Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[I:18]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[I:18]
Reactant: ClI
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: CC(=O)O
Product: Cc1ccc2nc(-c3ccc(N)c(I)c3)sc2c1
Yield: 66.6 %

Procedure:
2-(4'-Aminophenyl)-6-methylbenzothiazole (0.6 g, 2.5 mmol) was treated with iodine monochloride (0.5 g, 3.02 mmol) in acetic acid according to the above-described general procedure for iodination. Crude product was purified by flash chromatography on silica gel, using ethyl acetate-hexane (1:3) as eluent, to give brown small crystals (0.61 g, 66.7%), m.p. 176.2-177.9° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[NH2:17]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:17][C:16]2[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: ClCCl
Product: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)cc(OC)c1
Reaction time: 1 h
Yield: 64 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (590 mg, 2.79 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (3 ml) and TEA (283 μl, 2.03 mmol) was added. To this solution, 3,5-dimethoxyaniline (312 mg, 2.04 mmol) dissolved in 3 ml dichloromethane was added dropwise and the mixture was stirred for 60 min. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude (684 mg, 62% purity, 64% yield) was used in the next synthetic step without further purification.
Reaction SMILES: [CH2:1]([CH:3]([CH2:35][CH3:36])[CH:4]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[CH:20][CH:19]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:35]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:22][CH:23]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:36]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C)C(CC)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a mixture of ethyl 3-{[(4-{[2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl]amino}phenyl)carbonyl](methyl)amino}propanoate (261 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (231 mg, 94%) as a pale-brown solid.
Reaction SMILES: Cl.[C@@H:2]12[CH2:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:11][CH2:10]1.[C:23](O)([CH3:26])([CH3:25])[CH3:24].[Cl-].[Cl-].[Cl-].[Al+3]>[N+](C1C=CC=CC=1)([O-])=O>[C@@H:2]12[CH2:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:13][CH2:14]1
Reactant: CC(C)(C)O
Reactant: COc1ccccc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(C)(C)C)cc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-4-(2-methoxyphenyl)piperidine hydrochloride (397, 64 mg, 0.20 mmol) was suspended in nitrobenzene (1.0 mL) and treated with 1.0 eq tert-butanol (15 mg), followed by 3.0 eq of aluminum trichloride in nitrobenzene (600 μL 1.0 M solution, 0.60 mmol). The reaction was stirred at room temperature for 2 hours, then quenched with 1.0 N HCl (5.0 mL). The aqueous layer was separated, basified with 1.0 N NaOH (pH 12) and extracted with dichloromethane (10 mL). The extract was dried (Na2SO4), filtered, concentrated in vacuo and dissolved in methanol:acetonitrile (1.0 mL, 1:1 v/v). The solution was filtered (Whatman 0.2 μm PTFE) and subjected to reverse-phase HPLC purification (5-50% CH3CN/0.08% TFA) to yield [1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-4-(5-tert-butyl-2-methoxy-phenyl)piperidine] (compound no. 325) as the TFA salt. LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 342.2 [M+H]+, retention time 2.70 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7]
Reactant: CC(C)(C)OC(=O)COC(=O)c1cccs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 2-tert-butoxy-2-oxoethyl thiophene-2-carboxylate (945 mg, 3.90 mmol) in DCM (6 ml) kept at 0° C., TFA (6.00 ml, 78 mmol) was added dropwise. The solution was stirred at room temperature overnight, then volatiles were evaporated obtaining 2-(thiophene-2-carbonyloxy)acetic acid as a white solid (710 mg, 3.81 mmol, 98% yield, MS/ESI+ 186.7 [MH]+) that was used in the following reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8]O)=[CH:4][CH:3]=1.[OH-:10].[Na+].Cl.[Cl-].[Na+]>O>[CH3:8][C:7]1[C:5](=[O:6])[CH2:4][CH:3]([OH:10])[C:2]=1[CH3:1]
Reactant: [OH-]
Reactant: Cc1ccc(CCO)o1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC1=C(C)C(O)CC1=O
Temperature: 50 °C
Reaction time: 22 h

