Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[NH:18][CH2:17][CH2:16]2.C(=O)([O-])[O-].[K+].[K+]>C(O)CCCC>[Cl:14][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:18]3[CH:19]4[CH2:22][CH2:23][N:15]([CH2:21][CH2:20]4)[CH2:16][CH2:17]3)[S:3][C:4]=2[C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1c(Cl)ccc2nc(Cl)sc12
Reactant: C1CN2CCC(CC2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: O=[N+]([O-])c1c(Cl)ccc2nc(N3CCN4CCC3CC4)sc12
Temperature: 150 °C

Procedure:
1.29 g (5.15 mmol) of 2,6-dichloro-7-nitrobenzothiazole, 0.65 g (5.15 mmol) of 1,4-diazabicyclo[3.2.2]nonane, 0.71 g (5.15 mmol) of potassium carbonate and 60 ml of pentan-1-ol are successively introduced into a 250 ml round-bottomed flask. The mixture is heated at 150° C. for 14 h and is then cooled to ambient temperature before being filtered. The solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with a 98/2/0.2 mixture of chloroform, ethanol and aqueous ammonia. After recrystallizing from isopropyl alcohol, 0.54 g of crystals is collected by filtration.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-])=O)(=[O:4])=[O:3].[H][H]>C(#N)C.[Pt]>[CH3:1][S:2]([CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])(=[O:4])=[O:3]
Reactant: [H][H]
Reactant: CS(=O)(=O)CCOCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CC#N
Product: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12

Procedure:
Solid Pt/C (0.9 g of 5%) was added to a suspension of N-{2-[2-(methylsulfonyl)ethoxy]ethyl}-3-nitroquinolin-4-amine (9 g, 26.5 mmol) in acetonitrile (133 mL) in a Parr vessel. The vessel was placed on a shaker and then pressurized with hydrogen to 50 psi (3.4×105 Pa). After 3 hours the reaction mixture was purged with nitrogen and then filtered through a layer of CELITE filter agent. The filter cake was washed with acetonitrile (200 mL) until the washes were clear. The filtrate was concentrated under reduced pressure to provide N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine as a yellow oil.
Reaction SMILES: COC1C=CC([C:9]2[C:10]([N+]([O-])=O)=[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19](C4C=CC(OC)=CC=4)[C:18]=3[N+:32]([O-])=O)[CH:12]=[CH:13][C:14]=2Cl)=CC=1.C[C:39](C)=[O:40].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:11]2[CH:10]=[CH:9][C:14]([O:40][CH3:39])=[CH:13][CH:12]=2)=[C:18]([CH:19]=1)[NH2:32]
Reactant: COc1ccc(-c2c(Cl)ccc(Oc3ccc(Cl)c(-c4ccc(OC)cc4)c3[N+](=O)[O-])c2[N+](=O)[O-])cc1
Reactant: CC(C)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(Oc2ccc(Cl)cc2N)cc1

