Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].Cl.[C:16](Cl)(Cl)=[O:17]>>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:16]([OH:17])=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: O=C(Cl)Cl
Agent: Cl
Product: CC1(C)C(=O)Nc2cc3[nH]c(O)nc3cc21
Reaction time: 0.17 h

Procedure:
Into a solution of 4.00 g. (0.021 mole) 5,6-diamino-3,3-dimethylindolin-2-one in 60 ml. 2N hydrochloric acid is passed phosgene at ambient temperature for 1 hour. Thereafter, nitrogen is passed through the solution for 10 minutes and the solution then left to stand for 15 hours. The precipitate is filtered off and crystallised from methanol. There are obtained 2.80 g. (62% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][NH:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[N:7]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][NH:5][C:6]1[C:11]([NH:12][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[N:7]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(N)c(NCC(OC)OC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)CNc1ccc(OC)nc1NCC(OC)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N2-[2,2-bis(methyloxy)ethyl]-6-(methyloxy)-2,3-pyridinediamine (2.2 g, 10 mmol), ethyl bromoacetate (1.1 mL, 1.65 g, 10 mmol) and potassium carbonate (2.1 g, 20 mmol) in acetonitrile (50 mL) and DMF (5 mL) was stirred at room temperature overnight. The mixture was filtered and evaporated. The residue was dissolved in ethyl acetate and washed with water and brine. The organic extract was concentrated and added to a silica column which was then eluted with 0-100% ethyl acetate in hexane affording product (2.5 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4].[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)n[nH]1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)nn1C
Reaction time: 2.5 h
Yield: 17.4 %

Procedure:
To a solution of 5-hydroxy-2H-pyrazole-3-carboxylic acid methyl ester (2.3 g, 16 mmol) in DMF (10 mL) at room temperature was added cesium carbonate (5.27 g, 16 mmol) and methyl iodide (2.3 g, 1.0 mL, 16 mmol) and the resulting mixture stirred for 2.5 h. The mixture was then filtered off to afford the title compound (434 mg, 17%) as a white solid after trituration with ethyl acetate. MS: m/e=157.2 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].C(OC(Cl)=O)C(C)C.C(N(CC)CC)C.[CH2:43]([NH:61]CCCCCCCCCCCCCCCCCC)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]>O1CCCC1>[CH2:43]([NH:61][C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH:8]1[C:12]2([CH3:27])[CH:11]([CH:16]3[CH:15]([CH2:14][CH2:13]2)[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([OH:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Yield: 172.2 %

Procedure:
Lithocholic acid (81) (9.78 g, 26 mmol) was sissolved in anhydrous tetrahydrofuran (60 mL). Isobutylchloroformate (3.55 g, 3.55 mL, 26 mmol) was added followed by the addition of triethylamine (5.26 g, 7.25 mL, 52 mmol) and dioctadecylamine (7 g, 26 g). The reaction mixture was brought to ambient temperature and allowed to stir over night. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (250 mL). The organic layer was washed with 5% sodium bicarbonate, 3% aqueous HCl and water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to afford amide 88 (14.5 g) in 89% yield. This was used as such for the next step.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:9][C:8]2[N:10]=[CH:11][C:12]([CH:14]=[CH:15][C:16]([OH:18])=O)=[CH:13][C:7]=2[CH2:6][NH:5][CH2:4]1.[Cl:19][C:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][C:21]=1[CH2:29][NH:30][CH3:31]>>[ClH:19].[Cl:19][C:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][C:21]=1[CH2:29][N:30]([CH3:31])[C:16](=[O:18])/[CH:15]=[CH:14]/[C:12]1[CH:11]=[N:10][C:8]2[NH:9][C:3](=[O:2])[CH2:4][NH:5][CH2:6][C:7]=2[CH:13]=1
Reactant: O=C(O)C=Cc1cnc2c(c1)CNCC(=O)N2
Reactant: CNCc1oc2ccccc2c1Cl
Agent: Cl
Product: CN(Cc1oc2ccccc2c1Cl)C(=O)/C=C/c1cnc2c(c1)CNCC(=O)N2
Yield: 34.1 %

