Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[N:34]=[C:35]=[O:36]>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[NH:34][C:35]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)[CH:3]=1)=[O:36]
Reactant: Nc1cccc(C2CN=C3c4ccccc4NC(=O)N3C2)c1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C2CN=C3c4ccccc4NC(=O)N3C2)c1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.4 %

Procedure:
To a solution of 3-(3-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (12.2 mg, 0.042 mmol) in 0.9 mL THF was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.0066 mL, 0.046 mmol) and the reaction stirred at rt. After 15 min, the reaction was briefly warmed to approximately 50° C. and then allowed to cool to rt. At 40 min the reaction was quenched with 1 mL MeOH, evaporated, and chromatographed eluting with 2% to 5% MeOH/CHCl3 gradient. The resulting solid was triturated with 40% EtOAc/hexane to give the title compound as a light tan solid (9.9 mg, 48%). 1H NMR (Acetone-d6) δ: 9.54 (br. s, 1H), 8.77-8.81 (m, 1H), 8.66 (s, 1H), 8.34 (d, J=2.9 Hz, 1H), 8.09-8.13 (m, 1H), 7.29-7.54 (m, 6H), 7.03-7.12 (m, 3H), 4.41 (ddd, J=12.9, 4.4, 2.9 Hz, 1H), 3.81-3.90 (m, 1H), 3.56-3.70 (m, 2H), 3.02-3.14 (m, 1H).
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:22])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2].[BH4-].[Na+].[C:25](O)(=O)[CH3:26]>>[CH2:1]([N:3]([CH2:25][CH3:26])[CH:4]([CH3:22])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3cc(C)ccc23)C1
Agent: [BH4-]
Agent: [Na+]
Product: CCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(C)ccc23)C1

Procedure:
Prepared by the method described for Example 59 from 3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.010 moles), glacial acetic acid (20 ml), and sodium borohydride (2.3 g, 0.061 moles). Recrystallization from ethanol gave the product (2.0 g) as the dihydrochloride, mp 254° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C1(C)C=CC(S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:23][C:22]([F:25])([F:24])[CH2:21][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCC(F)(F)F
Temperature: 140 °C
Yield: 86.7 %

Procedure:
A mixture of 2-nitrophenol (18.8 g, 135 mmol), 2,2,2-trifluoroethyl para-toluenesulfonate (34.36 g, 135 mmol), potassium carbonate (18.7 g, 135 mmol) and DMF (200 mL) was heated 16 hours at 140° C. The reaction mixture then was cooled, diluted with water (600 mL) and extracted with ether/hexanes (1:1; 3×400 mL). The combined extracts were washed with saturated sodium bicarbonate (3×100 mL) and brine, dried (Na2SO4), filtered and concentrated to give 1-(2,2,2-trifluoroethoxy)-2-nitrobenzene (27 g, 117 mmol) as an oil.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C.Cl>CCCCCC.C1COCC1>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[B:20]([OH:23])[OH:21]
Reactant: COB(OC)OC
Reactant: Brc1ccc2oc3ccccc3c2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2oc3ccccc3c2c1
Temperature: -40 °C
Yield: 71.7 %

