Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CNC.[CH3:39][OH:40]>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([O:40][CH3:39])=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Agent: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCn1c(OC)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Temperature: 50 °C
Yield: 10.1 %

Procedure:
To a solution of 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.05 g, 0.136 mmol) in THF (5 ml) under argon was added Diisopropyl ethyl amine (0.05 g, 0.407 mmol) and 1M dimethyl amine in methanol (0.061 g, 1.36 mmol). The reaction mixture was heated at 50° C. for overnight. The reaction mixture concentrated under reduced pressure. The residue obtained was purified by column chromatography to obtain 8-(1-Benzyl-1H-pyrazol-4-yl)-2-methoxy-1-propyl-1,7-dihydro-purin-6-one (0.005 g, 10%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](C1N=CC2C(C=1)=CC=CC=2)=[O:17].[C:38]([OH:41])(=O)[CH3:39]>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][N:11]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:4]1[CH:9]=[CH:39][C:38]([OH:41])=[N:1][CH:5]=1
Reactant: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1cc2ccccc2cn1
Reactant: CC(=O)O
Product: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccc(O)nc1
Reaction time: 0.5 h

Procedure:
To a solution of the above amine (63 mg, 0.14 mmol) in acetic acid (2 mL) was added hydrobromide saturated acetic acid (2 mL). The reaction mixture was stirred for 30 minutes. Then it was triturated with diethyl ether four times to afford the title compound as a white solid (80 mg), which was dried in vacuo. 1H NMR (D2O) δ 1.81-2.01 (m, 4H), 2.16-2.20 (m, 1H), 2.37-2.41 (m, 1H), 2.50-2.59 (m, 1H), 2.87-2.92 (m, 1H), 3.00 (br s, 2H), 3.11-3.16 (m, 1H), 3.37-3.42 (m, 1H), 3.53 (q, 1H, J=6.0 Hz), 4.25 (ABq, 2H, J=43.8, 15.3 Hz), 4.57-4.79 (m, 1H), 6.36 (d, 1H, J=9.6 Hz), 7.46-7.48 (m, 2H), 7.53 (s, 1H), 7.57-7.63 (m, 3H), 7.85 (t, 1H, J=6.3 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.65 (d, 1H, J=5.4 Hz). 13C NMR (D2O) δ 20.33, 20.45, 36.87, 47.77, 48.22, 59.04, 114.10, 119.38, 125.90, 126.99, 130.69, 137.16, 139.46, 139.85, 140.66, 148.01, 150.87, 151.39. ES-MS m/z 457 [M+H]+. Anal. Calcd. for C26H28N6O2−.3.0HBr.3.4H2O.0.2C4H10O: C, 41.52; H, 5.17; N, 10.84; Br, 30.92. Found: C, 41.70; H, 4.90; N, 10.71; Br, 30.63.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[CH:38]=[C:39]([NH:43][C:44](=[O:48])[CH:45]([CH3:47])[CH3:46])[CH:40]=[CH:41][CH:42]=2)[CH2:33][CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]([NH:27][CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44](=[O:48])[CH:45]([CH3:46])[CH3:47])[CH:38]=3)[CH2:33][CH2:32]2)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1OC[C@H](c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)N3C(=O)OC[C@@H]3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure AF and Scheme H using 4-nitrophenyl (4S)-4-(3,4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 529.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[CH2:5][CH2:4][CH:3]1[CH2:17][CH2:18][OH:19].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>N1C=CC=CC=1>[C:11]1([C:8]2[C:7]3[CH:2]([OH:1])[CH:3]([CH2:17][CH2:18][O:19][S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH2:4][CH2:5][C:6]=3[O:10][N:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1CCc2onc(-c3ccccc3)c2C1O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2CCc3onc(-c4ccccc4)c3C2O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
In 30 ml pyridine was dissolved 4-hydroxy-5-(2-hydroxyethyl)-3-phenyl-4,5,6,7-tetrahydro-1,2-benzisoxazole (2.1 g) and the mixture was cooled to 0° C. Tosyl chloride (1.54 g) was added and the solution was stirred at 0° C. for 30 minutes. The reaction mixture was poured into ice water, then extracted four times with ether. The mixture was dried (Na2SO4) and then concentrated at room temperature to yield 2.67 g of 3-phenyl-5-(2-tosyloxyethyl)-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[CH2:14].[CH:20](OCC)=[O:21].[Cl-].[NH4+]>O1CCCC1>[CH:13]([N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=[O:21])=[CH2:14]
Reactant: C=Cn1ccnc1
Reactant: CCOC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=Cn1ccnc1C=O
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