Procedure:
According to the method of example 43d, 3-(2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)-acrylic acid hydrochloride (152 mg, 0.5 mmol) and (3-chloro-benzofuran-2-ylmethyl)methylamine (108 mg, 0.55 mmol) were coupled to yield crude product which was triturated with methanol and ether several times and dried. The residue was re-solvated in methylene chloride (5 mL) and a solution of 2M HCl in ether (2 mL) was added to precipitate the hydrogen chloride salt. The precipitate was collected by filtration and dried to give the title compound (42 mg, 19%) as a white solid and as a mixture of amide rotomers. 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.45 (s, 1H), 8.01 (s, 1H), 7.38-7.68 (m, 6H), 4.88-5.08 (rotamers, 2s, 2H), 3.90 (s, 2H), 3.63 (s, 2H), 3.31 (s, 3H); MS (ESI) m/e 411 (C21H19ClN4O3+H)+.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][OH:8])([O-:3])=[O:2].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([O:8][CH2:7][CH2:6][CH2:5][O:4][N+:1]([O-:3])=[O:2])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])OCCCO
Solvent: CCN(CC)CC
Product: O=C(OCCCO[N+](=O)[O-])c1ccccc1
Temperature: 3 °C
Reaction time: 24 h

Procedure:
16.5 mmol 3-Nitrooxypropanol dissolved in 10 ml TMBE and 18.2 mmol Triethylamine were cooled to 3° C. 18.2 mmol benzoylchloride in 5 ml TMBE were dropped over a period of 7 minutes at 3 to 6° C. After 24 hours and 30 minutes stirring without cooling, the reaction mixture was extracted with sated. NaHCO3, water, 1N HCl, twice with water, washed with brine, dried over Na2SO4 and the solvent was removed in vacuo leaving 3.3 g.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:10]=1[C:25](OCC)=[O:26]>C1(C)C=CC=CC=1>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][C:10]=1[C:25]([NH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)=[O:26]
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Reactant: Cc1cc(N)no1
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)C2=C(O)c3ccccc3N(c3ccccc3)C2)no1
Yield: 54.1 %

Procedure:
A solution of 2.0 g of 3-amino-5-methylisoxazole and 5.5 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 260 ml of toluene was refluxed for 10 hours in a soxhlet apparatus containing 10 g of 4Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 3:1 ethyl acetate-hexane as the eluent) to yield 3.5 g (51%) of 1,2-dihydro-4-hydroxy-N-(5-methyl-3-isoxazolyl)-1-phenyl-3-quinolinecarboxamide. Recrystallization from dichloromethane afforded the analytical sample, m.p. 148°-150° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[C:19]([O:21][CH3:22])=[O:20].C(N(CC)C(C)C)(C)C>CC(C)CC(=O)C>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:16]2[CH2:17][CH2:18][N:13]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH:14]([C:19]([O:21][CH3:22])=[O:20])[CH2:15]2)=[N:3][N:4]=1
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: CC(=O)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)OC(C)(C)C

Procedure:
1,4-dichlorophthalazine (741 mg, 3.72 mmol), 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (1.00 g, 4.09 mmol), N,N-diisopropylethylamine (0.972 mL), and 4-methyl-2-pentanone (6 mL) were heated at 120° for 16 hours. The solvent was removed and the residue purified by chromatography over silica using a gradient of hexanes/0-70% ethyl acetate. The compound was obtained as a white solid. MS (M+H)+=407.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][NH2:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CO>[C:21]([NH:20][CH2:19][C:13]1[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Cn1c(CN)nc2c(N)nc3ccccc3c21
Solvent: CO
Product: CC(=O)NCc1nc2c(N)nc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanamine (1.1 g; 0.004 mol, Example 14) was added to acetic anhydride (3 mL). The mixture was stirred at room temperature for 5 hrs. The solution was then diluted with methanol (50 mL) and refluxed for 1 hr. The solution was concentrated and the residue made basic with aqueous sodium bicarbonate solution. The oily residue was extracted into dichloromethane. The extracts were dried over magnesium sulfate and evaporated to dryness. The residue was recrystallized from ethyl acetate to yield pure product m.p. 214°-218° C. Analysis: Calculated: C, 65.6; H, 6.8; N, 22.5. Found: C, 65.1; H, 6.6; N, 22.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1C1C=CC=CC=1O)([CH3:4])([CH3:3])[CH3:2].[P:22]([O:37]C1C=CC=CC=1)([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[O-].[Na+]>>[P:22]([O:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[O:37][C:6]1[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(-c2ccccc2O)c(C(C)(C)C)c1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(OP(Oc2ccccc2)Oc2ccccc2)c(C(C)(C)C)c1

