Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH2:32][CH3:33])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29](O)=[O:30])[CH2:24]2)[O:12]1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:68]([C:72]1[CH:73]=[C:74]([NH2:79])[C:75]([NH2:78])=[CH:76][CH:77]=1)([CH3:71])([CH3:70])[CH3:69]>C(Cl)Cl.O>[NH2:79][C:74]1[CH:73]=[C:72]([C:68]([CH3:71])([CH3:69])[CH3:70])[CH:77]=[CH:76][C:75]=1[NH:78][C:29](=[O:30])[CH2:28][CH2:27][CH:25]1[CH2:26][CH:23]([N:22]([CH2:21][C@@H:13]2[C@@H:14]3[C@@H:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]3)[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH2:1])[O:12]2)[CH2:32][CH3:33])[CH2:24]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CCN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: CCN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)Nc2ccc(C(C)(C)C)cc2N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(ethyl)amino)cyclobutyl)propanoic acid (2 g, 4.35 mmol), HOAT (768 mg, 5.65 mmol), HATU (2.2 g, 5.65 mmol) and TEA (3 mL, 21.3 mmol) in DCM (40 mL) was added 4-tert-butylbenzene-1,2-diamine (785 mg, 4.79 mmol) and the mixture was stirred at rt for 2 h. Water (15 mL) was added and the mixture was extracted with DCM (30 mL×2). The combined organic phase was washed with H2O (20 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude was purified by SGC (DCM: MeOH-70:1-20:1) to obtain the target (1.6 g, yield: 61%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.28-8.27 (m, 1H), 8.24-8.23 (m, 1H), 7.10-6.92 (m, 2H), 6.81-6.76 (m, 1H), 6.22 (s, 1H), 5.54-5.52 (m, 1H), 5.03 (s, 1H), 4.36 (s, 1H), 3.03-2.50 (m, 5H), 2.32-2.26 (m, 2H), 2.16-1.80 (m, 4H), 1.73-1.69 (m, 2H), 1.59 (s, 3H), 1.39 (s, 3H), 1.28-1.24 (m, 9H), 0.94-0.85 (m, 3H) ppm; ESI-MS (m/z): 607.3 [M+1]+.
Reaction SMILES: [NH2:1][CH:2]1[C:30](=[O:31])[N:4]2[CH:5]([C:10]3[N:14]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:18][CH:17]=4)[N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.N1C=CC=CC=1.[C:38]1([CH2:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[C:38]1([CH2:44][C:45]([NH:1][CH:2]2[C:30](=[O:31])[N:4]3[CH:5]([C:10]4[N:14]([CH2:15][C:16]5[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)=[CH:20][CH:21]=5)[N:13]=[N:12][N:11]=4)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]23)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnnn1Cc1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1c1nnnn1Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.75 h
Yield: 86 %

Procedure:
To a stirred solution of 189 mg of 6-amino-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam in 4 ml of chloroform, is added, at ambient temperature, 0.038 ml of pyridine followed by 0.057 ml of phenylacetyl chloride. Stirring is continued for a further 45 minutes, and then the reaction mixture is diluted with 25 ml of chloroform and then washed with water. The organic phase is dried using anhydrous magnesium sulfate and then evaporated in vacuo. The residue is 209 mg (86% yield) of 6-(2-phenylacetamido)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam. The NMR spectrum (in CDCl3) shows absorptions at 7.50-6.70 ppm (multiplet, aromatic hydrogens), 6.4 ppm (doublet, amide hydrogen), 5.80-5.20 ppm (multiplet, benzyl hydrogens and C-5 and C-6 hydrogens), 5.10 ppm (singlet, C-3 hydrogen), 5.05 ppm (singlet, benzyl hydrogens), 3.60 ppm (singlet, phenylacetyl methylene hydrogens), 1.30 ppm (singlet, C-2 methyl hydrogens) and 0.85 ppm (singlet, C-2 methyl hydrogens).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH3:27].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:10]([O:28][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH3:27]
Reactant: CCC=CCC=CCC=CCCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 110 °C