Procedure:
Under an argon atmosphere, 400 mL of anhydrous THF were added to 24.7 g (100 mmol) of 2-bromodibenzofuran, and then 63 mL (100 mmol) of a solution of n-butyllithium in hexane having a concentration of 1.6 M were added to the mixture during the stirring of the mixture at −40° C. The reaction solution was stirred for 1 hour while being heated to 0° C. The reaction solution was cooled to −78° C. again, and then a solution of 26.0 g (250 mmol) of trimethyl borate in 50 mL of dry THF was dropped to the solution. The reaction solution was stirred at room temperature for 5 hours. 200 milliliters of 1N hydrochloric acid were added to the solution, and then the mixture was stirred for 1 hour. After that, the aqueous layer was removed. The organic layer was dried with magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resultant solid was washed with toluene. Thus, 15.2 g of dibenzofuran-2-boronic acid were obtained (in 72% yield). The resultant was identified as Intermediate 6 by FD-MS analysis because a main peak having a ratio m/z of 212 was obtained with respect to C12H9BO3=212.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C([O-])([O-])=O.[K+].[K+].[OH:12][CH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.CCOCC>CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][O:20][C:16]1[CH:15]=[C:14]([CH2:13][OH:12])[CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCBr
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OCc1cccc(OCCCBr)c1
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
1,3-dibromopropane (23 mL, 0.22 mol) is gradually added to a suspension of K2CO3 (3.2 g, 23 mmol) and 3-(hydroxymethyl)phenol (5 g, 40.3 mmol) in dimethylformamide (DMF) (30 mL) stirred beforehand for 5 min at 65° C. The reaction medium is maintained under stirring for 45 min at the same temperature. After cooling to room temperature (RT), Et2O (150 mL) is added and the organic phase is extracted 4 times with a saturated NaCl aqueous solution. The organic phase is dried on Na2SO4. After evaporation of the solvent under reduced pressure, a viscous colorless oil is obtained (6.7 g, 68%) which gradually crystallizes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[Mg].[CH3:11][O:12][C:13]([C:15]12[CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:21][C:20](=[O:30])[CH:19]1[CH2:18][N:17]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:16]2)=[O:14].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH3:11][O:12][C:13]([C:15]12[CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:21][C:20]([OH:30])([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=3)[CH:19]1[CH2:18][N:17]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:16]2)=[O:14]
Reactant: Cc1ccc(Br)cc1C
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C)c(C)c1)CCC2c1ccccc1
Temperature: -7 °C
Reaction time: 4 h

Procedure:
2.3 cm3 of 4-bromo-ortho-xylene and 0.42 g of magnesium turnings in a mixture of 20 cm3 of diethyl ether and 20 cm3 of tetrahydrofuran were heated at reflux for one hour. After cooling to a temperature in the region of -7° C., a solution of 3.11 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 20 cm3 of diethyl ether was added over 25 minutes. The reaction mixture was stirred for four hours at a temperature in the region of 25° C. and then hydrolysed by 50 cm3 of a saturated aqueous ammonium chloride solution. The aqueous phase was separated by settling and extracted with 25 cm3 of ethyl acetate. The organic phases were combined, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture, 1.995 g of methyl(3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(3,4-dimethylphenyl)-4-phenyl-octahydroisoindole-3a-carboxylate were obtained, the characteristic of which compound, used as it was in the following stage, was as follows:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[N:8]=2)[CH:6]=1.C[Sn](C)(C)[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:4]2[N:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C@H:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:15])[N:8]=3)[CH:6]=[C:2]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:3]=2)=[CH:23][CH:24]=1
Reactant: C[C@H](Nc1nccc(-n2cc(Br)nc2-c2ccc(F)cc2)n1)c1ccccc1
Reactant: C[Sn](C)(C)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](Nc1nccc(-n2cc(-c3ccncc3)nc2-c2ccc(F)cc2)n1)c1ccccc1
Yield: 78.4 %

Procedure:
4-Bromo-2-(4-fluorophenyl)-1-(2-[1-(S)-phenylethyl]amino-4-pyrimidyl)imidazole (1.0 g; 2.28 mmol), 4-trimethylstannylpyridine (660 mg; 2.74 mmol) and PdCl2(PPh3)2 (160 mg; 0.228 mmol) are dissolved in xylenes (23 ml) and refluxed for 4 h. The reaction mixture is poured on saturated Na2CO3 solution and extracted with ethyl acetate three times. The combined organic phases were dried over Na2SO4, filtered, evaporated to dryness and purified via SiO2 chromatography (TBME/MeOH/NH3conc 99/9/0.1) to yield the title compound as a yellow foam (780 mg; 68%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]5[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Fc1ccc(Cc2cccc(Br)n2)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Cc5ccc(F)cc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(4-fluoro-benzyl)-pyridine.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30](O)=[O:31])[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[S:68][C:67]([C:69]#[N:70])=[CH:66][CH:65]=1>>[C:69]([C:67]1[S:68][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:70]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)s1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C#N)s2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Yield: 26.6 %

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.46 g, 0.79 mmol), was reacted with diisopropylethylamine (0.51 g, 4 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with 5-amino-thiophene-2-carbonitrile prepared in Example 186 (0.15 g, 1.2 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-thiophen-2-yl)-amide as a yellow solid (Yield 0.12 g, 26%).
Reaction SMILES: [OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C:20](=[CH:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:4]I.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C:20](=[CH:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:4][N:35]1[CH2:36][CH2:37][N:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)[CH2:33][CH2:34]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CN1CCN(c2ccccn2)CC1

