Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>>[C:7]([NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)(=[O:9])[CH3:8]
Reactant: Nc1nnn[nH]1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nnn[nH]1
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A mixture of 6.18 g (60 mmoles) of 5-aminotetrazole with 56.3 ml of acetic anhydride was stirred at 20°-25° C. overnight. The so separated white precipitate was recovered by filtration, washed with a small volume of ethyl acetate and dried to give 3.5 g of 5-acetylaminotetrazole (Yield 45.8%). Thereafter, 10 ml of N,N-dimethylformamide and 120 mg of powdery sodium hydroxide were added to 571 mg (4.5 mmoles) of 5-acetylaminotetrazole and the resulting mixture was stirred at 20°-25° C. for one hour. Then, 1.77 g (3 mmoles) of 2,3,3-triiodoallyl-p-toluenesulfonic acid ester were added thereto and stirring was continued for 5 hours. To the reaction mixture was added water, the so separated white crystal was recovered by filtration, washed with a small volume of water and dried to give 578 mg of 5-acetylamino-1-(2',3',3'-triiodoallyl)tetrazole.
Reaction SMILES: [ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[C:8]([CH3:18])[CH:7]=1)([CH3:5])([CH3:4])C.[C:19](C1C=CC(CC#N)=C(C)C=1)(C)(C)C>>[ClH:1].[CH3:18][C:8]1[CH:7]=[C:6]([CH:2]([CH3:4])[CH3:5])[CH:11]=[C:10]([CH3:19])[C:9]=1[CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1
Reactant: Cc1cc(C(C)(C)C)ccc1CC1=NCCN1
Reactant: Cc1cc(C(C)(C)C)ccc1CC#N
Agent: Cl
Product: Cc1cc(C(C)C)cc(C)c1CC1=NCCN1

Procedure:
2-[(4-t-Butyl-2-methylphenyl)methyl]-4,5-dihydro-1H-imidazole hydrochloride, from 4-t-butyl-2-methylphenylacetonitrile (Example 4e); white solid, mp 255° C., Anal. C15H22N2.HCl.0.25H2O: C, H, N.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[C:6](=[S:14])[NH:5][C:4](=[O:15])[CH:3]=1.[N:16]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:16][C:3]1[C:4](=[O:15])[NH:5][C:6](=[S:14])[N:7]([CH2:8][C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[C:2]=1[NH2:1]
Reactant: Nc1cc(=O)[nH]c(=S)n1Cc1cc[nH]n1
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1c(N)n(Cc2cc[nH]n2)c(=S)[nH]c1=O
Yield: 68.1 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(c) by using 6-amino-1-(1H-pyrazol-3-ylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.87 g, 3.88 mmol, obtained from Example 13(b)), sodium nitrite (0.30 g, 4.27 mmol) and sodium dithionite (1.35 g, 7.77 mmol) which gave the title compound (0.63 g, 67% yield).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[N+:23]([O-])=O)=[CH:10][C:11]=3[C:12]2([CH3:16])[CH3:15])=[CH:4][CH:3]=1.P(OCC)(OCC)OCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:7]=[C:8]4[NH:23][C:18]5[C:17](=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:9]4=[CH:10][C:11]=3[C:12]([CH3:15])([CH3:16])[C:13]=2[CH:14]=1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(-c3ccccc3[N+](=O)[O-])cc21
Agent: CCOP(OCC)OCC
Product: CC1(C)c2cc(Br)ccc2-c2cc3[nH]c4ccccc4c3cc21

