Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3].[CH3:18][CH:19]([OH:21])[CH3:20].N1C=CC=CC=1.C1(C)C(C)=CC=CC=1>O>[CH:19]([O:21][C:2]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3])([CH3:20])[CH3:18]
Reactant: CC(C)O
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of 4-chlorocarbonylphenoxy phenyl methane (12.3g.; 0.05 mole), propan-2-ol (3.6g.; 0.6 mole), pyridine (5g) and xylene (50ml) were boiled under reflux for 18hr. The cooled mixture was poured into water and extracted with dichloromethane. The organic extract was washed well with water and dried (anhyd. MgSO4), filtration and evaporation yielded 4-isopropoxycarbonylphenoxy phenyl methane, m.p. 62°-3° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH2:19]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[N:7]1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CBr
Reactant: COc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(cnn2CC(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.5 %

Procedure:
A solution of 5-methoxy-1H-indazole (5.00 g, 33.7 mmol) in DMF (100 mL) was treated with K2CO3 (5.83 g, 42.2 mmol) and stirred at room temperature for 15 minutes. To this solution was added 1-bromo-2-methylpropane (5.09 g, 37.1 mmol) and the resulting mixture was heated to 110° C. for 18 hours. Another equivalent of 1-bromo-2-methyl-propane was added and the mixture continued to heat for 48 hours more. The mixture was concentrated under reduced pressure and dissolved in dichloromethane. The solution was washed with 1N HCl, filtered, and concentrated under reduced pressure. The residue was chromatographed on Biotage eluting with hexanes/ether (5:1) to afford 2.51 g of orange oil (36% yield).
Reaction SMILES: C([C:3]([CH3:5])=[O:4])=C.CS[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.C(N(CC)CC)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.Cl>[CH2:8]1[CH2:15][CH2:14][CH2:11][CH2:10][CH2:9]1.[C:12]([O:4][CH2:3][CH3:5])(=[O:13])[CH3:11]
Reactant: CSc1ccc(C=O)cc1
Reactant: C=CC(C)=O
Agent: CC[n+]1csc(CCO)c1C
Agent: Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Product: C1CCCCC1
Product: CCOC(C)=O
Temperature: 75 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
Methyl vinyl ketone (1.16 g, 0.016 mol) and p-methylsulfanylbenzaldehyde (2.4 g, 0.016 mol) were reacted in the presence of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (0.837 g, 0.0032 mol) and triethylamine (1.14 g, 0.011 mol). b) Stir the reaction mixture at 75° C. under a nitrogen atmosphere for 24 h. c) Cool the mixture to room temperature, add ice and 30 mL of concentrated HCl to the mixture until pH 2. d) Stir for 30 min. e) Extract with ethyl acetate and neutralize the combined organic fractions with an aqueous solution of NaHCO3. f) Dry the organic fraction on anhydrous sodium sulphate for 3 h. g) Purify the product by column chromatography on aluminium oxide (Brockmann grade II-III), eluting with a 3:1 cyclohexane/ethyl acetate mixture (53% yield). 1′) Alternative Method of Preparation of Compound having Formula 4a
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](NCC3CCCO3)=O)[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])C.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26].[CH2:34]([N:36](CC)CC)C>CN(C=O)C>[C:34]([CH2:16][C:13]1[S:14][CH:15]=[C:11]([C:7]2[S:6][C:5]([NH:4][C:1]([NH:32][CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:33])=[O:3])=[N:9][C:8]=2[CH3:10])[N:12]=1)#[N:36]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)NCC3CCCO3)n2)s1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)CN
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)NCC(=O)OC(C)(C)C)sc1-c1csc(CC#N)n1
Reaction time: 0.75 h
Yield: 124.8 %

Procedure:
N-[2-(cyanomethyl)-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide (Intermediate 6) (160 mg; 0.48 mmol; 1 eq) is dissolved in DMF (8 ml). A solution of glycine tert-butyl ester (63.5 mg; 0.48 mmol; 1 eq) in DMF (1 ml) and triethylamine (74 μl; 0.53 mmol; 1.10 eq) are added. After less than 1 min the mixture becomes homogeneous. After 45 min, the reaction is complete. DMF is removed under reduced pressure to afford 235.8 mg of a dark brown solid, which is purified by preparative HPLC. The purified fractions are neutralized with NaHCO3 sat. solution and the desired product is extracted with DCM. The combined organic layers are dried over MgSO4, filtered and concentrated, affording Compound (65) as a brown solid (27.30 mg; 14%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:36])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:15][CH:14]=1.[CH3:37][C:38]1[S:42][CH:41]=[N:40][CH:39]=1>C1(C)C=CC=CC=1>[Br-:1].[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][N+:40]2[CH:39]=[C:38]([CH3:37])[S:42][CH:41]=2)=[O:36])=[CH:14][CH:15]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: Cc1cncs1
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Nc2ccccc2CBr)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Nc2ccccc2C[n+]2csc(C)c2)cc1
Product: [Br-]
Yield: 80.3 %

