Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[I:43][CH:44](O)[CH3:45].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:45][CH2:44][I:43])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(O)I
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)OCCI)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 55 %

Procedure:
In a manner similar to the method described in Example 1, chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200 mg, 0.324 mmol) was reacted with iodoethanol (Aldrich, 220 mg, 1.28 mmol) in the presence of bis(2-oxo-3-oxazolidinyl)phosphinic chloride (Aldrich, 121.6 mg, 0.478 mmol), triethylamine (203 mg, 2.00 mmol) to give chiral 2-iodoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as an off-white solid (137.4 mg, 55% yield). MS (ES+) m/z calcd. for C33H33Cl2F2IN3O4: [(M+H)+]: 770. found: 770.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=1>C(O)(=O)C.Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:8]=1
Reactant: CCCCC(=O)Cc1ccc(OC)cc1
Agent: Br
Solvent: CC(=O)O
Product: CCCCC(=O)Cc1ccc(O)cc1
Yield: 36.5 %

Procedure:
A solution of 1-(4-methoxyphenyl)hexanone (5 g) in acetic acid (50 ml) and 48% HBr was heated overnight at 120°. The reaction mixture was poured onto ice and extracted with ethylacetate (500 ml). The ethyl acetate layer was washed with NaHCO3 (200 ml), dried, and evaporated. Chromatography of the residue using 30% ethylacetate in hexane afforded 1.7 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[CH3:17])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Br:20]Br.O>ClCCl>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][C:14]([Br:20])=[C:11]([CH:10]=1)[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=O)cc1OCc1ccccc1
Reactant: BrBr
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1cc(Br)c(C=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 3-benzyloxy-4-methylbenzaldehyde (0.39 g) in a mixed solvent of dichloromethane (1 mL) and methanol (1 mL) was added a solution of bromine (0.410 g) in dichloromethane (0.2 mL) at 0° C. and this mixture was stirred at room temperature for 2 hours. This mixture was poured into water and the resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.39 g).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[NH:8])=[CH:12][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: N#Cc1ccccc1
Product: N=C(Nc1ccc(F)cc1)c1ccccc1
Yield: 85.1 %

Procedure:
The title compound was prepared from benzonitrile (13.9 g, 135 mmol) and 4-fluoroaniline (15 g, 135 mmol) by following the procedure described in preparation 10 (24.6 g, yield 85.1%, purity 99.7% by HPLC). MS m/z:215.2 (M+).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[OH-].[Na+].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[F:18]>C(O)C>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])=[CH:12][C:11]=1[F:18]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: CC(=O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)C=Cc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
A solution of pyruvic acid (1.9 mL, 27.1 mmol) in ethanol (6.0 mL) was added to a 0.5 M sodium hydroxide solution (74.0 mL). The reaction mixture was stirred at room temperature for 5 minutes and then a solution of 4-bromo-3-fluorobenzaldehyde (5.0 g, 24.6 mmol) in ethanol (20.0 mL) was slowly added thereto at room temperature for 1 hour. The reaction mixture was stirred at room temperature for 18 hours and then filtered. The resulting solid washed with ethyl acetate, diluted with a 1N hydrochloric acid solution and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 3.2 g of the titled compound as a yellow solid.
Reaction SMILES: [CH:1]([OH:3])=O.OO.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2C[CH2:16][CH2:15][CH:14]=2)=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:14][CH2:15][CH2:16][C:1]2=[O:3])=[CH:9][CH:8]=1
Reactant: Clc1ccc(C2=CCCC2)cc1
Reactant: O=CO
Agent: OO
Product: O=C1CCCC1c1ccc(Cl)cc1
Temperature: 40 °C
Yield: 34.9 %