Procedure:
A mixture of 57.0 g (0.300 mole) of 5-bromo-2-furoic acid, 119.0 g (0.450 mole) of 9,12,15-octadecatrienol, and 84.0 g (0.750 mole) of potassium tert-butoxide in dry toluene is stirred with heating. The tert-butanol formed in the reaction is allowed to distill off and the mixture is refluxed at 110° C with stirring for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with ice-water. The toluene organic layer is separated, washed with water, then extracted three times with 5% sodium bicarbonate solution. The combined aqueous extracts are cooled and acidified with 10% HCl solution to give 5-(9,12,15-octadecatrien-1-yloxy)-2-furoic acid.
Reaction SMILES: [BrH:1].C(O)(=O)C.[N:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH:22]C(OCC3C=CC=CC=3)=O)[CH3:21])=[C:16]([F:33])[CH:15]=2)=[CH:8][CH:7]=1>>[BrH:1].[BrH:1].[N:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH2:22])[CH3:21])=[C:16]([F:33])[CH:15]=2)=[CH:8][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Nc2ccncc2)cc1F
Agent: Br
Solvent: CC(=O)O
Product: C[C@@H](N)c1ccc(C(=O)Nc2ccncc2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 25% hydrogen bromide-acetic acid solution (8 ml) was added to (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)-3-fluorobenzamide (550 mg), and the mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was evaporated under reduced pressure. The obtained crystals were washed with ether, and recrystallized from methanol to give 360 mg of (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)-3-fluorobenzamide dihydrobromide having a melting point of 294° C. (dec.).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][CH2:24][C:25]([O:27]CC)=O)=[C:17]([N:30]2[CH:34]=[CH:33][CH:32]=[CH:31]2)[CH:16]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>O1CCCC1>[CH3:13][O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][CH2:24][C:25]([N:46]2[CH2:45][CH2:44][N:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][CH3:35])[CH2:48][CH2:47]2)=[O:27])=[C:17]([N:30]2[CH:31]=[CH:32][CH:33]=[CH:34]2)[CH:16]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)CCc1cc(OC)c(OC)cc1-n1cccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(CCC(=O)N2CCN(c3ccccc3OC)CC2)c(-n2cccc2)cc1OC
Reaction time: 1 h

Procedure:
In 20 ml of tetrahydrofuran was dissolved 1.20 g of N,N-carbonyldiimidazole, and a solution of 2.0 g of ethyl 3-(4,5-dimethoxy-2-(1-pyrrolyl)phenyl)propionate in 40 ml of tetrahydrofuran was added to the solution at room temperature while stirring. The stirring was continued at that temperature for additional 1 hour, 2.98 g of 1-(2-methoxyphenyl)piperazine was added thereto, followed by stirring at 40° to 60° C. for 6 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel colunun chromatography (chloroform-methanol) to yield 1.9 g of a colorless oily substance. Recrystallization from ethanol gave the title compound as a colorless crystal.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][C:5]1[C:14]2[CH2:15][N:16]3[C:21](=[O:22])[C:20]4[CH2:23][O:24][C:25]([C@:27]([OH:30])([CH2:28][CH3:29])[C:19]=4[CH:18]=[C:17]3[C:13]=2[N:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([OH:31])[CH:9]=[CH:10]2)=[O:26].[C:32]([O:40][CH2:41]Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1>CN(C=O)C>[C:32]([O:40][CH2:41][O:31][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]3[C:17]4[N:16]([CH2:15][C:14]3=[C:5]([CH2:4][CH3:3])[C:6]=2[CH:7]=1)[C:21](=[O:22])[C:20]1[CH2:23][O:24][C:25](=[O:26])[C@@:27]([CH2:28][CH3:29])([OH:30])[C:19]=1[CH:18]=4)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1
Reactant: O=C(OCCl)c1cccnc1
Reactant: CCc1c2c(nc3ccc(O)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c2c(nc3ccc(OCOC(=O)c4cccnc4)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
NaH (0.012 g, 0.51 mmol, 1.0 eq) was added portion wise to a solution of SN-38, (S)-4,11-diethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione [4150] (0.20 g, 0.51 mmol, 1.0 eq) in DMF (2 ml) under N2 atmosphere at 0° C. The resulting reaction mixture was stirred at 0° C. for an additional 30 min. To the reaction mixture, chloromethyl nicotinate [259] (0.087 g, 0.51 mmol, 1.0 eq) dissolved in DMF was added dropwise while maintaining the temperature at 0° C. The reaction was then allowed to come to RT and stirred overnight. The reaction mass was quenched with addition of water. The reaction mixture was extracted with DCM (2×100 ml). The organic layers were combined and washed with brine, dried over Na2SO4 and evaporated. The resultant crude product was purified on column chromatography (2% MeOH: DCM, silica gel 100-200 mesh) to yield a pale yellow solid, (S)-column chromatography (2% MeOH: DCM, silica gel 100-200 mesh) to yield a pale yellow solid, (S)-((4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl nicotinate [305] (0.036 g, 13%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=O.P(Cl)(Cl)([Cl:9])=O.[CH:12]1([C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH2:17])[CH2:14][CH2:13]1>ClCCCl>[ClH:9].[CH:12]1([C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH:17][C:2]2[CH2:3][CH2:4][CH2:5][N:1]=2)[CH2:14][CH2:13]1
Reactant: Nc1ccccc1C1CC1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCCN1
Solvent: ClCCCl
Product: Cl
Product: c1ccc(C2CC2)c(NC2=NCCC2)c1
Temperature: 60 °C