Procedure:
17α-Hydroxy-21-iodopregna-4,9(11)-diene-3,20-dione (4.53 g) is stirred in acetonitrile (50 ml) with 1-(2-pyridinyl)piperazine (1.63 g) and potassium carbonate (1.34 g) at 60° for 5 hr and at 20°-25° for 17 hr. The reaction is partitioned between ether and aqueous sodium bicarbonate. The organic phase is washed with saline, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel with methanol/methylene chloride (4/96) to give the title compound.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:19])=O)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[NH2:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1Cc2ccccc2NC1=O
Temperature: 25 °C

Procedure:
(R)-3-t-butyloxycarbonylamino-3,4-dihydrocarbostyril (178 mg) was dissolved in 4 M hydrogen chloride in 1,4-dioxane solution (10 mL) at 0° C. After 1 h the solution was slowly warmed to room temperature over 2 h. The solvent was evaporated under vacuum, and the residue was twice taken up in toluene (10 mL) and evaporated under vacuum to provide (R)-3-amino-3,4-dihydrocarbostyril hydrochloride, a white solid (132 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[N:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccncc1)c1cnc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccncc1)c1cnc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=441.1, tR (minutes, Method F)=2.43
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH:11]1([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OC2CCCC2)c(O)c1
Temperature: 77.5 °C
Reaction time: 1 h

Procedure:
A suspension of 3,4-dihydroxy benzaldehyde (50.0 g, 0.3623 mol), cyclopentyl bromide (135 g, 0.9058 mol) and potassium carbonate (50.0 g, 0.3623 mol) in N,N-dimethylformamide (500 mL) was stirred at about 75-80° C. for about 1.0 hr. 4×12.5 g potassium carbonate was then added after every 1.0 hr. The reaction mixture was cooled to ambient temperature and filtered to remove inorganic materials. The residue obtained after concentration of the filtrate was diluted with toluene (250 mL), and extracted with 5-10% aqueous sodium hydroxide solution (6×50 mL). The combined aqueous layer was acidified to pH about 3 to 5 by 5N aqueous hydrochloric acid solution. The solid which separated was filtered, washed with water and dried to give 4-cyclopentyloxy-3-hydroxy benzaldehyde.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([CH3:12])[C:8]=2[CH:13]=1)N.O.Cl.[NH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>>[CH3:12][C:9]1[C:8]2=[C:13]3[C:4](=[CH:5][CH:6]=[C:7]2[S:11][CH:10]=1)[NH:2][C:19]1[CH2:20][CH2:21][NH:16][CH2:17][C:18]3=1
Reactant: O=C1CCNCC1
Reactant: Cc1csc2ccc(NN)cc12
Agent: Cl
Solvent: O
Product: Cc1csc2ccc3[nH]c4c(c3c12)CNCC4

Procedure:
The compound is formed analogously to that described in Example 2, from 5 g of 5-hydrazino-3-methylbenzothiophene hydrochloride and 5 g of 4-piperidone hydrochloride monohydrate. Melting point: 234° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:29]5[CH:28]=[CH:27][N:26]=[C:25]([F:24])[CH:30]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3ccnc(F)c3)ccc1-2
Yield: 30 %

Procedure:
Following the procedures for 128, 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-fluoropyridin-4-ylboronic acid to give 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-(2-fluoropyrid-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.60 g, 30%). MS (ESI(+): m/z 408.0 (M+H)
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[ClH:32]>C(O)(C)C.O1CCOCC1>[ClH:1].[ClH:32].[N:26]1([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:2]3[N:11]=[C:10]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:25][CH:24]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Clc1nc(Nc2ccccc2)c2ccccc2n1
Reactant: Nc1ccc(N2CCCCC2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: c1ccc(Nc2nc(Nc3ccc(N4CCCCC4)cc3)nc3ccccc23)cc1

