O-]
Agent: [K+]
Product: CCP(=O)(CCCO)OCCO
Temperature: 200 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
To 416 g (2 mol) of butyl ethyl(3-hydroxypropyl)phosphinate (produced as in Example 11) are added 155 g (2.5 mol) of ethylene glycol and 0.4 g of potassium titanyloxalate, followed by stirring at 200° C. for 2 h. Volatiles are distilled off by gradual evacuation to leave 439 g (98% of theory) of 2-hydroxyethyl ethyl(3-hydroxypropyl)phosphinate.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH2:18]2.CO[Na].Cl>C1C=CC=CC=1>[CH2:18]1[C:19]2[C:15](=[C:14]([NH:13][C:4](=[O:6])[C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=3[CH3:1])[CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1ccccc1C
Reactant: Nc1cccc2c1CCC2
Agent: CO[Na]
Agent: Cl
Solvent: c1ccccc1
Product: Cc1ccccc1C(=O)Nc1cccc2c1CCC2
Reaction time: 10 h
Yield: 65.4 %

Procedure:
A mixture of 2.0 g of ethyl o-methylbenzoate (12.2 m mol), 1.62 g of 4-aminoindan (12.2 m mol), 0.72 g of CH3ONa and 30 ml of benzene is stirred for 10 hours under reflux. After ice-cooling, the mixture is added to dilute hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and concentrated. The resulting crystals are washed with n-hexane to give 2.0 g of N-4-indanyl-o-methylbenzamide (yield: 65.4%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[O:21].C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>O>[CH3:36][C:35]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[O:21])=[CH:18][C:17]=1[O:16][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][CH3:15])[N:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1O
Reactant: CNc1cc(-c2cccnc2Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(-c2cccnc2Oc2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc2C)ncn1
Temperature: 125 °C

Procedure:
[6-(2-Chloro-pyridin-3-yl)-pyrimidin-4-yl]-methyl-amine (55 mg, 0.25 mmol), 3-hydroxy-4-methyl-N-(3-trifluoromethyl-phenyl)-benzamide (81 mg, 0.27 mmol), Cs2CO3 (162 mg, 0.50 mmol) and DMSO (0.8 mL) were combined. The mixture was heated overnight at 125° C. in a sealed tube. The resulting mixture was cooled to RT, diluted with water and extracted with EtOAc. The aqueous layer was neutralized (pH˜7) with TFA and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield the title compound. MS m/z=480 [M+1]+. Calc'd for C25H20F3N5O2: 479.47.
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[F:25].[Br:26]C(Cl)(Cl)C(Br)(Cl)Cl>C1COCC1>[Br:26][C:18]1[C:17]([F:25])=[C:16]([Cl:15])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(Cl)c(F)c1Br
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a cooled (−78° C.) solution of DIEA (4.9 mL, 48 mmol) in THF was added dropwise n-BuLi (132 mL, 2.3 eq, 2.5 M). The mixture was stirred at −30° C. for 30 min. Again the reaction mixture was cooled to −78° C., and a solution of 4-chloro-3-fluorobenzoic acid (25 g, 143 mmol) in THF was added over 1 h. The reaction was stirred at −78° C. overnight. The next day a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (87 g, 267 mmol) in THF was added and the reaction was stirred at −78° C. for further 2 h and then rt for 4 h. The reaction mixture was quenched with H2O, organic layer was separated and aqueous layer washed with Et2O. Aqueous layer acidified with 1.5 N HCl and extracted in EtOAc (2×200 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford Intermediate 12A (30 g, 83.3%). MS (ESI) m/z: 252.6 (M−H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)=[C:9]([CH3:29])[O:8][N:7]=1)=O)C.O.[NH2:31][NH2:32]>C(O)C>[CH3:29][C:9]1[O:8][N:7]=[C:6]2[C:10]=1[C:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=1)=[N:32][NH:31][C:4]2=[O:3]
Reactant: CCOC(=O)c1noc(C)c1C(=O)c1ccc(OCCCN2CCCCC2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1onc2c(=O)[nH]nc(-c3ccc(OCCCN4CCCCC4)cc3)c12
Temperature: 0 °C
Reaction time: 21 h

