Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]([CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37])[CH:31]=[C:32]([F:34])[CH:33]=1.Cl>>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:39][C:36]([CH3:37])([CH3:38])[CH2:35][C:30]2[CH:29]=[C:28]([F:27])[CH:33]=[C:32]([F:34])[CH:31]=2)[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(N)Cc1cc(F)cc(F)c1
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Agent: Cl
Product: CC(C)(Cc1cc(F)cc(F)c1)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2

Procedure:
Prepared from 1.73 g (4.84 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.80 g (4.32 mmol) of 2-(3,5-difluorophenyl)-1,1-dimethylethylamine in the usual way. Yield: 1.50 g (58%, hydrochloride); melting point: 240° C.-244° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][CH2:34][CH:35]3[O:39][CH2:38][CH2:37][O:36]3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:23]=[C:22]([S:33]([CH2:34][CH:35]3[O:39][CH2:38][CH2:37][O:36]3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:30][CH:29]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(SCC3OCCO3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)CC3OCCO3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.19 g (80%) of 3-chloroperbenzoic acid in 100 ml. of dichloromethane is added dropwise to a solution of 1.99 g. of [4,5-bis(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-ylmethyl)sulfide in 150 ml. of dichloromethane. The mixture is stirred for 4 hours at room temperature, then washed with sodium bicarbonate solution; the organic solution is dried over sodium sulfate and concentrated under vacuum. The residue is crystallized from ethyl acetate/hexane. After recrystallization from ethyl acetate/hexane, 1.43 g. of [4,5-bis-(4-methoxyphenyl)-2-imidazolyl]-(1,3-dioxolan-2-ylmethyl)-sulfoxide is obtained, m.p. 203°-204°.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([SH:13])[S:12][C:8]=2[CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1.O>[OH:3][CH2:4][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([SH:13])[S:12][C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1ccc2nc(S)sc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2nc(S)sc2c1
Yield: 97.2 %

Procedure:
A solution of 6-ethoxycarbonyl-2-mercaptobenzothiazole (1.14 g, 4.64 mmol) in anhydrous tetrahydrofuran (14 mL) was heated to reflux under a nitrogen atmosphere and stirred while 1M lithium aluminum hydride in tetrahydrofuran (4.7 mL) was added dropwise. The resulting mixture was stirred and heated at reflux for one hour, then cooled in an ice bath and cautiously treated with 2N hydrochloric acid. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×25 mL). The combined extracts were washed with brine (25 mL), dried over sodium sulfate, filtered and evaporated under vacuum to provide 6-hydroxymethyl-2-mercaptobenzothiazole (0.89 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH2:21][NH2:22])[CH2:13][CH2:12]1)[CH3:3].[CH3:26][CH:27]1[CH2:33][C:32](=O)[O:31][C:29](=[O:30])[CH2:28]1>C1COCC1>[CH3:26][CH:27]1[CH2:28][C:29](=[O:30])[N:22]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH:2]([CH3:1])[CH3:3])[CH2:12][CH2:13]3)[CH:19]=2)[C:32](=[O:31])[CH2:33]1
Reactant: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CN)c2)CC1
Reactant: CC1CC(=O)OC(=O)C1
Solvent: C1CCOC1
Product: CC1CC(=O)N(Cc2cccc(CN3CCN(c4ccccc4OC(C)C)CC3)c2)C(=O)C1
Temperature: 100 °C