Procedure:
5 mmol (425 mg) of 2-pyrrolidinone and 5 mmol (766 mg) of phosphorus oxychloride are added to a solution of 5 mmol (666 mg) of 2-cyclopropylaniline in 30 ml of 1,2-dichloroethane. The whole is heated at 60° C. for 3.5 hours. After evaporation of the solvent, the residue is taken up in water, rendered alkaline with the aid of sodium carbonate, and extracted twice with 100 ml of ether. The organic phase is then dried, concentrated and purified by chromatography on silica gel to yield the expected product. The corresponding hydrochloride is obtained by the action of a titrated solution of hydrochloric acid in ethanol.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[N:7][C:6]([CH3:10])=[C:5]2[S:11][CH:12]=[CH:13][C:4]=12)[CH3:2].[H-].[Na+].Cl.[CH3:17][N:18]([CH2:20][CH2:21]Cl)[CH3:19].O>CN(C=O)C>[CH2:1]([C:3]1[C:8]([O:9][CH2:21][CH2:20][N:18]([CH3:19])[CH3:17])=[N:7][C:6]([CH3:10])=[C:5]2[S:11][CH:12]=[CH:13][C:4]=12)[CH3:2]
Reactant: CCc1c(O)nc(C)c2sccc12
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(OCCN(C)C)nc(C)c2sccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.2 %

Procedure:
4-Ethyl-7-methylthieno[2,3-c]pyridin-5-ol (2.00 g, 10.3 mmol) was added to a suspension of NaH (60% in oil, prewashed with hexanes, 0.46 g, 11.4 mmol) in DMF (30 ml) and stirred at room temperature for two hours. To this was added a mixture of dimethylaminoethylchloride hydrochloride (3.0 g, 20.6 mmol) and NaH (60% in oil, prewashed with hexanes, 546 mg, 22.8 mmol) in DMF (30 ml). The reaction mixture was stirred for two days at room temperature, poured into H2O (300 ml) and extracted with CH2Cl2 (3×200 ml). The combined organic phases were washed with H2O (2×200 ml) and dried over MgSO4. The solvent was removed in vacuo to give an oil (3 g), which was purified by flash chromatography on silica gel 60 (100 g) eluted with 7% MeOH in CH2Cl2 to give an oil (1.5 g, 56% yield). The product was dissolved in CH2Cl2 (100 ml), washed with 1N aqueous NaOH (2×100 ml) and dried over MgSO4. The solvent was removed in vacuo to give the product (0.950 g, 35% yield) as a yellow oil; IR (neat) 1590 and 1440 cm-1 ; mass spectrum m/z 264 (M+); 1H NMR (CDCl3) δ 1.18 (t, J=7 Hz, 3H, CH2CH3), 2.35 (s, 6H, N(CH3)2), 2.63 (s, 3H, 7-CH3), 2.63-3.10 (m, 4H, CH2CH2N, CH2CH3), 4.53 (t, J=6 Hz, 2H, CH2CH2N), 7.27 and 7.53 each (d, J=5 Hz, 1H, thiophene-H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br>CN(C)C=O>[CH3:29][O:30][C:31](=[O:34])[CH2:32][O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: COC(=O)CBr
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-ol (0.23 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.11 g) and bromoacetic acid methyl ester (0.075 mL) was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure and the residue diluted with ethyl acetate and this mixture was washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:1 by volume) gave title compound, 0.11 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[C:6]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[CH2:5]2.C(O)(=O)C.N1CCCC1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7]3[C:6]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:5]2)[CH2:13][CH2:14][C:15](=[O:17])[CH:16]=3)=[CH:9][C:10]=1[F:11]
Reactant: CCCCC1(CCC(C)=O)Cc2cc(N)c(F)cc2C1=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Solvent: CC(=O)O
Product: CCCCC12CCC(=O)C=C1c1cc(F)c(N)cc1C2
Temperature: 100 °C
Yield: 76.9 %

