Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH2:9]=[O:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([O:10][CH2:9][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CCOP([O-])OCC
Reactant: C=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(COS(=O)(=O)c1ccc(C)cc1)OCC
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A 12 L, 3-neck round bottom flask was equipped with a mechanical stirrer, condenser, thermometer and heating mantle. The flask was flushed with nitrogen and charged with diethyl phosphite (554 g, 3.77 mol), paraformaldehyde (142 g, 4.72 mol), toluene (2 L) and triethylamine (53 mL, 5.76 mol). The mixture was stirred at 85-90° for 2 h, then at reflux for 1 h. The resulting yellow solution was cooled to 4° C. (ice bath) and p-toluenesulfonyl chloride (718 g, 3.77 mol) was added. The condenser was replaced with an addition funnel and triethylamine (750 mL) was added slowly with stirring, maintaining the temperature <10° C. After the addition was complete (45 min.), the resulting mixture was stirred at ambient temperature for 14 h. The mixture was filtered and the filtercake was washed with toluene (2×250 mL). The combined filtrate and washings were washed with water (2×1 L, dried (MgSO4, 200 g), filtered through Celite 521, and concentrated under reduced pressure to provide 1004 g of a cloudy yellow oil (77.6%). 1H NMR (CDCl3): NMR (DMSO): 7.82 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 4.36 (d, J=9.6 Hz, 2H), 4.00 (m, 4H), 2.41 (s, 3H), 1.16 (m, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=40% EtOAc/hexanes, Rf=0.24.
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH2:5][NH2:6].[OH-].[Na+].[C:10](=[NH:17])(OC)[CH2:11][CH2:12][CH2:13][CH3:14].C(O[CH:23](OCCCC)[N:24]([CH3:26])[CH3:25])CCC>CO>[CH2:11]([C:10]1[NH:17][C:4](=[O:3])[C:5](=[CH:23][N:24]([CH3:26])[CH3:25])[N:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)CN
Reactant: CCCCC(=N)OC
Reactant: CCCCOC(OCCCC)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC1=NC(=CN(C)C)C(=O)N1
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
5.00 g (39.42 mmol) of glycine methyl ester hydrochloride was added in a single portion to a solution of 1.59 g (39.42 mmol) of sodium hydroxide in 13 ml of methanol, at 0° C. The temperature dropped to -10° C. Then, the mixture was stirred for 15 minutes. During this time, the temperature rose again to 0° C. 4.73 g (39.42 mmol) of methyl pentanimidate was added, and the mixture was stirred at room temperature for 3 hours. 9.00 g (43.36 mmol) of N,N-dimethylformamide dibutyl acetal then was added, during the course of 5 minutes, and the reaction mixture was stirred for a further 3 hours. Then, the solvent was removed on the Rotavapor, and the residue was treated with 40 ml of CH2Cl2 and 15 ml of water. After phase separation, the organic phase was washed with 10 ml of water. The organic phase was dried (MgSO4), filtered and concentrated on the Rotavapor, and the residue was dried in a high vacuum. 6.92 g of 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one was obtained; the product had a content of about 80 percent according to H-NMR. This corresponds to a yield of about 72 percent, based on the methyl pentanimidate.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:10]=[CH:9][C:8]=1[C:24]#[N:25].N1C=CC=CC=1.N>C(Cl)(Cl)Cl.C(O)C>[C:24]([C:8]1[CH:9]=[N:10][N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:21])([F:22])[F:20])=[CH:14][C:13]=2[Cl:23])[C:7]=1[NH:6][C:1](=[O:4])[CH2:2][CH3:3])#[N:25]
Reactant: CCC(=O)Cl
Reactant: N#Cc1cnn(-c2ccc(OC(F)(F)F)cc2Cl)c1N
Agent: N
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1c(C#N)cnn1-c1ccc(OC(F)(F)F)cc1Cl
Reaction time: 20 h
Yield: 75.3 %

Procedure:
10 ml (0.11 mole) of propionyl chloride are added to 2.9 g (0.01 mole) of 5-amino-4-cyano-1-(2-chloro-4-trifluoromethoxy-phenyl)-pyrazole in 30 ml of chloroform at 0° C., with stirring, and a solution of 1.8 ml (0.02 mole) of pyridine in 15 ml of chloroform is then added, also at 0° C. When the addition has ended, stirring is continued at room temperature for 20 hours, the solvent is stripped off, the residue is taken up in 50 ml of ethanol, aqueous ammonia is added until the reaction is alkaline, the volatile constituents are removed in vacuo, the residue is taken up in 100 ml of chloroform, the mixture is washed with water, then with 2N aqueous hydrochloric acid and again with water and dried over sodium sulphate and the solvent is removed in vacuo. 2.7 g (75.3% of theory) of 4-cyano-1-(2-chloro-4-trifluoromethoxy-phenyl)-5-propionylamino-pyrazole of melting point 127° C. are obtained.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH2:14])(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH2:15]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[CH:1]([N:4]1[CH2:15][NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[S:5]1(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)NS(=O)(=O)c1cnccc1N