Procedure:
A mixture of 1.8 g of N-[2-(bromomethyl)phenyl]-2-[4-(hexadecyloxy)phenoxy]acetamide and 1.59 g of 5-methyl thiazole in 25 ml of toluene is refluxed under argon for 6 hours. The solvent is evaporated to a residue which is stirred with ether and the solid collected by centrifugation, washed with ether and vacuum dried to give 1.7 g of the desired product as an off-white solid, m.p. 121°-124° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.CN(C)C=O.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>[Cu](I)I.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.O>[CH3:21][Si:22]([C:25]#[C:26][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:24])[CH3:23]
Reactant: Brc1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
A mixture of 150 g of 97% bromo iodo benzene, 500 ml of anhydrous dimethylformamide, 100 ml of triethylamine, 50 g of trimethylsilyl acetylene, 2.1 g of copper iodide and 2.22 g of bis-(triphenylphosphine)-palladium (II) dichloride was stirred for 2 hours and then 500 ml of ice-cooled water were added. The mixture was extracted 3 times with 500 ml of ethyl acetate and the organic phase was washed with salt water, then dried over sodium sulfate, and evaporated under reduced pressure to obtain 136.542 g of a brown oil which was purified by distillation under reduced pressure to obtain 106.979 g of the expected product with a boiling point of 75°-82° C. under 0.2 mbar and a melting point of 62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([Cl:24])[CH:15]=2)[N:10]=1)[NH2:5].O=[C:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:26]2[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:22])[CH3:23])=[C:16]([Cl:24])[CH:15]=2)[N:10]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(N)cc3Cl)n2)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(NC4CC(C(=O)O)C4)cc3Cl)n2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (200 mg, 0.549 mmol) and 3-oxocyclobutanecarboxylic acid (62.7 mg, 0.549 mmol) in methanol (1280 μl) at room temperature was added acetic acid (842 μl, 14.72 mmol). The reaction mixture was stirred at room temperature for 10 minutes before addition of sodium cyanoborohydride (17.25 mg, 0.275 mmol) as a single portion. The reaction mixture was stirred at room temperature overnight. LCMS (2007—9476) indicated a 43% by ELSD (2.90 min)s conversion to (M+H) 462.16. The solvent was removed and the crude material purified by FCC (50% EA/Hept) to afford 3-(3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)cyclobutanecarboxylic acid (135 mg, 0.292 mmol, 53.2% yield) as a white solid. LCMS (Table A, Method b) indicated 100% by UV (3.06 mins) to (M+H)+ 364.12.
Reaction SMILES: C[N:2]([CH3:21])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19])[CH:10]=[CH:11][CH:12]=1)=O.N[C:23]1[C:27]([C:28]#[N:29])=C[NH:25][N:24]=1>>[C:28]([C:27]1[CH:23]=[N:24][N:25]2[C:5]([C:7]3[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:21]=12)#[N:29]
Reactant: CCOC(=O)NCCc1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Product: CCOC(=O)NCCc1cccc(-c2ccnc3c(C#N)cnn23)c1