Procedure:
Bis (tetrahydroabietyl)-2,4 di-tert-butyl phenyl phosphite was prepared by first reacting 206 g (1 mol) of 2,4 di-tert-butylphenyl phenol with 310 g (1 mol) of triphenyl phosphite catalyzed with 2 g of sodium methylate (or phenate) to obtain a nominal 2,4 di-tert-butylphenyl diphenyl phosphite. Phenol was distilled through a 20 cm Raschig ring packed column to 150° C. and 30 mm. The reaction terminates at 190° C. at 4 mm after distilling the calculated 1 mol of phenol. The product mixture contained approximately 85% of the desired 2,4,di-tert-butylphenyl diphenylphosphite. The remainder was identified as being predominantly a mixture of bis (2,4 -di-tert-butylphenyl) phenyl phosphite and unreacted triphenyl phosphite.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][C:6]1[C:18]2[C:17](=O)[C:16]3[CH:15]=[N:14][CH:13]=[CH:12][C:11]=3[C:10]=2[C:9]2[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([CH3:24])[C:8]=2[N:7]=1.[CH3:27][O:28][NH2:29]>>[CH3:27][O:28][N:29]=[C:17]1[C:18]2[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:26])[CH3:1])=[N:7][C:8]3[C:23]([CH3:24])=[C:22]([OH:25])[CH:21]=[CH:20][C:9]=3[C:10]=2[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:16]1=2
Reactant: CON
Reactant: Cc1c(O)ccc2c3c(c(NCCN(C)C)nc12)C(=O)c1cnccc1-3
Product: CON=C1c2cnccc2-c2c1c(NCCN(C)C)nc1c(C)c(O)ccc21

Procedure:
This compound was prepared from the compound of 6-(2-dimethylamino-ethylamino)-3-hydroxy-4-methyl-5,9-diaza-benzo[c]fluoren-7-one (Example 46) and O-methylhydroxylamine in a similar manner to 52. The desired product was obtained as an orange powder. ESI−MS: m/z 378 (MH+); 1H-NMR (CDCl3): δ2.45 (6H, s), 2.56 (3H, s), 2.79 (2H, t, J=6 Hz), 3.86 (2H, quartet like, J=ca 6 Hz), 4.31 (3H, s), 6.78 (1H, d, J=9 Hz), 7.10 (1H, brt, J=ca 6 Hz), 7.72 (1H, d, J=9 Hz), 7.76 (1H, d, J=5 Hz), 8.66 (1H, d, J=5 Hz), 9.41 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16]
Reactant: CC(C)(C)N
Reactant: O=c1c2cccc(Br)c2nc(Cl)n1C1CC1
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1C1CC1
Temperature: 90 °C
Yield: 92.8 %

Procedure:
8-bromo-2-chloro-3-cyclopropylquinazolin-4(3H)-one (723) (213 mg, 0.711 mmol) was treated with tert-butylamine (0.90 mL, 8.56 mmol) and heated at 90° C. in a sealed tube for 24 h. The reaction mixture was concentrated to remove the excess t-BuNH2 and the crude residue was chromatographed on an ISCO Combiflash RF (12 g Redisep column, using a gradient of 0-5% MeOH in DCM) affording 8-bromo-2-(tert-butylamino)-3-cyclopropylquinazolin-4(3H)-one (224 mg, 0.66 mmol, 94% yield) as an off-white crystalline solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (1H, dd, J=8.0, 1.4 Hz), 7.82 (1H, dd, J=7.7, 1.5 Hz), 6.94 (1H, t, J=7.7 Hz), 5.42 (1H, s), 2.62-2.71 (1H, m), 1.61 (9H, s), 1.28-1.35 (2H, m), 0.87-0.95 (2H, m). m/z (ESI, +ve) 335.9/337.9 (M+1)+.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9](=[O:24])[CH2:10][C:11]1[C:12]([CH3:23])=[N:13][NH:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[Cl:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1.Cl>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:7][O:8][C:9](=[O:24])[CH2:10][C:11]1[C:12]([CH3:23])=[N:13][N:14]([C:29]2[CH:28]=[N:27][C:26]([Cl:25])=[N:31][CH:30]=2)[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1c(C)n[nH]c1-c1ccc(Cl)cc1
Reactant: OB(O)c1cnc(Cl)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Cc1c(C)nn(-c2cnc(Cl)nc2)c1-c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
0.515 g (3 mmol) of copper(II) acetate and 0.306 ml (4 mmol) of pyridine were added to 0.5 g (2 mmol) of methyl[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]acetate in 10 ml of dichloromethane. 0.598 g (4 mmol) of 2-chloropyrimidine-5-boronic acid was then added, and the mixture was stirred at 20° C. for 24 h. The mixture was then added to 1 M HCl and extracted with dichloromethane. The combined organic phases were dried with magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC. This gave 0.015 g of product (2% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[NH:19][N:18]=[CH:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[I:20]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[CH:12]=[C:13]3[NH:19][N:18]=[C:17]([I:20])[C:14]3=[N:15][CH:16]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(-c2cnc3cn[nH]c3c2)c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: COc1cc(OC)cc(-c2cnc3c(I)n[nH]c3c2)c1
Yield: 94.4 %