Procedure:
An 80.0 g. portion of the above nitro derivative in 800 ml. of acetone is added to 320.0 g. of sodium hydrosulfite in 800 ml. of water. The mixture is heated to reflux on a steam bath for one hour, cooled and extracted with benzene. The benzene extract is washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo to a yellow oil. Treatment in hexane, with cooling produces crystals of 5-chloro-2-(p-methoxyphenoxy)-aniline.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:12]1[N:17]=[C:16]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=3)=[CH:23][CH:22]=2)[C:15]([F:39])=[CH:14][N:13]=1>CN(C)C=O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][O:18][C:16]3[C:15]([F:39])=[CH:14][N:13]=[C:12]([O:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:17]=3)=[CH:26][CH:25]=2)=[CH:29][C:30]=1[C:35]([F:36])([F:38])[F:37]
Reactant: OCc1ccccc1
Reactant: Fc1cnc(Cl)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cnc(OCc2ccccc2)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of phenylmethanol (100 μL, 0.965 mmol) in N,N-dimethylformamide (DMF) (8 mL) was added sodium hydride (232 mg, 5.79 mmol) 0° C., the 2-chloro-4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-fluoropyrimidine (432 mg, 0.965 mmol) was added at 0° C. after 10 min. The reaction mixture was stirred for 30 min, and poured into ice-water (100 mL), extracted with ethyl acetate (50 mL) twice. Combined organic parts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification via ISCO system afforded the title product (370 mg). LC-MS (ESI): m/z 519[M+H]+; 6.26 min (ret time).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:17]2[C:12](=[CH:13][C:14](I)=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]1.[CH2:25]([NH:27][C:28]([NH:30][C:31]1[CH:36]=[C:35]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=2)[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)=[O:29])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:25]([NH:27][C:28](=[O:29])[NH:30][C:31]1[N:32]=[CH:33][C:34]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[N:8]([C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]2[OH:1])[CH:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]3=[O:19])=[C:35]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=2)[CH:36]=1)[CH3:26]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1cn([C@@H]2CCCC[C@@H]2O)c2ccc(I)cc2c1=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H]2CCCC[C@@H]2O)cn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Palladium (II) acetate (0.027 g, 0.12 mmol) and 1,1′-bis(di-t-butylphosphino)ferrocene (0.058 g, 0.12 mmol) were dissolved in 1 ml of acetonitrile. Ethyl 1-(cis-2-hydroxycyclohexyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 121, 0.539 g, 1.22 mmol) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 17, 0.444 g, 1.23 mmol) were added along with an additional 2 ml of acetonitrile. Potassium carbonate (0.253 g, 1.83 mmol) was dissolved in water (1.333 mL) then added to the mixture. The reaction was stirred at 100° C. for 30 min, then cooled to room temperature and quenched with water (2 ml). The precipitate was filtered off and washed with water, ethyl acetate and hexanes, then dried in a vacuum oven at 50° C. for 18 h to give 0.606 g (78%) of ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(cis-2-hydroxycyclohexyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a light brown solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])(=O)C.[OH-].[Li+].C(OCC)(=O)C.[Cl-].[Na+]>CO.O>[OH:4][C:5]1[CH:6]=[C:7]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)Oc1cc(CC(=O)OC(C)(C)C)cc(C)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(CC(=O)OC(C)(C)C)cc(O)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 104.2 %

Procedure:
A solution of t-butyl 3-acetoxy-5-methyl-4-nitrophenylacetate (0.5 g, Reference Example 12) in methanol (6 mL) was treated with lithium hydroxide (0.2 g) in water (1.5 mL). After stirring for 2 hours the mixture was carefully acidified to pH 5 and then treated with ethyl acetate and sodium chloride. The organic layer was evaporated and the residue was dissolved in dichloromethane. This solution was dried and then evaporated to give the title compound (0.45 g) as a yellow green oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[C:19]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH2:22][CH2:23][NH:24][CH:25]3[CH3:30])=[C:18]([CH3:31])[O:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:26](=[CH:27][CH:28]=[CH:29][C:20]=4[C:19]4[C:15]([CH3:14])=[N:16][O:17][C:18]=4[CH3:31])[CH:25]3[CH3:30])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1noc(C)c1-c1cccc2c1CCNC2C
Product: Cc1noc(C)c1-c1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:18])([F:17])[C:13]1[N:11]2[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Product: N#Cc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 4-formylbenzonitrile was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]piperazin-1-yl]methyl]benzonitrile.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([OH:18])=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2].[N:19]1([CH2:25][CH2:26]Cl)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].C(O)C>CC(C)=O>[C:1]([NH:4][C:5]1[C:6]([O:18][CH2:26][CH2:25][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: COc1c(NC(C)=O)c(O)c(OC)c2occc12
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1c(NC(C)=O)c(OCCN2CCCCC2)c(OC)c2occc12

