Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([CH3:9])=[C:4]([F:10])[C:3]=1[NH:11][C:12](=O)[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:16]=[CH:15][C:14]=1[F:26]>C1COCC1>[F:1][C:2]1[C:3]([NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH:16]=[CH:15][C:14]=2[F:26])=[C:4]([F:10])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8]
Reactant: Cc1cc(O)c(F)c(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1F
Solvent: C1CCOC1
Product: Cc1cc(O)c(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 60 °C
Yield: 75 %

Procedure:
N-(2,6-difluoro-3-hydroxy-5-methyl-phenyl)-2-fluoro-5-(3-fluorophenyl)benzamide (285 mg, 0.76 mmol, 1.0 eq) was dissolved in THF (20 mL). A solution of BH3 (1M in THF, 4.56 mL, 4.56 mmol, 6.0 eq) was added and the reaction mixture heated at 60° C. under nitrogen for 2 h. After cooling, the reaction was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 30:1 to 20:1) to give the title compound as a colorless oil (206 mg, 75%).
Reaction SMILES: N1C=CC=CC=1O[C:8](=[S:16])OC1C=CC=CN=1.[CH2:17]([N:20]([CH2:32][CH2:33][CH3:34])[CH:21]1[CH2:30][C:29]2[C:24](=[C:25]([NH2:31])[CH:26]=[CH:27][CH:28]=2)[NH:23][CH2:22]1)[CH2:18][CH3:19]>C1COCC1>[CH2:32]([N:20]([CH2:17][CH2:18][CH3:19])[CH:21]1[CH2:30][C:29]2[C:24]3=[C:25]([NH:31][C:8](=[S:16])[N:23]3[CH2:22]1)[CH:26]=[CH:27][CH:28]=2)[CH2:33][CH3:34]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: CCCN(CCC)C1CNc2c(N)cccc2C1
Solvent: C1CCOC1
Product: CCCN(CCC)C1Cc2cccc3[nH]c(=S)n(c23)C1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
Di (2-pyridyl)thiocarbonate (1.6 g, 7.2 mmol) was added to a stirred solution of 1,2,3,4-tetrahydro-N3,N3 -dipropyl-3,8-quinolinediamine (1.6 g, 6.7 mmol) in THF (50 mL). The solution was stirred for 1 hour, evaporated, and partitioned between chloroform and water. The chloroform phase was evaporated and chromatographed on silica gel using ethyl acetate:hexane (1:9) as the initial eluant to give 1.6 g of product. Crystallization from cyclohexane gave 1.3 g (67% of 5-(dipropylamino)-5,6-hydro-4H-imidazo(4,5,1-ij)quinolin-2(1H)-thione, mp 150°-151° C. Anal. Calcd. for C16H23N3S: C, 66.39; H, 8.01; N, 14.52; S, 11.08. Found: C, 66.50; H, 8.18; N, 14.56; S, 11.02.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH4-].[Na+].O>C(O)C>[CH2:22]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15][CH2:14]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A solution (150 ml) of 5-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)pentylamine (5.0 g) and benzaldehyde (2.0 g) in ethanol was stirred at 70° C. for 3 hr. After cooling, sodium borohydride (1.40 g) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 3.7 g of N-benzyl-5-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)pentylamine.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:10]([N:12]3[CH2:14][CH:13]3[CH3:15])=[N:9][C:8]([CH3:16])=[N:7][C:6]=2[C:5]([CH3:17])=[N:4]1)[CH3:2].[I-].[Na+]>CC(C)=O>[CH2:1]([N:3]1[C:11]2[C:10]3[N:9]([CH2:15][CH:13]([CH3:14])[N:12]=3)[C:8]([CH3:16])=[N:7][C:6]=2[C:5]([CH3:17])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)c2nc(C)nc(N3CC3C)c21
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCn1nc(C)c2c1C1=NC(C)CN1C(C)=N2
Yield: 71.2 %