To a cold (-78° C.) solution of 6.55 ml (0.047 mole) of diisopropylamine in 125 ml of tetrahydrofuran was added 16.99 ml (, 042 mole) of a 2.5M solution of n-butyl lithium over a period of 15 minutes and the resulting reaction allowed to stir for 30 minutes. 1-Vinylimidazole (3.85 ml 0.042 mole) was added over a 10 minute period and the mixture stirred for one hour. Ethyl formate (3.43 ml, 0.042 mole) was then added over 5 minutes and the mixture stirred for one hour and was then poured into a saturated ammonium chloride solution. The product was extracted with ethyl acetate, and the extracts combined, dried over magnesium sulfate and concentrated to an orange oil. The residue was chromatographed on 200 g of silica gel using 10% ethyl acetate in chloroform to give 2.23 g of the product as a crystalline material.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10]Br.[NH2:13][CH2:14][C:15]1[O:19][N:18]=[C:17]([C:20]2[N:21]=[CH:22][N:23]3[C:29]4[CH:30]=[CH:31][S:32][C:28]=4[C:27](=[O:33])[N:26]4[CH2:34][CH2:35][C@H:25]4[C:24]=23)[N:16]=1>CN(C)C=O>[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10][C:14]([CH2:10][CH:9]=[C:8]([CH3:12])[CH3:7])([NH2:13])[C:15]1[O:19][N:18]=[C:17]([C:20]2[N:21]=[CH:22][N:23]3[C:29]4[CH:30]=[CH:31][S:32][C:28]=4[C:27](=[O:33])[N:26]4[CH2:34][CH2:35][C@H:25]4[C:24]=23)[N:16]=1
Reactant: CC(C)=CCBr
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCC(N)(CC=C(C)C)c1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
2.5 g of potassium carbonate and 0.48 ml (4.1 mmol) of dimethylallyl bromide were added to a solution of 660 mg (2 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 20 ml of dimethylformamide and the mixture was stirred at room temperature for 12 hours. The reaction solution was subsequently filtered and the filtrate was partitioned between methylene chloride and water. The aqueous phase was back-extracted three times with methylene chloride; the combined organic phases were subsequently dried over sodium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 300:10:1) and there were obtained 650 mg (70%) of (S)-1-[5-[bis-(3-methyl-but-2-enyl)-aminomethyl]-1,2,4-oxadiazol-3-yl]-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.16 (silica gel, methylene chloride/methanol/aqueous ammonia 300:10:1).
Reaction SMILES: C([O:5][C:6](=[O:59])[CH2:7][C:8]([N:10]([CH2:16][C@:17]12[CH2:55][CH2:54][C@@H:53]([C:56]([CH3:58])=[CH2:57])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:52])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]2[CH:51]=[CH:50][C:42]([C:43]([O:45]C(C)(C)C)=[O:44])=[CH:41][CH:40]=2)=[CH:25][CH2:24]3)[CH2:21][CH2:20]1)[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[O:9])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:6]([CH2:7][C:8]([N:10]([CH2:16][C@:17]12[CH2:55][CH2:54][C@@H:53]([C:56]([CH3:58])=[CH2:57])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:52])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]2[CH:40]=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:50][CH:51]=2)=[CH:25][CH2:24]3)[CH2:21][CH2:20]1)[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[O:9])([OH:59])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.3 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-tert-butoxy-N-(2-(dimethylamino)ethyl)-3-oxopropanamido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (31 mg, 0.038 mmol) in dichloromethane (1 ml) was added TFA (0.25 ml, 3.24 mmol). The mixture was stirred at rt for 3 h then was concentrated under reduced pressure. The residue was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to afford 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-carboxy-N-(2-(dimethylamino)ethyl)acetamido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid as a white solid (15 mg, 0.021 mmol, 56.1% yield). LCMS: m/e 701.5 (M+H)+, 2.11 min (method 6). 1H NMR (500 MHz, Acetic acid-d3 acid-d) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.31 (d, J=8.24 Hz, 2H), 5.38 (d, J=5.19 Hz, 1H), 4.85 (d, J=16.17 Hz, 1H), 4.69 (d, J=15.56 Hz, 1H), 3.86-4.13 (m, 2H), 2.97-3.82 (m, 6H), 2.62-2.73 (m, 1H), 2.13-2.24 (m, 2H), 1.06-1.92 (m, 38H), 1.03 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C(O)CCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: NCCCCCCCCCCCCCCCCC(=O)O
Temperature: 20 °C
Yield: 42 %

