Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22]Cl)[CH:18]=2)[N:13]([CH3:24])[C:12]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35].[K+].[Br-]>CN(C=O)C.O.CC#N>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][N:36]([CH2:37][CH3:38])[CH2:34][CH3:35])[CH:18]=2)[N:13]([CH3:24])[C:12]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)c2cc(OCCCl)ccc2n1C
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CCN(CC)CCOc1ccc2c(c1)c(C(=O)OCc1ccccc1)c(C)n2C
Temperature: 100 °C
Reaction time: 21 h

Procedure:
To a mixture of 1-methyl-5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.576 mmol, 0.206 g, Example 8, Step A) in 5.76 mL of DMF was added potassium carbonate (0.576 mmol, 0.080 g), potassium iodide (0.0576 mmol, 0.010 g), and diethylamine (2.30 mmol, 0.238 mL, Aldrich). The mixture was heated at 100° C. for 20 hours, an additional 2.30 mmol of diethylamine was added and heating was continued for 21 hours. The solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (4×15 mL). The combined extracts were washed with water (10 mL), saturated aqueous NaCl (10 mL), dried over MgSO4, and concentrated to a brown oil (0.234 g). The product was purified by silica gel flash column chromatography (5-10% MeOH/CH2Cl2) to give a tan solid (0.114 g, 50/o): mp 73-74° C.; IR (KBr) 2968, 2918, 1692, 1186, 1101 cm−1; 1HNMR (400 MHz, DMSO-d6) δ 0.92 (t, J=7.08 Hz, 6H, N(CH2CH3)2), 2.46-2.51 (m, 4H, 2 NCH2), 2.66 (s, 3H, ArCH3), 2.68-2.73 (m, 2H, NCH2), 3.65 (s, 3H, NCH3), 3.85 (t, J=6.11 Hz, 2H, CH2OAr), 5.28 (s, 2H, CO2CH2Ph), 6.75 (dd, J=8.79, 2.44 Hz, 1H, ArH), 7.28-7.32 (m, 1H, ArH), 7.35-7.39 (m, 4H, ArH), 7.46 (d, J=7.57 Hz, 2H, ArH); MS(APCI+): m/z 395.1 (M+1). HPLC (ALLTECH/ALLTIMA C-18,50:50-2:98H2O/CH3CN+0.05% TFA): retention time=3.617 min, 96.84% purity.
Reaction SMILES: [OH:1][C:2]([C:27]([F:30])([F:29])[F:28])([CH3:26])[CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24].CO.C(Cl)Cl>[Pd].O>[OH:1][C:2]([C:27]([F:29])([F:30])[F:28])([CH3:26])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24]
Reactant: CNC(=O)CCN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CC(C)(O)C(F)(F)F)cc12
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CNC(=O)CCN1CCC[C@@H]1Cc1c[nH]c2ccc(CCC(C)(O)C(F)(F)F)cc12

Procedure:
Obtained from the title compound of Example 98 by a procedure similar to that described in Example 2, but using 10% palladium on charcoal as catalyst, as a foam. Rf 0.45 (SS 7). [α]D25 +39° (c=0.1, CH3OH). Found: C,59.07; H,7.16; N,9.21. C22H30F3N3O2 ; 0.05 CH2Cl2 ; H2O requires C,59.15; H,7.22; N,9.39%. LRMS: m/z 426.4 (M+1)+.