Procedure:
A solution of 4.2 g (0.02 mol) of 7-chloro-3,5-dimethyl-1-ethyl-1H-pyrazolo[4,3-d]pyrimidine (Ex. 16), 3 ml of triethylamine and 5 ml of 2-methylaziridine in 100 ml of methylene dichloride is allowed to stand at room temperature 20 hours. The solution is washed with saturated sodium bicarbonate solution, dried (MgSO4), and evaporated in vacuo to give 4 g of 1-ethyl-3,5-dimethyl-7-(2-methylaziridinyl)pyrazolo[4,3-d]pyrimidine as an oil, characterized by IR and NMR. The aziridine (4 g, 0.017 mol) in 40 ml of acetone is refluxed 1.5 hours with 3 g (0.02 mol) of sodium iodide. The solution is evaporated in vacuo. The residue is partitioned in 100 ml of methylene dichloride and 30 ml of 20% sodium carbonate solution. The organic layer is separated, dried over magnesium sulfate, and the solvent is evaporated in vacuo to give 2.8 g (71%) of the title compound, mp 145°-147° C. from ethyl acetate-pet ether.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1.[N:29]1[C:38]2[C:37](=O)[CH2:36][CH2:35][CH2:34][C:33]=2[CH:32]=[CH:31][CH:30]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]([CH3:26])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)[CH:37]1[C:38]2[N:29]=[CH:30][CH:31]=[CH:32][C:33]=2[CH2:34][CH2:35][CH2:36]1
Reactant: O=C1CCCc2cccnc21
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CN(Cc2ncc[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.5 %

Procedure:
The compound (203.5 mg) obtained in Example 9-2 was dissolved in anhydrous methanol (8.1 ml) and added with 6,7-dihydro-5H-quinolin-8-one (117.7 mg) which was synthesized by a known method and sodium cyanoborohydride (99.9 mg). After the solution was adjusted to pH 5 with acetic acid, the whole was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (69.5 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:9]([Br:10])=[C:8]([CH3:11])[C:7]([Br:12])=[CH:6][N:5]=1)([O-:3])=[O:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:31]NC(=O)CCC(N)=O>C1C=CC=CC=1>[N+:1]([C:4]1[C:9]([Br:10])=[C:8]([CH2:11][Br:31])[C:7]([Br:12])=[CH:6][N:5]=1)([O-:3])=[O:2]
Reactant: Cc1c(Br)cnc([N+](=O)[O-])c1Br
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ncc(Br)c(CBr)c1Br
Temperature: 110 °C
Yield: 33.2 %

Procedure:
To a solution of 2-nitro-3,5-dibromo-4-methylpyridine(10.7 g, 36.15 mmol) in benzene(20 ml) was added benzoyl peroxide(1.0 g, 5.42 mmol) and N-bromosuccinamide(7.75 g, 42.18 mmol). The mixture was stirred at 110° C. and irradiated with a 150-W floodlight for 48 hrs. The solvent was evaporated and chromatography of the resulting solid on silica gel (10%EtOAc/Hexane) gave the desired product(4.5 g, 33%). 1H NMR (CDCl3): δ 8.56 (s, 1H), 4.76 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1[C:21](=[O:43])[C:22]2[CH:27]=[N:26][C:25](S(C)(=O)=O)=[N:24][C:23]=2[N:32]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[CH2:39][CH2:38][CH2:37]3)[CH:33]=1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[C:21](=[O:43])[C:22]2[CH:27]=[N:26][C:25]([NH:1][C:2]3[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]4[CH2:11][O:10][C:9](=[O:12])[NH:8]4)=[CH:4][CH:3]=3)=[N:24][C:23]=2[N:32]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[CH2:39][CH2:38][CH2:37]3)[CH:33]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: Nc1ccc(C[C@H]2COC(=O)N2)cc1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(C[C@H]4COC(=O)N4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from (4S)-4-(4-amino-benzyl)-1,3-oxazolidin-2-one (46 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a white solid (56 mg, 44%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.00 (br, 1H), 8.42 (s, 1H), 7.50 (br, 1H), 7.33 (d, J=7.9 Hz, 1H), 7.28 (br, 2H), 7.18 (s, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.81 (br, 2H), 5.88 (s, 1H), 4.41 (t, J=8.2 Hz, 1H), 4.31 (q, J=7.0 Hz, 2H), 4.05 (m, 1H), 3.98 (m, 1H), 2.99 (t, J=7.4 Hz, 2H), 2.92 (t, J=7.4 Hz, 2H), 2.79-2.66 (m, 2H), 2.15 (m, 2H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C@@H:11]2[C@@:15]([CH2:17][O:18][C:19](=[O:28])[C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[OH:27])([OH:16])[C@@:14]([OH:30])([CH3:29])[C@:13]([NH:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])([C@@H:31]([OH:33])[CH3:32])[C@H:12]2[NH:40]C(OCC2C=CC=CC=2)=O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]>[OH-].[OH-].[Pd+2].CO>[CH3:26][C:25]1[C:20]([C:19]([O:18][CH2:17][C@:15]2([OH:16])[C@@:14]([OH:30])([CH3:29])[C@:13]([NH:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])([C@@H:31]([OH:33])[CH3:32])[C@@H:12]([NH2:40])[C@@H:11]2[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([CH3:2])=[O:3])[CH:5]=2)=[O:28])=[C:21]([OH:27])[CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1cccc(N[C@H]2[C@H](NC(=O)OCc3ccccc3)[C@@](NC(=O)N(C)C)([C@H](C)O)[C@@](C)(O)[C@@]2(O)COC(=O)c2c(C)cccc2O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1cccc(N[C@H]2[C@H](N)[C@@](NC(=O)N(C)C)([C@H](C)O)[C@@](C)(O)[C@@]2(O)COC(=O)c2c(C)cccc2O)c1
Yield: 89.5 %

