Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=S)[NH:10][NH2:11])=[CH:4][CH:3]=1.Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: NNC(=S)Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccc(Cl)cc2)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
A suspension of 20.1 g (0.10 mole) of 4-(4-chlorophenyl)-3-thiosemicarbazide in 80 mL of absolute ethanol was treated with 16.5 g (0.10 mole) of ethyl 2-chloroacetoacetate and the mixture stirred for 1.0 hr at room temperature. Alcoholic hydrogen chloride (2N, 60 mL) was added and the dark precipitate dissolved while heating the mixture at reflux for 1.0 hr. The solution was filtered while hot, and the filter cake washed with absolute ethanol. The filtrate was evaporated under reduced pressure and the residue triturated in cold absolute ethanol and filtered. Both filter cakes were found to be the same compound by TLC (10% methanol in benzene on silica gel). The two were combined, dissolved in hot absolute ethanol (the hydrochloride salt was water insoluble), partially neutralized with saturated aqueous sodium bicarbonate, and the solid filtered (10.4 g, mp 212°-226° C.). A second crop was obtained by treating the filtrate with saturated aqueous sodium bicarbonate (11.5 g, mp 220°-225° C.). The second crop was recrystallized from absolute ethanol to give 3.8 g of product, mp 223°-225° C. This solid was dried at 100° C./0.1 mmHg/3 hr; then for ~16 hr at RT/0.1 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8](=[N:23][OH:24])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH3:35])[CH3:34].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8](=[N:23][O:24][CH:33]([CH3:35])[CH3:34])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:21])[F:20])=[N:6][CH:7]=1
Reactant: CC(C)I
Reactant: O=C(NCC(=NO)c1ncc(Br)cc1Cl)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 63.8 %

Procedure:
To a suspension of 1.80 g of the N-[2-(5-bromo-3-chloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide prepared in Step 3 in Synthetic Example 20 and 0.86 g of potassium carbonate in 10 ml of N,N-dimethylformamide, 1.30 g of 2-iodopropane was added, and the mixture was stirred at room temperature for 13 hours. After completion of the reaction, the reaction mixture was mixed with 100 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:4 to 2:2) as the eluent to obtain 1.26 g of the desired product as a pale yellow resinous substance.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:26][C:34](=[O:35])[NH:28][N:27]=3)[N:8]=[C:9]2[NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3ccc(F)cc23)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(F)cc23)C1
Yield: 29 %

Procedure:
To a solution of (S)-tert-butyl 3-((7-fluoro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (0.35 g, 1 mmol) in dioxane (10 mL) was added CDI (0.36 g, 2 mmol) under a nitrogen atmosphere. The mixture was heated to reflux for 2 hours and was subsequently concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (120 mg, 34%). ESI-MS m/z [M+H]+ 415.2.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH2:19].CCN(C(C)C)C(C)C>CC#N>[Cl:11][C:9]1[C:8]([F:12])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([F:13])[CH:15]=2)[N:10]=1
Reactant: NCCc1cccc(F)c1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc(F)c(Cl)nc1NCCc1cccc(F)c1
Yield: 49 %

Procedure:
A mixture of 2,6-dichloro-5-fluoronicotinic acid (1.26 g, 6.0 mmol), 3-fluorophenethyl amine (1.25 mL, 9.0 mmol), DIEA (3.14 mL, 18 mmol) and MeCN (6 mL) was refluxed for 48 hrs and concentrated. The residue was dissolved in EtOAc (120 mL) and washed with saturated citric acid, water, brine, dried and concentrated. The organic layers were combined, dried (MgSO4) and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 6-chloro-5-fluoro-2-(3-fluorophenethylamino)nicotinic acid as a solid (920 mg, 49%). LRMS (M+H+) m/z 313.0.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Li].[O:13]1[C:17](C(Cl)=O)=[CH:16][CH:15]=[N:14]1.Cl>C1COCC1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][C:1]([C:17]1[O:13][N:14]=[CH:15][CH:16]=1)=[O:9])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1ccno1
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccno1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of diethyl malonate (2.6 ml, 2.74 g) in THF (40 ml) under an atmosphere of nitrogen at −60° C. was added nbutyl lithium (2.5 M, 18.9 ml) dropwise over 15 mins, keeping the temperature constant. The reaction became a cloudy white colour from the formation of the di-lithium salt then became yellowish. After 10 mins, the reaction was cooled to −78° C., when a solution of Isoxazole-5-carbonyl chloride (1 g) in THF (10 ml) was added dropwise over 15 mins. The reaction then warmed to −45° C. and stirred for 1 h, the solution had gone pale brown. The reaction was then poured into 1M HCl solution (50 ml) with stirring and extracted with CH2Cl2 (2×150 ml). The combined organic layers were washed with sat. NaCO3 soln (1×30 ml), dried over MgSO4, filtered and concentrated in vacuo to give the product as a pale oil which was used as such in the next step. Yield 1.1 g, 35.1%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][N:22]([CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:23]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH2:29][O:30][CH:25]([CH2:24][N:22]([CH3:23])[CH3:21])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CN(C)CC1CNCCO1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: CN(C)CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(dimethylaminomethyl)morpholine, the reaction is similarly carried out as Example 1 to give 1-cyclopropyl-7-[2-(dimethylaminomethyl)morpholino]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 182°-183° C.
Reaction SMILES: [N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10]CC)=[O:9])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.O>[CH2:16]([O:15][C:13]([N:1]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1)=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)CC1
Yield: 81.8 %