Procedure:
A mixture of 93.8 g (238 mmol) of 7-bromo-2-(2-nitrophenyl)-9,9-dimethyl-9H-fluorene and 290.3 ml (1669 mmol) of triethyl phosphite is heated under reflux for 12 h. The triethyl phosphite remaining is subsequently distilled off (72-76° C./9 mmHg). Water/MeOH (1:1) is added to the residue, and the solid is filtered off and recrystallised. Yield: 74 g (205 mmol, 87%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[C:31]([CH3:39])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[C:31]([CH3:39])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Cc1ccc(C(F)(F)F)c2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(F)(F)F)c2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 51.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methyl-7-trifluoromethylbezothiazole (116 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 94 mg (52%) of the title compound as an amorphous foam. mp 50°-54°. FDMS: m/e=476.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][C:24]([OH:26])=O)[CH:11]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCN(CC)CC.C(Cl)Cl>[CH2:16]([O:15][C:12]1[CH:11]=[C:10]([CH:22]=[CH:23][C:24]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])=[O:26])[CH:9]=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:13]=1[OH:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Nc1ccccc1O
Reactant: CCCCCCOc1cc(C=CC(=O)O)cc(OCCCCCC)c1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCOc1cc(C=CC(=O)Nc2ccccc2O)cc(OCCCCCC)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To the solution of 3-(3,5-bishexyloxy-4-hydroxyphenyl) acrylic acid (40 mg, 0.11 mmol) in DMF (1 ml) and Et3N (17 μl), was added 2-aminophenol (13 mg, 0.12 mmol) at 0° C. and was added the solution of BOP (53 mg, 0.12 mmol) in CH2Cl2 (0.6 ml). The solution was stirred for 30 minutes at 0° C. and then was stirred for 1.5 hours at room temperature. And then CH2Cl2 was evaporated in vacuo and the obtained residue was poured into ice water. The residue was extracted with EtOAc and washed with HCl (aq) and NaHCO3 (aq). And then the water was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by column chromatography (EtOAc:Hexane=1:5), yielding 17 mg (34%) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:3]1.[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:2]12([O:18][CH2:17][CH2:16][O:1]1)[C:11]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:5][C@@H:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:3]2
Reactant: COC(=O)[C@H]1CC(=O)c2ccccc2C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1Cc2ccccc2C2(C1)OCCO2
Reaction time: 20 h
Yield: 85.9 %

Procedure:
To the stirred solution of (R)-methyl 4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (4.5 g, 22.03 mmol) in benzene (40 mL), ethane-1,2-diol (3.69 mL, 66.1 mmol) and a catalytic amount of p-toluenesulfonic acid was added. The reaction mixture was heated to reflux temperature and further maintained for 20 hours. After 20 hours, the reaction mixture was allowed to RT, concentrated under vacuum to yield 12 g of crude compound. Crude material was purified by flash chromatography (Biotage) using 7% ethyl acetate:hexane get title compound (4.7 g) m/z 248.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Li]CCCC.[C:32](=[O:34])=[O:33]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([C:8]([C:32]([OH:34])=[O:33])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C=O
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3ccnc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)O)cnc23)cc1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To 6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (1.00 g, 2.754 mmol) in THF (20 mL) at −78° C. was added n-BuLi (1.32 mL, 3.305 mmol, 2.5 M in hexanes). After 30 minutes, a stream of CO2 gas was introduced into the reaction mixture for 20 minutes at −78° C. and at room temperature for additional 20 minutes. The reaction mixture was quenched with H2O (25 mL) and extracted with DCM (3×100 mL). The combined organic layer was washed with saturated NaHCO3 (100 mL) and water (100 mL), dried Na2SO4, filtered and concentrated in vacuo to give 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid (0.629 g, 56% yield)) as a yellow solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=3.736 minutes. [M+H]=409.02.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:30]([O:29][C:27]([CH2:26][O:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[CH2:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[O:9][CH:7]([CH3:8])[C:6]([OH:37])=[O:5])=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-[2-(2-benzyloxycarbonylmethoxy-5-chloro-benzyl)-4-chloro-phenoxy]-propionic acid tert-butyl ester (1.736 g, 3.18 mmol) in DCM (10 mL) is treated with TFA (5 mL) and allowed to stir at RT for 1 hour. The solvent is removed in vacuo to yield the titled compound as an off-white solid.
Reaction SMILES: [CH:1]([CH:3]([CH:9]([CH3:13])[C:10]([O-:12])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.S(O)(O)(=O)=O.[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)(=[NH:21])[NH2:20].C(O[K])(C)(C)C>>[CH2:28]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[N:21]=[C:10]([OH:12])[C:9]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:1])=[CH:13][N:20]=2)[CH2:27][CH2:26]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)C(C=O)C(C)C(=O)[O-]
Agent: CC(C)(C)O[K]
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1O
Yield: 18.4 %