Procedure:
A 4-mL vial was charged with salicylate 16 (0.0075 g, 0.01 mmol, 1.0 equiv), and Pd(OH)2/C (20 wt. %, 0.005 g). MeOH (1 mL) was added and the vial was sealed with a Teflon cap. The atmosphere was replaced by H2 (balloon, ˜1 atm.) and stirred until TLC analysis indicated complete consumption of the starting material, typically 20 min. The resulting suspension was filtered through a pad of CELITE® 545 (diatomaceous earth, filter aid) and washed with MeOH. The homogeneous solution was concentrated in vacuo. The crude residue was purified by flash chromatography (98:2 CH2Cl2:MeOH) affording pactamycin (0.005 g, 82%) as a pale yellow solid. Analytical data: [α]D19+27.4 (c=0.40, CHCl3); 1H NMR (600 MHz, CDCl3): δ 10.98 Or s, 1H), 7.91 (d, J=10.8 Hz, 1H), 7.26-7.23 (m, 4H), 7.18-7.16 (m, 2H), 6.81-6.78 (m, 2H), 6.64 (d, J=7.2 Hz, 1H), 5.78 (br s, 1H), 5.67 (d, J=10.8 Hz, 1H), 4.84 and 4.79 (ABq, J=12.6 Hz, 2H), 3.93 (m, 1H), 3.80 (d, J=10.2 Hz, 1H), 2.99 (s, 6H), 2.95 (s, 1H), 2.55 (s, 3H), 2.38 (s, 3H), 1.55 (s, 3H), 1.04 (d, J=6.0 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 198.5, 172.6, 162.8, 159.2, 146.6, 141.2, 138.3, 134.6, 129.6, 123.0, 118.7, 118.4, 115.7, 112.0, 110.8, 88.8, 84.9, 74.3, 71.5, 68.7, 65.4, 63.2, 36.9, 29.7, 26.7, 24.1, 21.1, 18.1; HRMS (ESI1) Calcd. for C28H38N4O8+H, 559.2762. Found, 559.2763. IR (thin film, cm−1) 3393, 2938, 2359, 2341, 1698, 1652, 1520, 1473, 1418, 1338, 873, 668; TLC (95:5 CH2Cl2/MeOH): Rf=0.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:10]=2[N:11]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:9]1[C:10]2[N:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=c1[nH]cnc2ccc(Cl)nc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2ncnc(Cl)c2n1
Temperature: 110 °C
Yield: 86.3 %

