Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[NH:27][C:26]5[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:25]=5[N:24]=4)[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6][C:3]=1[C:4]#[N:5].ClC1N=C(C2C=CC(CN3CCC(N4C5C=CC=CC=5NC4=O)CC3)=CC=2)C(C2C=CC=CC=2)=CC=1C#N.[C:77]([O:81][CH3:82])(=[O:80])[CH2:78][OH:79].C[O-].[K+]>CN(C=O)C>[NH2:5][C:4]1[C:3]2[C:2](=[N:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([C:23]5[NH:27][C:26]6[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:25]=6[N:24]=5)[CH2:19][CH2:18]4)=[CH:14][CH:15]=3)=[C:7]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:6]=2)[O:79][C:78]=1[C:77]([O:81][CH3:82])=[O:80]
Reactant: COC(=O)CO
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(c4nc5ccc(F)cc5[nH]4)CC3)cc2)nc1Cl
Agent: C[O-]
Agent: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1oc2nc(-c3ccc(CN4CCC(c5nc6ccc(F)cc6[nH]5)CC4)cc3)c(-c3ccccc3)cc2c1N

Procedure:
The solution of 2-chloro-6-(4-{[4-(6-fluoro-1H-benzimidazol-2-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (3-1, synthesis made in a similar manner as shown in Scheme 1, compound 1-6; 0.026 g, 0.05 mmol), methyl glycolate (0.01 g, 0.11 mmol) and potassium methoxide (0.009 mg, 0.11 mmol) in DMF (1 mL) was heated to 70° C. for 1 h. The mixture was purified by reverse phase HPLC (5-100% CH3CN/H2O+0.1% TFA) to give Methyl 3-amino-6-(4-{[4-(6-fluoro-1H-benzimidazol-2-yl)piperidin-1-yl]methyl}phenyl)-5-phenylfuro[2,3-b]pyridine-2-carboxylate (3-2). LRMS m/z (M+H) Calcd: 576.6, found: 576.2.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]#[N:37]>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]#[N:37]
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccsc3C#N)c2)OC1(C)C
Product: N#Cc1sccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]thiophene-2-carbonitrile as described in Example 65 to give 3-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenyl]thiophene-2-carbonitrile as a yellow solid: δH (400 MHz, CDCl3) 7.32 (1H, d, J 7), 7.44-7.47 (2H, m), 7.63-7.66 (1H, m), 7.72 (1H, d, J 5), 7.88 (1H, dd, J 7 and 2), 8.12 (1H, s), 9.09 (1H, d, J 7).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:11]Br>>[Br:11][CH:9]([CH3:10])[C:2](=[O:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)CC
Reactant: BrBr
Product: CCOC(=O)CC(=O)C(C)Br

Procedure:
reacting methyl 3-oxovalerate (commercially available) with bromine to give methyl 4-bromo-3-oxovalerate, or reacting ethyl 3-oxovalerate (commercially available) with bromine to give ethyl 4-bromo-3-oxovalerate,
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5]2[C:8]3[C:13]([CH:14]=[CH:15][C:4]=2[N:3]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH2:16]([O:18][P:19]([CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O:21][CH2:22][CH3:23])=[O:20])[CH3:17]>>[CH3:7][N:6]1[C:5]2[C:8]3[C:13]([CH:14]=[CH:15][C:4]=2[N:3]=[C:2]1[NH:1][C:29]([C:28]1[CH:32]=[CH:33][C:25]([CH2:24][P:19](=[O:20])([O:18][CH2:16][CH3:17])[O:21][CH2:22][CH3:23])=[CH:26][CH:27]=1)=[O:30])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Reactant: Cn1c(N)nc2ccc3ccccc3c21
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2nc3ccc4ccccc4c3n2C)cc1)OCC