Procedure:
At r.t. to a solution of 6-(3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-b]pyridine (0.38 g, 1.5 mmol) in methylene chloride (5 mL) was added N-iodosuccinimide (0.352 g, 1.56 mmol) with stirring. The mixture was stirred at r.t. overnight. Then the solvent was removed, the residue was treated with methanol. The solid was collected by filtration to afford the desired product (0.54 g) which was directly used in next step reaction without further purification. LCMS (M+H)+=382.1.
Reaction SMILES: C([O:6][C:7]1[C:13]([Cl:14])=[C:12]([Cl:15])[C:10]([OH:11])=[C:9]([Cl:16])[C:8]=1[Cl:17])CCCC.Cl[C:19]1[C:20](=O)[C:21](C#N)=C(C#N)[C:23](=O)[C:24]=1Cl>CO>[CH2:23]([C:13]1([Cl:14])[CH:12]([Cl:15])[C:10](=[O:11])[C:9]([Cl:16])=[C:8]([Cl:17])[C:7]1=[O:6])[CH2:24][CH2:19][CH2:20][CH3:21]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCCCCOc1c(Cl)c(Cl)c(O)c(Cl)c1Cl
Solvent: CO
Product: CCCCCC1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C1Cl
Reaction time: 2 h

Procedure:
To a solution of 110 mg (0.388 mmol) of 3 in methanol, 880 mg (10 eq) of 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was added. The reaction mixture was stirred for 2 hr, and then the solvent was removed. Silicagel chromatography (hexane: EA=20:1) gave 4 as an orange solid with quantitative yield.
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C1N=C[N:19]([C:22](N2C=NC=C2)=[S:23])C=1>C1COCC1>[F:2][C:3]1([F:9])[CH2:8][CH2:7][N:6]([C:22]([NH2:19])=[S:23])[CH2:5][CH2:4]1
Reactant: FC1(F)CCNCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=S)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
Commercially available 4,4-difluoropiperidine hydrochloride (883 mg, 5.60 mmol) and triethylamine (0.85 mL, 6.10 mmol) were added to a solution of 1,1-thiocarbonyldiimidazole (1.05 g, 5.89 mmol) in THF (20 mL) under ice-cooling, followed by stirring at room temperature for 3 hr in an argon atmosphere. The reaction solution was concentrated. Concentrated aqueous ammonia (30 mL) was added to the residue, followed by stirring overnight at room temperature. The precipitated crystals were collected by filtration, washed with water, and dried to obtain 4,4-difluoropiperidinothiocarboxamide (850 mg, 4.72 mmol) as a light yellow powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:13][CH2:12][CH2:11][CH2:10][C:5]=2[C:6]=1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH2:22][C:23]([NH:1][C:2]1[S:3][C:4]2[CH2:13][CH2:12][CH2:11][CH2:10][C:5]=2[C:6]=1[C:7]([NH2:9])=[O:8])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1c(NC(=O)CCl)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a mixture of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (30 g, 0.153 mol) and triethylamine (18.5 g, 0.183 mol) in DCM (200 ml) was added chloro-acetyl chloride (20.57 g, 0.183 mol) slowly at 0° C., and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to half of the volume to afford the solid product which was filtered, washed with 10 ml of DCM and dried to provide 2-(2-chloro-acetylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid amide (35 g, 84%) as off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.65-1.75 (m, 4H), 2.58-2.72 (m, 4H), 4.49 (s, 2H), 7.29 (s, 1H), 7.42 (s, 1H), 12.23 (s, 1H); LC-MS: [M+H]=272.8, 275.1, 257.9 & 255.9 m/z.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[F:24][C:25]1[CH:30]=[C:29]([O:31][C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:27][C:26]=1Br>>[F:24][C:25]1[CH:30]=[C:29]([O:31][C:32]([F:33])([F:34])[F:35])[CH:28]=[CH:27][C:26]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: Fc1cc(OC(F)(F)F)ccc1Br
Product: Nc1cnc(-c2ccc(-c3ccc(OC(F)(F)F)cc3F)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-fluoro-4-(trifluoromethoxy)bromobenzene. MS (ESI): mass calcd. for C17H10F5N3O, 367.07; m/z found, 368.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.03-7.96 (m, 2H), 7.78 (m, 1H), 7.56-7.49 (m, 3H), 7.37 (d, J=8.2, 1H), 6.75 (s, 2H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[O:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Reactant: c1ccoc1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4ccco4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and furane
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH2:12])=[N-]>CCOCC>[CH:1]1([C:7]([O:9][CH3:12])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C1CCCCC1
Solvent: CCOCC
Product: COC(=O)C1CCCCC1
Temperature: 0 °C
Yield: 67.2 %

