Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].[C:6](=O)([O:15]C1C=CC=CC=1)[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[NH2:4][CH2:3][CH2:2][CH2:1][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCCN
Reactant: O=C(OCc1ccccc1)Oc1ccccc1
Solvent: CCO
Product: NCCCNC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 1,3-propanediamine (6.50 g, 87.0 mol) in 250 mL of abs. EtOH was added benzyl phenyl carbonate (20.0 g, 87.0 mmol). The solution was stirred overnight. A white precipitate formed. The solvent was removed in a rotary evaporator, and the residue was taken up with 100 ml of distilled H2O. This was followed by acidification with 2M HCl to pH 1-2, and 4× extracting with 250 mL of CH2Cl2 each time. The aqueous phase was rendered strongly alkaline with 2M NaOH and extracted 4× with 250 mL of CH2Cl2 each time. The combined organic phases were dried over Na2SO4, subsequently the solvent was removed in a rotary evaporator to obtain the product as a viscid white mass (4.70 g, 26%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[O:14][CH2:13][CH:12]([OH:15])[CH2:11][O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:16]I>C1COCC1.O>[CH3:16][O:15][CH:12]1[CH2:13][O:14][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH2:11]1
Reactant: CI
Reactant: OC1COC(c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1COC(c2ccccc2)OC1
Temperature: 0 °C

Procedure:
Sodium hydride (0.7 g, 18 mmol) was added in three portions to a solution of 2-phenyl-1,3-dioxan-5-ol. (3.0 g, 17 mmol) in THF (50 mL) at −10° C. The reaction mixture was stirred at 0° C. until no gas was generated. MeI (3.5 g, 25 mmol) was then added at room temperature, and reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with water (50 mL). The solvent was removed; the residue was extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown crude oil which was recrystallized from THF/hexane to afford 5-methoxy-2-phenyl-1,3-dioxane as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.51-7.48 (m, 2H), 7.41-7.37 (m, 3H), 5.56 (s, 1H), 4.25-4.19 (m, 2H), 4.07-4.03 (m, 2H), 3.48 (s, 3H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9](O)=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].S(Cl)([Cl:18])=O>CN(C)C=O>[Cl:18][C:9]1[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:11][N:10]=1
Reactant: CCS(=O)(=O)c1cnc(O)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cnc(Cl)c([N+](=O)[O-])c1

Procedure:
To a solution of 5-(ethylsulfonyl)-3-nitropyridin-2-ol (Step C, 575 mg, 2.5 mmol) in thionyl chloride (7 mL) was added N,N-dimethylformamide (one drop). The mixture was stirred under reflux for 2 h and concentrated to afford the crude title compound as a white solid.
Reaction SMILES: Cl.C[O:3][C:4](=[O:9])[C@H:5](CO)N.[C:10](=[NH:20])([O:17][CH2:18][CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.ClCCl>[C:11]1([C:10]2[O:17][CH2:18][CH:19]([CH2:5][C:4]([OH:9])=[O:3])[N:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(O)CC1COC(c2ccccc2)=N1

Procedure:
567 mg (3.6 mmol) of L-serine methyl ester hydrochloride are dissolved in 0.5 ml of water, and 610 mg (3.6 mmol) of ethyl benzimidate in 10 ml of dichloromethane are added thereto. After 48 h at reflux, the mixture is concentrated to a volume of 50 ml of dichloromethane and washed with NaHCO3 (3×10 ml), and the aqueous phase is extracted with ethyl acetate (2×10 ml). Column chromatography (15×5 cm, hexane/ethyl acetate 1:1) yields 3.0 g of A2a (91% of theory).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:9][CH:8]=2)=[O:4].[Li+].[OH-].O>C1COCC1>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][O:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[NH:6]2
Reactant: COC(=O)c1cc2c(OCC(C)(C)C)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)COc1cccc2[nH]c(C(=O)O)cc12
Reaction time: 48 h

Procedure:
4-(2,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid methyl ester 90 (270 mg, 1.03 mmol) is dissolved in 20 ml of THF. A 2M-solution of LiOH in water (5.2 ml, 11 mmol) is added and the mixture is stirred for 48 hours. The solvent is then evaporated and the residue is partitioned between water and ether. The water layer is acidified with HCl and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a yellow powder.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: OCCCCCCCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: BrCCCCCCCCCOC1CCCCO1
Yield: 89 %