Reaction SMILES: [CH2:1]1[C:6]2=[C:7]3[CH:16]([CH:17]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:5]2[CH2:4][CH2:3][CH2:2]1)[O:15][C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[O:8]3.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH:1]1[C:6]2[C:7]3[O:8][C:9]4[C:14]([O:15][C:16]=3[CH:17]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][CH:12]=[CH:11][CH:10]=4
Reactant: COC(=O)C1=CC2Oc3ccccc3OC2=C2CCCCC12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(c3ccccc13)Oc1ccccc1O2

Procedure:
Under an inert atmosphere, 370 mg of methyl 1,2,3,4,4a,6a-hexahydro-7,12-dioxabenz[a]anthracene-5-carboxylate in solution in 10 ml of toluene are brought to reflux for 6 hours in the presence of 986 mg of DDQ. After cooling, the reaction mixture is washed with 8% sodium hydroxide solution. The organic phase is dried over magnesium sulfate and then concentrated under vacuum. Purification is performed by chromatography on silica gel (eluent: petroleum ether/ethyl acetate, 95:5).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:11]=[CH:12][C:13]=1[CH3:14].C([O:25][C:26](=O)[C:27]([NH:29][CH:30]1[CH2:32][CH2:31]1)=[O:28])C.O1CCCC1>CN1CCCC1=O.[Cl-].[NH4+].C(OCC)(=O)C>[CH:30]1([NH:29][C:27](=[O:28])[C:26]([NH:22][C:21]2[C:16]([NH:15][C:10]3[CH:11]=[CH:12][C:13]([CH3:14])=[C:8]([F:7])[CH:9]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:25])[CH2:32][CH2:31]1
Reactant: Cc1ccc(Nc2ncccc2N)cc1F
Reactant: CCOC(=O)C(=O)NC1CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1ccc(Nc2ncccc2NC(=O)C(=O)NC2CC2)cc1F
Temperature: 120 °C

Procedure:
Potassium tert-butoxide (4.54 g, 40.5 mmol) was added to a solution of N2-(3-fluoro-4-methylphenyl)pyridine-2,3-diamine (C2) (from the previous step, 5.87 g, 24.4 mmol) and ethyl(cyclopropylamino)(oxo)acetate (P1) (6.36 g, 40.5 mmol) in 1-methylpyrrolidin-2-one (27 mL). The reaction mixture was heated at 120° C. for 10 minutes, cooled to room temperature and diluted with aqueous ammonium chloride solution. Tetrahydrofuran was added to assist solubilization, followed by ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the crude product (13.0 g). A portion of this material was used directly in the following step. LCMS m/z 329.0 [M+H]+.
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[O:18]>[Ni]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH2:9][OH:10])[CH2:2][NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[O:18]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Agent: [Ni]
Product: NC(=O)NCCC[C@H](NCC(O)C(O)C(O)CO)C(=O)O

Procedure:
The product was made from D-ribose and L-(+)-citrulline using Raney nickel as a catalyst and heating for 2 hours to 50° C. and for 4 hours to 70° C. The product obtained had a melting point of 172° to 175° C. (decomposition) and an RF -value of 0.52 (determined as indicated under Example T).
Reaction SMILES: [CH:1]1[C:13]([NH2:14])=[CH:12][C:11]2[CH2:15][CH2:16][CH2:17][N:9]3[C:10]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=13.[C:18](Cl)(=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21]>ClC(Cl)C>[CH:1]1[C:13]([NH:14][C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:12][C:11]2[CH2:15][CH2:16][CH2:17][N:9]3[C:10]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=13
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1
Reactant: CC(C)CC(=O)Cl
Solvent: CC(Cl)Cl
Product: CC(C)CC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1
Yield: 49.8 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-amine (0.10 g, 0.44 mmol), isovaleryl chloride (0.054 mL, 0.44 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided N-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-yl-3-methylbutanamide (68 mg). MS m/z 311; HPLC purity 100% at 210-370 nm, 10.5 min.; 99.4% at 250 nm, 10.5 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C20H26N2O+H+, 311.21179; found (ESI, [M+H]+), 311.2122.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]([CH2:18][N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[N:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=[CH:20]1)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].FC(F)(F)C(O)=O>C(Cl)Cl>[F:50][C:2]([F:1])([F:49])[C:3]([CH2:18][N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[NH:29])[CH:21]=[CH:20]1)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ccc(=NC(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc21)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ccc(=N)c2ccccc21)C(F)(F)F