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)N1CNc2ccncc2S1(=O)=O
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of N-isopropyl-4-aminopyridine-3-sulfonamide (Preparation 7) and 0.5 g of paraformaldehyde in 15 cm3 of isopropanol to which 50 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 24 hours. After this lapse of time, the solvent is removed under partial vacuum. The residue is redissolved in 20 cm3 of methanol. The possible insoluble material is removed by filtration. The filtrate, treated with 40 cm3 of water and stored for 2 hours at +4° C., produces a precipitate of the isopropoxymethylenated derivative of Preparation 7. It is collected on a filter, washed with water, dried and recrystallized from a CHCl3 /petroleum ether (40°-60° C.) (1/2) mixture. The dry product is introduced into an open round-bottomed flask and brought to a temperature of 180°-190° C. After 15 to 30 minutes, the molten mass solidifies. It is then cooled and then dissolved in a small volume of chloroform. The addition of 1 volume of petroleum ether (40°-60° C.) causes precipitation of crystals of the title compound. They are collected on a filter, washed with petroleum ether (40°-60° C.) and dried.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH3:34])=[CH:28]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH3:34])=[CH:28]2
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 85 °C
Yield: 54.8 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (100 mg, 0.29 mmol), 5-hydroxy-2-methylindole (53 mg, 0.36 mmol), (prepared as described for the starting material in Example 48), and potassium carbonate (62 mg, 0.44 mmol) in DMF (2 ml) was heated at 85° C. for 3 hours, followed by heating at 95° C. for 2 hours. After cooling, ice/water (15 ml) was added and the precipitate was collected by filtration and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (95/5) followed by methylene chloride/methanol/3M ammonia in methanol (95/3/2) to give 6-methoxy-4-(2-methylindol-5yloxy)-7-(3-piperidinopropoxy)quinazoline (71 mg, 54%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11](I)=[C:10]([F:15])[CH:9]=1.[F:16][C:17]1[C:22]([F:23])=[C:21]([Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=1B1OCC(C)(C)CO1>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[CH:20][C:21]([Si:24]([CH3:25])([CH3:27])[CH3:26])=[C:22]([F:23])[C:17]=2[F:16])=[C:10]([F:15])[CH:9]=1
Reactant: CC1(C)COB(c2ccc([Si](C)(C)C)c(F)c2F)OC1
Reactant: Fc1cc(Br)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)c1ccc(-c2ccc(Br)cc2F)c(F)c1F
Yield: 88 %

Procedure:
A solution of 16.6 g (120 mmol) of K2CO3 in 50 ml of water is added to a solution of 15 g (50 mmol) of 4-bromo-2-fluoro-1-iodobenzene, 14.9 g (50 mmol) of 6 and 2.31 g (2 mmol) of [Pd(PPh3)4] in 100 ml of dioxane, and the mixture is refluxed overnight. The organic phase is washed with water and sat. NaCl, dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, petroleum ether is added to the oily residue, and the product is recrystallised at −25° C. (yield: 88%, m.p. 78.0° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=1)[CH3:20].ClCCl>C(#N)C.[Cu]I>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:29]#[C:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Reactant: C#Cc1ccc(OCC)cc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1ccc(C#Cc2ccc(CC(C)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
To 5.00 g (13.8 mmol) [2-(4-iodo-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (I52.5) and 2.02 g (13.8 mmol) 4-ethoxyphenylacetylene in 80 mL ACN are added 4.46 mL (32.2 mmol) TEA, 135.6 mg (0.17 mmol) [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and 32.3 mg (0.17 mmol) CuI, and the reaction mixture is stirred at r.t. over night. The precipitate is filtered and washed with ACN. The resulting crude product is purified by column chromatography (CyH/EtOAc 100/0→90/10).