Procedure:
A mixture of formic acid (60 mL, 84 mmol) and hydrogen peroxide (15 mL, 84 mmol) was warmed at 40° C. for 10 min. The resulting solution was carefully added to 1-chloro-4-cyclopentenylbenzene (15 g, 84 mmol) under stirring. The two-phase system was initially stirred at room temperature. After a certain period of time, a spontaneous exothermic reaction took place, and the temperature rose to about 50° C. The reaction mixture was stirred at room temperature for 1 h. The LC/MS analysis of the reaction mixture shows the disappearance of the starting material and the formation of the product. The reaction mixture was quenched by careful addition of a saturated sodium bicarbonate solution. Ether was added and the reaction mixture was vigorously shaken. The organic layer was separated and the aqueous layer was extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-(4-chlorophenyl)cyclopentanone (5.7 g, 29.3 mmol, 34.9% yield) as a colorless oil. LC-MS (M+H)+=195.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.21-7.37 (2H, m), 7.11 (2H, d, J=8.5 Hz), 3.25 (1H, dd, J=11.6, 8.5 Hz), 2.44 (2H, d, J=6.1 Hz), 2.15-2.31 (1H, m), 1.96-2.15 (3H, m), 1.78-1.95 (1H, m).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]([F:27])([F:26])[C:15]1[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.Br.[Cl:39][C:40]1[C:49]([OH:50])=[C:48]([OH:51])[C:47]([Cl:52])=[C:46]2[C:41]=1[CH2:42][CH2:43][NH:44][CH2:45]2>CCOC(C)=O.O>[Cl:39][C:40]1[C:49]([OH:50])=[C:48]([OH:51])[C:47]([Cl:52])=[C:46]2[C:41]=1[CH2:42][CH2:43][N:44]([C:23](=[O:25])/[CH:22]=[CH:21]/[C:18]1[CH:19]=[N:20][C:15]([C:14]([F:13])([F:27])[F:26])=[CH:16][CH:17]=1)[CH2:45]2
Reactant: Oc1c(O)c(Cl)c2c(c1Cl)CCNC2
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)nc1
Agent: Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(/C=C/c1ccc(C(F)(F)F)nc1)N1CCc2c(Cl)c(O)c(O)c(Cl)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of CDI (83 mg, 0.51 mmol) in EtOAc (2 mL) was added (E)-3-(6-(trifluoromethyl)pyridin-3-yl)acrylic acid (100 mg, 0.46 mmol). The resulting mixture was heated at reflux for 1 h after which HOBt (35 mg, 0.23 mmol) and 5,8-dichloro-1,2,3,4-tetrahydroisoquinoline-6,7-diol hydro bromide (145 mg, 0.46 mmol) were added. Heating at reflux was continued for 3 h before the reaction mixture was allowed to cool to rt. It was then poured into water (15 mL) and the water-phase was extracted with EtOAc (3×15 mL). Combined organics were washed with water (10 mL) and brine (10 mL) and dried (MgSO4). After filtration and evaporation, the crude was purified by column chromatography (SiO2, EtOAc:petroleum ether 50:50) to give a bright yellow solid which was purified further by precipitating the product in EtOAc via addition of petroleum ether. After decantation of the solvent and drying, the title compound (110 mg, 0.25 mmol, 55%) was obtained as a light reddish solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:4]1=2.[OH-].[Na+]>CO.O>[CH3:1][O:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:4]1=2
Reactant: COC(=O)c1ccc2c(c1)C(OC)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC1c2ccccc2COc2ccc(C(=O)O)cc21

Procedure:
Dissolve 695 mg of the ester of Step A in 15 ml of methanol. Add 10 ml of 20% aqueous sodium hydroxide and reflux for 10 minutes. Dilute with 200 ml of water and extract with ether. Acidify the aqueous fraction with concentrated hydrochloric acid and extract into ether. Evaporate to dryness and crystallize from methanol to obtain the title product (m.p. 185° C. dec.).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:32]=[CH:31][N:30]=[CH:29][C:13]3=[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=3)[CH:15]=2)[N:10]=[CH:9]1.[CH3:33][Mg]Br>>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:32]=[CH:31][N:30]=[CH:29][C:13]3=[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH:27]=[CH2:33])=[CH:22][CH:21]=3)[CH:15]=2)[N:10]=[CH:9]1
Reactant: CC(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cc1
Reactant: C[Mg]Br
Product: C=CC(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cc1

Procedure:
3-[(1S,2S)-2-Hydroxycyclohexyl]-6-[4-(1-hydroxyprop-2-en-1-yl)benzyl]pyrido[3,4-h]quinazolin-4(3H)-one was prepared by the procedure described for the synthesis of 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[4-(1-hydroxyethyl)benzyl]pyrido[3,4-h]quinazolin-4(3H)-one in Example 11, substituting vinylmagnesium bromide for methylmagnesium bromide.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24][CH3:25])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc2c1c1c(n2CC2CCCCC2)CCCC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1c1c(O)cccc1n2CC1CCCCC1
Yield: 22.5 %

Procedure:
A solution of 9-[(cyclohexyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (1.16 g, 3.42 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (853 mg, 3.76 mmol) in 20 mL of toluene was heated at 80° C. for 3 hours. The mixture was purified directly by column chromatography on silica gel (elution with CH2Cl2) to afford 259 mg (0.768 mmol; 22%) of 9-[(cyclohexyl)methyl]-4-hydroxy-5-carbomethoxy carbazole as a yellow oil which slowly solidified. MS (ES) m/e 338 (M+1), 336 (M−1).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21]1([C:31](Cl)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>ClCCl>[C:21]1([C:31]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc2ccccc12)N1CCN(c2ccc(O)cc2)CC1
Reaction time: 3 h