Procedure:
To a stirred solution of 1-benzyl 4-ethyl azepane-1,4-dicarboxylate (500 mg, 1.64 mmol) in THF (3 ml) was added LiOH (96 mmol, 2.30 mmol) dissolved in water (3 ml). After 16 hours the mixture was concentrated, diluted with dichloromethane (30 ml), washed with 1M aq. HCl (15 ml), water (15 ml), dried (MgSO4), filtered and concentrated giving the title product as colourless oil (372 mg, 82%) that was used without and further purification.
Reaction SMILES: CCOCC.[CH:6]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[N+:19]([O-])([OH:21])=[O:20]>O>[CH:6]1([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(C2CCCCC2)ccc1O
Temperature: 25 °C

Procedure:
To a stirred mixture of 50 ml of water, 50 ml of ether and 10.0 g of 4-cyclohexylphenol, was added dropwise 12.6 ml of 60% nitric acid while cooling with ice. The temperature of the mixture was raised to room temperature and the reaction was carried out for a day. After 500 ml of water was added, the reaction mixture was extracted with 500 ml of ethyl acetate, washed with water and a brine successively and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away. The residue was purified by subjecting to silica-gel column-chromatography [eluent:chloroform] to give 6.92 g of 4-cyclohexyl-2-nitrophenol.
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)C2C=CC=CC=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:12]
Reactant: c1ccc(CCNCn2nnc3ccccc32)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.1 %

Procedure:
To a mixture of 3.63 g (0.056 g-atom) of zinc powder (−325 mesh) and 60 mL of anhydrous tetrahydrofuran was added 5.3 mL (0.042 mole) of chlorotrimethylsilane in one portion. After stirring for 20 minutes, a solution of 5.4 mL (0.042 mole) of ethyl bromodifluoroacetate in 5 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature below 35 degrees. The mixture was stirred for 20 minutes and then cooled to −10 to 0 degrees. A solution of 7 g (0.028 mole) of benzotriazol-1-ylmethyl-phenethyl-amine in 30 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature at −10 to 0 degrees. After 10 minutes the reaction mixture was warmed to room temperature and stirred for 3 hours at room temperature. The solution was cooled to −10 to 0 degrees and quenched by the addition of saturated aqueous sodium bicarbonate at a rate to maintain the internal temperature −10 to 0 degrees. Ether was added, the mixture was stirred for 15 minutes at room temperature and then filtered through Celite, washing with ether. The filtrate was extracted 3 times with ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ether and hexane were added to the residue, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient, 100:0-80:20) to give 0.8 g of 2,2-difluoro-3-phenethylamino-propionic acid ethyl ester as a oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[Li]CCCC.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([O:38][CH:39]([CH3:41])[CH3:40])[C:24]([F:37])=[C:25]([CH:36]=1)/[CH:26]=[N:27]/[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)[CH3:19]>C1COCC1>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:27]([CH2:26][C:25]1[CH:36]=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=[C:23]([O:38][CH:39]([CH3:41])[CH3:40])[C:24]=1[F:37])[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)[CH:11]=[CH:10]2
Reactant: Clc1ccc2nc(Br)ccc2c1
Reactant: CCOc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(OC(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2ccc3cc(Cl)ccc3n2)c(F)c(OC(C)C)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
To a solution of Intermediate 90.1 (100 mg, 0.412 mmol) in 2 mL THF at −78° C., was added BuLi (1.4 M in hexanes, 324 μL, 0.454 mmol). The mixture was stirred at −78° C. for 10 min, then a solution of Intermediate 7.3 (134 mg, 0.412 mmol) in 0.7 mL THF was added. The mixture was stirred 15 min at −78° C., allowed to warm to rt over 30 min, then was quenched with sat. NH4Cl and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes gradient) to afford 112 mg of Intermediate 90.2 as a pale orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1([CH3:33])[O:30][C:29](=[O:31])[CH2:28][C:27](=[O:32])[O:26]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:24][C:25]1([CH3:33])[O:30][C:29](=[O:31])[CH:28]([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[C:27](=[O:32])[O:26]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)nc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)nc1)C(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoic acid (2.4 g, 7.2 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (1.1 g, 7.9 mmol), and N,N-dimethylpyridin-4-amine (1.4 g, 11 mmol) in 30 mL DCM were cooled in an ice-water-sodium chloride bath (−5° C.). N-((cyclohexylimino)methylene)cyclohexanamine (1.6 g, 7.9 mmol) in 50 mL DCM was added dropwise in about 40 minutes. The reaction mixture was stirred for 16 hours at room temperature. The suspension was filtered, and the solid was washed with DCM. The filtrate was washed with 5% KHSO4 (4×50 mL) and once with brine, and dried over MgSO4. After removing the solvent, the product was obtained as a white solid (3.0 g, 91%). LCMS (API-ES) m/z (%): 461.0 (100%, M+H+).
Reaction SMILES: CN(C=O)C.[CH2:6]([N:10]1[C:14](=[O:15])[C:13](O)=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[S:11]1(=[O:25])=[O:24])[CH2:7][CH2:8][CH3:9].C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl>[CH2:6]([N:10]1[C:14](=[O:15])[C:13]([Cl:29])=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[S:11]1(=[O:25])=[O:24])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCN1C(=O)C(O)=C(c2cccc(Cl)c2)S1(=O)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Cl)=C(c2cccc(Cl)c2)S1(=O)=O
Yield: 92.7 %