Procedure:
A mixture of 25.1 g (0.1 mole) of 5-acetamido 4,7-dimethoxy 6-hydroxy benzofuran, 22.2 g (0.15 mole) of 2-piperidino chlorethane and 41.6 g (0.3 mole) of potassium carbonate in 250 ml of acetone was brought to reflux for 2 hours. Then it was filtered, the solvent evaporated, the residue obtained was taken up again in acetone and 20 ml of 7 N hydrochloric ethanol were added. It was filtered and recrystallized in 400 ml of propanol.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:3]1([CH3:26])[CH3:25].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:25][C:3]1([CH3:26])[CH2:2][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]1[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc([N+](=O)[O-])cc1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc([N+](=O)[O-])cc1)N2
Yield: 81.6 %

Procedure:
To a solution of methyl 4-hydroxy-3,3-dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (61 mg 0.18 mmol) and triethylsilane (0.06 mL, 0.34 mmol) in dichloromethane (10 mL) was added dropwise a solution of trifluoroacetic acid (0.04 mL, 0.51 mol) in dichloromethane (5 mL) below 0° C. Upon completion of addition, the resultant mixture was stirred at room temperature for 24 h, then was quenched with sodium bicarbonate solution and separated. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to afford 50 mg of methyl 3,3-dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid Yield: 78%. Methyl-3,3-dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (110 mg, 0.32 mmol) was dissolved in methanol/water Solution, iron powder (25 mg, 3.2 mmol) was added. The reaction mixture was heated to reflux for 2 hrs The mixture was filtered, the filtration was concentrated and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=4:1) to afford 95 mg of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid. (yield: 96%). MS (ESI+APCI) M+1=311.5.
Reaction SMILES: BrCC1C=CN2C=1C(Cl)=NC=N2.C([O-])(O)=O.[Na+].Cl[C:19]1[C:24]2=[C:25]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:26]=[CH:27][N:23]2[N:22]=[CH:21][N:20]=1.[CH2:34]([N:41]1[C:49]2[C:44](=[CH:45][C:46]([NH2:50])=[CH:47][CH:48]=2)[CH:43]=[N:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.FC1C=C(C=CC=1)CN1C2C(=CC(N)=CC=2)C=N1.C(Cl)C1C=CC=CC=1>COCCO.C(Cl)Cl.CC#N>[CH2:34]([N:41]1[C:49]2[C:44](=[CH:45][C:46]([NH:50][C:19]3[C:24]4=[C:25]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:26]=[CH:27][N:23]4[N:22]=[CH:21][N:20]=3)=[CH:47][CH:48]=2)[CH:43]=[N:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COCCOCc1ccn2ncnc(Cl)c12
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Agent: Clc1ncnn2ccc(CBr)c12
Agent: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Agent: O=C([O-])O
Solvent: CC#N
Solvent: COCCO
Solvent: ClCc1ccccc1
Product: COCCOCc1ccn2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 21 %