Procedure:
A 2.0 g portion of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]ethylcarbamic acid, ethyl ester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13, giving 2.52 g of the desired product, mp 133°-135° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1B(O)O>COCCOC.O.[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>[F:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: COc1ccc(B(O)O)c(F)c1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(OC)cc1F
Yield: 69.3 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and 2-fluoro-4-methoxyphenylboronic acid (0.085 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.072 g (68%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[CH:16])[CH:14]=1.I[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH:14]=1
Reactant: C#Cc1cncc(Br)c1
Reactant: FC(F)(F)c1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
Add triethylamine (6.2 mL, 44 mmol), copper (I) iodide (120.3 mg, 1.10 mmol) and bis(triphenylphosphine)palladium (II) dichloride (386 mg, 0.55 mmol) to a solution of 3-bromo-5-ethynylpyridine, (prepared essentially as described in PREPARATION 23), (2.0 g, 11 mmol) and 1-iodo-3-trifluoromethylbenzene (1.53 mL, 11 mmol) in ethyl acetate (12 mL). Stir at room temperature for 18 h. Concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 100:50 hexanes:ethyl acetate to give the title compound (2.1 g, 61%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:32])[CH2:30][NH2:31])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29](=[O:32])[CH2:30][NH:31][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=2)=[O:15])[CH2:27][CH2:28]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOC(=O)N1CCN(C(=O)CN)CC1
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4.0 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 7 g of 4-(2-Amino-acetyl)-piperazine-1-carboxylic acid butyl ester in 40 ml of DMF, 3.3 g of HOBT and 4.1 g of EDC was added and the reaction mixture was stirred for 4 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was used in the next reaction step. Yield: 4.5 g.
Reaction SMILES: ON1C2N=CC=CC=2N=N1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[N:20][C:21]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=3)[C:26]([CH3:36])=[CH:25]2)=[N:22][CH:23]=1.[O:37]1[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]1.C(N(C(C)C)CC)(C)C>ClCCl>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[N:20][C:21]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]([N:39]4[CH2:40][CH2:41][CH2:42][O:37][CH2:38]4)=[O:34])[CH:31]=3)[C:26]([CH3:36])=[CH:25]2)=[N:22][CH:23]=1
Reactant: C1CNCOC1
Reactant: Cc1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCCOC3)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
EDCxHCl (109 mg, 0.57 mmol) and 1-hydroxy-7-azabenzotriazole (17 mg, 0.12 mmol) were added to a solution of acid 89b) (200 mg, 0.50 mmol), 1,3-oxazinane (43.1 mg, 0.50 mmol) and diisopropylethylamine (0.13 mL, 0.74 mmol) in dichloromethane (2 mL) and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue purified by column chromatography [silica, heptane with 5 to 100% ethyl acetate]. White solid. Yield: 51 mg. HPLC-MS: m/z [M+H]+=417.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH3:32])=[O:30])[NH2:25]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:25][C:24]3[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:22]([Cl:21])[CH:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: COC(=O)c1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1Cl
Yield: 45.4 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (340 mg, 1 mmol) and m-chloro-p-methoxycarbonylaniline (200 mg, 1.08 mmol) to give 230 mg of the title compound (45%): mp 167° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.04 (bs, 1H), 10.48 (s, 1H), 7.89 (d, 1H, J=2 Hz), 7.86 (d, 2H, J=8.6 Hz), 7.53 (dd, 1H, J=8.6, 2 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 5.17~5.26 (m, 1H), 3.83 (s, 3H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.84 (dm, 1H, J=17.1 Hz), 2.57~2.69 (m, 2H), 2.12 (dm, 1H, J=13.5 Hz), 1.83~1.97 (m, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([N:9]([OH:11])[CH3:10])=[O:8].[OH:25]OS([O-])=O.[K+]>CO.O>[CH3:1][S:2]([C:3]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][C:4]=1[CH:5]=[CH:6][C:7]([N:9]([OH:11])[CH3:10])=[O:8])=[O:25]
Reactant: CSc1ccc(CCCc2ccccc2)cc1C=CC(=O)N(C)O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(O)C(=O)C=Cc1cc(CCCc2ccccc2)ccc1S(C)=O
Reaction time: 0.58 h

Procedure:
In methanol (15 ml) is placed 2-(methylthio)- 5-(3-phenylpropyl)-N-hydroxy-N-methylcinnamamide (0.35 g, 1.02 mmol) prepared according to Example 27 and the solution cooled in an ice bath. In 3 ml of water is placed oxone (0.33 g, 0.533 mmol) which is then added to the cooled methanol solution and stirred for 35 minutes. The reaction mixture is poured into 80 ml of water and extracted twice with 75 ml portions of ethyl acetate. The organic layers are washed with brine and dried over MgSO4 to afford the title compound.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:10]=[C:9]([NH2:18])[CH:8]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:26]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][C:28]([C:34]([OH:36])=O)=[N:27]1.[I-].Cl[C:39]1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[N+:31]([C:30]1[N:26]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)[N:27]=[C:28]([C:34]([NH:18][C:9]2[CH:8]=[C:7]([C:2]3[CH:1]=[CH:6][C:5]([CH3:39])=[CH:4][CH:3]=3)[N:11]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:10]=2)=[O:36])[CH:29]=1)([O-:33])=[O:32]
Reactant: O=C(O)c1cc([N+](=O)[O-])n(C2CCCCO2)n1
Reactant: C[n+]1ccccc1Cl
Reactant: Cc1ccccc1-c1cc(N)nn1C1CCCCO1
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(-c2cc(NC(=O)c3cc([N+](=O)[O-])n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
5-Tolyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (97 mg, 0.38 mmol) was added to a solution of 1-(tetrahydro-2H-pyran-2-yl)-5-nitro-1H-pyrazole-3-carboxylic acid (100 mg, 0.41 mmol), 2-chloro-1-methylpyridinium iodide (145 mg, 0.56 mmol) and N,N′-diisopropylethylamine (193 L, 1.13 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 16 hrs. The reaction was diluted with water and extracted with DCM. The organic layer was washed with brine, dried with Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (PE-EtOAc, 8:2) and gave 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-yl)-1H-pyrazole-3-carboxamide (60 mg, 33%).
Reaction SMILES: CN(C)[CH:3]1[C:8](=O)[CH2:7][CH2:6][N:5]([C:10]2[CH:11]=[C:12]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[O:14])[C:4]1=C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([NH2:42])=[NH:41])=[CH:35][CH:34]=1.[C:43]([O-])(=O)C.[Na+]>C(O)C.O>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:40]2[N:42]=[CH:43][C:3]3[CH2:4][N:5]([C:10]4[CH:11]=[C:12]([CH:26]=[CH:27][C:28]=4[CH3:29])[C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=4)=[O:14])[CH2:6][CH2:7][C:8]=3[N:41]=2)=[CH:37][CH:38]=1
Reactant: N=C(N)Nc1ccc(Cl)cc1
Reactant: CC(=O)[O-]
Reactant: C=C1C(N(C)C)C(=O)CCN1c1cc(C(=O)Nc2cccc(C(F)(F)F)c2)ccc1C
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1N1CCc2nc(Nc3ccc(Cl)cc3)ncc2C1
Temperature: 25 °C