Procedure:
Dry DMF (0.17 mL, 2.21 mmol) was added to a solution of 2-butyl-5-(3-chlorophenyl)-4-hydroxyisothiazol-3(2H)-one 1,1-dioxide (697 mg, 2.21 mmol) in dry DCM (15 mL) at rt and under an atmosphere of nitrogen. Oxalyl chloride (0.37 mL, 4.41 mmol) was added dropwise and the mixture was heated to reflux for 2.5 h. The reaction mixture was evaporated to dryness. The residue was dissolved in EtOAc and it was washed with several portions of water, dried with MgSO4, and evaporated to give the title compound (685 mg, 84%) as a brown oil which was used without further purification; 1H NMR (500 MHz, CDCl3): δ 7.96 (t, 1H), 7.84-7.88 (m, 1H), 7.57-7.61 (m, 1H), 7.50-7.55 (t, 1H), 3.79 (t, 2H), 1.80-1.87 (m, 2H), 1.39-1.51 (m, 2H), 1.00 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 161.5, 155.9, 142.4, 135.8, 132.8, 131.0, 129.0, 127.3, 125.1, 41.0, 30.4, 20.1, 13.7.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22].CN(C1C=CC=CN=1)C.[C:34](O)([CH3:37])([CH3:36])[CH3:35].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.C(O)C>[C:1]([O:24][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22]
Reactant: CC(C)(C)O
Reactant: C#CCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C#CCCCCCCCCCCCCCCCCCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
The acid (32) (6.4 g, 0.019 mol) was dissolved in dry, ethanol free, chloroform (120 ml) at room temperature under nitrogen and sequentially treated with dimethylaminopyridine (2.55 g, 0.0209 mol), tert butanol (14.09 g, 0.19 mol), dimethylaminopyridine-trifluoroacetic acid complex (4.94 g, 0.0209 mol) and dicyclohexylcarbodiimide (4.31 g, 0.0209 mol). The resulting solution was stirred at room temperature overnight then filtered, the organic layer washed with 5% acetic acid in water, then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel (50 g). Elution with 10% ether in petrol gave the title compound (33) as white crystals (6.45 g, 86%) mp 44°-45° C.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[O:4].[OH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[O:25][CH3:26].C(O)C>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:22][C:21]2[CH:23]=[CH:24][C:18]([OH:17])=[C:19]([O:25][CH3:26])[CH:20]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Reactant: COc1cc(N)ccc1O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)C2C(=O)N(C)C(=O)N(C)C2=O)ccc1O
Temperature: 25 °C