Procedure:
A solution of 2.16 g (10 mmoles) of ethyl 2-formyl-3-methylsuccinate [Zhur. Obshche i Khim., 30, 2250 (1960)] was added to a mixture of 2.67 g (10 mmoles) of 1-amidino-4-benzylpiperazine sulfate, 1.12 g (10 mmoles) of tert-C4H9OK and 12 ml of tert-C4O9OH. The mixture was then refluxed for 6 hours. The reaction mixture was cooled, and extracted by adding water and CHCl3. The CHCl3 layer was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 :CH3OH=95:5) to give 0.68 g (yield 23%) of 2-(4-benzylpiperazino)-5-(1-ethoxycarbonylethyl)-4-hydroxypyrimidine.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]2)=[S:19])=[C:10]([F:26])[CH:9]=1.[C:27](Cl)(Cl)=[S:28]>C(Cl)Cl>[Cl:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([N:17]=[C:18]2[N:20]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[C:27](=[S:28])[S:19]2)=[C:10]([F:26])[CH:9]=1
Reactant: S=C(Cl)Cl
Reactant: O=[N+]([O-])c1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
While maintaining a reaction temperature of -5° C., 7.75 g (0.0850 mole) of pyridine was added dropwise to a stirred solution of 9.0 g (0.028 mole) of N-(4-chloro-2-fluoro-5-nitrophenylaminothiocarbonyl)perhydropyridazine in 250 mL of methylene chloride. To this mixture was added dropwise 3.25 g (0.0282 mole) of thiophosgene. This mixture was stirred at -5° C. for 30 minutes, then was allowed to warm to room temperature and was stirred for approximately 18 hours. The reaction mixture was washed with an aqueous, 5% hydrochloric acid solution followed by an aqueous, saturated sodium chloride solution. The washed reaction mixture was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a solid residue. The residue was purified by recrystallization to yield 4.5 g of 9-(4-chloro-2-fluoro-5-nitrophenyl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione, mp 171°-173° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](Cl)=[O:35].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)=[O:35])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added 2-naphthoyl chloride (164 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (175 mg, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:31])[CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](OCC)=[O:27])=[CH:16][CH:15]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.[C:35]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42](=[O:54])[O:43][CH:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][NH:52][CH3:53])[CH2:46][CH2:45]1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(O)C.O.ClCCl>[C:35]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42](=[O:54])[O:43][CH:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][N:52]([C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:17]2[CH:18]=[CH:19][C:14]([C:12](=[O:13])[CH2:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:31])=[CH:15][CH:16]=2)[CH3:53])[CH2:46][CH2:45]1
Reactant: CCOC(=O)CCCCCNc1ccc(C(=O)CCCN(C)C(=O)OC(C)(C)C)cc1
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)CCCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
The compound (470 mg, 1.08 mmol) obtained in Example 77b was dissolved in a mixed solvent of ethanol (5 mL) and water (5 mL), a 1 N aqueous sodium hydroxide solution (1.62 mL, 1.62 mmol) was added, and the mixture was stirred at room temperature. After the reaction was completed, a 1 N aqueous hydrochloric acid solution was added, and then the mixture was extracted with dichloromethane (×3). The solvent was evaporated under reduced pressure, the resulting residue and 1-[2-(methylamino)ethyl]piperidin-4-yl biphenyl-2-ylcarbamate (346 mg, 0.981 mmol) were dissolved in dichloromethane (10 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (375 mg, 1.96 mmol) was added, and the mixture was stirred at room temperature for 14 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with dichloromethane (×3). The resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, then the residue was purified by NH silica gel column chromatography (elution solvents, hexane:ethyl acetate=9:1→1:1→0:1, v/v) and then by silica gel column chromatography (elution solvents, ethyl acetate:methanol=10:0→9:1, v/v) to give the title compound (298 mg; yield, 41%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][NH:13]1>CO>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C[C@H]1COCCN1
Solvent: CO
Product: C[C@H]1COCCN1c1ccc([N+](=O)[O-])cn1
Temperature: 150 °C
Yield: 97.9 %