Procedure:
To 291.3 mg of 5-methyl-4-[4-(3-piperidin-1-ylpropoxy)benzoyl] isoxazole-3-carboxylic acid ethyl ester (0.7057 mmol) in 1.54 mL of ethanol at room temperature was added 49.4 μL of hydrazine monohydrate (0.988 mmol). After 21 h, the heterogeneous reaction was cooled to 0° C. and filtered. The white solid was washed with cold ethanol then diethyl ether and dried at 65° C. under high vacuum. Yield 120 mg (46%) of a white solid Mp 178-9; MS m/z 369 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].O=[CH:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:13]1
Reactant: CCOC(=O)C1(CC=O)CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccncc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)C1(CCNc2cnccc2C)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 24 h

Procedure:
4-Methylpyridin-3-amine (36.0 mg, 0.000333 mol) was added to a solution of 1-tert-butyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate (0.095 g, 0.00032 mol) in 1,2-dichloroethane (1.9 mL, 0.025 mol) and followed by sodium triacetoxyborohydride (0.20 g, 0.00095 mol) and the mixture was stirred for 24 h. The mixture was poured into pre-cooled water, extracted with ethyl acetate. The organic layer was separated, dried and concentrated. The product was purified by CombiFlash using CH2Cl2/EtOAc (max EtOAc 50%). LC-MS: 392.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][NH:19][CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:18][N:19]([CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CNCC(OC)OC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(CN(C)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])OC
Reaction time: 1 h

Procedure:
4-Chloro-3,5-dinitrobenzotrifluoride (5.4 grams; 0.02 mole) dissolved in benzene was charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. N-Methyl-N-2,2-dimethoxyethylamine (2,4 grams; 0.02 mole) and triethylamine (2.02 grams; 0.02 mole) both dissolved in benzene (50 ml) were then added dropwise with stirring. After the addition was completed stirring was continued for a period of 1 hour resulting in the formation of a precipitate. The reaction mixture was filtered to remove the acid acceptor salt and was chromatographed. The solution was then evaporated to yield a solid product. This solid was recrystallized from hexane to yield the desired product N-methyl-N-(2,2-dimethoxyethyl)-2,6-dinitro-4-trifluoroemethylaniline melting at 48° to 50° C.
Reaction SMILES: [CH3:1][C:2]([N+:9]([O-])=O)([CH3:8])[CH2:3][NH:4][CH2:5][CH2:6][OH:7]>CO.[Ni].O>[NH2:9][C:2]([CH3:8])([CH3:1])[CH2:3][NH:4][CH2:5][CH2:6][OH:7]
Reactant: CC(C)(CNCCO)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CC(C)(N)CNCCO
Reaction time: 48 h
Yield: 93.3 %

Procedure:
To a solution of 2-((2-methyl-2-nitropropyl)amino)ethanol (9.7 g, 60 mmol) in Methanol (65 ml) was added a slurry of 50% Raney Nickel® in H2O (3 ml). The vessel was pressurized with H2 (450 psi) and the suspension stirred for 48 h. The mixture was filtered through Celite® and concentrated in vacuo to give 7.4 g of a crude liquid, which was used directly in the next step without purification. LRMS (ESI/APCI) m/z 133 [M+H]+.
Reaction SMILES: [CH2:1](I)[CH3:2].[OH:4][C:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:16])(=[O:15])[NH:7][C:6]=1[C:17]([NH:19][C:20]1[S:21][C:22]([CH3:25])=[CH:23][N:24]=1)=[O:18]>CO.[OH-].[Na+]>[CH2:1]([N:7]1[C:6]([C:17]([NH:19][C:20]2[S:21][C:22]([CH3:25])=[CH:23][N:24]=2)=[O:18])=[C:5]([OH:4])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8]1(=[O:16])=[O:15])[CH3:2]
Reactant: CCI
Reactant: Cc1cnc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN1C(C(=O)Nc2ncc(C)s2)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
0.94 gm (6 millimols) of ethyl iodide were added to a solution of 0.7 gm (2 millimols) of 4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide in 30 ml of methanol and 2.0 ml of 1N sodium hydroxide. The reaction mixture was stirred for 24 hours at room temperature, then neutralized and evaporated in vacuo. The residue was purified by column chromatography (Merck-silica gel 60, particle size: 0.2-0.5 mm; eluant: chloroform/ethanol 95:5), yielding 0.35 mgm (48% of theory) of 2-ethyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide after recrystallization from xylene.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]3[C:18]4[C:23]([CH2:24][CH2:25][C:14]=23)=[CH:22][C:21]([CH:26]=C)=[CH:20][CH:19]=4)=[CH:9][C:6]=1[C:7]#[N:8])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:32]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH:26]([C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:15]1=[N:16][O:17][C:13]([C:10]3[CH:11]=[CH:12][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([CH:9]=3)[C:7]#[N:8])=[C:14]1[CH2:25][CH2:24]2)=[O:32]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)c(C#N)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C#N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 71.3 %