Procedure:
A solution of 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzyl amine (2.32 g, 6.84 mmol; prepared as described in Example 7), 3-methylglutaric anhydride (0.88 g, 6.84 mmol), and THF (20 mL) was stirred at room temperature for 3 h and then concentrated to an oily residue. This material was dissolved in acetic anhydride (25 mL), heated at 100° C. for 4 h, cooled, and added slowly to saturated aqueous NaHCO3. Extraction with CH2Cl2, separation of the organic layer, drying, filtration and evaporation afforded an oil. This material was chromatographed on flash grade silica using 97:3/CH2Cl2 :MeOH to give 4-methyl-1-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]piperidine-2,6-dione as an oil. This was dissolved in ether and added to ethereal HCl causing a solid to form. Filtration afforded 4-methyl-1-[[3-[[ 1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]piperidine-2,6-dione dihydrochloride (1.43 g, 40%), m.p. 196°-200° C. H-1 NMR and mass spectral analysis supported the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:11])[C:7]=1[C:8]([OH:10])=[O:9].Cl.[CH3:13][N:14]([CH3:16])O.C(N(CC)CC)C.O>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][N:14]([CH3:16])[CH3:13])=[O:9])=[C:6]([OH:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(O)cccc1Cl
Reactant: CN(C)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)OC(=O)c1c(O)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.73 Grams of 6-chlorosalicylic acid was dissolved in 20 ml of tetrahydrofuran, and 1.95 g of N,N'-carbonyldiimidazole was added. After stirring at room temperature for 30 minutes, 1.47 g of N,N-dimethylhydroxylamine hydrochloride and 1.52 g of triethylamine were added, and the resulting mixed solution was stirred at room temperature for 7 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to column chromatography to obtain 1.1 g of 3-chloro-2-(N,N-dimethylaminooxycarbonyl)phenol.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Br[C:32]1[N:33]=[C:34]2[CH:40]=[C:39]([C:41]3[C:49]4[C:44](=[CH:45][CH:46]=[C:47]([O:50][CH3:51])[CH:48]=4)[N:43]([CH3:52])[CH:42]=3)[N:38]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:35]2=[N:36][CH:37]=1.[NH:61]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[NH2:62].CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:51][O:50][C:47]1[CH:48]=[C:49]2[C:44](=[CH:45][CH:46]=1)[N:43]([CH3:52])[CH:42]=[C:41]2[C:39]1[N:38]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:35]2=[N:36][CH:37]=[C:32]([NH:62][NH:61][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[N:33]=[C:34]2[CH:40]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3nc(NNC(=O)OC(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 80 °C
Yield: 70.1 %

Procedure:
A round bottom flask was charged with tris(dibenzylidineacetone)dipalladium(0) (0.066 g, 0.072 mmol) and di-tert-butyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.061 g, 0.14 mmol) in 1,4-dioxane (10 mL) to give a black solution which was degassed via vacuum/nitrogen purge (3 times). The mixture was heated to about 80° C. for about 10 min. To the reaction mixture were added 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.35 g, 0.72 mmol, Example #20, Step D) and tert-butyl hydrazinecarboxylate (0.142 g, 1.08 mmol), followed by sodium tert-butoxide (0.104 g, 1.08 mmol). The mixture was heated at about 80° C. for about 20 min. The reaction mixture was cooled and filtered through Celite®. The filter pad was further rinsed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure and purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to give tert-butyl 2-(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazine-carboxylate (0.272 g, 70%): LC/MS (Table 1, Method d) Rt=1.78 min; MS m/z: 539 (M+H)+.
Reaction SMILES: ClS([N:5]=C=O)(=O)=O.[Br:8][C:9]1[N:10]([O:25][CH3:26])[C:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:12]([Br:17])[C:13]=1[C:14](O)=O.CN(C)C=O>O.C(Cl)Cl.C(OCC)(=O)C>[Br:8][C:9]1[N:10]([O:25][CH3:26])[C:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:12]([Br:17])[C:13]=1[C:14]#[N:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COn1c(Br)c(C(=O)O)c(Br)c1-c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COn1c(Br)c(C#N)c(Br)c1-c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
Chlorosulfonyl isocyanate (1.66 g, 0.0117 mol) is added to a 5° C. stirred solution of 2,4-dibromo-5-(p-chlorophenyl)-1-methoxypyrrole-3-carboxylic acid (2.0 g, 0.0049 mol) in acetronitrile. The solution is heated to 45°-50° C. for 2 hours, acetronitrile is added, cooled to 5° C. and dimethylformamide (1.9 mL, 0.0244 mol) is added. The reaction mixture is stirred at room temperature for 3 hours, diluted with water and extracted with chloroform. The combined chloroform extracts are washed sequentially with water and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow solid. Chromatography using silica gel, methylene chloride and 3% ethyl acetate in methylene chloride as eluent yields the title compound as an off-white solid (0.23 g, 12%), mp 195°-197° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]1[O:12][C:10](=[O:11])[C@@H:8]([OH:9])[C@H:6]1[OH:7])[OH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[O:11]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[C@@H:10]1[O:12][C@@H:5]2[C@@H:3]([C:2]([O:7][C@@H:6]2[C@H:8]1[OH:9])=[O:1])[OH:4]
Reactant: O=C[C@H](O)[C@H]1OC(=O)[C@@H](O)[C@H]1O
Reactant: CCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCCO[C@@H]1O[C@H]2[C@H](OC(=O)[C@H]2O)[C@H]1O
Temperature: 110 °C