Procedure:
The diketone from step 1 (0.6 g, 2.14 mmol) was dissolved in toluene (15 mL) and treated with acetic acid (0.236 mL, 4.12 mmol) and pyrrolidine (0.344 mL, 4.12 mmol). The resulting solution was stirred and heated in an oil bath at 100° C. for 1.5 hours. After cooling to room temperature, the mixture was filtered through a pad of silica gel and the product was washed off with EtOAc. The filtrate and washings were concentrated under vacuum. The residue was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 4:1 to 3:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to provide 7-amino-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.45 g, 80%) as a yellow solid.
Reaction SMILES: C([Cl:4])(=O)C.[ClH:5].[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[O:16].[H][H]>C(O)C.[Pt]>[ClH:4].[ClH:5].[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[OH:16]
Reactant: CC(=O)Cl
Reactant: O=C(c1ccncc1)c1nc2ccccc2[nH]1
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: CCO
Product: OC(c1nc2ccccc2[nH]1)C1CCNCC1
Reaction time: 0.08 h

Procedure:
To stirred ethanol (50 ml) at 0° C. was added acetyl chloride (2.5 ml, 35 mmol) dropwise. After stirring 5 minutes, this ethanolic HCl was added to lH-benzimidazole-2-yl-4-pyridinyl-methanone (5.0 g, 22.4 mmol) in ethanol (200 ml). This solution was charged with platinum IV oxide (0.5 g) and hydrogen (50 lb/in2) and shaken for 20 hours. The solution was filtered, concentrated, and the resulting solid was recrystallized from methanol with 2-butanone to afford lH-benzimidazol-2-yl-4-piperidinyl-methanol dihydrochloride as the desired product m.p. 270-272° C.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:33]([O-])([O-])([O-])[O:34][CH2:35][CH2:36][CH3:37]>>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]2[C:7]3[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=[CH:16][C:6]=3[N:5]=[C:33]2[O:34][CH2:35][CH2:36][CH3:37])=[CH:20][CH:21]=1)#[N:32]
Reactant: CCCOC([O-])([O-])[O-]
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Solvent: CC(=O)O
Product: CCCOc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2-[(2′-cyanobiphenyl-4-yl)methyl]aminobenzoate (0.9 g) in propyl orthocarbonate (5 ml). The mixture was stirred at 80° C. for one hour. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueoues solution of sodium hydrogen carbonate. The solvent was evaporated to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (0.72 g, 68%), m.p. 90-92° C. Elemental Analysis for C27H25N3O3:
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:3]=1[NH:4][C:5]1[C:10]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[O:12])=[CH:9][N:8]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:7](=[O:26])[CH:6]=1.[OH-].[Na+].CCOC(C)=O.CO>CCO>[F:1][C:2]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:3]=1[NH:4][C:5]1[C:10]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[O:12])=[CH:9][N:8]([CH2:18][C:19]([OH:21])=[O:20])[C:7](=[O:26])[CH:6]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)NCCCO)c(Nc2ccc(I)cc2F)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: O=C(O)Cn1cc(C(=O)NCCCO)c(Nc2ccc(I)cc2F)cc1=O
Yield: 86 %