Procedure:
A solution of 3.4 g of 17-phthalimidoheptadecanoic acid in 60 cm3 of methanol is stirred for 1 hour, at a temperature in the region of 80° C., in the presence of 1.67 g of hydrazine hydrate. The solution is cooled to around 20° C. and the solid is separated by filtration and dried in air. The residue (1.92 g) is taken up in 180 cm3 of distilled water. The solid is separated by filtration, washed with a total of 45 cm3 of distilled water and dried under reduced pressure (13.5 Pa) at a temperature in the region of 40° C. 980 mg of 17-aminoheptadecanoic acid are obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[C:6]([O:13][CH3:14])[CH:5]=1)(O)=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:1][C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:11])[OH:12])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: COc1cc(C(=O)O)ccc1B(O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1B(O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Carboxy-2-methoxyphenylboronic acid (500 mg, 2.5 mmol) was dissolved in THF (25 mL) and cooled to 0° C. At this temperature LAH (2 M solution in THF; 3.3 mL, 6.6 mmol) was added drop wise and the reaction mixture allowed to stir for 1 h at 0° C. and then allowed to warm to rt and stirred for 16 h. The reaction mixture was recooled to 0° C. and quenched by addition of MeOH. Celite and Na2SO4 were added, stirred for 15 min and then filtered. The filtrate was concentrated and the residue was dried under high vacuum to give the title compound which was used without further purification. tR: 0.46 min (LC-MS 2).
Reaction SMILES: S(O[CH2:8][CH3:9])(OCC)(=O)=[O:2].[CH2:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11].C(O)C.[OH-].[Na+]>>[OH-:2].[CH2:10]([N+:12]([CH2:8][CH3:9])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCN(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC[N+](CC)(CC)CC
Temperature: 140 °C
Reaction time: 4 h
Yield: 410.2 %