Procedure:
6.85 g of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid and 4.2 g of 4-hydroxy-3-methoxyaniline are suspended in 60 ml of toluene, and the suspension is heated under reflux for 3 hours, whereupon ethanol escapes. On cooling to room temperature a precipitate forms which is isolated by filtration, washed with ethanol and dried. Yield: 8.3 g (86% of theory). Melting point: 252°-253° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:16]Br.O>C(O)(=O)C>[Br:16][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15]
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
In 150 ml of acetic acid, 20 g (96.9 millimole) of 2,4-di-tert-butylphenol was dissolved, and the solution was cooled on ice. Then, 5.0 ml (96.9 millimole) of bromine was added thereto drop by drop. After finishing dropwise addition, the temperature was elevated up to a room temperature, and the solution was stirred for 8 hours. Then, the reaction mixture was thrown into ice and water, and the aqueous layer was extracted with diethyl ether. The organic layer was dried on anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 19.96 g (yield: 72.0%) of 2-bromo-4, 6-di-tert-butylphenol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][CH2:6][C:7]([OH:9])=O.[CH2:14]1COC[CH2:15]1.C([Mg]Br)=C.Cl>COCCOC>[CH:14]([C:7]([CH2:6][O:5][C:4]1[CH:10]=[CH:11][C:12]([F:13])=[C:2]([F:1])[CH:3]=1)=[O:9])=[CH2:15]
Reactant: C1CCOC1
Reactant: O=C(O)COc1ccc(F)c(F)c1
Agent: C=C[Mg]Br
Agent: Cl
Solvent: COCCOC
Product: C=CC(=O)COc1ccc(F)c(F)c1
Reaction time: 18 h

Procedure:
To a suspension of 3,4-difluorophenoxy acetic acid (5.00 g, 25.7 mmol) lithium salt in DME (20 mL) was added to a 1M THF solution of vinyl magnesium bromide (38 mmol). After a period of 18 h, the resulting clear solution was poured over 1N HCl (67 mL). The aqueous phase was then extracted with Et2O. The ethereal phase was washed with H2O, 1M K2CO3 then H2O. After drying over MgSO4 and evaporation an orange oil was obtained and used as such for the next step.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][C:26]#[N:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[N-:30]=[N+:31]=[N-:32].[Na+].CN(C)C=O.[Cl-].[NH4+]>O>[O:29]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][C:26]3[NH:32][N:31]=[N:30][N:27]=3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCC#N)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCc3nnn[nH]3)c2c1
Temperature: 80 °C
Yield: 17.8 %

Procedure:
A mixture of 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propanenitrile (100 mg, 0.25 mmol), sodium azide (48 mg, 0.98 mmol), dimethyl formamide (2 ml) and ammonium chloride (52.6 mg, 0.98 mmol) was heated at 80° C. in an oil bath overnight. The resulting mixture was diluted with water and extracted with dichloromethane (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in dichloromethane) to afford 20 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 450, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (m, 1 H), 7.92 (t, 1 H), 7.86 (s, 1 H), 7.60 (m, 1 H), 7.58-7.52 (m, 3 H), 5.89 (s, 1 H), 5.27 (s, 2 H), 4.52 (brs, 2 H), 3.86 (t, 2 H), 3.72 (t, 2 H), 3.33 (t, 2 H), 2.47 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[Cl:9][Sb-:10]([Cl:15])([Cl:14])([Cl:13])([Cl:12])[Cl:11].[CH3:16][O+](C)C>CCOCC>[Cl:9][Sb-:10]([Cl:15])([Cl:14])([Cl:13])([Cl:12])[Cl:11].[CH3:16][N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7]
Reactant: C[O+](C)C
Reactant: Clc1nsc(Cl)c1Cl
Agent: Cl[Sb-](Cl)(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: C[n+]1sc(Cl)c(Cl)c1Cl

Procedure:
Trichloroisothiazole (10 ml) and trimethyloxonium hexachloroantimonate (7.9 g, 0.02 mol) were heated at 90° for 30 min. After cooling ether (150 ml) was added and the solid collected to yield 7.8 g (73%) of product, mp >240. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]([C:16]#[N:17])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+].O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]([C:16]1[NH:22][N:21]=[N:20][N:17]=1)=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2[nH]c(=O)c(C#N)cc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc2[nH]c(=O)c(-c3nnn[nH]3)cc2c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
6-tert-Butyl-3-cyano-1,2-dihydroquinolin-2-one (1.74 g, 7.7 mmol) was dissolved in DMF (20 ml), and ammonium chloride (1.65 g, 30.8 mol) and sodium azide (2.00 g, 30.8 mol) were added to the resultant mixture. The mixture was stirred at a bath temperature of 120° C. for 16 hours. Water was added to the reaction mixture. After removal of the precipitates by filtration, the reaction mixture was recrystallized from DMF-methanol. The crystals that precipitated were collected, to thereby obtain the title compound as yellow powder (1.08 g, 4.0 mmol, 52%).