Procedure:
Huning's base (1.18 mL, 6.77 mmol) was added to a solution of 6-chloropyrido[3,2-d]pyrimidin-4(3H)-one (820 mg, 4.52 mmol) in POCl3 (8.42 mL, 90.0 mmol) at room temperature, and the reaction mixture was heated at 110° C. for 5 h. After cooled to room temperature, the excess POCl3 was removed by evaporation. Toluene was added to the residue, and the azeotrope was removed under reduced pressure. DCM was poured into the residue, and the suspension was treated carefully with aq. NaHCO3 at 0° C. to pH 7˜9. The insoluble solid was filtered off, and the filtrate was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM:EtOAc=10:1) to give 4,6-dichloropyrido[3,2-d]pyrimidine (780 mg, 86%) as a pale yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.86 (1H, d, J=8.8 Hz), 8.34 (1H, d, J=8.8 Hz), 9.14 (1H, s). m/z=199.01 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].[Cl:14][C:15]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:30]([O-:32])=[O:31])=[C:22]([CH:29]=1)[C:23]([O:25][CH2:26][CH2:27][OH:28])=[O:24].N1C=CC=CC=1>C(Cl)Cl>[Cl:14][C:15]1[CH:36]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:30]([O-:32])=[O:31])=[C:22]([CH:29]=1)[C:23]([O:25][CH2:26][CH2:27][O:28][C:6](=[O:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1])=[O:24]
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Reactant: O=C(OCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(COc1ccc(Cl)cc1Cl)OCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 1.5 %

Procedure:
2,4-Dichlorophenoxyacetyl chloride (5.3 g, 0.25 mole), was added portionwise to a solution of 2-hydroxyethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (10 g, 0.25 mole) and pyridine (70 ml). The resulting mixture was heated to 60° C. for 1 hr., cooled and taken into 500 ml CH2Cl2. The methylene chloride solution was washed two times with water, dried and concentrated to 12.5 g of gummy material. The crude gum was chromatographed through silica gel (3:10, ethyl acetate:hexane) to give 2.3 g of pure 2-(2,4-dichlorophenoxyacetoxy)ethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate; nmr (DMSO) 4.20-4.76 (m, 4H), 5.04 (S, 2H), 6.96-8.42 (m, 9H); ir (CHCl3) 1755, 1770 Cm-1.
Reaction SMILES: [BH4-].[Na+].C(O)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](OCC)=[O:16])=[C:9]([N+:25]([O-])=O)[CH:8]=1>O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:10]([CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:16])[NH:25]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(=Cc1ccc(Cl)cc1[N+](=O)[O-])C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1Cc2ccc(Cl)cc2NC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
Sodium borohydride (2.082 g) was added to an ethanol (200 ml) solution of diethyl 2-[(4-chloro-2-nitrophenyl)methylidene]malonate(34.92 g). The reaction mixture was stirred at 0° C. for one hour, to which was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. Iron (26.70 g) was added to an aqueous acetic acid (300 ml) solution of the residue, which was heated under reflux. The reaction mixture was left standing for cooling, and ethyl acetate (300 ml) was added to the reaction mixture. The precipitated insoluble substances were removed by filtration and the filtrate was concentrated. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried and concentrated. The obtained crude crystals were washed with IPE to give the entitled compound (14.50 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([OH:11])C#C)=[CH:4][CH:3]=1.FC1C=CC(C(C2C=CC(F)=CC=2)=O)=CC=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: C#CC(O)(c1ccc(N)cc1)c1ccc(F)cc1
Agent: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Product: Nc1ccc(C(=O)c2ccc(F)cc2)cc1

Procedure:
Referring now to FIG. 2, wherein one non-limiting approach to the 1-(4-aminophenyl)-1-(4-fluorophenyl)-2-propyn-1-ol is presented, 4,4′-difluorobenzophenone (7) is reacted with a secondary amine HNR′″R″″ to give the 4-amino-4′-fluorobenzophenone 8, where R′″ and R″″ may be the same as R36 and R37, respectively, as set forth and claimed herein. Acetylide anion, for example, sodium acetylide in acetylene saturated dimethylformamide, is added to the carbonyl of 4-amino-4′-fluorobenzophenone 8 to give, upon aqueous workup, 1-(4-aminophenyl)-1-(4-fluorophenyl)-2-propyn-1-ol 9.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]([CH3:16])([CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:5]([O:7][CH3:8])=[O:6].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:27]=[C:26](Cl)[C:25]3=[CH:29][C:30]([CH3:32])=[CH:31][N:24]3[CH2:23][C:22]=2[CH:33]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:27]=[C:26]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][C:4]([CH3:16])([CH3:3])[C:5]([O:7][CH3:8])=[O:6])[CH2:11][CH2:12]3)[C:25]3=[CH:29][C:30]([CH3:32])=[CH:31][N:24]3[CH2:23][C:22]=2[CH:33]=1
Reactant: COC(=O)C(C)(C)CN1CCNCC1
Reactant: Cc1cc2n(c1)Cc1cc(Cl)ccc1N=C2Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(Cl)cc3Cn3cc(C)cc32)CC1
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 58.3 %

