Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36][CH2:37][CH3:38])=[O:35])CC[CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[CH3:41]C1(C)[C@@H]2[C@H]1C(=O)OC2=O>>[Br:1][C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:30]2([CH3:41])[CH3:31])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Reactant: CC1(C)[C@@H]2C(=O)OC(=O)[C@@H]21
Product: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)C1(C)C

Procedure:
The title compound was prepared using analogous conditions to those described for ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate using racemic cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione. MS (ESI): mass calcd. for C32H30BrN3O3, 583.15; m/z found, 584.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[NH2:19])=[CH:12][CH:11]=2)=[CH:5][C:4]=1[O:23][CH3:24])#[N:2].C(N(CC)CC)C.Cl[C:33]([O:36]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl>C(Cl)Cl>[CH3:21][C:18]1([CH3:20])[C:17](=[O:22])[N:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([O:23][CH3:24])[CH:5]=3)=[CH:15][CH:14]=2)[C:33](=[O:36])[NH:19]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccc(NC(=O)C(C)(C)N)cc2)ccc1C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccc(N3C(=O)NC(C)(C)C3=O)cc2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
N1-(4-{[4-cyano-3-(methyloxy)phenyl]oxy}phenyl)-2-methylalaninamide (Intermediate 191, 77.0 mg) was dissolved in DCM (10 mL). Triethylamine (0.218 mL, 1.57 mmol) was added and the obtained mixture was cooled at 0° C. Bis(trichloromethyl)carbonate (68.1 mg, 0.22 mmol) was dissolved in 5 mL of DCM and the obtained solution was added dropwise to the reaction mixture. The reaction mixture was stirred at 0° C. After 15 min, the reaction mixture was evaporated in vacuo to obtain the crude product that was purified by silica gel chromatography (from 100:0 to 50:50 Cyclohexane/EtOAc in 10 CV; then 50:50 Cyclohexane/EtOAc for 10 CV) to obtain 65.1 mg of the title compound as a white solid
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH:3]=O.O.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]=1[OH:23])([CH3:12])([CH3:11])[CH3:10].CNC>CO>[C:19]([C:15]1[CH:16]=[C:17]([CH2:3][C:2]([CH3:1])([CH3:7])[CH:5]=[O:6])[CH:18]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:14]=1[OH:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C=O)CO
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: CNC
Solvent: O
Solvent: CO
Product: CC(C)(C=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 92 %

Procedure:
125 g (1 mol) of 80% strength aqueous 2,2-dimethyl-3-hydroxypropanal (crude mixture from the synthesis, reduced to a water content of 20% by distillation), 185 g (0.9 mol) of 2,6-di-t-butylphenol, 12 g (0.11 mol) of 40% strength aqueous dimethylamine and 700 g of methanol are reacted in a stirred autoclave at 180° C. and under the autogenous pressure of 20-30 bar for 10 h. Workup of the reaction mixture by distillation yields 238 g (92%) of 3-(3,5-di-t-butyl-4-hydroxyphenyl)-2,2-dimethylpropanal (boiling point 126°-127° C.; melting point 75°-77° C.).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.[CH:19]1([C:22](N2C3C=CC=CC=3N=N2)=[O:23])[CH2:21][CH2:20]1.O>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH2:17][C:22]([CH:19]2[CH2:21][CH2:20]2)=[O:23])=[CH:12][CH:11]=1
Reactant: O=C(C1CC1)n1nnc2ccccc21
Reactant: CC(=O)c1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)C1CC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a −78C solution of LDA (generated from 8 ml of 2.5 M nBuLi and 2.1 ml of diisopropylamine) in THF (120 ml) was added dropwise, over 80 min, a solution a 4′-bromoacetophenone (2.98 g, 14.97 mmol) in THF (45 ml). The mixture continued to stir at −78C for 1 h, followed by addition of 1-(cyclopropylcarbonyl)-1H-1,2,3-benzotriazole (2.56 g, 13.65 mmol) in THF (45 ml). The mixture was warmed to rt overnight. The yellow mixture was poured into water and extracted with Et2O (2×300 ml). The combined organic phases were washed with water, dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (CH2Cl2/hexanes, 10:90 to 30:70) to yield 1-(4-bromophenyl)-3-cyclopropyl-1,3-propanedione as an orange solid (1.60 g, 44%).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1.[Li]C(CC)C.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>C1COCC1.O>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[O:9]2)=[CH:4][C:3]=1[B:27]([OH:32])[OH:28]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCC1CCC(C2CCc3ccc(F)c(F)c3O2)CC1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCC(C2CCc3cc(B(O)O)c(F)c(F)c3O2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7,8-difluoro-2-(4-propylcyclohexyl)chroman (3.82 g) obtained in Example 2 was dissolved in THF (38 mL). To the solution was added dropwise sec-BuLi (0.99 M solution, 15.5 mL) at −70 to −75° C. and stirred after the end of dropping at the same temperature for additional 1 hour. To the solution was added dropwise a THF solution (5 mL) of triisopropyl borate (2.15 g) at −70 to −75° C. After the end of dropping, it was stirred at the same temperature for additional 3 hours. Then temperature thereof was gradually raised to room temperature. The solution was left stirring overnight. While cooling on ice, to the reaction mixture was added 2 M hydrochloric acid and stirred at room temperature for additional 2 hours. The reaction mixture was poured to water, which was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated residue was further washed with heptane to obtain crude 7,8-difluoro-6-dihydroxyboryl-2-(4-propylcyclohexyl)chroman. The product was used in a second step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][O:42][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Oc1ccccc1F
Reactant: OCC1CCN(Cc2ccccc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(OCC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 24 %