Procedure:
tert-Butyl (4-(2-fluoro-4-iodoanilino)-5-{[(3-hydroxypropyl)amino]carbonyl}-2-oxo-1(2H)-pyridinyl)acetate was dissolved in EtOH and treated with 1 M NaOH, as for example 1, step C, to hydrolyse the t-butyl ester to give (4-(2-fluoro-4-iodoanilino)-5-{[(3-hydroxypropyl)amino]carbonyl}2-oxo-1(2H)-pyridinyl)acetic acid as a white solid (86%), m.p. (EtOAc/MeOH) 199-202° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.12 (s, 1H), 8.39 (t, J=5.3 Hz, 1H), 8.22 (s, 1H), 7.74 (dd, J=10.2, 1.9 Hz, 1H), 7.57 (br d, J=8.4 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 5.54 (s, 1H), 4.53-4.42 (m, 3H), 3.45 (t, J=6.3 Hz, 2 H—by D2O exchange), 3.24 (t, J=7.0 Hz, 2 H—by D2O exchange), 1.66 (pentet, J=6.6 Hz, 2H). HRMS (FAB+) calcd C17H18FIN3O5 (MH+) 490.0275, found 490.0279.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]2([CH3:17])[CH3:16])#[CH:2].[CH3:18][O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=1[F:29].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:18][O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([OH:13])[CH:12]=2)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]3([CH3:17])[CH3:16])=[CH:24][C:23]=1[F:29]
Reactant: C#Cc1cc(O)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following General Procedure B and using 6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.05 g, 0.22 mmol), 2-fluoro-4-iodo phenyl acetic acid methyl ester (0.096 g, 0.33 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh), and preparative normal phase HPLC using 10% ethyl acetate in hexane as the mobile phase, the title compound was obtained (0.037 g, 43%).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C@@:14]4([CH3:19])[C:16]([CH3:18])([CH3:17])[C@H:11]([CH2:12][CH2:13]4)[C:10]=3[C:9](=[O:20])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[CH2:21]([N:8]1[C:9](=[O:20])[C:10]2[C@@H:11]3[C:16]([CH3:17])([CH3:18])[C@@:14]([CH3:19])([CH2:13][CH2:12]3)[C:15]=2[N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)[nH]n1-c1ccccc1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(Cc2ccccc2)n1-c1ccccc1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A mixture of (4S,7R)-1-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 8; 1.00 g, 3.7 mmol) and benzyl bromide (0.9 mL, 7.6 mmol) in N,N-dimethylformamide (30 mL) was heated at 100° C. overnight. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Isco 80 g column, eluting with 5-75% ethyl acetate/hexanes to give (4S,7R)-2-benzyl-7,8,8-trimethyl-1-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.01 g, 76%) as a brown oil. ES(+)-MS (M+H) 359.
Reaction SMILES: [CH2:1]([OH:18])[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][CH2:16][CH3:17].[NH2:19][C:20](N)=[O:21]>[Ni]>[C:20](=[O:21])([O:18][CH2:1][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][CH2:16][CH3:17])[NH2:19]
Reactant: NC(N)=O
Reactant: CCCCCCCCCCCCCCCCCO
Agent: [Ni]
Product: CCCCCCCCCCCCCCCCCOC(N)=O
Yield: 94 %

Procedure:
A mixture of 256 parts of heptadecyl alcohol, 60 parts of urea and 5 parts of a cation exchanger which is commercially available under the registered name Amberlite 200 and, having been treated in accordance with Example 1, contains nickel, is heated in a stirred vessel to 140°-145° C., whilst stirring. After filtering off the exchanger whilst the reaction solution is hot, 280 parts of heptadecyl carbamate are obtained. This corresponds to a yield of 94% of theory. The product has a melting point of 53°-54° C.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH3:27])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH3:27])[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)CC(=O)CC
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cccc2nonc12
Product: CCOC(=O)C1=C(CC)Nc2n[nH]cc2C1c1cccc2nonc12

Procedure:
The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl 3-ketopentanoate in the same manner as in Example 1.