Procedure:
20 g of Glucurono-6,3-lactone (0.11 mole), 0.2 g p-toluenesulfonic acid (1.05×10-3 mole) and 164.0 g of dodecanol (0.88 mole) were placed in a three-necked flask equipped with a mechanical stirrer, thermometer and short path distillation head. The mixture was heated to 110° C. until D-glucurono-6,3-lactone dissolved. The reaction mixture was neutralized with 1 ml of 1N methanolic KOH at 25° C., filtered over silica and washed with methanol. A vacuum was applied to remove the methanol and dodecanol yielding a syrup. Hexane was added and dodecyl β-D-glucofuranosidurono-6,3-lactone crystallized selectively. The yield was 15.9 g (42%). The product was recrystallized from hexane/ether mixture. MP 88°-89° C. (99.9% pure).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2[CH:17]=[CH:18][S:19][C:13]=2[N:12]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:11]1=[O:24].[CH3:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[CH:35]=[O:36]>O1CCCC1>[OH:36][CH:35]([C:18]1[S:19][C:13]2[N:12]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:11](=[O:24])[N:10]([CH3:9])[C:15](=[O:16])[C:14]=2[CH:17]=1)[C:27]1[N:26]([CH3:25])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Reactant: Cn1c(C=O)nc2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(O)c3nc4ccccc4n3C)sc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
A solution of lithium diisopropylamide (3.15 mmol) in anhydrous tetrahydrofuran (5 ml) was added to a solution of 3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (500 mg) in anhydrous tetrahydrofuran (20 ml) at −78° C. After 10 minutes, 1-methylbenzimidazole-2-carboxaldehyde (600 mg) was added and the resultant solution kept at −78° C. for 1 hour. The reaction mixture was allowed to warm to ambient temperature and quenched with saturated sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate and washed with saturated sodium hydrogen carbonate and then brine, then dried over a mixture of magnesium sulfate and silica, filtered, and evaporated. Purification by HPLC over silica eluting with an isohexane:ethyl acetate gradient (4:1 to 0:1) gave the title compound (0.13 g).
Reaction SMILES: CC1(C)O/[C:5](=[CH:7]/[C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])/[CH2:4][O:3]1.[NH:16]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17]>C(O)C>[Cl:24][C:23]1[C:18]([N:16]2[C:8]([OH:14])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][C:5]([CH2:4][OH:3])=[N:17]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(=O)/C=C1\COC(C)(C)O1
Reactant: NNc1ncccc1Cl
Solvent: CCO
Product: CCOC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.1 %

Procedure:
The mixture of ethyl (3E)-3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate (21.4 g, 0.1 mol) and 2-hydrazino-3-chloropyridine (21.4 g, 0.15 mol) in 150 ml of ethanol was stirred for 8 hours at RT. Ethanol was removed in vacuo and the residue was taken up in 200 ml of methyl tert-butyl ethyl. The organic phase was washed three times with in each case 50 ml of 1% HCl and concentrated by evaporation. This gave 36 g (86% yield) of the product as a viscous oil with a purity (HPLC) of 97%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2CCC[N:9]2C)=[CH:4][CH:3]=1.F[B-](F)(F)F.F[B-](F)(F)F.C1(P(C2CCCCC2)CCCP(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-:54].[K+].[K+].NC1C=CC(C)=C(C2C=C3C(C=C(NC(C4CC4)=O)N=C3)=CC=2)C=1.CN(C)C=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]([NH2:9])(=[O:54])[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CN1CCCC1c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: C1CCC(P(CCCP(C2CCCCC2)C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Reaction time: 15 h