Procedure:
Using 2-amino-1-methyl-1H-naphtho[1,2-d]imidazole (commercially available) and 4-[(diethoxyphosphoryl)methyl]benzoyl chloride, the procedure of Example 1 was otherwise repeated to provide the objective compound.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]([CH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)=[O:16].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>O1CCCC1>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][C:17]1([C:15]([O:14][CH3:13])=[O:16])[C:25]2[C:20](=[CH:21][C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)C1CCc2cc(C3CCCCC3)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC1(C(=O)OC)CCc2cc(C3CCCCC3)ccc21
Temperature: -20 °C

Procedure:
23.6 ml of butyl-lithium (20% strength in hexane) are slowly added dropwise to a solution of 7.6 g of diisopropylamine (absolute) in 80 ml of absolute tetrahydrofurane at -10° to -15°C under a dry nitrogen atmosphere, whilst stirring, and 15 minutes after completion of the addition a solution of 15.5 g of 5-cyclohexyl-1-indanecarboxylic acid methyl ester in 40 ml of absolute tetrahydrofurane is added. The reaction solution is cooled to -20°C and a solution of 16.5 g of ethyl bromoacetate in 40 ml of absolute tetrahydrofurane is rapidly added dropwise. In the course thereof, the temperature rises to 0°C. The reaction solution is partitioned between three times 200 ml of methylene chloride and three times 200 ml of 2 N hydrochloric acid. The combined organic phases are washed with water, dried over sodium sulphate and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum yields 1-methoxycarbonyl-5-cyclohexyl-1-indaneacetic acid ethyl ester in the fraction boiling at 140°-142°C/0.04 mm Hg.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[N:20]1([C:26]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:27]=2[C:28](Cl)=[O:29])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([O:5][C:6](=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:28](=[O:29])[C:27]3[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:26]=3[N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: CCCCOC(=O)c1ccc(N2CCNCC2)cc1
Product: CCCCOC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 4-Piperazin-1-yl-benzoic acid butyl ester (CAS: 86620-18-0) and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (example B) (yield :16%, MS (m/e): 497.3 (M+H, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20].C(OCC)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:25][C:24]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:9][C:19](=[O:20])[C:18]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH3:10]
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1OC
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc2c(O)c(-c3ccccc3OC)c(=O)[nH]c2c1
Temperature: 280 °C
Yield: 90.7 %

Procedure:
A mixture of 2.7 g of m-anisidine and 5.32 g of diethyl 2-methoxyphenylmalonate in 20 ml of diphenyl ether was placed in a flask equipped with an air condenser, and heated at 270-290° C. for 2.5 hours. After cooling, to the reaction mixture there was added 80 ml of diethyl ether. The precipitates were collected by filtration, and washed with diethyl ether to obtain 5.39 g of 4-hydroxy-7-methoxy-3-(2-methoxyphenyl)-2-quinolone (yield: 90.7%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:28]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][C:10]2[CH:18]=[C:17]([CH3:19])[C:16]3[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=3)[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.NN>CO>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([NH2:28])[CH2:9][C:10]2[CH:18]=[C:17]([CH3:19])[C:16]3[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=3)[CH:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CC(c2cccc(Br)n2)N2C(=O)c3ccccc3C2=O)cc2cn(COCC[Si](C)(C)C)nc12
Agent: NN
Solvent: CO
Product: Cc1cc(CC(N)c2cccc(Br)n2)cc2cn(COCC[Si](C)(C)C)nc12

Procedure:
A solution of (±)-2-(1-(6-bromopyridin-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethyl)isoindoline-1,3-dione (1 mmol) in methanol (10 mL) was treated with hydrazine (0.16 mL, 5 mmol) at room temperature for 30 min and at 70° C. for 5 h. The mixture was concentrated in vacuo and the residue was partitioned between 1N sodium hydroxide and ethyl acetate. The organic layer was washed with water, brine, dried and concentrated. The pale yellow oil (100%) was pure enough to carry on. MS (ESI) [M+H]+=461. HPLC tR=1.62 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH2:21]([N:28]1[CH:32]=[C:31]([C:33](O)=[O:34])[N:30]=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33]([C:31]3[N:30]=[N:29][N:28]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:32]=3)=[O:34])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1cn(Cc2ccccc2)nn1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cn(Cc2ccccc2)nn1