Procedure:
To a 1.5 L autoclave equipped with a stirrer and a heating means were added 154 g (1.0 mol) of diethyl sulfate, 101 g (1.0 mol) of triethyl amine and 690 g (15 mol) of ethanol. Stirring was initiated after the autoclave was sealed. The autoclave was heat to 140° C., and pressure was 1.0 MPa. The reaction was kept at 140° C. for 4 h. Then the reaction mixture was cooled to room temperature and discharged into a 1 L three-necked flask. 80 g (2.0 mol) of sodium hydroxide was added thereto. The reaction mixture was heated to 45° C. for 4 h while stirring. After filtration, part of ethanol was distilled off from the filtrate. Then 500 g of water was added while ethanol was distilled off (part of water was entrained out), to give 604 g of tetraethyl ammonium hydroxide solution. The content of tetraethyl ammonium hydroxide was found as 23.3 wt.-% and the total reaction yield was 95.7%.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:10]#[CH:11])[CH2:3][O:4][CH:5]1[CH2:9][CH2:8][O:7][CH2:6]1.[CH3:13][O:14][C:15]([C:17]1[S:18][C:19](I)=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1)[C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])=[O:16].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:11]#[C:10][C:2]([CH3:12])([CH3:1])[CH2:3][O:4][CH:5]2[CH2:9][CH2:8][O:7][CH2:6]2)=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:33][CH2:34][CH:35]([OH:38])[CH2:36][CH2:37]1)[C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])=[O:16]
Reactant: C#CC(C)(C)COC1CCOC1
Reactant: COC(=O)c1sc(I)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)COC2CCOC2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Yield: 75.8 %

Procedure:
A solution of 3-(2,2-dimethyl-but-3-ynyloxy)-tetrahydro-furan (169 mg, 1.00 mmol), 3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxylic acid methyl ester (404 mg, 0.80 mmol) and triethylamine (1.2 mL, 8.61 mmol) in DMF (1.2 mL) was degassed for 10 minutes with nitrogen. PdCl2(PPh3)2 (25 mg, 0.036 mmol) and CuI (6.0 mg, 0.031 mmol) was added and the resulting mixture was degassed with nitrogen for an additional 5 minutes after which the reaction was placed in a 65° C. oil bath and heated for 2.5 h. The reaction was cooled and partitioned between ethyl acetate and sat. NaHCO3. The organic layer was separated, washed with 5% LiCl, brine, dried over Na2SO4 and concentrated to give a dark brown foam. Purification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes then 5% methanol in ethyl acetate provided 5-[3,3-dimethyl-4-(tetrahydro-furan-3-yloxy)-but-1-ynyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (331 mg, 75%) as a pale yellow foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[C:11]([CH3:18])[CH:12]=[CH:13][N:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[N:27]=1>CN(C)C=O>[Br:25][C:26]1[N:27]=[C:28]([CH2:32][N:9]2[C:10]3[C:15](=[N:14][CH:13]=[CH:12][C:11]=3[CH3:18])[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(C(=O)c2c[nH]c3c(C)ccnc3c2=O)cc1C
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3c(C)ccnc3c2=O)cc1C

Procedure:
Experimental conditions analogous to described for Step 3 of Example 1 were used with 93 mg (0.318 mmol) of 3-(3,4-Dimethyl-benzoyl)-8-methyl-1H-[1,5]naphthyridin-4-one, 15 mg (0.382 mmol, 60% dispersion in oil) of sodium hydride, 95.8 mg (0.382 mmol) of 2-bromo-6-bromomethyl-pyridine and 3.0 mL of N,N-dimethylformamide. The crude brown solid was purified by flash column chromatography using 30-100% ethyl acetate in hexane to yield 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-8-methyl-1H-[1,5]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C24H20BrN3O2 [M+H]: 462.07 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 3.0 min.
Reaction SMILES: [OH:1][CH:2]([CH2:44][OH:45])[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([N:27](CC3C=CC(OC)=CC=3OC)[C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[F:49][C:48]([F:51])([F:50])[C:46]([OH:52])=[O:47].[OH:1][CH:2]([CH2:44][OH:45])[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[C:14]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:25])=[O:26])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4CC(O)CO)nccc3c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3CC(O)CO)nccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2-(2,3-dihydroxypropyl)-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.120 g, 0.182 mmol) was dissolved in DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated and the material was triturated in diethyl ether. The solids were filtered and washed with diethyl ether, then vacuum dried overnight to afford 1-(2-(2,3-dihydroxypropyl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide 2,2,2-trifluoroacetate as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.89 (br. s., 1H), 8.71 (dd, J=2.0, 5.7 Hz, 1H), 8.59 (d, J=4.1 Hz, 1H), 8.25-8.12 (m, 1H), 7.94-7.83 (m, 2H), 7.76-7.64 (m, 2H), 7.51 (t, J=7.8 Hz, 1H), 7.28 (d, J=4.4 Hz, 1H), 6.88 (d, J=4.6 Hz, 1H), 4.04 (d, J=4.9 Hz, 1H), 3.53-3.44 (m, 1H), 3.29 (d, J=3.8 Hz, 1H), 3.10-3.02 (m, 1H), 3.02-2.94 (m, 1H), 2.87 (dd, J=4.0, 14.3 Hz, 1H), 2.37-2.29 (m, 1H). m/z (ESI) 510.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][N:19]=[C:20]=[O:21].O1CCCC1>CN(C)C=O>[CH3:18][NH:19][C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Reaction time: 3.5 h
Yield: 23 %