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To a solution of 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-[4-(tritylimino)-4H-quinolin-1-ylmethyl]pentan-2-ol (470 mg) in methylene chloride (50 mL) was added trifluoroacetic acid (2 mL). After 2 hours, another portion of trifluoroacetic acid (1 mL) was added and the mixture was stirred for another 4 hours. The reaction was quenched by slow addition of saturated aqueous sodium bicarbonate solution and was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 8 to 10% methanol-methylene chloride) to give the title compound (84.2 mg), m.p. 137° C.-140° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N(CC)CC)C.[F:37][C:38]([F:45])([F:44])[CH2:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29][S:40]([CH2:39][C:38]([F:45])([F:44])[F:37])(=[O:42])=[O:41])=[CH:27][CH:28]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(CC3(C)OCCO3)ccc2n1Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(CC3(C)OCCO3)ccc2n1Cc1ccc(NS(=O)(=O)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 105.4 %

Procedure:
To a solution of crude 1-(4-amino-benzyl)-5-(2-methyl-[1,3]dioxolan-2-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester (2 g, ≈5 mmol) in methylene chloride (25 ml) stirring at about -78° C. under nitrogen was added triethylamine (1.28 g, 1.76 ml, 12.7 mmol). The mixture was stirred for about two minutes, and 2,2,2-trifluoroethanesulfonyl chloride (2.03 g, 1.23 ml, 12.7 mmol) was added dropwise via syringe over about five minutes. The mixture was stirred at about -78° C. for about 45 minutes, then diluted with methylene chloride and water and warmed to room temperature. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to an oil. The oil was taken up in methanol (30 ml) and triethylamine (1 ml) and stirred for about two hours at room temperature. The mixture was poured into half-saturated ammonium chloride and extracted into ethyl acetate. The ethyl acetate was washed with brine, dried over sodium sulfate, filtered, and evaporated to give the title compound (2.85 g) as a foam containing some impurities, which was reacted without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:19].C(=O)([O-])[O-].[Na+].[Na+].[C:31]([NH:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:33])[CH3:32].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([NH:34][C:35]1[CH:40]=[C:39]([C:2]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:4]([CH:5]=[C:6]3[C:14]4[C:9](=[CH:10][C:11]([NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:19])[CH:3]=2)[CH:38]=[CH:37][CH:36]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: COc1ccc(C=C2C(=O)Nc3cc(NC(C)=O)ccc32)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(C=C2C(=O)Nc3cc(NC(C)=O)ccc32)cc1-c1cccc(NC(C)=O)c1
Reaction time: 12 h
Yield: 43.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.01 g) was added to a solution of N-[3-(3-bromo-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide (0.14 g) in toluene (1 ml) and ethanol (1 ml) followed by addition of 2M aqueous sodium carbonate (0.72 ml). To this mixture was 3-acetylamino-phenylboronic acid (0.07 g), and the mixture was held at 100° C. in a sealed tube for 12 hours. The reaction mixture was added to water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml), dried over magnesium sulfate and concentrated. Chromatography (silica, dichloromethane then 5-10% methanol/dichloromethane) afforded 0.07 g (43%) of N-[3-(3′-acetylamino-6-methoxybiphenyl-3-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide as a yellow solid. About 26% isomer by 1HNMR.