Procedure:
To a stirring mixture of 4-(1-piperazinyl)phenol (5.54 g) and triethylamine (10.83 ml) in dichloromethane (140 ml) was added dropwise, 1-naphthalenecarbonyl chloride (9.83 ml). The resulting reaction mixture was stirred under a nitrogen atmosphere for 3 h. The mixture was partitioned between dichloromethane and water and the organic phase was washed with saturated brine, dried (MgSO4) and evaporated to dryness. The residue was suspended in 6:4 tetrahydrofuran-methanol (370 ml) and treated with a saturated solution of potassium carbonate in methanol (45 ml). The mixture was stirred at room temperature under a nitrogen atmosphere for 20 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic phase was washed with saturated brine, dried (MgSO4) and evaporated to give an oil (15.5 g), part of which (14.5 g) was purified by chromatography on a silica SPE bond elut cartridge eluting with 10% -80% ethyl acetate-cyclohexane gradient to give the title compound (8.9 g). LCMS RT=2.97 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:41][CH3:42])=[C:38]([OH:40])[CH:39]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:41][CH3:42])=[C:38]([OH:40])[CH:39]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: COc1ccc(CCN)cc1O
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: COc1ccc(CCNc2nccc(-c3cccc(CN(CCCN)S(C)(=O)=O)c3)n2)cc1O

Procedure:
Intermediate 4 from above was coupled with 5-(2-Amino-ethyl)-2-methoxy-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 486. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 8.0 (d, 1H) 7.6 (m, 1H) 7.5 (m, 1H) 7.2 (m, 1H) 6.8 (s, 1H) 6.6 (s, 2H) 4.5 (s, 2H) 3.8 (m, 2H) 3.7 (s, 3H) 3.3 (m, 2H) 2.9 (m, 7H) 1.8 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:12]([N:20]=[C:21]=[S:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:21]([NH:20][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[S:22])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: S=C=NCCc1ccccc1
Reactant: NCc1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: S=C(NCCc1ccccc1)NCc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
(1H-indol-5-yl)methylamine (8.5 mg) prepared in Step 1 was dissolved in dimethylformamide (100 μl) and the solution was diluted with dichloromethane (1 ml). To the diluted solution was added phenethylisothiocyanate (40 μl) and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and the obtained residue was chromatographed on a silica gel column eluting with ethyl acetate/hexane (2/3) to yield 1-(1H-indol-5-ylmethyl)-3-phenethylthiourea (15 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:19]#[N:20])[CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: N#Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C#N)c3)n2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-cyano-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.70 min; [M+H]+=417.70.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)[C:8](=[O:19])[C:7]=3[O:20][C:21]=2[CH:22]=[CH:23][CH:24]=1.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:12](=[O:14])[C@@H:11]([N:9]1[CH2:10][C:6]2[CH2:5][C:4]3[C:3]([O:2][CH3:1])=[CH:24][CH:23]=[CH:22][C:21]=3[O:20][C:7]=2[C:8]1=[O:19])[CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: Nc1nccs1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)Nc2nccs2)C1
Yield: 27.4 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (100 mg, 0.30 mmol), commercially available 2-amino-thiazole (37 mg, 0.36 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (66 mg, 0.33 mmol), and N-hydroxybenzotriazole (HOBt) (44 mg, 0.33 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid thiazol-2-ylamide (34 mg, 27.2%), as an off white solid. 1H NMR (DMSO-d6) δ: 12.58 (br. s., 1H), 7.50 (d, J=3.4 Hz, 1H), 7.12-7.34 (m, 2H), 6.76 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.04 (d, J=5.9 Hz, 1H), 4.36 (d, J=19.1 Hz, 1H), 4.05 (d, J=18.6 Hz, 1H), 3.82 (s, 3H), 3.55 (br. s., 2H), 1.83 (d, J=9.3 Hz, 1H), 1.68 (br. s., 1H), 1.45 (br. s., 1H), 0.93 (t, J=7.3 Hz, 6H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC1.C1(NC2C=CC=CC=2)C=CC=CC=1.[CH:27](=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(O)(=O)C.[OH-].[Na+]>>[CH2:29]([C:28](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:27]=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=Cc1ccccc1
Reactant: CCCCCCCC=O
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: C1CCNC1
Solvent: CC(=O)O
Product: CCCCCCC(C=O)=Cc1ccccc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
The reaction was carried out in a 2.5 litre double-walled glass reactor provided with a cooler, turbine stirrer (6 blades), thermocouple and a submerged metering tube. A mixture of 1065 grams of benzaldehyde (10.0 mol), 48.8 grams of pyrrolidine (0.679 mol) and 1.8 grams of diphenylamine was heated to 85° C. Over a period of 180 minutes, 878 grams of acidified (0.34 meq/gram) octanal (6.648 mol) were metered in at 85° C. Acidification of the octanal was effected with 16.9 grams of acetic acid (0.281 mol). The reaction was allowed to continue at 85° C. for a further 15 minutes. The reaction mixture was cooled to 65° C. and washed at 50° C., for 15 minutes, with 500.3 grams of 5% strength aqueous NaOH solution (0.625 mol). After neutralization with 78 grams of acetic acid (1.30 mol) for 15 minutes at 50° C., the reaction mixture was separated at 50° C., over a period of 5 to 6 minutes. The organic layer (1869.8 grams) contained 25.5% of benzaldehyde, 2.1% of octanal, 59.8% of α-hexylcinnamaldehyde and 4.6% of α-hexyldecenal. The degrees of conversion of benzaldehyde and octanal were 55.2% and 95.5%, respectively. The selectivity in producing α-hexylcinnamaldehyde was 93.5% with respect to benzaldehyde and 81.4% with respect to octanal.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][Si:6]([O:17][Si:18]([CH3:21])([CH3:20])[CH3:19])([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[O:7][Si:8]([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30].O>C(OCC)C>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][Si:6]([O:7][Si:8]([CH3:9])([CH3:10])[CH3:11])([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[O:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[C:28](=[O:32])[C:29]([CH3:31])=[CH2:30]
Reactant: C=C(C)C(=O)Cl
Reactant: CNCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: C=C(C)C(=O)N(C)CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
In 200 ml of ethyl ether was dissolved 32.6 g of the N-methyl-3-[tris(trimethylsiloxy)silyl]propylamine obtained above, and the solution was added with 11 g of pyridine. The mixture was cooled in ice bath to 0°-5° C. Separately, 14.5 g of methacryloyl chloride was dissolved in 45 ml of ethyl ether. The methacryloyl chloride solution was placed in a separating funnel and dropped therefrom to the above mixture over about one hour. The mixture was continuously stirred for 16 hours. After the stirring, 200 ml of water was added to the reaction mixture, and the resulting mixture was stirred and then supernatant was separated. The supernatant was combined with the extract from the bottom layer with ethyl ether, and then ethyl ether was removed by heating. The residue was distilled in vacuo to give 33.0 g of a distillate at 155° C./3 mmHg.
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH:13]=[N:14][C:3]=12.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].Cl>C1COCC1.CC(O)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH:13]=[N:14][C:3]=12
Reactant: Nc1cccc(Br)c1
Reactant: Clc1c2ncncc2cc2ocnc12
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Brc1cccc(Nc2c3ncncc3cc3ocnc23)c1
Yield: 45.5 %