Procedure:
Benzyl-1H-[1,2,3]triazole-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-benzyl-1H-[1,2,3]triazole-4-carboxylic acid. MS calcd. for C26H21ClN5O2 [(M+H)+] 470.1, obsd. 469.9.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([CH2:20][CH2:21][CH3:22])[CH3:19])[CH:13]=[CH:12]2)C1C=CC=CC=1>CO.[Pd]>[CH3:19][CH:18]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(C)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Product: CCCC(C)n1ccc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
5-(Benzyloxy)-1-(pentan-2-yl)-1H-indole (8) (3.80 g, 12.9 mmol) was dissolved in methanol (MeOH, 30.0 mL) and 10% palladium on activated charcoal (Pd/C, 1.37 g, 0.129 mmol, 10 mol % Pd) was added. The mixture was placed under an atmosphere of hydrogen (double balloon), stirred overnight at room temperature, and then filtered over Celite® (MeOH eluent, 500 mL). Evaporation of the solvent under reduced pressure afforded 1-(pentan-2-yl)-1H-indol-5-ol (9) (2.60 g, 100%) as an oil. 1H NMR (500 MHz, CDCl3): δ 7.25 (d, J=9.0, 1H), 7.18 (d, J=3.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.80 (dd, J=9.0, 2.0, 1H), 6.41 (d, J=3.0 Hz, 1H), 4.56 (bs, 1H), 4.43 (m, 1H), 1.87 (m, 2H), 1.52 (d, J=6.5, 3H), 1.26 (m, 2H), 0.90 (t, J=7.5, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](Cl)=[N:6][NH:7][C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH2:17][C:18]#[CH:19])[CH3:2].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:19]=[C:18]2[N:7]([N:6]=1)[C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH2:17]2)=[O:21])[CH3:2]
Reactant: C#CCCOc1ccc(Br)cc1NN=C(Cl)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Temperature: 120 °C
Yield: 85.1 %

Procedure:
A mixture of chloro-(5-bromo-2-but-3-ynyloxyphenylhydrazono)acetic acid ethyl ester (3.28 g, 8.78 mmol) and triethylamine (12.2 mL, 88 mmol) in dry toluene (900 mL) was heated at gentle reflux (120° C.) for 54 h. The cooled mixture was filtered, the residue washed with ethyl acetate and the filtrate concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 10 to 15% ethyl acetate in cyclohexane) to give 9-Bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid ethyl ester as a yellow solid (2.52 g, 85%). LCMS: RT=4.52 min, M+H+=337/339, [M+Na]+=359/361.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CI.[C:21](=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([CH3:21])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCNC2
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCc2c(sc(N)c2C(=O)c2ccccc2)C1
Temperature: 65 °C
Yield: 77 %

Procedure:
2-Amino-3-benzoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2 mmol), as prepared in Example 8, and methyl iodide (3 mmol) were dissolved in dry dimethyformamide (20 mL). Finely ground anhydrous potassium carbonate (1.9 g) and sodium iodide (0.2 g) were added to the solution and the resulting mixture was warmed to 65° C. overnight under nitrogen. After this period (TLC control), the reaction mixture was cooled, diluted with water, extracted with diethyl ether (3×50 mL), and dried on sodium sulfate. The crude product was isolated and then purified by column chromatography eluting with ethyl acetate and petroleum ether solutions to give the desired compound. (m.p. 164-165° C.; 77% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])[CH2:13][CH2:12]1)=[O:10].Cl[CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>>[O:30]=[S:29]1(=[O:31])[CH2:28][CH2:27][CH2:26][N:1]1[C:2]1[CH:7]=[C:6]([N:8]2[CH2:26][CH2:27][CH2:28][S:29]2(=[O:31])=[O:30])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])[CH2:13][CH2:12]1)=[O:10]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3N)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1

Procedure:
Using (2,4-diaminophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (847 mg) described in Preparation Example 150 and 3-chloropropane-1-sulfonyl chloride (0.85 mL) and by the reaction and treatment in the same manner as in Example 78, the title compound (843 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[OH:10][C:11]1[C:18]([CH3:19])=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:10][C:11]1[C:12]([CH3:20])=[CH:13][C:14]([CH:15]=[O:16])=[CH:17][C:18]=1[CH3:19]
Reactant: Fc1ccccc1CBr
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OCc1ccccc1F

