Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH3:11]>CC(O)=O.[Fe]>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1cc(N)ccc1Cl
Product: Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 167.8 %

Procedure:
Iron powder (150 g, 2.68 mol) and AcOH (600 mL) were charged into a 2 L round bottom flask equipped with a mechanical stirrer and thermometer. The mixture as warmed to 80° C. 4-Chloro-3-methylnitrobenzene (150 g, 0.87 mol) in AcOH (200 mL) was added slowly to the flask over 4 h, keeping the reaction temperature below 90° C. Upon consumption of the reactants, the mixture was filtered through a pad of Celite and the filter cake was washed with methanol (200 mL). The filtrate was concentrated and the residue was poured into 1.5 L of ice water (1:1) and the resulting precipitate was filtered. The crude product was dissolved in 300 mL 6N HCl in water/dioxane (1:1) and stirred at 100° C. for 3 h. It was then cooled to room temperature and the precipitate was filtered and dried to provide 130 g of 4-chloro-3-methyl-phenylamine hydrochloride as a colorless powder.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[NH2:20]>C(O)(=O)C.C(Cl)Cl>[Cl:5][C:6]1[C:7]2[N:20]=[N:1][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Nc1c(Cl)ncnc1Nc1ccccc1Cl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccccc1-n1nnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
Sodium nitrite (0.298 g, 4.31 mmol) was added to 6-chloro-N4-(2-chlorophenyl)pyrimidine-4,5-diamine (Intermediate AP1) (1 g, 3.92 mmol) in acetic acid (50% Aq, 25 mL) and DCM (25 mL) at room temperature. The resulting solution was stirred at room temperature for 15 minutes. The reaction mixture was separated and the organic phase was washed with water (10 mL), dried (MgSO4) and evaporated to give crude product (0.600 g) that was used without further purification. 1H NMR (400 MHz, CDCl3) δ δ7.52-7.65 (m, 3H), 7.68-7.73 (m, 1H), 8.97 (s, 1H); m/z (ES+), (M+H)+=266.21; HPLC tR=2.33 min
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O-:13])=[O:12].[CH2:14](N(CC)CC)C.O>O1CCCC1.C(OCC)C>[N:5]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccsc1C(=O)[O-]
Reactant: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1sccc1N=C=S
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Thiophosgene (1.1 mL, 1.1 eq) is added dropwise to a solution cooled down to 0° C. of 3-amino-2-thiophenecarboxylate (2 g, 1 eq) and triethylamine (3.9 g, 3 eq in tetrahydrofuran (100 ml). The mixture is stirred for 15 min at 0° C. then water (70 ml) and diethyl ether (150 ml) are added. After decantation and extractions, the organic phases are combined, washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane 100% to heptane/ethyl acetate 7:3) produces the expected compound in the form of a beige powder (2.15 g, 85% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]([CH2:16][OH:17])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]([CH2:16][O:17][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C=Cc1ccccc1C2CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)C=Cc1ccccc1C2COS(=O)(=O)c1ccc(C)cc1
Yield: 79.8 %

Procedure:
To a solution of 2-methoxy-5-hydroxymethyldibenzo[a,d]cycloheptene (10.5 g) in dry dichloromethane (150 ml) was added p-toluenesulphonyl chloride (8.1 g), pyridine (6.6 g) and 4-dimethylamino pyridine (300 mg). The reaction mixture was refluxed for 15h, cooled, washed with water (2×200 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica chromatography using 15% ethyl acetate in hexane as eluent to give the title compound as an oil (13.5 g). δ(360 MHz, CDCl3), 2.44 (3H, s, Ar--CH3), 3.78 (3H, s, OCH3), 4.19-4.31 (3H, m CH-CH2 --OSO2Ar). 6.58 (1H, d, J=11.9 Hz, Ar--CH=CH--Ar), 6.65 (1H, d, J=11.9 Hz, Ar--CH=CH--Ar), 6.68 (1H, d, J=2.7, CH=C(OCH3)--CH), 6.85 (1H, dd, J=8.4 and 2.7 Hz, CH=C(OCH3)--CH) and 7.16-7.42 (9H, m, aromatics). m/e 406 (M+).
Reaction SMILES: O[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.S(Cl)([Cl:21])=O>>[ClH:21].[ClH:21].[Cl:21][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: OCc1nc2ccc(Oc3ccncc3)cc2[nH]1
Reactant: O=S(Cl)Cl
Product: Cl
Product: ClCc1nc2ccc(Oc3ccncc3)cc2[nH]1

