Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([NH:21]S(C(C)(C)C)=O)[CH2:18][CH2:19][OH:20].C(Cl)(=O)C>CO>[NH2:21][C:5]1([CH2:18][CH2:19][OH:20])[C:6]2[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([F:13])[C:7]=2[O:14][C:15]2[C:4]1=[CH:3][C:2]([Br:1])=[CH:17][CH:16]=2
Reactant: CC(C)(C)S(=O)NC1(CCO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Solvent: CC(=O)Cl
Solvent: CO
Product: NC1(CCO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of N-(7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide (5.8 g, 12.14 mmol) in dry MeOH (100 mL) at −20° C. was added a mixture of MeOH (80 mL)/acetylchloride (20 ml). The resulting reaction mixture was stirred at −20° C. for 30 min and then quenched with 10% aqueous solution of Na2CO3. DCM was added, the organic phase was separated and dried over Na2SO4. The solution concentrated under reduced pressure and the residue was purified by chromatography (0-50% EtOAc/hexanes) to afford 2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (4.0 g, 10.71 mmol, 88% yield) as a light yellow solid-foam.
Reaction SMILES: Cl.[N:2]1([C:7](=N)[NH2:8])C=CC=N1.CN(C=O)C.CCN(C(C)C)C(C)C.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>CCOCC>[OH:27][CH2:26][CH:25]([NH:24][C:7]([NH2:8])=[NH:2])[CH2:28][OH:29]
Reactant: NC(CO)CO
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N=C(N)NC(CO)CO
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 1H-pyrazole-1-carboximidamide hydrochloride (12 g, 82 mmol) and DMF (40 mL) at RT was added DIPEA (19 mL, 110 mmol) and 2-aminopropane-1,3-diol (5.0 g, 55 mmol) and the reaction was stirred overnight. Et2O (15 mL) was added and the reaction was stirred for 10 min before the reaction was allowed to settle and the ether layer was decanted. The remaining crude oil was concentrated under high vacuum to afford 7.3 g (100%) of 1-(1,3-dihydroxypropan-2-yl)guanidine (296) which contained residual DMF.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([O:18][CH3:19])[C:15]([OH:17])=[O:16])=[CH:9][C:8]=1[O:20][CH3:21])(C)(C)C.S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>>[CH2:29]([O:17][C:15](=[O:16])[CH:14]([O:18][CH3:19])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([OH:6])=[C:8]([O:20][CH3:21])[CH:9]=1)[CH3:30]
Reactant: CCO
Reactant: COc1cc(CC(OC)C(=O)O)ccc1O[Si](C)(C)C(C)(C)C
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 98 %

Procedure:
To a solution of 3-[4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (356 mg, 1.05 mmol) in absolute ethanol (8 mL) was added concentrated sulfuric acid (0.033 mL, 0.63 mmol). The reaction mixture was allowed to stir at room temperature for 17 hours. The solution was concentrated under vacuum, and water (10 mL) and solid NaHCO3 were added to neutralize the residue. The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated to produce 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid ethyl ester (260 mg, 98%). 1H-NMR (200.15 MHz, CDCl3): δ 6.83 (d, 1H, J=8.1 Hz), 6.76–6.69 (m, 2H), 4.19 (q, 2H, J=7.3 Hz), 3.97–3.90 (m, 1H), 3.87 (s, 3H), 3.36 (s, 3H), 2.96–2.92 (m, 2H), 1.25 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:7][CH:8]=1.C1CCN2C(=NCCC2)CC1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C=C1CCCCC1c1cccc(OC)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: CCOC(=O)CC1=C(c2cccc(OC)c2)CCCC1
Reaction time: 72 h
Yield: 93.3 %