Procedure:
A flask containing a mixture of 2-(4-bromophenyl)-1-methylpyrrolidine (58.8 mg, 0.245 mmol), palladium acetate (8.9 mg, 0.040 mmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (35.5 mg, 0.0582 mmol), potassium carbonate (79.0 mg, 0.572 mmol), and N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (89.0 mg, 0.280 mmol) in N,N-dimethylformamide (2.0 mL, 26 mmol) was evacuated purged with nitrogen five times, and then evacuated and purged three times with CO gas. The reaction was stirred under a CO gas balloon, at 100° C., for 15 hours. The reaction mixture was poured into ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-10% methanol in dichloromethane) followed by purification via reverse phase HPLC and lyophilized to yield 10.3 mg (8%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-4-(1-methylpyrrolidin-2-ye benzamide. LCMS (ESI): RT (min)=4.125, M+H=505.3, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.20 (s, 1H), 9.20 (s, 1H), 8.50 (s, 1H), 8.02 (s, 1H), 7.92 (t, J=8.2 Hz, 3H), 7.79 (s, 1H), 7.77-7.67 (m, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.3 Hz, 1H), 2.26 (s, 3H), 2.21-2.13 (m, 1H), 2.10 (m, 4H), 1.79 (m, 4H), 1.71-1.50 (m, 2H), 0.85 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[CH:13]([C:16]1[N:21]=[C:20]([NH2:22])[CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:22][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:13]([CH3:15])[CH3:14])[N:21]=2)[CH:7]=1
Reactant: CC(C)c1cccc(N)n1
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: COC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)C)n1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A stirred solution of methyl 4,6-dichloropyridazine-3-carboxylate (255 mg, 1.23 mmol) and 6-isopropylpyridin-2-amine (252 mg, 1.85 mmol) in acetonitrile (8.0 mL) was heated at 140° C. for 21 h. After cooling to room temperature the reaction mixture was concentrated in vacuo, then the residue purified by chromatography (silica, 20-45 μm, 80 g, Thomson, 0 to 10% acetone in dichloromethane, 20 min) to give methyl 6-chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxylate (113 mg, 30%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.64 (br. s., 1H) 9.39 (s, 1H) 7.63 (t, J=7.83 Hz, 1H) 6.94 (d, J=7.58 Hz, 1H) 6.78 (d, J=8.08 Hz, 1H) 4.12 (s, 3H) 3.01-3.19 (m, 1H) 1.31-1.42 (m, 6H). LCMS (EI/CI) m/z: 307 [M+H].
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH2:18])[CH2:14][CH2:15][CH2:16][NH2:17]>>[CH2:13]([NH:18][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH2:15][CH2:16][NH:17][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC1CO1
Reactant: NCCCCN
Product: CCCCCCCCCC(O)CNCCCCNCC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and 1,4-butanediamine affords N,N'-(1,4-butylene)-bis[2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = H, X = (CH2)4, Z = H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C@H:36]([C:40]([N:42]([CH:57]2[CH2:65][C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH2:58]2)[CH2:43][C:44]([NH:46][CH:47]([CH:54]([CH3:56])[CH3:55])[C:48](=[O:53])[C:49]([F:52])([F:51])[F:50])=[O:45])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])=[CH:29][CH:28]=1)(O)=[O:25]>>[CH2:12]([O:19][C:20]([CH2:21][NH:22][C:24]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:35][C@H:36]([C:40]([N:42]([CH:57]2[CH2:58][C:59]3[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH2:65]2)[CH2:43][C:44]([NH:46][CH:47]([CH:54]([CH3:56])[CH3:55])[C:48](=[O:53])[C:49]([F:51])([F:52])[F:50])=[O:45])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])=[CH:31][CH:32]=1)=[O:25])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)C(NC(=O)CN(C(=O)[C@@H](NC(=O)c1ccc(C(=O)O)cc1)C(C)C)C1Cc2ccccc2C1)C(=O)C(F)(F)F
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)C(NC(=O)CN(C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCC(=O)OCc2ccccc2)cc1)C(C)C)C1Cc2ccccc2C1)C(=O)C(F)(F)F
Yield: 97.1 %