Procedure:
0.5 M Solution of 1-bromomethyl-2-fluoro-benzene (1.50 g, 8.0 mmol) in DMF was added dropwise to a suspension containing 1.09 g of 4-hydroxy-3,5-dimethyl-benzaldehyde (7.3 mmol), 1.51 g of K2CO3 (11 mmol) and 120 mg of KI (0.73 mmol) in 100 ml DMF. The reaction followed the same procedure described in Example 3. The residue was purified on silica gel, obtaining a quantitative recovery of the title compound. (1.88 g)
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.Cl>O.CS(C)=O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]3[S:11][C:10](=[O:12])[NH:9][C:8]3=[O:13])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCc3ccc(Cl)cc3)cc2)S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
To 12 ml of dimethylsulfoxide is dissolved 1.12 g of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione, and 480 mg of 50% sodium hydride in oil is added to the solution. The mixture is stirred at room temperature for 15 minutes, to which is added 0.81 g of 4-chlorobenzyl chloride. The whole mixture is stirred at 50° C. for 4 hours. Water is added to the mixture and the mixture is acidified with 2 N--hydrochloric acid. The mixture is subjected to extraction with ether. The extract is washed with water and dried. Ether is distilled off to give an oily substance. The oily substance is subjected to column chromatography on 30 g silica gel, elution being carried out with cyclohexane-ethyl acetate (2:1). By the above procedure there was obtained 425 mg of 5-[4-(4-chlorobenzyloxy)benzyl]thiazolidine-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1ccc(F)c(F)c1
Agent: N
Product: Fc1ccc(-c2cc(-c3cncc(Cl)c3)no2)cc1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 4-ethynyl-1,2-difluorobenzene (Apollo, 41 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.63-7.81 (m, 2H), 7.82 (s, 1H), 8.02 (ddd, J=11.4, 7.6, 2.0 Hz, 1H), 8.41 (t, J=2.0 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 9.06 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+, 293 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][CH:4]([Cl:12])[C:5]([O:7][CH2:8][C:9](Cl)=[O:10])=[O:6].O>C(Cl)Cl>[CH3:1][NH:2][C:9](=[O:10])[CH2:8][O:7][C:5](=[O:6])[CH:4]([Cl:12])[Cl:3]
Reactant: CN
Reactant: O=C(Cl)COC(=O)C(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CNC(=O)COC(=O)C(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution was made by combining while cooling in an ice bath, 2.33 g (0.03 mole) of a 40% aqueous solution of methylamine and 100 ml of methylene chloride. A second solution containing 3.08 g (0.015 mole) dichloroacetoxyacetyl chloride dissolved in 5 ml methylene chloride was slowly added to the first solution. The mixture was stirred in the ice bath for one half hour. After remaining at room temperature for one hour, it was refluxed for ten minutes and cooled again. The reaction product was water washed twice and dried over magnesium sulfate. It was decolorized with a decolorizing agent and charcoal. The solvent was removed by reduced pressure evaporation and oil pumped. A semi-solid consisting of 1.5 g (50% yield) of N-methyl dichloroacetoxyacetamide was obtained. The structure was confirmed by infrared spectraphotometric analysis (IR).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1)=[O:4].[C:11]12([C:21](O)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2>>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8](=[N:10][C:21]([C:11]23[CH2:20][CH:15]4[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]4)[CH2:18]2)[CH2:12]3)=[O:22])[NH:7][CH:6]=1)=[O:4]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1cnc(N)s1
Product: COC(=O)c1c[nH]c(=NC(=O)C23CC4CC(CC(C4)C2)C3)s1
Yield: 357.5 %