Reaction SMILES: I[N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[CH:10][N:11]=[C:5]2[N:4]=[CH:3]1.[C:12]([C:14]1[CH:33]=[CH:32][C:17]([C:18]([NH:20][C@H:21]([C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:19])=[CH:16][CH:15]=1)#[CH:13].C(N(CC)CC)C.O>CN(C)C=O.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:8][C:7]1[N:2]([C:13]#[C:12][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:20][C@H:21]([C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:19])=[CH:32][CH:33]=2)[CH:3]=[N:4][C:5]2=[N:11][CH:10]=[CH:9][C:6]=12
Reactant: Oc1c2ccnc-2ncn1I
Reactant: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OC)C(=O)OC)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cn2cnc3nccc-3c2O)cc1)C(=O)OC
Reaction time: 2 h

Procedure:
To a mixture of 10 mmol of 3-iodo-4-hydroxypyrrolo[2,3-d]pyrimidine in 40 mL of dimethylformamide are added 4.0 g (13.19 mmol) of dimethyl N-(4-ethynylbenzoyl)-L-glutamate, 0.38 g of copper (I) iodide, 3 mL of triethylamine, and 1.0 g of tetrakis(triphenylphosphine) palladium. This mixture is stirred at ambient temperatures for two hours and then poured into 500 mL of water. The solid is collected by filtration, air dried, and then refluxed in 200 mL of methanol. The mixture is cooled and the solid collected by filtration, dissolved in two liters of 10% methanol in methylene chloride. There is obtained dimethyl N-[4-(4-hydroxypyrrolo[2,3-d]pyrimidin-3-ylethynyl)benzoyl]-L-glutamate which is purified by chromatography over silica, m.p. 160° C. (dec.). 1NMR (d6 -DMSO) δ1.98-2.15 (m, 2H), 2.45 (t, J=7.5 Hz, 2H), 3.57 (s, 3H), 3.64 (s, 3H), 4.40-4.45 (m, 1H), 7.51 ((d, J=2.5 Hz, 1H), 7.55 (d, J=8.2 Hz), 2H), 7.87 (s, 1H), 7.90 (d, J=8.2 Hz, 1H), 11.97 ((d, J=3.7 Hz, 1H), 12.31 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:10][N:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[N:20][N:21]=4)[N:18]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>>[CH:29]1([C:32]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:10][N:11]([C:13]4[CH:14]=[CH:15][C:16]5[N:17]([CH:19]=[N:20][N:21]=5)[N:18]=4)[CH:12]=3)[CH:5]=[CH:4][N:3]=2)=[O:33])[CH2:31][CH2:30]1
Reactant: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1)C1CC1
Yield: 37.3 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 200 mg (0.54 mmol) of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo-[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained by the same reaction as in Example 8-2), and using 59.0 mg (0.56 mmol) of cyclopropylcarbonyl chloride in place of acetic anhydride to obtain 88.6 mg of the title compound as a white powder. (Yield: 37%)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:10][N:11]([CH:13]([N:16](C)C)[O:14]C)C.NC(N)=O>>[N:7]1[CH:8]=[CH:9][C:4]([C:1]2[CH:2]=[CH:10][NH:11][C:13](=[O:14])[N:16]=2)=[CH:5][CH:6]=1
Reactant: COC(N(C)C)N(C)C
Reactant: CC(=O)c1ccncc1
Agent: NC(N)=O
Product: O=c1nc(-c2ccncc2)cc[nH]1
Temperature: 85 °C

Procedure:
A mixture of 4-acetylpyridine (25 ml, 226.0 mmol) and bis(dimethylamino)methoxymethane (44 ml 293.8 mmol) was heated at 85° C. for 30 min followed by evaporation to dryness to recover a solid of 3-(dimethylamino)-1-(4-pyridyl)-3-propen-1-one. Its ethanolic solution (2.00 ml) was transferred into ethanolic 1.13 N sodium ethoxide (200 ml) containing urea (16.3 g, 271 mmol) The mixture was heated to reflux overnight, then cooled down to ice-bath temperature. The precipitate was filtered, dissolved in a minimal amount of water and the aqueous solution was washed with dichloromethane. The title compound was precipitated from the aqueous solution by neutralization with 6N hydrochloric acid and filtered. More material was obtained from the original reaction filtrate which was concentrated, diluted with a minimal amount of water and washed with dichloromethane. The aqueous solution was neutralized with 6N hydrochloric acid and the precipitate filtered. MS (m/z): 174.1 (M+H)+; C9H7N3O requir. 173.2.