Procedure:
To 2-isopropoxy-5-(7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazol-3-yl)benzonitrile (Preparation 15C, 0.088 g, 0.247 mmol) in THF (1.5 mL) was added N-methylmorpholine-N-oxide (50% in water) (0.17 mL, 0.370 mmol) followed by osmium tetroxide (0.039 mL, 4.94 μmol) at room temperature. The contents were stirred at room temperature for 3.5 h. Sodium periodate (0.106 g, 0.494 mmol) dissolved in 0.5 mL of water was added over a period of 2 min. at room temperature and the contents were stirred at room temperature for 1 h. The reaction mixture was concentrated and partitioned between ethyl acetate (15 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield 5-(7-formyl-4,5-dihydronaphtho[1,2-c]isoxazol-3-yl)-2-isopropoxybenzonitrile (0.090 g, 0.176 mmol, 71% yield) as an orange-yellow solid. LC/MS M+1=359.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O>O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O([Si](C)(C)C)[Si](C)(C)C.ClCCCl>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: N#Cc1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A solution of 2-chloro-3-nitrobenzamide (1.02 g, 4.9 mmol) in P2O5/(TMS)2O/1,2-dichloroethane (30 mL) was heated at 85° C. for 18 hours. After it was cooled to 25° C., the solution was filtered through a plug of silica gel (60 mL), eluting with 5% methanol/CHCl3 (400 mL). The combined washes were concentrated under reduced pressure to give 2-chloro-3-nitrobenzonitrile as an off-white solid (0.66 g, 74%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:7]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:6][CH:5]=1.C1COCC1.[OH-].[Li+].Cl>O>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]2[C:7]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([OH:24])=[O:2])=[CH:15][CH:14]=1)#[N:17]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(C#N)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
In a 25 mL round-bottomed flask, the above prepared 5-(4-cyano-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid methyl ester (0.891 g, 2.65 mmol, Eq: 1.00) was combined with THF (7 mL) and water (3.5 mL) to give a light yellow biphasic system. Lithium hydroxide (127 mg, 5.3 mmol, Eq: 2) was added and the reaction mixture was stirred at 40° C. for 3 hours when TLC indicated the reaction to be complete. Work up: 10 mL H2O and 7 mL HCl 1N were added, the mixture extracted with AcOEt (2×50 mL), the organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. Trituration with heptane/EtOAc 9:1 afforded finally 794 mg of the desired title product as a white solid; MS (EI) 321.2 (M−H)−.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:6](O)=[O:7])=[O:2].S(Cl)([Cl:15])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:6]([Cl:15])=[O:7])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1cc(Cl)cc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1cc(Cl)cc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 3-formyl-5-chlorobenzoic acid (66.5 g, 0.36 moles), thionyl chloride (51.5 g, 0.43 moles), and dimethylformamide (1 ml), in toluene (400 ml) was slowly warmed to 70° C. and stirred at that temperature for 2 hours. The toluene was eliminated in the rotavap to yield 3-formyl-5-chlorobenzoyl chloride, used in the next step as such.