Procedure:
To a solution of ethyl [2-(3-methoxyphenyl)-cyclohexylidene]acetate (1.5 g) in benzene (20 ml) was added 1,8-diazabicyclo[5.4.0]-7-undecene (1 ml) and the mixture was stirred for 3 days under reflux. And then the mixture was washed with water, 1N-hydrochloric acid, saturated sodium bicarbonate aqueous solution, and brine. The dried solvent was evaporated to give 1-(3-methoxyphenyl)-2-(ethoxycarbonylmethyl)cyclohexene (1.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([CH:1]=[CH:17][N:18]([CH3:20])[CH3:19])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=CN(C)C)c([N+](=O)[O-])c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
Methyl 4-methyl-3-nitrobenzoate (5 g, 25.6 mmol) was dissolved in DMF (25 mL, 5 vol) and to this was added N,N-dimethylformamide dimethylacetal (4.4 mL, 33.3 mmol). The mixture was allowed to stir at 140° C. for 3 h. The resulting deep red solution was allowed to cool and concentrated under vacuum. The residue was triturated with methanol and filtered. The filtrate was washed with methanol and dried on the sinter to yield 4-(2-dimethylamino-vinyl)-3-nitrobenzoic acid methyl ester (5.2 g, 80%). 1H NMR (300 MHz, DMSO), δ: 2.98 (6H, s, 2×CH3), 3.87 (3H, s, CH3), 5.58 (1H, m, CH), 7.72-7.83 (3H, m, ArH), 8.32 (1H, m, CH).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:31]>O1CCOCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH2:31])=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: N
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(N)=O)c3)C(C)(C)C2=O)cc1
Temperature: 130 °C

Procedure:
To a solution of 250 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 5 mL of dioxane are added 6.5 mL of a 7N solution of ammonia in methanol. The reaction mixture is heated by microwave at 130° C. for 3 hours and concentrated under reduced pressure. The residue is purified by HPLC (gradient: water/acetonitrile containing 0.1% formic acid) to give 54 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyridin-2-yl)urea, the characteristics of which are as follows:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([S-:20])[CH3:19].[Na+]>C(S)C>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([S:20][CH2:18][CH3:19])=[NH:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CCS
Product: CCSC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and sodium ethanethiolate in ethanethiol there is obtained ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-thiocarboximidate and therefrom with hydrochloric acid in alcohol there is obtained the hydrochloride, m.p. 220° C. (with decomposition);
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH:9](=O)[CH:10]([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[CH:10]([CH:12]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][O:1]1)([CH3:11])[CH3:9]
Reactant: CC(C)C[C@H](N)CO
Reactant: CC(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)C[C@H]1COC(C(C)C)N1
Yield: 100.2 %

Procedure:
A solution of (1S)-1-(hydroxymethyl)-3-methylbutylamine (Method B1b; 152 g, 1.3 mol) and isobutyraldehyde (118 mL, 1.3 mol, 1.0 equiv.) in toluene (1.5 L) was heated at the reflux temp. until the theoretical amount of water had been collected in a Dean-Stark trap (23.4 mL). The reaction mixture was concentrated by distillation to approximately 700 mL. The resulting mixture was cooled to room temp. and was concentrated under reduced pressure to a constant weight to give (4S)-2-isopropyl-4-isobutyl-1,3-oxazolidine as a pale yellow oil (223 g, 100%): 1H NMR (CDCl3) δ0.88-0.99 (m, 12H), 1.18-1.35 (m, 1H), 1.42-1.56 (m, 1H), 1.61-1.79 (m, 4H), 3.08 (t, J=7.4 Hz 1H), 3.20-3.34 (m, 1H), 3.85 (t, J=7.4 Hz, 1H), 4.18 (dd, J=7.3, 3.4 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([F:15])=[C:11]2[F:14])=[CH:6][CH:5]=1)[CH3:2].[Li]CCCC.B(OC)(OC)[O:22]C.OO>C1COCC1.S([O-])([O-])(=O)=O.[Fe+2].[NH4+].O.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7](=[CH:6][CH:5]=1)[CH:8]=[C:9]([OH:22])[C:10]([F:15])=[C:11]2[F:14])[CH3:2]
Reactant: CCOc1ccc2ccc(F)c(F)c2c1
Reactant: COB(OC)OC
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc2cc(O)c(F)c(F)c2c1
Temperature: -10 °C
Reaction time: 18 h