Procedure:
A solution of 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.046 mL (0.78 mMol) methyl isocyanate in 6 mL 5:1 tetrahydrofuran:dimethylformamide was stirred at room temperature for 5 hours. At this point an additional 0.020 mL methyl isocyanate were added and stirring continued for another 3.5 hours. The reaction mixture was then concentrated under reduced pressure. The residue was partitioned between 3:1 chloroform:isopropanol and 1N sodium hydroxide. The phases were separated and the aqueous phase extracted well with 3:1 chloroform:isopropanol. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (2 mm silica gel plate), eluting with dichloromethane containing from 20-40% methanol and 1% ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure. The residue was crystallized from aqueous ethanol to provide 0.043 gm (34%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2cccc(C)c2C1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2cccc(C)c2C1=O

Procedure:
The mixture of 3.94 g of N-(4-nitro-o-tolyl)-3-methylphthalimide, 200 ml of ethyl acetate and 2.2 g of Raney nickel (pre-washed with water and ethyl acetate) is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is filtered, evaporated, the residue triturated with chloroform, filtered again, the filtrate evaporated and the residue recrystallized from methanol, to yield the N-(4-amino-o-tolyl)-3-methylphthalimide of the formula ##STR5## melting at 209°-211°.
Reaction SMILES: [CH2:1]1[C:8]2[C:7]3[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1.[C:14](Cl)(=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17]>N1C=CC=CC=1>[CH2:1]1[C:8]2[C:7]3[CH:9]=[C:10]([NH:13][C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1
Reactant: Nc1ccc2oc3c(c2c1)CCC3
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1ccc2oc3c(c2c1)CCC3
Yield: 65.1 %

Procedure:
Following the procedure of Example 1, 2,3-dihydro-1H-cyclopenta[b]benzofuran-7-ylamine (0.69 g, 4.0 mmol) and isovaleryl chloride (0.55 mL, 4.4 mmol) in pyridine (10 mL) provided N-(2,3-Dihydro-1 H-cyclopenta[b]benzofuran-7-yl)-3-methyl-butyramide (0.67 g). Mp 162.0-163.0° C.; Anal. Calcd. for C16H19NO2: C, 74.68; H, 7.44; N, 5.44; Found: C, 74.67; H, 7.70; N, 5.39.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](I)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:14]2[O:13][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH:15]=2)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: O=C1NCc2c(Cl)ccc(I)c21
Reactant: OB(O)c1cc2ccccc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1NCc2c(Cl)ccc(-c3cc4ccccc4o3)c21
Yield: 18.5 %

Procedure:
In a similar manner to Step 2 of Example 1, 4-chloro-7-iodoisoindolinone (80.0 mg, 0.273 mmol) was dissolved in acetonitrile (4.0 mL), and the solution was treated with 2-benzofuraneboronic acid (133 mg, 0.819 mmol), palladium acetate (7.4 mg, 0.033 mmol), tri(o-tolyl)phosphine (20 mg, 0.066 mmol) and triethylamine (0.381 mL, 2.73 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=15/1) to obtain Compound 170 (14.3 mg, yield 18%).