Procedure:
A solution of 9-bromo-1-nonanol (2.00 g, 8.96 mmol), 3,4-dihydro-2H-pyran (792 mg, 9.41 mmol), and pyridinium toluene-4-sulfonate (1.08 g, 4.30 mmol) in dichloromethane (34 mL) was stirred at room temperature for 16 h, then washed with 2 M aq. sodium carbonate solution and brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced 2-(9-bromo-nonyloxy)-tetrahydro-pyran (2.45 g, 89%). Colorless oil, m/e=324.1 ([M+NH4]).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@H:5]([CH3:15])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)[CH3:2].[CH2:17](I)[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[C@H:5]([CH3:15])[N:6]([C:7]1[CH:8]=[CH:9][C:10]([S:13][CH3:14])=[CH:11][CH:12]=1)[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:2]
Reactant: CCCCI
Reactant: CCOC(=O)[C@H](C)Nc1ccc(SC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN(c1ccc(SC)cc1)[C@@H](C)C(=O)OCC

Procedure:
N-(4-Methylthiophenyl)alanine ethyl ester (10.0 g, 42.0 mmol), n-butyl iodide (7.9 g, 42 mmol) and potassium carbonate were added to 150 mL of acetonitrile and the mixture was heated at reflux for 48 h under a nitrogen atmosphere. The reaction mixture was cooled and then partitioned between 300 mL ethyl acetate and 200 mL brine. The organic layer was separated, washed with 100 mL brine, dried over anhyd. sodium sulfate, and concentrated at reduced pressure. The resulting oil was charged onto a silica gel column and eluted with heptane:THF (5:1). The desired ester was isolated as a yellow oil (3.0 g, 24%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O.ClCCCl>[CH3:17][O:16][C:10]1[CH:15]=[CH:14][C:13]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:12][CH:11]=1
Reactant: COc1ccccc1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: CCC(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 66 %

Procedure:
525 ml of 1,2-dichloroethane and 209 g of aluminium chloride are added to a round flask which is fitted with a stirrer, thermometer, condenser and dropping funnel. The mixture is cooled to 0° C. and 127 g of propionic acid chloride are allowed to drop in at 0°-5° C. within 75 minutes. After the addition, the temperature is allowed to rise to 18° C. and then 141.6 g of anisole are added within 2 hours and at 20° C. The mixture is left to stand for 12 hours and then the product is poured into a mixture of 800 g of ice, 130 ml of water and 130 ml of concentrated hydrochloric acid. The aqueous phase is separated and extracted with two 250 ml portions of 1,2-dichloroethane. The combined organic phases are washed with three 200 ml portions of 2% sodium hydroxide and with 250 ml of water. The solvent is removed by evaporation under a vacuum and the residue (198 g) is distilled over a 25 cm column. There are obtained 142 g of p-methoxy-propiophenone (yield: 66.4% of theory). B.p.=90° C./0.4 mmHg; melting point 26° C.; nD20 =1.5451; d420 =0.9645.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:4](=[O:7])[O:5][CH3:6])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][Br:15])[C:4](=[O:7])[O:5][CH3:6])[CH3:2]
Reactant: CCN(C(=O)OC)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCN(C(=O)OC)c1ccccc1CBr
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A mixture of 30 g (0.155 mol) of methyl N-ethyl-N-(o-methylphenyl)-carbamate (Example 1b), 33 g (0.185 mol) of N-bromosuccinimide and 0.1 g of azoisobutyronitrile in 300 ml of carbon tetrachloride is exposed to a 300 W UV lamp for 6 hours. During this procedure, the contents of the flask heat up to about 70° C. Thereafter, the reaction mixture is washed four times with water, dried and evaporated down. The residue obtained comprises 41 g of a brown oil which contains the title compound in about 50% purity and is used without further purification in the next reaction.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C@@H:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15].N1C=CN=C1>CN(C)C=O>[Si:1]([O:18][C@H:13]([C:12]1[CH:19]=[CH:20][CH:21]=[C:10]([Cl:9])[CH:11]=1)[C:14]([O:16][CH3:17])=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](O)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
A solution of 31.6 g of t-butyldimethylsilyl chloride in 200 ml of dimethylformamide was added dropwise, whilst ice-cooling, to a solution of 28 g of methyl (R)-3-chloromandelate (prepared as described in Preparation 47) and 28.5 g of imidazole in 300 ml of dimethylformamide, and the resulting mixture was stirred at the same temperature for 30 minutes, after which it was allowed to stand overnight at 40° C. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with water and ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:15 by volume mixture of ethyl acetate and hexane as the eluent, to give the title compound as crystals, melting at 36°-38° C. [α]D23 -39.1° (c=1.014, chloroform)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][OH:28])=[N:24][CH:25]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][OH:28])=[N:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: Nc1ccc(CCO)nc1
Agent: Cl
Product: OCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cn1
Yield: 22.9 %

