Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11]O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.P(Br)(Br)[Br:21]>C1(C)C=CC=CC=1>[Br:21][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[C:8]=1[CH3:13]
Reactant: Cc1c(CO)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: Cc1c(CBr)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirring suspension (2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in toluene at 40° C. was added PBr3 and the reaction mixture stirred at 100° C. overnight. DCM/saturated aqueous NaHCO3 extraction of the cooled mixture gave 6-bromomethyl-2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O.C(OCC)(=O)C>[CH2:15]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCI
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCN1CCC(O)CC1
Reaction time: 2 h

Procedure:
4-Hydroxypiperidine was dissolved in N,N-dimethylformamide (20 ml) and treated with potassium carbonate (1.5 g, 10.8 mmol) and 1-iodoheptane (1.8 ml, 11.3 mmol). After stirring for 2 h the mixture was diluted with ethyl acetate, washed with water, brine, dried and evaporated.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:6][C:7]1[CH:8]=[C:9]([C:12](=[O:17])C(Cl)(Cl)Cl)[NH:10][CH:11]=1>C(#N)C>[I:6][C:7]1[CH:8]=[C:9]([C:12]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])[NH:10][CH:11]=1
Reactant: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Reactant: C1CCNC1
Solvent: CC#N
Product: O=C(c1cc(I)c[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Pyrrolidine (3 mL, 35.62 mmol) was added to a stirred solution of 4-iodo-2(trichloroacetyl)pyrrole (10 g, 29.69 mmol) in acetonitrile (50 mL) at room temperature. The mixture was stirred at room temperature for 1 hr. The white precipitate was filtered and washed with acetonitrile (25 mL) to give title compound as a white solid (7.3 g, 86%).; Mass Spec FIA MS 291.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([NH:28][NH2:29])=[O:27])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.[C:30]([CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([NH:28][NH:29][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1
Reactant: COc1cc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/C(=O)NNC(=O)CCCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
IPEA (2.5 mL) was added to a suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid hydrazide (500 mg) in methylene chloride (12 mL) at room temperature, and the reaction solution was stirred at room temperature for 10 minutes. 4-benzoylbutyric acid (334 mg) and BOPCl (442 mg) were added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for four hours. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 5-oxo-5-phenylpentanoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (692 mg). Imidazole (494 mg), carbon tetrabromide (2.36 g) and triphenylphosphine (559 mg) were added to a suspension of 5-oxo-5-phenylpentanoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (634 mg) in methylene chloride (15 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 515 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[I-].[NH2:16][N+:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])=[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)C#Cc1ccc(Cl)cc1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)C(=O)c1c(-c2ccc(Cl)cc2)nn2ccccc12
Yield: 43.4 %

Procedure:
Starting with 4.9 g (35.8 mmol) of 4-chloroethynylbenzene, 3.76 ml of isobutyryl chloride and 4.88 g ZnCl2, the corresponding 1-(4-chlorophenyl)-4-methylpent-1-yn-3-one was prepared using the same procedure as in Example 5(a) to obtain 9.21 g of crude oil intermediate. Starting with 9.21 g (35.8 mmol) of 1-(4-chlorophenyl)-4-methylpent-1-yn-3-one, 9.90 g (44 mmol) of 1-aminopyridinium iodide and 11 g DBU, the desired product was obtained—4.64 g (43%) of 1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one as in Example 5(b). Compound 1024.
Reaction SMILES: [C:1]([N:6]1[C:11](=[O:12])[CH:10]2[CH2:13][CH:7]1[CH:8]=[CH:9]2)(=[O:5])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].S(=O)(=O)(O)O.C(OCC)(=O)C>C(O)C>[C:1]([NH:6][CH:7]1[CH2:13][CH:10]([CH2:11][OH:12])[CH:9]=[CH:8]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)N1C(=O)C2C=CC1C2
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCC(=O)NC1C=CC(CO)C1
Temperature: -10 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
87 g of (±)-2-butyryl-2-azabicyclo [2.2.1]hept-5-en-3-one were dissolved in ethanol (400 ml) under nitrogen and cooled to −10° C. 15.68 g of sodium boro-hydride were added in portions over the course of 45 minutes. The reaction was stirred at 0° C. for 3 hours and then the pH was adjusted to 1.5 with conc. sulphuric acid. Ethyl acetate (200 ml) was added to this mixture, and the solids were filtered off. It was then completely evaporated. The residue was taken up in water, washed with methylene chloride, evaporated and dried under high vacuum. 60.55 g of product were obtained. The yield was 80% based on (±)-2-butyryl-2-azabicyclo[2.2.1]hept-5-en-3-one employed.