Procedure:
Dissolve methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate dihydrochloride (1.61 g, 5.89 mmoles) in water and load on to two SCX-2 (10 g) cartridges. Wash the cartridges with methanol and elute with 2M ammonia in methanol. Concentrate in vacuo, then dissolve the resultant oil in acetonitrile (40 mL). Add 7,11-dichloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.167 g, 4.4 mmoles) to the acetonitrile solution. Divide the acetonitrile solution and place in to 2 microwave tubes, add potassium carbonate (0.89 g, 6.79 mmoles) to each microwave tube and heat and stir at 140° C. in the microwave for 3.5 hr. Allow the reaction mixture to cool, filter, wash the solid collected on the sinter with acetonitrile then concentrate the filtrate in vacuo, add methanol and then evaporate to dryness. Treat with more methanol and collect the resultant precipitate, wash the precipitate with methanol to give methyl 3-[4-(7-chloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate as a crystalline solid (1.1 g). MS (m/z): 429.18 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]([CH2:10][CH3:11])([CH2:8][OH:9])[CH2:4][O:3]1.[H-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>O1CCCC1>[CH2:15]([O:9][CH2:8][C:5]1([CH2:10][CH3:11])[CH2:4][O:3][C:2]([CH3:12])([CH3:1])[O:7][CH2:6]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC1(CO)COC(C)(C)OC1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(COCc2ccccc2)COC(C)(C)OC1
Reaction time: 1 h

Procedure:
2,2-Dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane (10 g.) was added to a stirred suspension of sodium hydride (2.4 g., 50% dispersion in oil) in dry tetrahydrofuran (80 ml.) The mixture was refluxed with stirring for one hour. Benzyl chloride (9.2 ml.) was added and the mixture was refluxed with stirring for three hours. the mixture was poured into water and the aqueous mixture was extracted with ether. The ethereal extract was washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. 5-Benzyloxymethyl-2,2-dimethyl-5-ethyl-1,3-dioxane was obtained as a pale brown oil (15 g.) and was used without further purification.
Reaction SMILES: [F: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.[N:18]1([CH2:23][CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:28])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1cc(C(=O)NCCCN2CCCC2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.9 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide (68.5 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 2-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (93.2 mg, 79%).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([CH:48]([CH3:50])[CH3:49])=[C:37]([OH:51])[C:36]3=[O:52])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([CH:48]([CH3:50])[CH3:49])=[C:37]([O:51][CH3:3])[C:36]3=[O:52])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC(C)C1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1cccc(F)c1F
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCCO
Solvent: CO
Product: COC1=C(C(C)C)C(c2cccc(F)c2F)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/7.5 v/v, 17 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-4-isopropyl-3-hydroxy-1H-pyrrol-2(5H)-one (0.15 g, 0.34 mmol, 1 eq) and MeOH (10 ml), the product was further purified by prep TLC; yield: 0.040 g (10.4%); MS m/z: 384.1 [M+H]+;1H-NMR: (400 MHz, CDCl3) δ: 7.88 (s, 1H), 7.80 (bs, 1H), 7.52 (bs, 1H), 7.2-6.88 (m, 4H), 6.0 (s, 1H), 4.08 (s, 3H), 2.61 (bs, 1H), 1.1-1.04 (m, 6H); HPLC (METHOD [A]): rt 14.51 min (96.9%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][CH3:12])[C:4]=1[NH2:5].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C1(C)C=CC=CC=1>[C:13]1(=[N:5][C:4]2[C:6]([O:11][CH3:12])=[CH:7][C:8]([CH3:10])=[CH:9][C:3]=2[O:2][CH3:1])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C)cc(OC)c1N
Reactant: O=C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)cc(OC)c1N=C1CCCCC1

Procedure:
4.2 g of 2,6-dimethoxy-4-methylaniline are dissolved in 50 ml of toluene, 2.45 g of cyclohexanone are then added and the reaction mixture is heated at reflux for 18 hours. The water which is formed is removed as it is formed in the reaction mixture using a Dean and Stark apparatus. The toluene is evaporated and the oily N-cyclohexylidene-2,6-dimethoxy-4-methylaniline residue obtained is used without addition of purification in the following stage.