Procedure:
30.0 g (about 0.1 mol) of 7-ethoxy-1,2-difluoronaphthalene are initially introduced in 300 ml of THF, and 130.0 ml (0.21 mol) of n-BuLi (15% soln. in hexane) are added at −75° C. After 1 h at this temperature, 25.0 ml (0.22 mol) of trimethyl borate are added dropwise, and the batch is warmed to −10° C. 50 ml of dilute acetic acid (about 30%) are added, and the mixture is warmed to 30° C. 40 ml of hydrogen peroxide solution (35%) are carefully added, and the mixture is stirred vigorously for 18 h. Water is added, and ammonium iron(II) sulfate is added to the batch. The solution is extracted a number of times with MTBE, and the combined organic phases are washed successively with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (SiO2, toluene:ethyl acetate=9:1), giving 6-ethoxy-3,4-difluoronaphthalen-2-ol as a pale-brown solid.
Reaction SMILES: [C:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)(=O)[CH2:2][CH2:3][CH3:4].[CH:17]([NH2:19])=[O:18]>C(O)=O>[CH:17]([NH:19][CH:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4])=[O:18]
Reactant: CCCC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: NC=O
Solvent: O=CO
Product: CCCC(NC=O)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of the ketone produced as described above (21 g) and 98% formic acid (6 ml) was added over a period of one and a half hours to formamide (15 ml) at 160° C. After completion of the addition the temperature was raised to 180° to 185° C. and maintained in this range for five hours. The mixture was cooled and extracted with chloroform to yield a thick gum which on heating with petroleum ether (b.p. 60°-80°) gave a colourless solid which was recrystallised from petroleum ether (b.p. 60°-80°) to yield N-formyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine (m.p. 97.5° to 98.5° C.) (Formula I R1 =propyl; R2 =H; R3 =H; R4 =CHO; R5 =4-Cl; R6 =H).
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4](O)=[O:5].[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH3:25])[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(=O)O
Reactant: CNC
Product: CC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(=O)N(C)C

Procedure:
3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid and dimethylamine were reacted in the same manner as in Preparation Example 9 to obtain the desired product as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])[C:9]([O:17][CH3:18])=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])[C:9]([O:17][CH3:18])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OCCCCl
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COc1cc(C#N)c(N)cc1OCCCCl
Temperature: 25 °C
Yield: 65.3 %

Procedure:
A mixture of 2-nitro-4-chloropropoxy-5-methoxy-benzonitrile (0.563 g, 2.24 mmol), Pd/C (0.035 g) and anhydrous ethanol (25.0 mL) were added into a round bottom flask. The solution was stirred and heated under reflux. Cyclohexene (1.15 mL) was added and refluxed until the disappearance of the starting materials as monitored by TLC. After cooling, the resulting mixture was filtered and washed with ethanol. The filtrate was concentrated to yield a solid product. The crude product was suspended in anhydrous ethanol (4 ml), stirred at 40° C. to react for 30 min, then cooled to room temperature, filtered and air-dried to yield light yellow solid product (0.352 g) with a recovery rate of 71%.
Reaction SMILES: F[C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:20][O-:21].[Na+].CO>>[CH3:20][O:21][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Fc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Yield: 89 %