Procedure:
A mixture of 4 fluorophenol (6.01 g, 54 mmol), triphenylphosphine (6.87 g, 64 mmol), and 1-benzyl-4-hydroxymethylpiperidine (11.0 g, 54 mmol) in benzene (300 mL) was stirred at 10°-15° C. Diethyl azodicarboxylate (11.2 g, 10.1 mL, 64 mmol) was added dropwise. The reaction mixture was heated to reflux temperature and stirred for 24 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; the organic solution was washed with water three times, a 2N sodium hydroxide solution three times, dried over magnesium sulfate and filtered. Solvent was removed in vacuo to give crude product. Column chromatography (ethyl acetate:hexanes::1:1) gave, after removal of solvent, a pale yellow oil (3.88 g, 24% yield): 7.40-7.25 (m, 5H), 7.0-6.7 (m, 4H), 3.75 (d, 2H, J=4), 3.50 (s, 2H), 2.9 (br d, 2H, J=4), 2.1-1.25 (m, 7H); IR (neat): 3084(m), 3062(m), 2921(s), 2802(s), 2758(s), 1601(m), 1505(s), 1467(s), 1454(s), 1394(s); HR-MS: Calcd. for C19H22FNO: 299.1684; Found: 299.1685.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:16])=[C:10]2[O:14][CH:13](O)[CH2:12][C:11]=12)=[O:5])[CH3:2].C(OC(C1C=CC(F)=C2OC(OC)CC=12)=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:16])=[C:10]2[O:14][CH:13]=[CH:12][C:11]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(F)c2c1CC(O)O2
Agent: CCOC(=O)c1ccc(F)c2c1CC(OC)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(F)c2occc12
Reaction time: 5 h