Reaction SMILES: [CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH:1]1([C:4]([CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:16][CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(C1CC1)C(c1ccccc1F)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(C(C(=O)C2CC2)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 50 ml of dichloromethane, 8.0 g (28.9 mmol) of 1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4-hydroxypiperidine were dissolved, followed by the addition of 2.92 g (28.9 mmol) of triethylamine. To the resulting mixture, a solution of 3.31 g (28.9 mmol) of methanesulfonyl chloride in 10 ml of dichloromethane was added dropwise under ice cooling, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and triethylamine hydrochloride so precipitated was filtered off. The filtrate was concentrated by evaporation under reduced pressure, whereby crude 1-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4-methylsulfonyloxypiperidine was obtained. To the crude product, 50 ml of dimethylsulfoxide (DMSO) and 19.8 g (170 mmol) of potassium thioacetate were added and the resulting mixture was stirred at 50° C. for 4 hours. After the addition of water, the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to chromatography on a silica gel column (eluting solvent: toluene/ethylacetate=19/1), whereby a reddish brown oil was obtained. The resulting oil was crystallized from hexane, whereby 3.6 g of the title compound were obtained as light brown crystals (yield: 37%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH:14]([CH2:21][C:22]2([CH2:28][CH3:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15]3=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C1(C)C=CC=CC=1.OS(O)(=O)=O>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14]([CH2:21][C:22]2([CH2:28][CH3:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:15]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(CC2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC1(CC2=Cc3cccc(-c4ccc(C(C)(C)C)cc4)c3C2)CCCCC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 97.3 %

Procedure:
24.0 g of crude 4-(4-tert-butyl-phenyl)-2-[(1-ethylcyclohexyl)methyl]indan-1-one (˜82% purity), 2.4 g (63.4 mmol) of NaBH4 and 60 ml of toluene are charged in a flask equipped with reflux condenser, dropping funnel and magnetic stirring bar. The mixture is warmed to 50° C. and 12 ml of methanol are slowly added with stirring and stirring is continued for 2.5 h to ensure a complete reaction. Excess NaBH4 is carefully hydrolyzed with approx. 35 ml of 2n H2SO4. The organic phase is separated and the water phase is washed with another 30 ml of toluene. The combined organic phases are twice extracted with 2n H2SO4 and dried over anhydrous MgSO4. Most of the solvent is removed in a vacuum and replaced by fresh toluene up to a total volume of 90 ml and 0.26 g of p-toluenesulfonic acid are added. The reaction flask is fitted with a water separator and the reaction mixture is heated to reflux for 1.5 h. The conversion can be monitored by TLC. Once the dehydration is complete, the solution is washed with a saturated NaHCO3 solution and dried over anhydrous MgSO4. The solvent is thoroughly removed in a vacuum and 22.4 g of a brown oil is obtained. Purification of the indene is carried out via a column chromatography. Yield: 15.3 g (˜81%) of 7-(4-tert-Butyl-phenyl)-2-[(1-ethylcyclohexyl)methyl]-1H-indene.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[C:39]([O:40][CH3:41])=[CH:38][N:37]=[C:36]([S:42][CH3:43])[N:35]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.ClC1C=CC=C(C(OO)=[O:61])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:48][C:47]([F:50])([F:49])[C:45]1[CH:44]=[C:5]([CH:4]=[C:3]([C:2]([F:51])([F:1])[F:52])[CH:46]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=1[C:34]1[C:39]([O:40][CH3:41])=[CH:38][N:37]=[C:36]([S:42]([CH3:43])=[O:61])[N:35]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2nc(SC)ncc2OC)nc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2nc(S(C)=O)ncc2OC)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(5-methoxy-2-methylsulfanyl-pyrimidin-4-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (162 mg) is dissolved in chloroform (5 ml) and thereto is added m-chloroperbenzoic acid (70%) (63 mg) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution are added saturated aqueous sodium thiosulfate solution and chloroform, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→19:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2-methanesulfinyl-5-methoxy-pyrimidin-4-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (143 mg). MS (m/z): 780 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=[S:15])[NH:7][C:6]=2[CH:16]=1.[OH-].[K+].S([O-])(O[CH3:23])(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([S:15][CH3:23])=[N:7][C:6]=2[CH:16]=1