Procedure:
To a solution of 3-(3-Dimethylamino-methylene-4-oxo-piperidin-1-yl)-4-methyl-N-(3-trifluoromethyl-phenyl)benzamide (17.9 gm, 41.7 mmol) in Ethanol (250 ml) were added N-(4-Chloro-phenyl)-guanidine (28.32 gm, 167 mmol) and sodium acetate (27.32 gm, 334 mmol) and solution was heated under reflux for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was washed with brine and dried [sodium sulfate] and evaporated. The crude product obtained was purified by silica gel chromatography using 5-10% methanol/chloroform as eluent to give pure desired product i.e., 3-[2-(4-Chloro-phenylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-4-methyl-N-(3-trifluoromethyl phenyl)benzamide [28] as off white solid. [yield: 1.83 gm, 8.2%]
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[CH3:38][C:39]1[C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=[C:44]2[C:40]=1[CH:41]=[N:42][NH:43]2>CN(C)C=O.C(OCC)(=O)C>[CH3:38][C:39]1[C:47]([C:48]([NH:8][CH:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)=[O:49])=[CH:46][CH:45]=[C:44]2[C:40]=1[CH:41]=[N:42][NH:43]2
Reactant: Cc1c(C(=O)O)ccc2[nH]ncc12
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NC2CCOCC2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.4 %

Procedure:
Tetrahydro-2H-pyran-4-ylamine monohydrochloride (228 mg, 1.66 mmol), triethylamine (0.5 ml, 3.59 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (367 mg, 1.91 mmol) and hydroxybenzotriazole (190 mg, 1.41 mmol) were added to a solution of 4-methyl-1H-indazole-5-carboxylic acid (225 mg, 1.28 mmol) in N,N-dimethylformamide (5.5 ml), and the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution. A small amount of the insoluble material was collected by filtration and then dried to obtain 4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (41 mg). The filtrate was extracted with ethyl acetate and chloroform, and the combined organic layer was dehydrated over magnesium sulfate and then filtered. The filtrate was concentrated and the resulting residue was suspended in chloroform. The resulting suspension was filtered and the precipitate was dried to obtain 4-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (134 mg, 52.7%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[ClH:1].[NH:17]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)[NH2:18]
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cl
Product: NNc1ccnc2cc(C(F)(F)F)ccc12

Procedure:
A mixture of 4-chloro-7-trifluoromethylquinoline (21.95 g.) in ethanol (100 ml.) and hydrazine hydrate (60 g.) was refluxed overnight. The solvent and the excess of reagent were removed in vacuo to give 4-hydrazino-7-trifluoromethylquinoline hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][C:15]=4[C:16]=3[OH:17])=[N:9]2)=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][C:15]=4[C:16]=3[O:17][CH3:26])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2oc(-c3ccc4ccc(Cl)cc4n3)c(O)c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2oc(-c3ccc4ccc(Cl)cc4n3)c(OC)c2c1
Yield: 49.1 %

Procedure:
A mixture of 7-chloro-2-(5-methoxycarbonyl-3-hydroxybenzofuran-2-yl)quinoline (1.0 g), potassium carbonate (0.39 g), and methyl iodide (0.40 g) in a mixture of tetrahydrofuran (20 ml) and N,N-dimethylformamide (8 ml) was stirred under reflux. After being cooled, the appeared precipitates were collected by filtration and washed with acetone to give 7-chloro-2-(5-methoxycarbonyl-3-methoxybenzofuran-2-yl)quinoline (0.51 g).