Procedure:
A mixture of 7-fluoro-2-hydroxy-2,3-dihydro-benzofuran-4-carboxylic acid ethyl ester and 7-fluoro-2-methoxy-2,3-dihydro-benzofuran-4-carboxylic acid ethyl ester (1.15 g, see above) in toluene (6.0 mL) is added dropwise to a solution of PTSA (0.25 mmol) in toluene (5.0 mL) which is heated to reflux. Heating is continued for 5 h, an additional portion of PTSA (0.25 mmol) is added and the mixture is again heated to reflux for 7 h. The solvents are removed in vacuo and the residue is purified by FC (gradient: heptane to heptane/EtOAc 95/5) to give the desired product.
Reaction SMILES: [F-:1].[K+].[F:3][CH:4]([F:25])[C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7](Cl)[C:6]=1[C:21]([O:23][CH3:24])=[O:22].O>CC#N.C1OCCOCCOCCOCCOCCOC1>[F:3][CH:4]([F:25])[C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]([F:1])[C:6]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: [F-]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1F
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
The reagent was prepared by dissolving 0.37 g (0.001 mol) of 18-crown-6 in 30 ml of dry CH3CN (distilled over CaH2) and then adding 3.25 g (0.056 mol) of dry KF (dried in an oven at 50° C./67 Pa). After the heterogeneous system was mechanically stirred for 30 minutes, 10 g (0.028 mol) of product of Example 103 was added and the resulting mixture was refluxed for 6 days. The reaction mixture was poured into H2O, extracted with diethyl ether (2X), dried (MgSO4) and solvent removed in acuo affording 9.45 g of a brown oil. The crude product was purified by HPLC using 1ethyl acetate/cyclohexane as eluting solvent affording 6.72 g (70) of product as a white solid; mp 40-41° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
To a solution of 6-(trifluoromethyl)-1H-indole (250 mg, 1.350 mmol) in dry DMF (3 ml), sodium hydride (60% w/w dispersion in mineral oil, 64.8 mg, 1.620 mmol) was added at room temperature. After 10 minutes, methyl 2-bromoacetate (150 μl, 1.620 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude was purified by flash chromatography on silica gel column (hexane/ethyl acetate 90/10) to afford methyl 2-(6-(trifluoromethyl)-1H-indol-1-yl)acetate (120 mg, 0.467 mmol, 34.6% yield). MS/ESI+ 258.1 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29][CH2:30][OH:31].CCN(CC)CC.[S:39](Cl)([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15]([NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:29][CH2:30][O:31][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40]
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CC(CCO)c1cccc(Br)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2CC3(CCN(C(=O)NC4C5CC6CC(C5)CC4C6)CC3)c3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of (±)-7-bromo-N-(2-adamantyl)-3-(2-hydroxyethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (40 mg, 0.082 mmol) and Et3N (9.9 mg, 0.098 mmol) in dry CH2Cl2(5 mL) was added TsCl (15.6 mg, 0.082 mmol) at 0° C. The mixture was stirred overnight at rt. The mixture was concentrated to give the crude product, which was purified by preparative TLC to give (±)-7-bromo-N-(2-adamantyl)-3-(2-(p-toluenesulfonyloxy)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (50 mg, crude).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][CH2:23][CH2:24][N:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29].O>CS(C)=O>[CH2:30]([N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH2:31][CH2:32][CH3:33]
Reactant: Oc1ccc(Sc2ccncc2)cc1
Reactant: CCCCN(CCCC)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCN(CCCC)CCCOc1ccc(Sc2ccncc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 0.014 mol of 4-(4-hydroxy-phenylthio) pyridine and 3 g of finely crushed anhydrous potassium carbonate in 50 ml of dimethylsulphoxide was placed under stirring for 30 min. To this medium 0.016 mol of 1-chloro-3-(di-n-butylamino) propane was added and the stirring was maintained at room-temperature for 24 hours. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was washed with water, dried no sodium sulphate and filtered. After the solvent was evaporated off, an oil was provided which was purified by chromatography on a silica column (eluent: methanol). The required compound in free base form so obtained was then transformed into an oxalate by adding an ethereal solution of oxalic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[F:9][C:10]([F:35])([F:34])[C:11]1[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[N:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:27]([C:24]1[N:25]=[N:26][C:21]([N:18]2[CH2:17][CH2:16][N:15]([C:13](=[O:14])[C:12]3[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=3[C:10]([F:35])([F:34])[F:9])[CH2:20][CH2:19]2)=[CH:22][CH:23]=1)=[O:28]
Reactant: NCCc1cccs1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(NCCc1cccs1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 24, making variations only as required to use 2-thiophen-2-yl-ethylamine in place of 2,2-(dimethylcyclopropyl)methylamine to react with 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid, the title compound was obtained as a white powder (40% yield). 1H NMR (300 MHz, CDCl3) δ 8.01, 7.73, 7.58, 7.34, 7.12, 6.98, 6.90, 6.84, 4.03, 3.89-3.55, 3.33, 3.12. 13C NMR (75 MHz, CDCl3) δ 167.6, 163.1, 160.0, 145.2, 141.1, 134.2, 132.4, 129.5, 127.2, 127.0, 126.9, 125.3, 123.9, 121.8, 112.5, 46.4, 44.6, 44.4, 41.3, 40.9, 30.9. MS (ES+) m/z 490.0 (MeI).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[C:13](Cl)=[O:14].[NH2:16][C:17]1[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19][O:20][C:21]=1[CH3:22]>N1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[C:13]([NH:16][C:17]1[C:18]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:19][O:20][C:21]=1[CH3:22])=[O:14]
Reactant: Cc1cc(C(=O)Cl)c2cc(F)ccc2n1
Reactant: Cc1onc(-c2ccccc2)c1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(C(=O)Nc2c(-c3ccccc3)noc2C)c2cc(F)ccc2n1
Temperature: 70 °C
Yield: 61.9 %