Procedure:
In a reaction vessel, water (100 ml) and 5-methyl-2-furylmethylcarbinol (5 g) were charged, and the pH value was adjusted to 5.5 with an aqueous 1/3N NaOH solution and an aqueous 1/3N HCl solution. The temperature was elevated up to 100° C. to reflux, and the mixture was stirred under reflux for 16 hours while maintaining the pH value of 4.0 to 5.7 by the addition of an aqueous 1/3N NaOH solution and an aqueous 1/3N HCl solution. After cooling to 50° C., concentrated hydrochloric acid (10 g; corresponding to 0.9N) was added, and stirring was continued at 50° C. for 22 hours. After cooling, the reaction mixture was neutralized with an aqueous 20% NaOH solution and an aqueous 1/3N NaOH solution. Then, sodium chloride (30 g) was added thereto, and the mixture was extracted with toluene (50 ml) five times. The extract was concentrated at 60° C. under reduced pressure to remove toluene, whereby an oily substance (4.4 g) was obtained. The crude product was subjected to column chromatography with silica gel (60 g) (developing solvent, ethyl acetate-n-hexane (1:2 by volume)), and the objective fraction was concentrated to obtain 2-methyl-3-methyl-4-hydroxy-2-cyclopentenone (3.2 g). Yield, 64%.
Reaction SMILES: CO[C:3]1[C:4](=[O:22])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:6][CH2:7][C:8]=1[C:9](=O)[CH2:10][CH3:11].Cl.Cl.[CH:25]1([NH:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[CH:25]1([N:30]2[C:3]3[C:4](=[O:22])[N:5]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[CH2:6][CH2:7][C:8]=3[C:9]([CH2:10][CH3:11])=[N:31]2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NNC1CCCC1
Reactant: CCC(=O)C1=C(OC)C(=O)N(Cc2ccc(OC)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1nn(C2CCCC2)c2c1CCN(Cc1ccc(OC)cc1)C2=O
Temperature: 88 °C

Procedure:
3-Methoxy-1-(4-methoxybenzyl)-4-propionyl-5,6-dihydro-1H-pyridin-2-one (14.471 kg, 47.76 moles) was dissolved in tetrahydrofuran (10.5 gal, 39.7 L) in a clean and dry 100 gallon tank. Cyclopentylhydrazine dihydrochloride (7.664 kg, 44.3 moles) was added and the reaction mixture warmed slowly to 88° C. while nitrogen was swept over the reaction to remove methanol, THF, and HCl. The reaction was monitored by HPLC until the conversion was complete which required heating overnight in most cases. The pot reaction product was a thick dark oil. A sample of 1-cyclopentyl-3-ethyl-6-(4-methoxybenzyl)-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-one was isolated for characterization.
Reaction SMILES: Cl[C:2]1[N:7]2[C:8]([CH3:20])=[N:9][C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl.[NH2:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>>[CH2:27]([CH:26]([N:25]1[C:2]2[N:7]3[C:8]([CH3:20])=[N:9][C:10]([C:11]4[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=4[CH3:19])=[C:6]3[N:5]=[C:4]([CH3:21])[C:3]=2[CH2:22][CH2:23]1)[CH2:29][CH3:30])[CH3:28]
Reactant: Cc1cc(C)c(-c2nc(C)n3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Reactant: CCC(N)CC
Product: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)nc(C)n3c21
Reaction time: 8 h

Procedure:
A solution of 4-chloro-3-(2-chloroethyl)-8-mesityl-2,6-dimethylimidazo[1,5-a]pyrimidine (139 mg, 0.38 mmol) in 3-aminopentane (10 mL) was heated under reflux for five days. After overnight, the residue was purified by dry pack silica gel column chromatography (25-40% ethyl acetate/hexane), to give the title compound (69 mg) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26]>>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)COC(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OCC(C)C)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid isobutyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and isobutyl chloroformate (115 μl, 0.89 mmol). The title compound was obtained as brown solid (85 mg, 25%).
Reaction SMILES: [C:1]([NH:6][C:7](=[O:12])[O:8][CH:9]([CH3:11])[CH3:10])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C@@H:3]([CH3:4])[CH2:2][C:1]([NH:6][C:7](=[O:12])[O:8][CH:9]([CH3:11])[CH3:10])=[O:5])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)cc1
Reactant: C/C=C/C(=O)NC(=O)OC(C)C
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)NC(=O)C[C@H](C)Nc1ccc(Br)cc1
Reaction time: 0.33 h