Reaction SMILES: [C:1](=[O:21])([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[CH:5]=1.BrC1C=C(CO)C=CC=1.[CH3:31][C:32]1[C:61]([CH3:62])=[CH:60][CH:59]=[CH:58][C:33]=1[O:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]1[C:49]2[C:44](=[C:45](C3C=CC(CO)=CC=3)[CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][CH2:41]1)=[O:39]>>[C:1](=[O:21])([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:45]2[CH:46]=[CH:47][CH:48]=[C:49]3[C:44]=2[CH2:43][CH2:42][CH2:41][N:40]3[C:38](=[O:39])[CH2:37][CH2:36][CH2:35][O:34][C:33]2[CH:58]=[CH:59][CH:60]=[C:61]([CH3:62])[C:32]=2[CH3:31])=[CH:6][CH:5]=1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(CO)cc4)cccc32)c1C
Reactant: O=C(OCc1cccc(Br)c1)Oc1ccc([N+](=O)[O-])cc1
Agent: OCc1cccc(Br)c1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(COC(=O)Oc5ccc([N+](=O)[O-])cc5)cc4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 3-bromobenzyl 4-nitrophenyl carbonate except that (3-bromophenyl)methanol was replaced with 4-(2,3-dimethylphenoxy)-1-(5-(4-(hydroxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one. LCMS, [M+H]+=595.2. 1H NMR (400 MHz, CDCl3) δ 8.32-8.16 (m, 2H), 7.44 (d, J=7.8 Hz, 2H), 7.37 (d, J=9.1 Hz, 2H), 7.28-7.13 (m, 4H), 7.09 (s, 1H), 6.98 (t, J=7.8 Hz, 1H), 6.72 (d, J=7.4 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 5.31 (s, 2H), 3.92 (br. s, 2H), 3.76 (t, J=6.7 Hz, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.44 (br. s, 2H), 2.29-2.08 (m, 5H), 1.92 (s, 3H), 1.84-1.71 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:3][N:4]=[C:5]2[C:10]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:8][NH:7][C:6]2=[O:17].[H-].[Na+].Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]1[O:3][N:4]=[C:5]2[C:10]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:8][N:7]([CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[C:6]2=[O:17]
Reactant: Cc1onc2c(=O)[nH]nc(-c3ccccc3)c12
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1onc2c(=O)n(Cc3ccncc3)nc(-c3ccccc3)c12
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a stirred suspension of 3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one (1.5 g, 6.6 mmol) (Renzi, G.; Pinzauti, S., II Farmaco Ed. Sci. 1969, 24, 885-889), 60% sodium hydride (0.63 g, 15.8 mmol) was added portionwise and the mixture stirred for 15 minutes. Then 4-(chloromethyl)pyridine hydrochloride (1.3 g, 7.9 mmol) was added portionwise and the final mixture was stirred at 50° C. for 7 h, then poured onto water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo to yield a crude product that was crystallized from isopropyl ether/petroleum ether to yield the title compound (1.66 g, 79% yield) as a light brown solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:40]=[CH:39][C:14]([CH2:15][NH:16][C:17]2[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]([NH:29][C:30]3[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=3)[CH:18]=2)=[CH:13][CH:12]=1.[C:41]([O:45][C:46](=[O:54])[NH:47][CH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][NH2:51])([CH3:44])([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[OH:10][C:11]1[CH:40]=[CH:39][C:14]([CH2:15][NH:16][C:17]2[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])[N:20]=[C:19]([NH:29][C:30]3[CH:38]=[CH:37][C:33]([C:34]([NH:51][CH2:50][C:49]([CH3:53])([CH3:52])[CH2:48][NH:47][C:46](=[O:54])[O:45][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:35])=[CH:32][N:31]=3)[CH:18]=2)=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
iPr2NEt (0.5 mL) was added into a solution of 6-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxyl)pyrimidin-4-yl)amino)nicotinic acid (340 mg), tert-butyl(3-amino-2,2-dimethylpropyl)carbamate (316 mg) and TBTU (501 mg) in THF (10 mL). The reaction was stirred at room temperature for 16 hours before being quenched by water (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give the crude product, tert-butyl 3-(6-(6-(4-hydroxybenzylamino)-2-(2,2,2-trifluoroethoxyl)pyrimidin-4-ylamino)nicotinamido)-2,2-dimethylpropylcarbamate, which was purified by silica gel chromatography.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:23][O:24][C:25]1[CH:44]=[CH:43][C:28]([C:29](Cl)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:26]=1>N1C=CC=CC=1.O1CCCC1>[CH2:1]([O:17][CH2:18][CH:19]([OH:22])[CH2:20][O:21][C:29]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a mixture of 84.5 g of 3-(hexadecyloxy)-1,2-propanediol in 265 ml of dry pyridine, stirred in an ice bath under nitrogen, was added in a steady stream a solution of 115.5 g of 4-methoxytrityl chloride in 150 ml of dry tetrahydrofuran. This mixture was stirred in the ice bath for 30 minutes, then at room temperature for 2 hours, then refrigerated at 0° C. overnight. The mixture was concentrated to remove the volatile solvents. The residual solution was dissolved in 400 ml of chloroform, washed twice with 200 ml portions of 10% aqueous sodium bicarbonate and twice with 200 ml portions of water, dried and evaporated. The residue was evaporated twice from toluene, taken up in ether, chilled and filtered. The filtrate was taken to dryness, giving a syrup. A 30 g portion of this syrup was dissolved in petroleum ether and chromatographed on a silica gel column eluting with 20% ether in petroleum ether. The product fractions 6-20 (200 ml each) were combined and evaporated, giving 21 g of the desired compound.