Procedure:
3(RS)-[[4-[(Benzyloxycarbonyl)methylaminocarbonyl]phenylcarbonyl]-L-valyl-N-(2-indanyl)glycyl]amino-1,1,1 -trifluoro-4-methyl-2-oxopentane (250 mg) was prepared from glycine benzyl ester p-toluenesulfonate (118 mg) and 3(RS)-[(4-carboxyphenylcarbonyl)-L-valyl-N-(2-indanyl)glycyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (206 mg) by a similar method to that of Example 1.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=O)[CH2:12][CH2:11]1.[NH2:35][C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=1)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:35][C:36]2[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=2)[C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:12][CH2:11]1)=[O:28]
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
The compound (100 mg, 0.215 mmol) obtained in Example 4g was dissolved in ethanol (6 mL), tert-butyl 3-aminobenzoate (54 mg, 0.279 mmol) and sodium triacetoxyborohydride (59 mg, 0.279 mmol) were added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (80.0 mg; yield, 58%) as a colorless oily substance.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@:5]([C:11]([N:13]2[CH2:18][C@@H:17]3[CH2:19][C@H:14]2[CH2:15][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:12])([CH2:7][CH:8]([F:10])[F:9])[CH:4]=[CH:3]1.[H][H]>[Pd].CO>[NH2:1][C@@H:2]1[CH2:3][CH2:4][C@@:5]([C:11]([N:13]2[CH2:18][C@@H:17]3[CH2:19][C@H:14]2[CH2:15][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:12])([CH2:7][CH:8]([F:9])[F:10])[CH2:6]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@]1(CC(F)F)C=C[C@@H](N)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@]1(CC(F)F)CC[C@@H](N)C1

Procedure:
A mixture of tert-butyl (1S,4S)-5-{[(1S,4S)-4-amino-1-(2,2-difluoroethyl)cyclopent-2-en-1-yl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (6.50 g, 17.5 mmol) and 5% palladium on carbon in methanol (100 ml) was stirred at room temperature under 46 psi of hydrogen for 21 hours. The reaction was filtered through celite and the filter cake washed with methanol. The filtrate and washings were concentrated under reduced pressure to give tert-butyl (1S,4S)-5-{[(1S,3R)-3-amino-1-(2,2-difluoroethyl)cyclopentyl]carbonyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as a brown oil (6.67 g, theoretical yield 6.54 g) which was used without further purification in the next step.
Reaction SMILES: N=[C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[C:5](=[O:19])[C:4]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[NH:3]1.Cl.C(=O)([O-])[OH:27].[Na+]>C(O)C>[O:27]=[C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[C:5](=[O:19])[C:4]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[NH:3]1
Reactant: N#Cc1ccc(N2C(=N)NC3(CCCCC3)C2=O)cc1C(F)(F)F
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(N2C(=O)NC3(CCCCC3)C2=O)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
1.10 g of the product obtained in Stage 2 above, 3 ml of 6N hydrochloric acid and 8 ml of ethanol are introduced, the mixture is taken to reflux for one hour, cooled down to ambient temperature, neutralized by the addition of sodium hydrogen carbonate, extracted with ethyl acetate. The organic phases are combined, washed with water, dried, filtered and concentrated. After chromatography on silica eluting with methylene chloride-acetone: 9-1, then recrystallization from isopropanol, 470 mg of expected product (white solid) is obtained. M.p.=187° C.