Procedure:
A 250-ml round-bottomed flask equipped with a stirrer and a condenser is charged with 3.18 g (13.2 mmol) of 2-hydroxymethyl-5-(4-pyridyloxy)benzimidazole obtained in Example 1 and 40 ml of thionyl chloride. The mixture is brought to reflux for 2 hours and then cooled. The precipitate is filtered off, washed with ether and dried, and yields the expected product.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C1COCC1>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:38][CH:37]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCOCC3)cc2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.240 mmol) and THF (1 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (47.08 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified via flash silca gel chromatography (5% MeOH/95% CHCl3) yielding 67% (94 mg, 0.163 mmol) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].[C:15](Cl)(Cl)=[O:16]>C(Cl)Cl.ClC1C=CC(C)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:5]=[C:15]=[O:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C=Nc1ccc(N2CCOCC2)c(F)c1

Procedure:
A mixture of 3-Fluoro-4-morpholinylaniline (PREPARATION 1, 12.01 g, 61.21 mmol) in methylene chloride (100 ml) is added to a mixture of phosgene (1.93 M in toluene, 63.4 ml, 122.4 mmol, 2.00 eq) in p-chlorotoluene (60 ml) over 15 min, a while maintaining the temperature from about −12 to 3°. The material is rinsed in with methylene chloride (30 ml). The mixture is then warmed to 130° under atmospheric pressure with concomitant distillation of methylene chloride, phosgene, toluene and hydrogen chloride gas into a caustic scrubber. The mixture is cooled to 25° and filtered. The precipitate is washed with methylene chloride (3×15 ml). The filtrate is concentrated under reduced pressure. Heptane (200 ml) is added to the concentrated filtrate and the resultant slurry cooled to −32°. The product is collected by filtration with reduced pressure, washed with heptane cooled to −30°, and dried in a nitrogen stream to give the title compound, HPLC (stationary phase is 4.6×250 mm zorbax RX C-8 column; mobile phase is acetonitrile (650 ml), triethylamine (1.85 ml) and acetic acid (1.30 ml) and water of sufficient amount to make 1,000 ml; flow rate=3.0 ml/min; UV detection at 254 nm) RT=1.08 min. Upon derivatizing as N-carbomethoxy-3-fluoro-4-morpholinylaniline by dissolving in methanol; NMR (CDCl3) 3.05, 3.86 and 6.78-6.89 δ; CMR (CDCl3) 50.90, 66.89, 113.11, 119.15, 120.83, 124.67, 127.65, 138.06 and 155.40 δ; MS (EI), m/z (relative intensity) 222 (37) and 164 (100).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[NH:15])[CH2:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])[CH3:3].[C:16](N)(=O)C(NN)=O.CN>CN(C)C=O>[CH2:2]([O:4][C:5](=[N:15][CH3:16])[CH2:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])[CH3:3]
Reactant: NNC(=O)C(N)=O
Reactant: CCOC(=N)Cc1c(F)cccc1F
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(Cc1c(F)cccc1F)=NC
Reaction time: 1 h