Procedure:
A mixture of 1 g (6.18 mmol) of 2-chloro-5-nitropyridine and 1.31 g (12.36 mmol) of (S)-3-methylmorpholine is heated in a Biotage microwave machine for 1 hour at 150° C. The reaction medium is taken up in MeOH and then evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0 v/v) up to (95/5 v/v) to give 1.35 g of (S)-3-methyl-4-(5-nitropyridin-2-yl)morpholine.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([O:12][C:13](=[O:18])[C:14]([CH2:16]O)=[CH2:15])[CH3:11]>ClCCl>[CH2:10]([O:12][C:13](=[O:18])[C:14]([CH2:16][F:7])=[CH2:15])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: C=C(CO)C(=O)OCC
Solvent: ClCCl
Product: C=C(CF)C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of (diethylamino)sulfur trifluoride (DAST) (363 μl, 2.76 mmol) in dichloromethane (1 ml) was slowly added at −78 C a solution of 2-hydroxylmethyl acrylic acid ethyl ester (300 mg, 2.31 mmol) in dichloromethane (3 ml). The reaction mixture was allowed to warm to room temperature, re-chilled to −78 C and additional DAST (100 μl, 0.76 mmol) was added to ensure complete reaction. The reaction mixture was let to warm to room temperature and quenched with saturated sodium carbonate. Organic layer was isolated, washed with water, brine and dried (MgSO4). The dichloromethane solution was directly passed through a short silica gel pad, eluted with dichloromethane and the product fractions were collected. The combined fractions (ca. 12 ml) will be directly used in the next step synthesis without further concentration.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=1.[Na].Br[CH2:21][C:22]([O:24]CC)=[O:23].Cl>O1CCCC1.O>[C:22]([CH2:21][O:3][C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=1)([OH:24])=[O:23]
Reactant: O=c1c2ccccc2sc2ccc(O)cc12
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24 g sodium hydroxide was refluxed in 400 ml tetrahydrofuran for five minutes. 22.8 g (0.1 mols) 2-hydroxythioxanthone was added and reflux was continued for 1 hour, during which time the colour changed to bright red, indicating the formation of the sodium salt of 2-hydroxythioxanthone. 35.1 g (0.21 mols) of ethyl bromoacetate was added and reflux was continued for three hours. After cooling to room temperature, 400 ml of deionised water was added, with stirring, and the tetrahydrofuran was distilled out to yield a clear red solution. Reflux was continued for a further 2 hours in order to hydrolyse all the ester intermediate. The solution was then cooled to 50° C., and 400 ml 1.0 M hydrochloric acid was added, with stirring, causing the solid product to precipitate out. After refluxing for a further five minutes to be sure that all the sodium salt was converted to free acid, the solution was cooled to room temperature and stirred for two hours before filtering off the solid, washing with 400 ml deionised water and drying in a vacuum oven at 80° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[N:5](C(=O)C(F)(F)F)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][C:2]1([CH3:34])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: Cc1cccnc1N1CCN(C(=O)Nc2ccc3c(c2)N(C(=O)C(F)(F)F)CCC3(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cccnc1N1CCN(C(=O)Nc2ccc3c(c2)NCCC3(C)C)CC1
Temperature: 60 °C

Procedure:
A suspension of N-(4,4-dimethyl-1-trifluoroacetyl-1,2,3,4-tetrahydroquinol -7-yl)-4-(3-methyl-2-pyridyl)-piperazine-1-carboxamide (100 mg, 0.210 mmol) and potassium carbonate (87 mg, 0.631 mmol) in methanol (5 ml) and water (5 ml) was heated at 60° C. for 3 h. After this period, the solvents were evaporated in vacuo and the residue partitioned between DCM (15 ml) and water (10 ml). The aqueous layer was re-extracted with DCM (2×15 ml) and then the combined organic layers dried (Na2SO4) and the solvents evaporated in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.16 (dd, 1H), 7.43 (dd, 1H), 7.05 (d, 1H), 6.88 (dd, 1H), 6.75 (d, 1H), 6.44 (dd, 1H), 6.29 (br, 1H), 3.85-3.95 (br, 1H), 3.55-3.65 (m, 4H), 3.25-3.30 (m, 2H), 3.15-3.25 (m, 4H), 2.29 (s, 3H), 1.65-1.70 (m, 2H), 1.26 (s, 6H). MS (ES): MH+ 380.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([O:8][C@H:9]1[O:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O.[CH2:37]1COCC1.C1(C)C=CC=CC=1>C[C-]1C=CC=C1.[C-]1(C)C=CC=C1.[Ti+2]>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:6]([O:8][C@H:9]2[O:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:10]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH2:37])[CH:28]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:30]=1
Reactant: O=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: [Ti+2]
Agent: C[c-]1cccc1
Solvent: Cc1ccccc1
Product: C=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 69 %

Procedure:
A solution of 2.50 g (4.9 mmol) of 2-(R)-(3,5-bis(trifluoro-methyl)benzoyloxy)-3-(S)-phenyl-4-benzyl morpholine (from Example 67) and 2.50 g (12.0 mmol) of dimethyl titanocene (from Example 68, Step A) in 35 mL of 1:1 v/v THF/toluene was stirred in an oil bath at 80° C. for 16 hours. The reaction mixture was cooled and concentrated in vacuo. Flash chromatography on 150 g of silica gel using 3:1 v/v hexanes/methylene chloride as the eluant afforded 1.71 g (69%) of the title compound as a solid.