Procedure:
A suspension of 5-bromomethyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (50 mg, 0.202 mmole and NaHCO3 (75 mg, 4.4 equiv) in 2-methoxyethanol (1.0 mL) under N2 was left stirring at RT for 6 hr. The reaction was diluted with DCM, extracted with water and dried (Na2SO4). Removal of the solvent left 4-chloro-5-(2-methoxy-ethoxymethyl)-pyrrolo[2,1-f][1,2,4]triazine (41 mg, 84%) as an oil. 1H NMR (CDCl3) δ 3.40 (s, 3H), 3.67 (m, 4H), 4.96 (s, 2H), 7.05 (d, 1H, J=3 Hz), 7.82 (d, 1H, J=1 Hz), 8.16 (s, 1H). A suspension of 4-chloro-5-(2-methoxy-ethoxymethyl)-pyrrolo[2,1-f][1,2,4]triazine (5 mg, 0.020 mmole), NaHCO3 (3 mg, 2 equiv) and 1-benzyl-1H-indazol-5-ylamine (4.5 mg, 1 equiv, prepared in the same manner as 1-(3-fluoro-benzyl)-1H-indazol-5-ylamine but using benzyl chloride) in dry CH3CN (0.5 mL) was left stirring at RT for 2 hr. The reaction was diluted with DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (1 mm silica gel plate, gradient elution with DCM containing 0 to 1% MeOH) afforded the product as and oil (1.8 mg, 21%). 1H NMR (CDCl3) δ 3.16 (s, 3H), 3.63 (m, 4H), 4.83 (s, 2H), 5.53 (s, 2H), 6.48 (d, 1H, J=3 Hz), 7.1-7.5 (m, 8H), 7.88 s, 1H), 7.96 (s, 1H), 8.11 (s, 1H), 9.56 (s, 1H); MS: 429 (M+H)+; HPLC Ret Time: 2.58 min (YMC C18 S5, 4.6×50 mm, 3 min gradient (starting with 0% solvent B and ending with 70% solvent B), 4 mL/min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=1[CH2:10][CH2:11][N:12]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[C:37]1([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>O1CCCC1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH2:11][CH2:10][C:9]1[CH:33]=[CH:34][CH:35]=[CH:36][C:8]=1[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:46]1[CH2:47][CH2:48][N:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:44][CH2:45]1)[CH3:21]
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OCCCCCBr)Cc1ccc(C(=O)OC)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCCCN(CCc1ccccc1OCCCCCN1CCN(c2ccccc2)CC1)Cc1ccc(C(=O)OC)cc1

Procedure:
200.0 mg (0.355 mmol) of methyl 4-{[{2-[(5-bromopentyl)oxy]phenethyl}(5-ethoxy-5-oxopentyl)amino]methyl}benzoate from Ex. 107, 69.21 mg of N-phenylpiperazine and 71.95 mg (0.711 mmol) of triethylamine in 2 ml of tetrahydrofuran are heated at reflux for 18 hours. The reaction solution is washed with water, concentrated and chromatographed over silica gel using the mobile phase ethyl acetate/methanol 10/1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][N:12]([CH3:25])[CH2:13][CH2:14][CH2:15][C:16]1[C:17]([CH3:24])=[C:18]([CH:22]=O)[NH:19][C:20]=1[CH3:21]>>[CH3:25][N:12]([CH3:11])[CH2:13][CH2:14][CH2:15][C:16]1[C:17]([CH3:24])=[C:18]([CH:22]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[NH:19][C:20]=1[CH3:21]
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Reactant: O=C1Cc2ccccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1CCCN(C)C
Yield: 52 %

Procedure:
2-Oxindole (133 mg, 1.0 mmol) was condensed with 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) using method B to give 168.3 mg (52%) of 3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][N:13]1[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]1=[O:23])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([CH3:31])[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][C:25]1[CH:26]=[C:27]([C:2]2[NH:3][C:4]3[C:9]([C:10]=2[CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]2=[O:23])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:28]=[C:29]([CH3:31])[CH:30]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1c(Br)[nH]c2ccccc12
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-[2-(2-bromo-1H-indol-3-yl)-ethyl]-isoindole-1,3-dione (150 mg in a mixture of 5 mL toluene and 5 mL ethanol) was added 3,5-dimethylphenyl boronic acid (85 mg) followed by 1.0 mL of 1M sodium carbonate. To the stirred solution was added lithium chloride (60 mg) followed by tetrakis(triphenylphosphine) palladium (28 mg) and the mixture heated to reflux on an oil bath. After 4 hours the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 5:1) gave the title compound (146 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.O=[C:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[NH2:23][C:22]1[C:3]2[C:2](=[CH:21][CH:20]=[CH:19][C:4]=2[O:5][CH2:6][CH:7]2[CH2:12][CH2:11][CH:10]([C:13](=[O:14])[NH:15][CH:16]([CH3:18])[CH3:17])[CH2:9][CH2:8]2)[N:1]=[C:25]([CH3:32])[C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CC(C)NC(=O)C1CCC(COc2cccc(N)c2C#N)CC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCC(C(=O)NC(C)C)CC3)c2c1N