Reaction SMILES: [OH:1][C:2]([C:9](=[O:27])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)([CH2:6][CH2:7][CH3:8])[C:3](O)=[O:4].[CH:28]1([CH2:31]N)[CH2:30][CH2:29]1.O.O[N:35]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH:28]1([CH2:31][N:10]([C@@H:11]2[C:17](=[O:18])[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13]3[CH:23]=[CH:24][CH:25]=[CH:26][C:12]2=3)[C:9](=[O:27])[C:2]([OH:1])([CH2:6][CH2:7][CH3:8])[C:3]([NH2:35])=[O:4])[CH2:30][CH2:29]1
Reactant: CCCC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: NCC1CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(O)(C(N)=O)C(=O)N(CC1CC1)[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of 70.0 mg (0.19 mmol) 2-hydroxy-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid and 14.9 mg (0.21 mmol) cyclopropanmethylamine in 3 ml tetrahydrofuran were cooled to 0° C. and 28.2 mg (0.21 mmol) 1-hydroxy-benzotriazole hydrate, 71 μl (0.42 mmol) diisopropylethylamine and 40.1 mg (0.21 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 90:10 to 50:50) yielded 50.0 mg (62%) (R/S)-N-cyclopropylmethyl-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-propyl-malonamide: MS (m/e): 422.4 (M+H)+.
Reaction SMILES: [CH:1](C1C=CC(O)=CC=1)([CH3:3])[CH3:2].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[CH3:13][C:11]1([CH3:14])[C:15]2[C:20](=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:1]([CH3:3])([CH3:2])[CH2:12]1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(C)c1ccc(O)cc1
Product: CC1(C)CC(C)(C)c2cc(O)ccc21
Temperature: 150 °C
Reaction time: 5 h
Yield: 48.3 %

Procedure:
68 g (1/2 mol) of 4-isopropyl-phenol, 150 g (1 mol) of 4-tert.-butyl-phenol and 30 g of an acid activated Fuller's earth were stirred for 5 hours at 150°C. The substance which collected in the deep cooling condenser was isobutane. After removal of the catalyst by suction filtration, fractional distillation yielded 46 g of 1,1,3,3-tetramethyl-5-hydroxy-indane in addition to phenol.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].CCN(CC)CC.O>CCOC(C)=O>[C:32]([O:31][C:30]([NH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[NH:22][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(C)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Yield: 79.5 %

Procedure:
A solution of methyl 6-chloro-4-cyano-2-(m-tolylamino)nicotinate (198 mg, 0.656 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (562 mg, 2.62 mmol) and Et3N (0.402 mL, 2.89 mmol) was stirred at reflux overnight. To the resulting mixture were added H2O and EtOAc. The aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, and evaporated. The residue was triturated with EtOAc. The resulting solid was filtered, rinsed with EtOAc, and dried to give the title compound as a yellow solid (250 mg, 79%). 1H NMR (500 MHz, CDCl3) δ ppm 1.23-1.77 (m, 17 H), 2.34 (s, 3 H), 3.94 (br s, 3 H), 3.98 (br s, 1H), 4.80 (s, 1H), 6.15 (s, 1 H), 6.91 (d, J=5.37 Hz, 1 H), 7.21 (t, J=7.81 Hz, 1H), 7.29 (s, 1H), 7.47-7.55 (m, 1 H), 10.64 (br s, 1 H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:20])[C@@H:5]([NH2:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[Br:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:20])[C@@H:5]([NH:19][C:27](=[O:28])[C:26]1[CH:30]=[C:22]([Br:21])[CH:23]=[CH:24][C:25]=1[OH:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Yield: 27.5 %

Procedure:
3-Biphenyl-4-yl-2-(S)-(5-bromo-2-hydroxy-benzoylamino)-propionic acid methyl ester (425 mg) was prepared from 2-(S)-amino-3-biphenyl-4-yl-propionic acid methyl ester-hydrochloride (1.0 g, 3.4 mmol), and 5-bromo-2-hydroxy-benzoic acid (744 mg, 3.4 mmol) as described in general procedure A except for an adapted work-up. After reaction completion, the reaction mixture was poured onto 150 mL of 1N HCl and 150 mL of EtOAc. The organic layer was washed with 1N HCl, saturated sodium bicarbonate, dried over sodium sulfate and evaporated. The crude material was purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]3[N:13]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:14]=[C:15]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[C:11]=3[CH2:10]S[C:8]=12.O[O:31][S:32]([O-:34])=O.[K+].CCOC(C)=O>C1COCC1.O>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]3[N:13]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:14]=[C:15]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[C:11]=3[CH2:10][S:32](=[O:34])(=[O:31])[C:8]=12
Reactant: O=S([O-])OO
Reactant: CNc1cccc2c1SCc1c(C(=O)N3CCOCC3)nn(-c3ccccc3)c1-2
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1cccc2c1S(=O)(=O)Cc1c(C(=O)N3CCOCC3)nn(-c3ccccc3)c1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-methyl-3-(morpholin-4-ylcarbonyl)-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazol-6-amine (90 mg, 0.22 mmol) in THF: H2O (1:1, 10 mL) is added oxone (545 mg, 0.88 mmol) and the reaction mixture is stirred at RT for 3 h. After this time, EtOAc is added to the reaction mixture that is washed with water. The organic layer is separated, dried over Na2SO4, concentrated under reduced pressure. The solid residue is purified by silica gel flash chromatography (40% EtOAc in pet.ether) the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.59-7.56 (m, 3H), 7.47-7.44 (m, 2H), 7.26-7.22 (t, J=8.1 Hz,1H), 6.80-6.74 (m, 2H), 5.98-5.96 (d, J=7.6 Hz,1H), 4.87 (s, 2H), 3.95-3.94 (m, 2H), 3.65 (m, 4H), 3.61-3.59 (m, 2H), 2.83-2.82 (d, J=4.7 Hz, 3H). MS (ESI+): 439.0. HPLC (max plot) 95.63%; Rt 4.39 min.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>>[CH2:20]([N:22]([CH2:23][CH3:24])[C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])[CH3:21]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: CCNCC
Product: CCc1cc(-c2cncc(C(=O)N(CC)CC)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and diethyl amine to afford the title compound. MS: m/e=314 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C@@H:5]([NH:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[C:6]([O:8][CH3:9])=[O:7].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:14]([O:13][C:11]([NH:10][C@H:5]([CH2:4][CH2:3][NH:2][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])[C:6]([O:8][CH3:9])=[O:7])=[O:12])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOC(=O)N[C@H](CCN)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)N[C@H](CCNS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of methyl 4-amino-2(R)-(N-butyloxycarbonylamino)butyrate hydrochloride (2.28 g, 8.5 mmol) and p-toluenesulfonyl chloride (1.62 g, 8.5 mmol) in 10 mL CHCl3 cooled in an ice bath was added diisopropylethylamine (4.5 mL, 26 mmol). The mixture was stirred at room temperature overnight and concentrated. Ethyl acetate was added and the solution was washed with citric acid, brine, NaHCO3 and brine, dried (MgSO4) and concentrated. Purification on a silica gel column using 40% ethyl acetate/hexane gave 2.16 g (66%) product. 1H-NMR: d (CDCl3) 7.75 (d, 2H ); 7.26 (d, 2H); 5.72 (t, 1H); 5.22 (d, 1H); 4.32 (m, 1H); 3.72 (s, 3H); 3.18 (m, 1H); 2.82 (m, 1H); 2.41 (s, 3H); 2.10 (m, 1H); 1.60 (m, 1H); 1.40 (s, 9H).