Procedure:
2-Amino-thiazole-5-carboxylic acid methyl ester (1.58 g, 10.0 mmole) and 1-adamantanecarboxylic acid (1.98 g, 1.1 mmol) were processed as described in Example 3B to afford 1.26 g (49%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.62-1.79 (m, 6H) 1.86 (d, J=3 Hz, 6H) 1.99 (s, 3H) 3.26 (s, 3H) 3.64-3.81 (s, 3H) 8.30 (s, 1H); MS (DCI/NH3) m/z 321 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]2[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5][C:4]=2[C:3]=1B(O)O.Br[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(O)C.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: COc1nc2cc(Cl)c(Cl)c(B(O)O)c2nc1OC
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1nc2cc(Cl)c(Cl)c(-c3ccncc3)c2nc1OC
Yield: 37.8 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxyquinoxaline-5-boronic acid (0.27 g, 0.89 mmol), 4-bromopyridine (0.14 g, 0.89 mmol) and tetrakis(triphenylphosphine)palladium(O) (0.031 g, 0.026 mmol) in a mixture of 2M aqueous sodium carbonate solution (1 mL), ethanol (0.5 mL) and toluene (10 mL) was heated under nitrogen under reflux for 24 hours. After being cooled the mixture was partitioned between water (20 mL) and dichloromethane (20 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give a brown solid which was purified by flash chromatography on silica gel, eluting with hexane:ethyl acetate (3:1, by volume) to afford the title compound (0.113 g, 38%) as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[Na+].Br[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1=[N:16][N:17]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]=[C:13]1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1c2c(nc3ccccc13)CCc1cn(CCc3ccccc3)nc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (4.36 g) in dry DMF (130 ml) was slowly added 922 mg of NaH (60%). The reaction was stirred at room temperature for one hour, then (2-bromoethyl)benzene (3.23 ml) was added and the reaction stirred for four hours. An additional 230 mg of NaH (60%) was added, and then the reaction was stirred for a half hour, after which 0.8 ml of (2-bromoethyl)benzene was added and the reaction was stirred at room temperature overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[Cl:12].[CH3:13][N:14]([CH3:16])[NH2:15]>>[CH3:13][N:14]([CH3:16])[NH:15][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([Cl:1])=[C:3]([Cl:12])[CH:4]=1
Reactant: CN(C)N
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Product: CN(C)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]

Procedure:
Reaction of 1,2,4-trichloro-5-nitrobenzene with 1,1-dimethylhydrazine as described in Example I gave the desired product, m.p. 138°-143° C.
Reaction SMILES: F[C:2]1C=CC(N(C2C=CC(OC3C=CN=CC=3)=CC=2)C(=O)CC(N)=O)=CC=1.Cl[C:29]1[N:34]=[CH:33]N=[C:31]([O:35][C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:43]([NH:45][C:46](=[O:55])[CH2:47][C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=3)=[S:44])=[CH:38][C:37]=2F)[CH:30]=1>>[F:54][C:51]1[CH:52]=[CH:53][C:48]([CH2:47][C:46]([NH:45][C:43]([NH:42][C:39]2[CH:40]=[CH:41][C:36]([O:35][C:31]3[CH:2]=[CH:33][N:34]=[CH:29][CH:30]=3)=[CH:37][CH:38]=2)=[S:44])=[O:55])=[CH:49][CH:50]=1
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(Cl)ncn2)c(F)c1
Reactant: NC(=O)CC(=O)N(c1ccc(F)cc1)c1ccc(Oc2ccncc2)cc1
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccncc2)cc1
Yield: 10 %

Procedure:
The title compound was prepared using 4-(4-aminophenoxy)pyridine (Compound A of Example 1) and a similar procedure outlined for the preparation of Compound C of Example 2. Yield: 10%. 1H NMR (CDCl3) δ 12.3 (s, 1H), 8.63 (s, 1H), 8.49, (d, 2H, J=6.2 Hz), 7.71 (d, 2H, J=8.9 Hz), 7.31-7.27 (m, 2H), 7.14-7.09 (m, 4H), 6.90 (dd, 2H, J=4.8, 1.4 Hz), 3.73 (s, 2H); MS(ESI+) m/z 382.2 (M+H)+.