Procedure:
To an ice-cooled and stirred solution of cyclohexanecarboxylic acid (7.4 g, 0.058 mol) in 30 ml of ether was slowly added an excess solution of diazomethane in ether. After concentration of ether, the residue was distilled under reduced pressure to give a colorless transparent liquid of methyl cyclohexanecarboxylate (5.6 g, 0.039 mol, yield 67.2%, b.p. 73°-74° C./16 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]4[C:23]([CH3:37])=[CH:24][C:25]([NH:29]C(=O)OC(C)(C)C)=[N:26][C:27]=4[CH3:28])=[O:19])[N:15]=[N:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C:25]1[N:26]=[C:27]([CH3:28])[C:22]([CH2:21][NH:20][C:18]([C:16]2[N:15]=[N:14][N:13]([CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:17]=2)=[O:19])=[C:23]([CH3:37])[CH:24]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc3ccc(Cl)cc3n2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cn(Cc2ccc3ccc(Cl)cc3n2)nn1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (5-((1-((7-chloroquinolin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-yl)carbamate (46.7 mg, 0.089 mmol) in DCM (0.6 ml) was added TFA (0.138 ml, 1.789 mmol). Reaction mixture was stirred overnight at 23° C.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH:25]=[CH:24]1.Cl.O>[OH-].[Na+].C(O)C>[C:14]([C:12]1[CH:13]=[C:8]([N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:23](=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27])[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1cc(Nc2ccccc2)cc(C(C)(C)C)c1O
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(N(C(=O)/C=C\C(=O)O)c2ccccc2)cc(C(C)(C)C)c1O
Temperature: 140 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 2.97 g (0.01 mole) of 4-anilino-2,6-di-t-butylphenol and 4.90 g 0.05 mole) of maleic anhydride was heated at 140° C. for 2 hours. The cooled reaction mixture was suspended in 10% sodium hydroxide, and was then acidified with 10% hydrochloric acid. The resulting precipitate was collected, rinsed with water, air dried, and recrystallized from a mixture of ethyl acetate and hexane to give a yellow solid. This material was dissolved in hot ethanol. The ethanol solution was acidified with 6N hydrochloric acid, and then saturated with water. The resulting precipitate was collected, rinsed with water and air dried. This material was purified by silica gel chromatography, eluting with ethyl acetate, followed by recrystallization from a mixture of ethyl acetate and hexane to give 0.5 g of yellow crystalline N-(3,5-di-t-butyl-4-hydroxyphenyl)-N-phenylmaleamic acid, m.p. 154°-157° C. Analysis: Calculated for C25H29NO4 :% C, 72.9; % H, 7.9; % N, 3.5. Found: % C, 73.2; % H, 7.7; % N, 3.3.