Procedure:
Following general procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.075 g, 0.25 mmol) was reacted with 2-(5-aminopyridin-2-yl)ethanol (0.045 g, 0.33 mmol), followed by formation of the hydrochloride salt to afford the desired product (0.023 g, 21%) as a white solid. MW=438.78. 1H NMR (DMSO-d6, 500 MHz) δ 14.38 (s, 1H), 10.12 (s, 1H), 8.72 (s, 1H), 8.10 (s, 1H), 7.98-7.95 (m, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.71-7.58 (m, 3H), 7.21 (s, 1H), 3.80 (t, J=8.0 Hz, 2H), 3.20 (t, J=8.0 Hz, 2H), 3.03 (t, J=7.5 Hz, 2H), 2.98 (t, J=7.5 Hz, 2H), 2.26 (quin, J=7.5 Hz, 2H); APCI MS m/z 366 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[N:8][NH:9][N:10]=1)[CH3:2].S(=O)(=O)(O)O.C(OCC)(=O)C.[OH-].[Na+].[CH3:25][C:26](O)([CH3:28])[CH3:27]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[N:8][N:9]([C:26]([CH3:28])([CH3:27])[CH3:25])[N:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nn[nH]n1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1nnn(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
To a solution of (2H-tetrazol-5-yl)-acetic acid ethyl ester (2.0 g, 13 mmol) in 2-methyl-propan-2-ol (2.6 mL) and trifluoroacetic acid (6 mL) was added concentrated sulfuric acid (0.35 mL, 6.4 mmol) and the reaction was stirred at room temperature for 12 h. Ethyl acetate was added and the solution was neutralized by addition of an aqueous sodium hydroxide solution (2 N). The solution was extracted several times with ethyl acetate, and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography to provide (2-tert-butyl-2H-tetrazol-5-yl)-acetic acid ethyl ester (2.0 g, 52% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:16]1C=CC(S(O)=O)=CC=1C(O)=O.C(I)C>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH3:16])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Solvent: CCO
Solvent: CCI
Product: CCS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Yield: 27 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 2-Chloro-5-methanesulfonyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and ethyl iodide in 20 ml ethanol/20 ml water and obtained in 27% yield. MS (m/e): 247.1 (MH−, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:7]=[C:8]([C:10](=O)[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:9]=1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:7]=[C:8]([C:10](=[S:34])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C(=O)Nc2cccc(F)c2F)cn1S(C)(=O)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=S)Nc2cccc(F)c2F)cn1S(C)(=O)=O
Yield: 143.7 %

Procedure:
To a solution of 4-(2,3-difluoro-phenylcarbamoyl)-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid methyl ester (410 mg, 1.14 mmol) in dry toluene (10 mL) was added Lawesson's reagent (320 mg, 0.79 mmol). The suspension was heated at reflux for 2 hours. The solvent was removed by evaporation and the residue was purified by flash column eluting with 30% of EtOAc/hexanes to afford the title compound as a yellow solid (425 mg, 99%). MS (ES+): m/e=375.1 (M+H); LC/Method A/3.61 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH:31]([NH2:33])[CH3:32].C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH:33][CH:31]([CH3:32])[CH2:30][N:29]([CH3:34])[CH3:28])[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: CC(N)CN(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)NC(C)CN(C)C)cc3)cc12

Procedure:
N2-(1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethyl)-N1,N1-dimethylpropane-1,2-diamine was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and N1,N1-dimethylpropane-1,2-diamine (commercially available) following the procedures described for Example 182. 1H NMR (Acetone-d6) TFA Salt: δ 8.83 (m, 2H), 8.40 (d, 1H), 7.46-7.51 (m, 3H), 7.43 (m, 1H), 7.37 (d, 2H), 4.54 (m, 1H), 3.74 (m, 1H), 3.19 (m, 4H), 2.90 (s, 3H), 2.77 (s, 3H), 2.55 (s, 3H), 2.41 (d, 2H), 1.66 (d, 3H), 1.39 (d, 3H). LRMS [M+H]=442.2.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:25])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21]Cl)=[C:14]([O:23][CH3:24])[CH:13]=2)[CH2:4][CH2:3]1.[CH3:26][NH:27][CH3:28]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:25])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:27]([CH3:28])[CH3:26])=[C:14]([O:23][CH3:24])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CNC
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCl
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCN(C)C