Procedure:
70.7 g (300 mmol) of 1-ethoxy-2-(2,6-difluorophenyl)-1-imino-ethane hydrochloride are added, while stirring, to a suspension of 30.9 g (300 mmol) of oxalic acid monoamide monohydrazide in 900 ml of N,N-dimethylformamide. The reaction mixture is heated to 80° and stirred at this temperature for 1 hour. During a period of 20 minutes 10.6 g of methylamine are passed into the resulting white suspension, which leads to the formation of a clear yellow solution. During a period of 1 hour a further 15.9 g of methylamine are passed into the solution. The solution is then stirred for another hour at 80°. The solvent is evaporated in vacuo. 400 ml of water are added to the residue. The aqueous mixture is stirred and the crystals are filtered off. 300 ml of water are added to the crystals. The mixture is again stirred and the crystals are filtered off. The crystals are dissolved in hot ethanol (ca. 500 ml). After the addition of activated charcoal the mixture is filtered over Hyflo. The filtrate is evaporated until crystallisation starts (ca. 230 ml) of ethanol have to be distilled off). The mixture is then cooled in an ice bath. The crystals are filtered off and dried overnight in vacuo, yielding the product of example 1.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:13]3[O:12][N:11]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:9]=3[CH:8]=[CH:7][C:6]=2[OH:20])[CH2:3][CH2:2]1.[Br:21][CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:1]1([CH2:4][C:5]2[C:13]3[O:12][N:11]=[C:10]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH:8]=[CH:7][C:6]=2[O:20][CH2:24][CH2:23][CH2:22][Br:21])[CH2:2][CH2:3]1
Reactant: Oc1ccc2c(-c3ccccc3)noc2c1CC1CC1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCOc1ccc2c(-c3ccccc3)noc2c1CC1CC1

Procedure:
A solution of 7-cyclopropylmethyl-3-phenyl-6-hydroxybenz-[4,5]-isoxazole (0.25 grams) in 2-butanone (3.0 mL) was treated with 1,3-dibromopropane (0.48 mL) and potassium carbonate (0.50 grams). The mixture was refluxed for 4 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once with water, then dried over magnesium sulfate. The organic was filtered and evaporated to an oil which was flitered through a silica gel plug using methylene chloride and hexane (1:2) to give 7-cyclopropylmethyl-3-phenyl-6-(3-bromopropyloxy)benz-[4,5]-isoxazole. A solution of 3-chloro-4-hydroxyphenylacetic acid methyl ester (42.0 mg) in DMF (1.0 mL) was treated with potassium carbonate (26 mg) and this mixture was stirred for 0.5 hours. Then 7-cyclopropylmethyl-3-phenyl-6-(3-bromopropyloxy)benz-[4,5]-isoxazole was added and the mixture was stirred over night. The reaction mixture was partitioned between ethyl acetate and 1 M HCl solution. The organic was dried over sodium sulfate and filtered. The solvent was removed in vacuo and the residue was chromatographed on silica gel using methlene chloride and hexane (1:1) to give an oil. A solution of methyl 3-chloro-4-(3-(3-phenyl-7-cyclopropylmethyl-6-benz-[4,5]-isoxazoloxy)-butyloxy)phenylacetic acid (0.04 grams) in methanol (1.5 mL) was treated with a solution of lithium hydroxide in water (1.01 M; 0.1 mL). The reaction was refluxed 1 hour. The reaction mixture was partitioned between isopropyl acetate and 0.1N HCl. The organic was dried over magnesium sulfate, filtered and concentrated to a solid. The solid was suspended in methylene chloride/cyclohexane (1:1; 2 mL). The mixture was refluxed briefly and cooled to 0° C. The title compound was isolated by filtration.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][C@H:9]([NH2:11])[CH2:8][CH2:7][C:5]=2[N:6]=1.[S:12]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)([O:15][CH2:16][CH2:17][CH3:18])(=[O:14])=[O:13]>CN(C)C=O>[CH2:16]([NH:11][C@@H:9]1[CH2:8][CH2:7][C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[CH2:10]1)[CH2:17][CH3:18].[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:20][CH:21]=1
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1nc2c(s1)C[C@H](N)CC2
Solvent: CN(C)C=O
Product: CCCN[C@@H]1CCc2nc(N)sc2C1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 75 °C