Procedure:
Similarly a second batch of 1-methylethyl (2E)-2-butenoylcarbamate (Intermediate 49, 8.51 g, 49.7 mmol) was stirred in Toluene (255 ml) under nitrogen and (R-BINAP)ditriflatebis(acetonitrile)palladium(II) (3.04 g, 2.73 mmol) added. The catalyst formed a gummy ball, the solution turned to an opaque yellow mixture and was stirred for 20 mins. 4-bromoaniline (12.83 g, 74.6 mmol) was added, the solution turned a clear light brown and the gummy catalyst dissolved further. The mixture was stirred overnight. The two reaction mixtures were combined and loaded on to a 1.5 kg Isco silica Redisep column. The column was eluted with DCM:MeOH (0%−>0.5%, 19 CV). The clean, product containing fractions were evaporated to a pale brown oil. The mixture was dried in a vacuum oven overnight at 40° C. to give a white solid (24.2 g, 67% overall).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[C:6]([NH:17][CH2:18][C:19]([NH:21][CH:22]2[CH2:25][NH:24][CH2:23]2)=[O:20])=[N:5]1)[CH:2]=[CH2:3].[CH:26]1([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:14])[F:15])=[CH:10][CH:11]=2)[C:6]([NH:17][CH2:18][C:19]([NH:21][CH:22]2[CH2:23][N:24]([CH:36]3[CH2:37][CH2:38][CH:33]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH2:34][CH2:35]3)[CH2:25]2)=[O:20])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: O=C1CCC(C2CCCCC2)CC1
Product: C=CCn1nc(NCC(=O)NC2CN(C3CCC(C4CCCCC4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 2-(1-allyl-5-trifluoromethyl-1H-indazol-3-ylamino)-N-azetidin-3-yl-acetamide and bicyclohexyl-4-one using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([OH:13])=O)[N:4]=1.S(Cl)([Cl:16])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([Cl:16])=[O:13])[N:4]=1
Reactant: COc1cc(OC)nc(C(=O)O)n1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(C(=O)Cl)n1

Procedure:
A mixture consisting of 1.1 g (6.0 mmol) of 4,6-dimethoxypyrimidine-2-carboxylic acid, obtained in accordance with a method descibed in the specification of WO 9318012 A1, 1.1 g (9.0 mmol) of thionyl chloride, one drop of N,N-dimethylformamide and 5 ml of toluene was stirred under heating and refluxing for 3 hours. After the reaction, excess thionyl chloride and the solvent were removed under reduced pressure to obtain crystal of 4,6-dimethoxypyrimidine-2-carbonylchloride. In a separate vessel, 0.30 g (2.0 mmol) of 6,6-difluoro-5-methyl-5-hexenole and 0.61 g (3.0 mmol) of 4,6-dimethoxypyrimidine-2-carbonylchloride were dissolved in 10 ml of tetrahydrofuran, followed by the drop-wise addition of 0.40 g (4.0 mmol) of triethylamine at room temperature, followed by stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:7) to obtain 0.20 g (yield: 21%) of 6,6-difluoro-5-methyl-5-hexenyl 4,6-dimethoxypyrimidine-2-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][C@@H:27]([F:30])[CH2:26]2)[CH2:20][CH2:19]1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]>>[Cl:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]3[CH2:29][CH2:28][C@@H:27]([F:30])[CH2:26]3)[CH2:20][CH2:19]2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CC[C@@H](F)C2)CC1)C1CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CC[C@@H](F)C2)CC1)C1CC1

Procedure:
Following general procedure D, (6-bromo-4-((trans-4-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone (47 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.16 mmol) to afford the desired product (33.9 mg, 63%) as a yellow solid. 1H NMR (500 MHz, CDCl3) 1H NMR (500 MHz, CDCl3) δ 10.78 (br s, 1H), 9.24 (s, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.84 (dd, J=8.7, 2.1 Hz, 1H), 7.44-7.39 (d, J=2.0 Hz, 1H), 7.29 (dd, J=11.1, 2.0 Hz, 1H), 5.25-5.10 (m, 1H), 4.10-4.04 (m, 1H), 2.91-2.65 (m, 4H), 2.51-2.27 (m, 5H), 2.24-2.01 (m, 5H), 1.65-1.50 (m, 3H), 1.31-1.21 (m, 1H), 1.13-1.04 (m, 4H). ESI MS m/z 540 [C30H32ClF2N3O2+H]+; HPLC>99% (AUC), tR=10.95 min.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=C.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: O=C(Cl)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=Cc1ccccc1
Temperature: 100 °C
Yield: 66 %

Procedure:
3.51 g (0.025 mol) of benzoyl chloride, 3.125 g (0.03125 mol) of ethyl acrylate, 5.79 g (0.03125 mol) of tri-n-butylamine, 50 ml of toluene and 0.0561 g (0.00025 mol) of palladium acetate are introduced into a 100 ml glass flask and heated to 100° C., with stirring. A slight evolution of gas is observed. After the mixture has been stirred for 4 hours, it is cooled and the contents of the flask are extracted by shaking twice with 25 ml of 2 N hydrochloric acid at a time. The toluene phase is dried with magnesium sulfate and distilled. After the toluene has been distilled off, 2.9 g (0.0165 mol) of ethyl cinnamate are obtained, corresponding to a yield of 66% of theory; boiling point=135°-138° C./17×102Pa; nD20 =1.5592.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:19](OC)=[N:18][S:17](=[O:22])[N:16]=2)[N:9]=1)[CH3:3].COC1C(OC)=NS(=O)[N:26]=1.N>>[NH2:26][C:19]1[C:15]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]2[N:9]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[S:6][CH:7]=2)=[N:16][S:17](=[O:22])[N:18]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: COC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1
Agent: N
Product: CN(C)Cc1nc(CSCCNC2=NS(=O)N=C2N)cs1