Procedure:
6-Fluoro-2-methylquinoline-4-carbonyl chloride (100 mg) and 4-amino-5-methyl-3-phenylisoxazole (200 mg) were dissolved in dichlorormethane (10 mL) and pyridine (0.3 mL). The reaction solution was heated at 70° C. overnight and then diluted with ethyl acetate (60 mL). The organic solution was washed with water (60 mL), dried, evaporated and purified by flash column chromatography (EtOAc/hexanes=1/1) to give 6-fluoro-2-methyl-N-(5-methyl-3-phenylisoxazol-4-yl)-4-quinolinecarboxamide (100 mg) as a white solid. 1H NMR (CDCl3): δ 2.58 (s, 3H), 2.76 (s, 3H), 7.14 (s, 1H), 7.44 (s, 1H), 7.49 (m, 4H), 7.67 (m, 2H), 7.82 (dd, J=2.7 and 9.9 Hz, 1H), 8.07 (dd, J=5.7 and 9.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ-111.63; LCMS: ret. time: 21.32 min.; purity: 99.44%; MS (m/e): 362.06 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.CS[C:20]1[N:21]=[C:22]([OH:29])[C:23]2[S:28][CH2:27][CH2:26][C:24]=2[N:25]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:20]3[N:21]=[C:22]([OH:29])[C:23]4[S:28][CH2:27][CH2:26][C:24]=4[N:25]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CSc1nc(O)c2c(n1)CCS2
Solvent: CC(=O)O
Solvent: O
Product: Oc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2
Temperature: 180 °C
Yield: 92.8 %

Procedure:
20.45 g 1-(4-chloro-phenyl)-piperazine are placed in 5.95 ml (104 mmol) glacial acetic acid and heated to 180° C. 8.01 g 2-methylsulphanyl-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ol are added, the non-stirrable reaction mixture is heated for 2.5 hours to 180° C. After cooling, water is added, the precipitate is suction filtered and dried in the air. The substance is treated with ethanol under ultrasound, suction filtered and dried. 12.95 g of the product are obtained as a powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:12](O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[CH:12][NH:9][C:4]=2[C:3]=1[O:10][CH3:11]
Reactant: COc1c(Br)ccc(N)c1N
Reactant: O=CO
Product: COc1c(Br)ccc2nc[nH]c12
Temperature: 100 °C