Reactant: Fc1ccc2c(c1)NC(=S)c1cscc1N2
Reactant: COS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: CSC1=Nc2cc(F)ccc2Nc2cscc21

Procedure:
In a similar manner 7-fluoro-4,9-dihydro-10H-thieno[3,4-b] [1,5] benzodiazepin-10-thione is reacted with potassium hydroxide and methyl sulfate to give 7-fluoro-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8](C(O)=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([N:21](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)(C)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([NH2:21])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 95 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (12.5 g, 38.3 mmol) in tert-butanol (250 mL) were added triethylamine (5.5 mL, 40 mmol) and diphenylphosphoryl-azide (8.6 mL, 40 mmol). The reaction mixture was stirred at 95° C. for 16 h, then allowed to cool down to RT, and concentrated in vacuo. The resultant residue was dissolved in ethyl acetate, washed successively with water, aqueous saturated sodium bicarbonate solution and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was dissolved in DCM (150 mL) and treated with trifluoroacetic acid (50 mL). The reaction mixture was stirred at RT for 3 h then concentrated in vacuo. The resulting residue was triturated with 20% ethyl acetate/cyclohexane and filtered to afford the title compound as an off-white solid (7.94 g, 70%). LCMS (Method A): RT=3.13 min, [M+H]+=297 and 299. 1H NMR (DMSO-d6): 8.01 (1H, d, J=8.6 Hz), 7.30-7.25 (1H, d, J=8.6, 2.1 Hz), 7.19 (1H, d, J=2.1 Hz), 4.27 (2H, t, J=5.1 Hz), 3.08 (2H, t, J=5.1 Hz).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23].CCCCCC>CS(C)=O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:23][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: COC(CN)OC
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COC(CNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1)OC
Temperature: 0 °C
Yield: 100.4 %

Procedure:
The starting material may be prepared as follows: To a suspension of 5.5 g of 2,6-dichloro-4-phenylquinazoline in 70 ml of dimethylsulfoxide was added 4.2 g of 2,2-dimethoxyethylamine. The mixture was heated at 90°-100° C. for 1.5 hours with stirring. After cooling, the mixture was poured into 400 ml of ice-water. The resulting mixture was stirred with a small quantity of n-hexane, and the precipitate that formed was collected by filtration, washed with water and dried to give 6.9 g of 6-chloro-2-(2,2-dimethoxyethylamino)-4-phenylquinazoline. Recrystallization from ethanol gave yellow needles, m.p. 122.5°-123° C.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4]([O:14][CH3:15])=[N:5][C:6](F)=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(O)C>[NH2:1][C:6]1[C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]([Cl:2])=[C:4]([O:14][CH3:15])[N:5]=1
Reactant: N
Reactant: COc1nc(F)c(C(F)(F)F)cc1Cl
Solvent: CCO
Product: COc1nc(N)c(C(F)(F)F)cc1Cl
Temperature: 110 °C
Reaction time: 15 h

Procedure:
16.2 g (0.954 mol) of gaseous ammonia were injected into an autoclave containing 36.5 g (0.159 mol) of 3-chloro-6-fluoro-2-methoxy-5-trifluoromethylpyridine and 150 ml of ethanol and the mixture was then stirred for 15 hours at 110° C. After cooling and releasing the pressure, the reaction mixture was concentrated and the residue was partitioned in methylene chloride/water. After 0.4 g of insoluble matter had been separated off, the organic phase was separated off, and the aqueous phase was reextracted twice using methylene chloride. The organic extracts were dried and concentrated, giving 30.6 g (85% of theory) of the title compound as an oil. NMR (400 MHz, CDCl3) δ 7.6 pyr (1/s); 3.95 CH3O (3/s); 4.9 NH2 (2/s). After silica gel chromatography with methylene chloride, a further 33.2 g (72% of theory) of the title compound were obtained as a colorless oil of ηD24 =1.5140 (Table II, No. 2.001).