Procedure:
A 1000 ml, three necked flask was equipped with an overhead stirrer, a temperature probe, a heating mantle, a claisen joint, a condenser, and a 250 ml addition funnel. The flask was charged with 25 grams of (6R)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, followed by 200 ml of dimethyl formamide (DMF). Under continuous stirring, the mixture was heated to a temperature of 75° C. The addition funnel was charged with a solution of 39.5 grams propyl tosylate and 32.5 ml diisopropylethyleamine in 50 ml DMF. This solution was added to the 1000 ml flask dropwise over a period of 1.0 hours. The reaction was monitored by analysis on HPLC.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH:11][N:12]=[CH:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][CH:15]=2)=[CH:9][C:8](=[O:24])[N:7]([CH3:25])[C:6]1=[O:26])[CH:2]([CH3:4])[CH3:3].[O:27]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[N:28]1.N1CCCC[CH2:35]1.O1C=CC=N1>CN(C)C=O.O.C(OCC)(=O)C>[Cl:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:13][N:12]1[C:35]([C:30]2[C:29]([CH3:32])=[N:28][O:27][CH:31]=2)=[C:9]2[C:10]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6](=[O:26])[N:7]([CH3:25])[C:8]2=[O:24])=[N:11]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccon1
Reactant: CC(C)Cn1c(NN=Cc2c[nH]c3ccc(Cl)cc23)cc(=O)n(C)c1=O
Agent: c1cnoc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nocc1-c1c2c(=O)n(C)c(=O)n(CC(C)C)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Chloro-1H-indole-3-carbaldehyde(3-isobutyl-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone (100 mg) was added to a solution of isoxazolaldehyde (86 mg) in dimethylformamide at RT. Piperidine (100 uL) was then added and brought to 80 C for 8 h. After cooling to RT, ethyl acetate (25 mL) was added to brown solution and water (25 mL) was added and extracted. The aqueous layer was back extract with ethyl acetate and then combined. The organic layer was dried over sodium sulfate, filtered and removal of solvent to give an amorphous solid. The isoxazole was submitted the Gilson Preparatory chromatography to give a 100 mg of white solids. ES M+H+467.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][NH2:18]>C1COCC1>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[N:18][CH3:17]
Reactant: CN
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CN=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A solution of 3,5-bis(trifluoromethyl)-benzaldehyde (412 μL) in dry THF (5 mL) was added dropwise to a solution of methylamine (2M in MeOH—3.12 mL) in dry THF (5 mL) at 23° C. under a nitrogen atmosphere. The reaction mixture was stirred overnight, then the solvent was evaporated in vacuo to give the title compound (385 mg) as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[CH3:12][O:13][C:14]1[C:21]([O:22][CH3:23])=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[I:24].[C:25](#[N:29])[CH2:26][C:27]#[N:28]>>[NH2:29][C:25]1[O:1][C:2]2[C:10]([CH:18]([C:17]3[CH:20]=[C:21]([O:22][CH3:23])[C:14]([O:13][CH3:12])=[C:15]([I:24])[CH:16]=3)[C:26]=1[C:27]#[N:28])=[CH:9][CH:8]=[C:7]1[N:6]([CH3:11])[CH:5]=[CH:4][C:3]=21
Reactant: N#CCC#N
Reactant: Cn1ccc2c(O)cccc21
Reactant: COc1cc(C=O)cc(I)c1OC
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2C)cc(I)c1OC

Procedure:
The title compound was prepared from 4-hydroxy-1-methylindole (40 mg, 0.27 mmol), 4,5-dimethoxy-3-iodo-benzaldehyde (80 mg, 0.27 mmol) and malononitrile (18 mg, 0.27 mmol) similar to Example 24 to yield 91 mg (69%) of white solids. 1H NMR (CDCl3): 7.19 (d, J=1.8 Hz, 1H), 7.07-7.02 (m, 2H), 6.77-6.74 (m, 2H), 6.57 (d, J=3.3 Hz, 1H), 4.76 (s, 1H), 4.69 (brs, 2H), 3.81-3.78 (m, 9H).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH3:35])[CH:27]=1)[CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:7]=1.[Li+].[OH-]>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([N:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[CH:10][C:6]([CH2:5][CH:4]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[C:3]([OH:36])=[O:2])=[N:7]2)=[CH:23][CH:22]=1
Reactant: COC(=O)C(Cc1cc(-c2ccc(C)cc2)n(-c2ccc(OC)cc2)n1)c1cn(C)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc(-n2nc(CC(C(=O)O)c3cn(C)c4ccccc34)cc2-c2ccc(C)cc2)cc1
Yield: 49 %