Procedure:
A 1 L four-necked round bottom flask fitted with a magnetic stirrer was dried and cooled under a stream of nitrogen then charged with 4-bromo-3-methoxy-benzene-1,2-diamine (61 g, 0.28 mol, 1.0 equiv.) in formic acid (200 mL). The reaction mixture was heated at 100° C. for 2 h, cooled and quenched with ice water (1 L). The reaction mixture was basified with 10% NaOH solution and extracted with ethyl acetate (2×1000 mL). The separated organic layers were combined, washed with brine solution (750 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (30-50% EtOAc) to afford 6-bromo-7-methoxy-1H-benzoimidazole (36 g, crude) as a brown solid. 1H NMR (300 MHz, DMSO-d6): δ 4.26 (br, 3H), 7.16 (s, 1H), 7.29-7.32 (d, 1H), 8.19 (s, 1H), 12.67 (br, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH3:10][N:11]1[C:15](=O)[CH2:14][CH2:13][CH2:12]1.FC1C=CC=CN=1>CCOC(C)=O>[F:9][C:4]1[CH:3]=[C:2]([NH:1][C:12]2[CH:13]=[CH:14][CH:15]=[CH:10][N:11]=2)[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: CN1CCCC1=O
Reactant: Nc1ccc(O)c(F)c1
Agent: Fc1ccccn1
Solvent: CCOC(C)=O
Product: Oc1ccc(Nc2ccccn2)cc1F
Temperature: 120 °C
Reaction time: 9 h

Procedure:
To 4-amino-2-fluorophenol (0.983 g, 7.73 mmol) was added NMP (3 mL) and 2-fluoropyridine (0.670 mL, 7.78 mmol). The reaction mixture was heated to 120° C. for 12.5 h and the temperature was increased to 150° C. After 9 h, the reaction mixture was diluted with EtOAc and the organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (10% to 70% EtOAc in hexanes) gave 2-fluoro-4-(pyridin-2-ylamino)phenol as a pale yellow oil. MS (ESI, pos. ion) m/z: 205.2 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Cl)=[CH:26][C:25]=2[O:24]1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C:27]3[CH:28]=[CH:29][C:30]4[O:31][CH2:23][O:24][C:25]=4[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: ClCCCCCOCc1ccc2c(c1)OCO2
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCc2ccc3c(c2)OCO3)CC1
Yield: 39.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.72 g) as starting compound and 5-((3,4-methylenedioxyphenyl)methoxy)pentyl chloride (0.5 g) were reacted and treated in the same manner as in Example 168 to give 0.4 g of 4-amino-5-chloro-N-((1-(5-((3,4-methylenedioxyphenyl)methoxy)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[NH:11][CH:10]=[C:9]([C:19](O)=[O:20])[C:8]2=[O:22])(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[NH:11][CH:10]=[C:9]([C:19]([Cl:25])=[O:20])[C:8]2=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2[nH]cc(C(=O)O)c(=O)c2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1cc2[nH]cc(C(=O)Cl)c(=O)c2cc1OC(C)=O

Procedure:
6,7-Diacetoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (70 mg) was heated under reflux for 2 hours in thionyl chloride (2 mL), and then the solvent was evaporated. To the residue was added benzene (30 mL). Benzene was evaporated and the residue was vacuum dried to give 6,7-diacetoxy-1,4-dihydro-4-oxoquinoline-3-carbonyl chloride.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[CH2:20]([OH:24])[CH2:21][C:22]#[CH:23]>[Pd](Cl)Cl.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.C(OCC)(=O)C>[OH:24][CH2:20][CH2:21][C:22]#[C:23][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1
Reactant: C#CCCO
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CCCO)cc1
Reaction time: 2.5 h
Yield: 100.8 %

Procedure:
To 50 ml of triethylamine were added 5.52 g of ethyl p-iodobenzoate, 1.54 g of 3-butyn-1-ol, 41 mg of cuprous iodide and 77 mg of bis(triphenylphosphine) palladium chloride, and the mixture was stirred for 2.5 hours under nitrogen flow. After adding 50 ml of ethyl acetate, the mixture was filtered to remove the precipitate, washed three times with 30 ml of water, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain 4.4 g of ethyl p-(4-hydroxy-1-butynyl)benzoate as a colorless oil.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[CH2:15](Br)[C:16]#[CH:17]>>[CH2:17]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)[C:16]#[CH:15]
Reactant: C#CCBr
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Product: C#CCn1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano[3,2-b]indol-4(5H)-one is alkylated with propargyl bromide to give 5.0 g of product, mp 144° C after recrystallization from methylene chloride-ether.