Procedure:
A solution of 7-fluoro-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (100 mg, 0.31 mmol) in 1M sodium methoxide-methanol (30 mL) is stirred under reflux for 42 h. The resulting mixture is concentrated under reduced pressure, diluted with water and neutralized with dilute HCl to give 7-methoxy-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (92 mg, 89%) as a white solid. 1H NMR (DMSO) δ 10.22 (1H, brs), 9.57 (1H, s), 8.63 (1H, s), 8.19 (1H, s), 7.86 (1H, brd, J=7.9 Hz), 7.39 (1H, t, J=7.9 Hz), 7.35 (1H, dd, J=7.9, 1.5 Hz), 6.96 (1H, s), 4.00 (3H, s).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[O-]S([O-])(=O)=O.[Mg+2].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.[BH4-].[Na+]>CO.CCN(CC)CC.C1COCC1>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:6][C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O:3][CH3:2])=[O:11])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@H](N)CC(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CC(C)C)NCc1ccc(F)cc1
Yield: 61.7 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using D-leucine methyl ester hydrochloride (2 gm, 11.0 mmol), THF (30 mL), MgSO4 (2.24 gm, 18.7 mmol), 4-fluorobenzaldehyde (2.37 mL, 22.0 mmol), Et3N (1.53 mL), sodium borohydride (833 mg, 22.0 mmol), and methanol (40 mL) to give 11f (1.72 gm, 62%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 0.84 (3H, d, J=6.59 Hz), 0.91 (3H, d, J=6.59 Hz), 1.4-1.52 (2H, m), 1.64-1.72 (1H, bs), 1.77 (1H, heptet), 3.27 (1H, t, J=7.41 Hz), 3.56 (1H, d, J=12.9 Hz), 3.72 (3H, s), 3.77 (1H, d, J=12.9 Hz), 6.99 (2H, t, J=8.78 Hz), 7.28 (2H, dd, J=5.49, 8.51 Hz). ESI-MS: 276.0 (M+23).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([N:8]2[C:12]3[C:13]4[CH:19]=[CH:18][S:17][C:14]=4[S:15][CH2:16][C:11]=3[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:4]=[CH:3]1.[OH-].[Na+].[CH3:27]I>O.C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:27][N:7]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[C:13]4[CH:19]=[CH:18][S:17][C:14]=4[S:15][CH2:16][C:11]=3[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)=[CH:6]1
Reactant: CI
Reactant: CCOC(=O)c1nn(-c2ccc(=O)[nH]c2)c2c1CSc1sccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1nn(-c2ccc(=O)n(C)c2)c2c1CSc1sccc1-2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl 1-(6-oxo-1,6-dihydropyridin-3-yl)-1,4-dihydrothieno[3′,2′:5,6]thiopyrano[4,3-c]pyrazole-3-carboxylate (75 mg, 0.208 mmol) in water/DCM (1:2) is added tetrabutylammonium bromide (0.135 g, 0.417 mmol), sodium hydroxide (17 mg, 0.417 mmol) and methyl iodide (0.13 mL, 2.08 mmol). The reaction mass is stirred at RT for 12 h after which reaction mixture is diluted with DCM and washed with water. The organic layer is separated, dried over Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography over (5% MeOH in DCM) to afford the title compound. MS (ESI+): 374.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH2:20])[N:14](C(C)(C)C)[N:15]=2)[CH:6]=[CH:7][CH:8]=1.[C:21]([NH:29][C:30]1[CH:39]=[CH:38][C:33]([C:34](OC)=[O:35])=[CH:32][CH:31]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[Al](C)C>C1(C)C=CC=CC=1.C(Cl)Cl.C(O)=O>[C:21]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([NH:20][C:13]2[NH:14][N:15]=[C:11]([CH2:10][CH2:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:12]=2)=[O:35])=[CH:38][CH:39]=1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1cccc(CCc2cc(N)n(C(C)(C)C)n2)c1
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Agent: C[Al](C)C
Solvent: O=CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(NC(=O)c4ccccc4)cc3)[nH]n2)c1
Temperature: 82 °C
Reaction time: 8 h