Procedure:
Prepared as in Example 2a from 4-((3-amino-2-cyanophenoxy)methyl)-N-isopropylcyclohexanecarboxamide (Example 126b) and ethyl 3-oxobutanoate as a pale yellow solid (37%). 1H NMR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.4 Hz, 6H), 1.32 (t, J=7.2 Hz, 3H), 1.38-1.81 (m, 8H), 1.88 (m, 1H), 2.25 (m, 1H), 2.55 (s, 3H), 3.82 (bro, J=7.6 Hz, 1H), 4.10 (d, J=6.4 Hz, 2H), 4.31 (q, J=7.6 Hz, 2H), 6.93 (d, J=7.6 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.50 (m, 2H), 8.09 (s, 2H). MS 428 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.O[CH2:24][CH2:25][C:26](=[O:28])[CH3:27]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: CC(=O)CCO
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: CC(=O)CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IIm was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 4-hydroxybutan-2-one following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [CH2:1]([N:3]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:4]([CH3:24])[CH2:5][C:6]1[CH:23]=[CH:22][C:9]2[O:10][CH:11]([CH2:13][NH:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[O:12][C:8]=2[CH:7]=1)[CH3:2].O[N:32]1[C:36](=[O:37])[CH2:35][CH2:34][C:33]1=[O:38].C(N=C=NCCCN(C)C)C>ClCCl>[O:38]=[C:33]1[CH2:34][CH2:35][C:36](=[O:37])[N:32]1[O:19][C:18](=[O:20])[CH2:17][CH2:16][C:15]([NH:14][CH2:13][CH:11]1[O:10][C:9]2[CH:22]=[CH:23][C:6]([CH2:5][CH:4]([N:3]([CH2:1][CH3:2])[C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH3:24])=[CH:7][C:8]=2[O:12]1)=[O:21]
Reactant: O=C1CCC(=O)N1O
Reactant: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)O)O2
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)ON1C(=O)CCC1=O)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
To 150 mg (0.34 mmol) of 2K was added 15 mL of dichloromethane (distilled over CaH2) followed by 99 mg (0.86 mmol) of N-hydroxysuccinimide and 166 mg (0.86 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide. The reaction mixture was allowed to stir at room temperature under argon atmosphere for 18 hours. The reaction mixture was diluted with an additional 40 mL of dichloromethane and washed with 2×25 mL of water, 3×25 mL of saturated sodium bicarbonate, and 2×25 mL of water. The organic layer was dried (Na2SO4) and concentrated to dryness to give 154 mg (0.29 mmol, 84%) of 2L as a white solid (M+Na, 552).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[C:15]([Br:26])[CH:14]=2)[S:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH:42]=[CH:43][CH2:44]O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH:42]=[CH:43][CH2:44][N:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[S:11][CH:12]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:9]=2)=[CH:14][C:15]=1[Br:26])[C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Nc1ccc(-c2nc(Cc3ccccc3)cs2)cc1Br)C(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCN(C(=O)C(F)(F)F)c1ccc(-c2nc(Cc3ccccc3)cs2)cc1Br
Yield: 97 %

Procedure:
4-(4-Benzyl-1,3-thiazol-2-yl)-2-bromo-1-trifluoroacetylaminobenzene and (R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene were used. Chromatography using elution with a 1-5% either gradient in methylene chloride afforded the title compound (97%) as a white foam: FAB LRMS (m/z, relative intensity) 686 (MH2+, 100), 685 (MH+, 60), 684 (M+, 90), 640 (23), 578 (15), 441 (17), 371 (20); FAB HRMS calculated for [C33H29BrF3N3O3S.H]+ [with 79Br and 32S] 664.1145, found 664.1157.