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[CH3:18][C:19]1([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=2[OH:32])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41]([O:43][CH3:44])=[O:42]>>[CH3:18][C:19]1([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=2[O:32][CH:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:34]=2)[C:41]([O:43][CH3:44])=[O:42])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: Cc1ccc(O)c(C2(C)CCCCC2)c1
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)C(Oc1ccc(C)cc1C1(C)CCCCC1)c1ccccc1
Yield: 91.2 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 0.496 g (2.4.3 mmol) of 2-(1-methylcyclohex-1-yl)-4-methylphenol was alkylated with 0.834 g (3.64 mmol) of methyl 2-bromophenylacetate to afford 0.780 g (91%) of the title compound.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[CH2:11][CH2:10][C:9](=[O:12])[CH:8]=2)=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([C:7]2[CH2:11][CH2:10][CH:9]([OH:12])[CH:8]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C2=CC(=O)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C2=CC(O)CC2)cc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution of 3-p-tolyl-cyclopent-2-en-1-one (5.0 g, 29.07 mmol) in ethanol (100 mL) was treated with CeCl3 (7.15 g, 29.07 mmol) followed portionwise by NaBH4 (1.32 g, 34.9 mmol) at room temperature. The reaction mixture was stirred for 0.5 h, then quenched with saturated aqueous NH4Cl and concentrated to remove ethanol. The concentrate was diluted with H2O and extracted with DCM (3×). The combined organic extracts were dried over MgSO4, filtered, concentrated in vacuo and purified by silica gel chromatography using 10-30% EtOAc/Heptane as the eluting solvent to afford 3.8 g (Yield 75%) of 3-p-tolyl-cyclopent-2-en-1-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.31 (m, 1 H) 1.55-1.73 (m, 1 H) 2.17-2.26 (m, 1 H) 2.22-2.32 (m, 3 H) 2.41-2.54 (m, 1 H) 2.66-2.78 (m, 1 H) 4.72 (d, 1 H) 4.74-4.80 (m, 1 H) 6.12-6.17 (m, 1 H) 7.13 (d, 2 H) 7.36 (d, 2 H)
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]3[CH:39]=[CH:38][C:18]([CH2:19][N:20]4[CH:24]=[C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:22]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:21]4)=[CH:17][CH:16]=3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]3[CH:39]=[CH:38][C:18]([CH2:19][N:20]4[CH:24]=[C:23]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:22]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:21]4)=[CH:17][CH:16]=3)=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
After a mixture of ethyl 3-[1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (1020 mg), 1N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (4 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (930 mg, yield: 97%). This was recrystallized from acetone-hexane. Melting point: 169–170° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:20][CH2:19][C:13]2([O:17][C:16](=[O:18])[NH:15][CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1O.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([O:17][C:16](=[O:18])[N:15]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[CH2:14]2)[CH2:19][CH2:20]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Oc1c(CBr)ccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccc3ccccc3c1)C(=O)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
Sodium hydride (82 mg, 60% dispersion in mineral oil, weight percent) was suspended under a nitrogen atmosphere in DMF (5 mL). Compound A3 (0.5 g, 1.95 mmol) was added thereto and the reaction mixture was stirred for 10 min at RT. 2-Bromomethylnaphthol (436 mg, 1.97 mmol) was added thereto. The reaction mixture was stirred for 18 h at RT, combined with water and extracted with EtOAc. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. The residue was dissolved in a mixture of ether and heptane. After removal of the ether, the desired product 3-naphthalen-2-ylmethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (A7) (260 mg, 34% of theoretical) was obtained as a white solid by filtration.