Procedure:
When a methanolic solution of 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide [prepared from 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide by the general procedure described in Example 34, Step F] is reacted with anhydrous ammonia according to the general procedure described in Example 35, the title compound is thereby produced.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>CN(C=O)C>[N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClCc1ccncc1
Reactant: O=[N+]([O-])c1cccc2[nH]cnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1ncn2Cc1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 500-mL round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet is charged with compound 3b (3.30 g, 30.6 mmol), potassium carbonate (8.95 g, 64.8 mmol), anhydrous DMF (200 mL) and 4-chloromethylpyridine hydrochloride (3.98 g, 24.3 mmol) and the mixture is then stirred under nitrogen for 24 h at ambient temperature. After such time the reaction is partitioned between water (200 mL) and ethyl acetate (200 mL). The aqueous layer is separated and extracted with ethyl acetate (6×250 mL). The combined organic extracts are dried with sodium sulfate, and the drying agent is filtered off. The filtrate is then concentrated under vacuum to give a brown solid, which is purified by column chromatography to afford compound 3c as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=1.[OH-].[Na+].O1CCCC1.Cl>O>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[N:21][C:12]=1[CH2:11][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cccc(OCc2ncc3ccccc3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(OCc2ncc3ccccc3n2)c1

Procedure:
A mixture of 5.50 g (0.01869 moles) of 3-(2-quinazolinylmethoxy)benzoic acid methyl ester, 30.1 ml (0.0301 moles) of 1N sodium hydroxide and 22 ml of tetrahydrofuran is heated at reflux for 50 minutes. The mixture is allowed to come to room temperature and evaporated in vacuo giving a solid residue. After the addition of water and filtration through Celite the filtrate is acidified with 2.4M hydrochloric acid. The resulting precipitate is filtered, washed with water until the washings are pH~6. The precipitate is dried overnight in a vacuum desiccator and azeotroped with toluene on a rotoevaporator. Drying in vacuo gives the title compound, 4.75 g colorless solid, m.p. 221°-224° C.; IR (KBr) 1695, 1576, 1285, 1220 cm-1 ; NMR (DMOS-d6) 9.73 (s, 1H), 7.34-8.22 (8H, aromatic) 5.56 (2H, s), 3.43 (1H, broad).
Reaction SMILES: [CH2:1]([N:13]([CH:31]([CH3:37])C(OCC)=O)[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CCC[C:71]([O:73][CH2:74][CH3:75])=[O:72])CCOC1C=CC(CCC(O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:1]([N:13]([CH2:31][CH2:37][C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH:25]([OH:30])[C:26]([F:28])([F:29])[F:27])=[CH:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(O)C(F)(F)F)cc1
Reactant: CCCCCCCCCCCCN(CCOc1ccc(/C=C/C(O)C(F)(F)F)cc1)C(C)C(=O)OCC
Product: CCCCCCCCCCCCN(CCOc1ccc(CCC(O)C(F)(F)F)cc1)CCC(=O)OCC
Yield: 92 %

Procedure:
[N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en-1-yl]phenoxy]ethylamino]propanoic acid, ethyl ester (620 mg, 1.17 mmol) was hydrogenated as described in the preparation of 4-[N-dodecyl-N-2-[4-[3-hydroxy-4,4,4-trifluorobutyl]phenoxy]ethylamino]butanoic acid, ethyl ester (Example 48) and afforded the title compound (573 mg, 92%) as a clear oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([C:21]([OH:24])([CH3:23])[CH3:22])[C:12]3[C@@H:25]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)[O:26][C:27]4([CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:45]I>CN(C)C=O.C(OCC)C>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([C:21]([O:24][CH3:45])([CH3:23])[CH3:22])[C:12]3[C@@H:25]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=4)[O:26][C:27]4([CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:11]=3[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC1(C)Cc2nc(C(C)(C)O)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(C)(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
25 mg 2-((3R,9S)-9-(tert-butyldimethylsilyloxy)-7,7-dimethyl-3-(4-(trifluoromethyl)phenyl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-4-yl)propan-2-ol are dissolved in 1 ml N,N-dimethylformamide, cooled to 0° C., treated with 3 mg sodium hydride (60% in mineral oil) and stirred for 1 minute. Then 5 μl methyliodide are added and the mixture is stirred for 4 hours at room temperature. The mixture is diluted with diethylether, washed with saturated aqueous ammonium chloride and dried with magnesium sulphate.