Procedure:
A mixture of 4-chlorooxazolo[5,4-g]quinazoline (0.24 g, 1.16 mmol) and 3-bromoaniline (0.25 mL, 2.33 mmol) in a THF/propan-2-ol mixture (1:1, 40 mL) containing a trace of concentrated HCl is heated under reflux for 15 min, then concentration to dryness under reduced pressure. The residue is triturated with EtOAc, and then partitioned between saturated aqueous NaHCO3 and EtOAc. Workup of the organic portion gives 4-(3-bromoanilino)oxazolo[5,4-g]quinazoline (0.18 g, 33%) as a yellow powder, mp (MeOH) 232 ° C. (dec.).
Reaction SMILES: [C:1]1([N:7]2C(OCC3OC3)=NN=N2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1N(C2C=CC=CC=2)N=NN=1>[NH2:7][CH:1]1[CH2:2][CH2:3][C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:6]1
Reactant: c1ccc(-n2nnnc2OCC2CO2)cc1
Agent: Cl
Agent: OC(CNC1CCc2ccccc2C1)COc1nnnn1-c1ccccc1
Solvent: CCO
Product: NC1CCc2ccccc2C1
Yield: 100.4 %

Procedure:
Following the procedure of Example 27, but starting from 1-(1-phenyltetrazol-5-yloxy)-2,3-epoxypropane (4.37 g) prepared as described in BE 866,278 and 2-aminotetralin (1.48 g) in absolute ethanol (60 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-phenyltetrazol-5-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 60, wherein Z=Z'=H and the chain is attached to position 2 of the tetralin moiety).