Procedure:
The title compound was prepared by Method 2 from (1-methyl-1H-indol-3-yl)-acetic acid methyl ester (0.10 g, 0.49 mmol), 3-bromoethyl-1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazole (89 mg, 0.25 mmol), sodium hydride (19 mg, 0.49 mmol) and DMF (4.0 mL), giving 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(1-methyl-1H-indol-3-yl)-propionic acid methyl ester, which was not isolated. The ester was converted to the acid in situ by adding 2.5 mL (4.9 mmol) LiOH solution giving 57 mg (49%) of 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-(1-methyl-1H-indol-3-yl)-propionic acid. HPLC: Rt=3.23 (Method B). MS (ES+): mass calculated for C29H27N3O3, 465.21; m/z found 466.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.15 (br s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.32 (s, 1H), 7.17-7.10 (m, 5H), 7.05-7.03 (m, 3H), 6.93 (d, J=8.9 Hz, 2H), 6.38 (s, 1H), 4.22 (dd, J=9.1, 5.9 Hz, 1H), 3.76 (s, 6H), 3.44 dd, J=14.7, 9.2 Hz, 1H), 3.04 (dd, J=5.9, 14.7 Hz, 1H), 2.27 (s, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][CH2:40][N:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=1.C([O-])([O-])=[O:47].[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40](=[O:47])[N:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)N1C=C(Br)C=CC1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (100 mg, 0.21 mmol) in 1,4-dioxane (2 mL) was added 5-bromo-1-isopropylpyridin-2(1H-one (54.2 mg, 0.25 mmol). Then catalysts of Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cs2CO3 (1 mL, 2 M) were added. The vessel was sealed with a septum and placed into the microwave cavity. Microwave irradiation of 100 W was used, the temperature being ramped from room temperature to 120° C. Once this temperature was reached, the reaction mixture was held at this temperature for 30 min. After the mixture cooled to rt, the mixture was filtered. The filtrate was extracted with EtOAc (20 mL×4), the organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product which was purified by preparative HPLC to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (22 mg, 21%). 1H NMR (CDCl3): 1.13 (s, 3H), 1.19 (s, 3H), 1.40 (6H), 1.53 (d, 3H), 2.18-2.30 (m, 4H), 2.40 (m, 1H), 2.88 (m, 1H), 5.31 (m, 1H), 5.70 (m, 1H), 6.73 (d, 1H), 7.02 (d, 2H), 7.15 (d, 2H), 7.27-7.38 (m, 5H), 7.43 (d, 1H), 7.50 (d, 1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>O1CCCC1.O>[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][C:10]([CH3:12])([CH3:11])[C:9]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrCc1ccccc1Br
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccccc1Br
Reaction time: 0.5 h
Yield: 169 %

Procedure:
Lithium diisopropylamide (2M in hexane, 1.5 mL, 3.0 mmol) was added to a solution of ethyl isobutyrate (233 mg, 2.01 mmol) in tetrahydrofuran (1 mL) at −78° C. and the reaction mixture was stirred at this temperature for 30 min. Then, a solution of 2-bromobenzyl bromide (250 mg, 1.00 mmol) in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for another 1 hr and then at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate, and concentrated to give 482 mg of ethyl 3-(2-bromophenyl)-2,2-dimethylpropanoate as a yellow oil. The crude intermediate was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:4][CH:3]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([NH2:28])=[O:27])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cc(N2CCCC2c2ccc(F)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)Nc1cc(N2CCCC2c2ccc(F)cc2)ccn1
Temperature: 50 °C
Yield: 55.5 %

Procedure:
4-[2-(4-Fluoro-phenyl)-pyrrolidin-1-yl]-pyridin-2-ylamine (61 mg, 0.24 mmol) and benzoyl isocynate (52 mg, 0.36 mmol) are mixed in DCM (2.0 mL). The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (2.0 mL) and potassium carbonate (49 mg, 0.36 mmol). The mixture is then heated at 80° C. for 45 min. The solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) followed by re-crystallization from DCM/heptane affords 40 mg of the titled product.