Reaction SMILES: [CH2:1]([C:8]1[C:17]([O:18]C)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([Br:20])=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.C(O)(=O)C>[CH2:1]([C:8]1[C:17]([OH:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([Br:20])=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ccc(Br)cc2nc1Cc1ccccc1
Agent: Br
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Product: Oc1cc2ccc(Br)cc2nc1Cc1ccccc1
Yield: 146.9 %

Procedure:
A mixture of 1.28 g of 2-benzyl-7-bromo-3-methoxyquinoline obtained in Example 209d, 990 mg of n-hexadecyl-tri-n-butylphosphonium bromide, 12 ml of 47% hydrobromic acid and 10 ml of acetic acid was heated under reflux for 12 hours. After cooling as it was, the reaction solution was slowly poured into an aqueous potassium carbonate solution and the mixture was extracted with diethyl ether. The organic phase was washed with brine and the solvent was removed, to give 1.8 g of the target compound (including n-hexadecyl-tri-n-butylphosphonium bromide) as a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)=O.[NH2:17][C:18](N)=[O:19].[OH-].[Na+]>C(O)(=O)C>[CH3:16][N:13]1[CH2:14][CH2:15][CH:10]([C:8]2[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:1][C:18](=[O:19])[N:17]=2)[CH2:11][CH2:12]1
Reactant: CN1CCC(C(=O)c2ccccc2N)CC1
Reactant: NC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCC(c2nc(=O)[nH]c3ccccc23)CC1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A stirred mixture of (2-aminophenyl)(1-methylpiperidin-4-yl)methanone (1.10 g, 4.58 mmol), urea (550 mg, 9.17 mmol) and acetic acid (15 mL) was heated to overnight. The mixture was cooled to rt, neutralized with 1 N sodium hydroxide and concentrated to ˜10 mL on a rotary evaporator. The aqueous residue was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated on a rotary evaporator to afford 4-(1-methylpiperidin-4-yl)quinazolin-2(1H)-one as a yellow solid (1.10 g, 97%).
Reaction SMILES: C([NH:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][NH:33]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:53]>>[ClH:53].[ClH:53].[ClH:53].[ClH:53].[NH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][NH2:20]
Reactant: c1ccc(C(NCCNCCCCCCNCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: NCCNCCCCCCNCCN

Procedure:
A mixture of N,N′-bis(2′-tritylaminoethyl)-1,6-diaminohexane (1.0 g 1.45 mmol) and 6 M HCl (30 ml) was refluxed for 3 h. Then the mixture was filtered and the filtrate was concentrated to about 3 ml over vacuo. Addition of methanol into the concentrated solution afforded a white salt.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH2:14])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>O1CCCC1.C(OCC)(=O)C>[CH2:1]([NH:14][CH2:13][CH:12]([O:15][CH2:16][CH3:17])[O:11][CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(CN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(CNCc1ccccc1)OCC
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A solution of benzaldehyde 5.1 ml (50.0 mmol) in 2,2-diethoxyethanamine 10.9 ml (75.0 mmol) was stirred at room temperature for 0.5 hour. The reaction mixture was diluted with tetrahydrofuran 450 ml and triacetoxyborohydride 32.0 g (150 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate 500 ml and washed with saturated sodium bicarbonate 500 ml, water 500 ml and brine 500 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=70:30 to 50:50) to obtain the title compound 7.8 g (yield 70%).