Procedure:
5-[2-(3-Methoxyphenyl)ethyl]-2-tert-butyl-pyrazol-3-amine (0.2 g, 0.73 mmol) was dissolved in toluene (10 ml) and to this was added methyl 4-benzamidobenzoate (200 mg, 0.80 mmol) and AlMe3 (0.93 ml, 1.8 mmol). The reaction was stirred overnight. The reaction was diluted with DCM (15 ml) and quenched with damp sodium sulfite. The reaction mixture was stirred for 20 mins before being filtered and the solvent removed in vacuo to yield a yellow gum. This gum was dissolved in formic acid (12 ml) and heated at 82° C. overnight. The reaction was evaporated to dryness and the resulting product was passed through a SCX column, eluting initially with methanol followed by 2N ammonia/methanol. After removal of the solvent, a yellow solid was obtained which was triturated with hot acetonitrile to afford a white solid. The solid was filtered and dried (66 mg, 21%); 1H NMR (400.132 MHz, DMSO) δ 2.91 (s, 4H), 3.74 (s, 3H), 6.46 (brs, 1H), 6.77 (d, 1H), 6.83 (s, 2H), 7.20 (t, 1H), 7.64-7.54 (m, 3H), 7.90 (d, 2H), 8.02-7.97 (m, 4H), 10.46 (s, 1H), 10.55 (s, 1H), 12.15 (s, 1H); MS: m/z 441 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:28])[N:14]([CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]3=[O:27])[C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)(C)(C)C.[ClH:30]>CO.C(Cl)Cl.CCOCC>[ClH:30].[NH2:7][CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:28])[N:14]([CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]3=[O:27])[C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1
Reactant: Cc1nc2cc(CNC(=O)OC(C)(C)C)ccc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Cc1nc2cc(CN)ccc2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 8 h

Procedure:
To a stirred brown solution of [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-7-ylmethyl]-carbamic acid tert-butyl ester (14.7 g, 36.8 mmol) in methanol (200 mL) and methylene chloride (200 mL), was added 2 M HCl in ether (320 mL), and the mixture was stirred overnight. The solvent was evaporated, and the residue was stirred in ether (100 mL) for 2 hours. The suspension was filtered to give 3-(7-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride as a light yellow solid (13.2 g, 106% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.9 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (50 mg, 51%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.CCCCCC.C(OCC)(=O)C>COCCOCCOC>[F:19][C:16]([F:17])([F:18])[C:12]1[CH:11]=[C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=3)=[CH:3][CH:4]=2)=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccc(O)cc1)c1cccc(C(F)(F)F)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: COCCOCCOC
Product: COc1cc2nccc(Oc3ccc(C(=O)c4cccc(C(F)(F)F)c4)cc3)c2cc1OC
Temperature: 160 °C
Yield: 27.7 %

Procedure:
Under argon, 3-trifluoromethylphenyl 4-hydroxyphenyl ketone (432 mg) obtained in Example 139 and 4-chloro-6,7-dimethoxyquinoline (363 mg) were dissolved in diethylene glycol dimethyl ether (10 ml), and the solution was then refluxed at 160° C. for 11 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate and then by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (5/1) to obtain 204 mg of the title compound (yield: 28%).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([F:18])[CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)C1C=CC=CC=1>CCO.CO.[OH-].[OH-].[Pd+2]>[F:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=1)[NH:8][CH2:17][CH2:16]2
Reactant: Fc1cccc2c1C(c1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Fc1cccc2c1C(c1ccc(C(F)(F)F)cc1)NCC2

Procedure:
A solution of 2-benzyl-8-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-isoquinoline (0.7 g, 2.1 mmol) in EtOH (20 mL) was stirred with 20% Pd(OH)2/C (0.20 g) under hydrogen atmosphere at 50 psi and at RT for 3 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC [gradient 10-90% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give the pure product which was dissolved in methanol (10 mL) and neutralized by passing the solution through a Polymer Lab-HCO3 Macroporous resin cartridge, and the filtrate was concentrated to give 8-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as an off-white solid. MS (ESI pos. ion) m/z: 296 (M+1).