Procedure:
Using 5 g of N-(trans-4-methylcyclohexyl) -4-(3-chloropropoxy)-3-methoxycinnamamide (Example 134), 100 ml of methylisobutylketone, and 150 ml of a 50% aqueous dimethylamine solution, a reaction similar to that conducted in Example 107 was carried out. As a result, 4.61 g of N-(trans-4-methylcyclohexyl)-4-(3-dimethylaminopropoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1.[C:14]1(=[O:18])[O:17][CH2:16][CH2:15]1.Cl>O.CN(C)C=O>[F:13][C:10]([F:11])([F:12])[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[O:3][CH2:16][CH2:15][C:14]([OH:18])=[O:17]
Reactant: O=C1CCO1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCOc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (550 mg) was added to an N,N-dimethylformamide (20.0 mL) solution of 3-hydroxybenzotrifluoride (2.0 g), and the reaction mixture was stirred at room temperature for one hour. β-Propiolactone (1.0 mL) was added thereto, and the solution was stirred at room temperature for 2.5 hours. Water was then added to the solution, and the pH was adjusted to 2 with 2 N hydrochloric acid. The solution was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and n-hexane was then added to the residue to perform crystallization. The title compound (2.2 g) was obtained as colorless crystals.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:11]([C:13]1[N:14]=[CH:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)[CH3:12].[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:15]1[O:16][C:17]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)=[C:13]([CH2:11][CH3:12])[N:14]=1
Reactant: CCc1ncoc1-c1ccc(C(F)(F)F)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
LiHMDS (1.0 M in THF, 26 mL, 26 mmol) was added dropwise to a solution of Example 43A (5.75 g, 23.8 mmol) in THF (100 mL) at −78° C. After 30 min solid hexachloroethane (6.21 g, 26.2 mmol) was added in one portion, and the reaction mixture was allowed to proceed for 18 hr with gradual warming to ambient temperature. The reaction was quenched with saturated aq NH4Cl solution (50 mL), and the mixture was partitioned between H2O and Et2O. The aqueous phase was extracted once with Et2O, and the combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified on silica gel (Analogix® Intelliflash 280™; SF40-150 g column; 100% hexane 7 min, then 0% to 20% EtOAc/hexanes eluant, 23 min) which yielded 6.23 g (95%) of the title compound as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.87 (d, J=8.5, 2H), 7.79 (d, J=8.5, 2H), 2.77 (q, J=7.5, 2H), 1.23 (t, J=7.5, 3H). MS (DCI+) m/z 276 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[OH:19])=[CH:6][CH:7]=1
Reactant: NCC(O)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCC(O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 67, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-amino-1-phenyl-ethanol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:13]1[CH:18]=CC(C(C2C=CC(O)=CC=2)(C)C)=C[CH:14]=1>>[OH:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:1]([CH3:4])([CH3:2])[CH2:3][C:13]2([CH3:18])[CH3:14]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC1(C)CC(C)(C)c2cc(O)ccc21

Procedure:
172.5 g (1.15 mol) of 4-tert.-butylphenol, 57.5 g (0.25 mol) of 2,2-bis-(4-hydroxyphenyl)-propane and 10 g of an acid-activated fuller's earth were heated with stirring in an autoclave for 6 hours to approximately 200° C. The hot reaction mixture is then filtered off from the catalyst under suction and the resulting 221.3 g reaction mixture subjected to fractional distillation in vacuo, giving 25.2 g (52 % of the theoretical) of 5-hydroxy-1,1,3,3-tetramethyl indane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1.[F:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([N:30]3[CH2:31][CH2:32][CH:27]([F:26])[CH2:28][CH2:29]3)=[O:19])[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1
Reactant: O=C(O)CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O
Reactant: FC1CCNCC1
Product: O=C(CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O)N1CCC(F)CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E13 starting from 2-(8-((3,4-difluorobenzyl)oxy)-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl)acetic acid and 4-fluoropiperidine.