Procedure:
A mixture of 2-chloro-4-phenylamino-quinazoline (0.18 g) and N-(4-aminophenyl)-piperidine (0.164 g) is heated for 3 min to produce a melt which is dissolved in isopropanol (4 ml). 4N HCl in dioxane (1 ml) is added. Recrystallization from ethanol and diethylether yields 2-[4-(piperidin-1-yl)-phenylamino]-4-phenylamino-quinazoline dihydrochloride, Rf (A1) 0.64, FAB-MS: (M+H)+ =396. m.p.: (decomposition).
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=1[C:36](=[O:38])[CH3:37]>CN(C)C=O.C(#N)C>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=4[C:36](=[O:38])[CH3:37])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1cc(C)ccc1OCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 95 °C
Yield: 46.2 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (2.87 g, 11.23 mmol), K2CO3 (2.5 g), 1-[2-(3-bromopropoxy)-5-methylphenyl]ethanone (3.74 g, 13.8 mmol) in dimethylformamide (10 ml) and acetonitrile (50 ml) was heated at 95° C. for 6 hours. At the end of the reaction, the solvent was concentrated and the mixture was extracted into dichloromethane (300 ml). The organic solution was washed with water and brine, dried over MgSO4, then concentrated down to a crude oil. The purification was done by flash chromatography over a silica gel column (SiO2, 60 g, eluted with 1% CH3OH:dichloromethane: 1.2 l; 3% CH3OH:dichloromethane: 600 ml). The material thus obtained was crystallized from a small volume of ether and hexane to provide 2.13 g (46%) of off-white 1-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-5-methylphenyl]ethanone, m.p.=92°-93° C.
Reaction SMILES: C(O[C:4]([NH:6][C:7]1[S:8][C:9]([CH3:18])=[C:10]([CH3:17])[C:11]=1[C:12]([O:14]CC)=O)=[O:5])C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(O)C.CN(C)C=O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:25]2[C:12](=[O:14])[C:11]3[C:10]([CH3:17])=[C:9]([CH3:18])[S:8][C:7]=3[NH:6][C:4]2=[O:5])=[CH:22][CH:21]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)Nc1sc(C)c(C)c1C(=O)OCC
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1sc2[nH]c(=O)n(Cc3ccc(Cl)cc3)c(=O)c2c1C
Yield: 68 %

Procedure:
A 1 g quantity of ethyl 2-ethoxycarbonylamino-4,5-dimethyl-3-thiophenecarboxylate and 1 g of 4-chlorobenzylamine were dissolved in a mixture of 3 ml of ethanol and 1 ml of N,N-dimethylformamide and the mixture was allowed to react in a sealed tube at 230° C. for 7 hours. The reaction mixture was concentrated and the residue was recrystallized from an acetone-ethanol-dimethylformamide mixture, giving 0.8 g of 3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione having a melting point of 291° to 292° C. in a yield of 68%.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.CN(C)CCN(C)C.[F:22][C:23]([F:43])([F:42])[C:24]1[CH:41]=[CH:40][C:27]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[O:29])=[CH:26][CH:25]=1>O.O1CCCC1>[CH3:6][O:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:28]([C:27]1[CH:40]=[CH:41][C:24]([C:23]([F:22])([F:42])[F:43])=[CH:25][CH:26]=1)([C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=1)[OH:29]
Reactant: COCn1ccnc1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
9.1 Ml. (0.015 mol) of n-butyl lithium solution (15% in n-hexane) were added dropwise with stirring at -60° C. and under a nitrogen atmosphere to a solution of 1.7 g (0.015 mol) of 1-(methoxymethyl)imidazole and 1.8 g (0.015 mol) of N,N,N',N'-tetramethylethylenediamine in 75 ml. of anhydrous tetrahydrofuran. Stirring was continued for 1.5 hours and then 2.9 g (0.0091 mol) of 4,4'-bis(trifluoromethyl)benzophenone in 50 ml. of anhydrous tetrahydrofuran were added dropwise under the same conditions, which made the colour change from light red into very dark brown. The reaction mixture was kept standing overnight at room temperature and it was then decomposed by addition of 40 ml. of water. The mixture was extracted with diethyl ether and the extract was concentrated. The residue was extracted with a mixture of 2 N hydrochloric acid and diethyl ether. The ethereal phase was dried over sodium sulphate and the ether was distilled off. The residue was boiled a few times with petroleum ether (boiling range 40°-60° C.) to remove ketone starting material and it was then once crystallised from a mixture of toluene and petroleum ether (boiling range 28°-40° C.) twice from petroleum ether (boiling range 100°-140° C.). 1-(Methoxymethyl)-α,α-bis(p-trifluoromethylphenyl)imidazole-2-methanol was obtained. Melting point 160°-161° C.