Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.CC(C)CCN.[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]([C:28]3[S:32][C:31]([C:33]([O-])=[O:34])=[CH:30][CH:29]=3)=[O:27])=[CH:20][C:19]=12.[Li+].[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>>[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]([C:28]3[S:32][C:31]([C:33]([N:5]4[CH2:6][CH2:7][CH2:8][C@@H:4]4[CH2:3][O:2][CH3:1])=[O:34])=[CH:30][CH:29]=3)=[O:27])=[CH:20][C:19]=12
Reactant: COC[C@H]1CCCN1
Reactant: O=C([O-])c1ccc(C(=O)NCc2ccn3ccnc3c2)s1
Agent: CC(C)CCN
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Product: COC[C@H]1CCCN1C(=O)c1ccc(C(=O)NCc2ccn3ccnc3c2)s1

Procedure:
The title compound was prepared as described in Example 1A, substituting), (R)-2-(methoxymethyl)pyrrolidine for 3-methylbutan-1-amine and lithium 5-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)thiophene-2-carboxylate for 4-nitrobenzoic acid. 1H NMR (300 MHz, DMSO-d6). δ ppm 9.23 (t, J=6.0 Hz, 1H), 8.49 (dd, J=6.9, 0.9 Hz, 1H), 7.90-7.88 (m, 1H), 7.79 (d, J=4.0 Hz, 1H), 7.60 (d, J=4.0 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.42-7.39 (m, 1H), 6.85 (dd, J=7.0, 1.7 Hz, 1H), 4.49 (d, J=5.9 Hz, 2H), 4.35-4.23 (m, 1H), 3.78-3.65 (m, 2H), 3.26 (s, 3H), 2.02-1.81 (m, 4H); MS (ESI(+)) m/e 399 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=3)[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C[N:30]([C:32](ON1N=NC2C=CC=NC1=2)=[N+:33](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:33][C:32]#[N:30])=[O:27])=[CH:23][CH:24]=3)[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CNC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A 8-mL vial was charged with 2-[4-[[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]acetic acid (95 mg, 0.23 mmol, 1 eq.), cyamide (15 mg, 0.36 mmol, 1.5 eq.), HATU (130 mg, 0.36 mmol, 1.5 eq.), diisopropylethylamine (90 mg, 0.69 mmol, 3 eq.) and DMF (1 ml). The resulting mixture was stirred at rt overnight until the starting acid was consumed. The mixture was added to NaHCO3 aq. (5 ml) and extracted with ethyl acetate (3×5 ml). The organic layers were combined and dried over Na2SO4. Removal of solvent gave a residue, which was purified by chromatography on silica gel using a preparation TLC plate and 2% of MeOH in DCM as mobile phase to give the title compound as a white solid (20 mg, 20% yield). MW=435.93. 1H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.43 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 3.69 (s, 2H), 3.18 (t, J=5.6 Hz, 2H), 2.94 (d, J=6.4 Hz, 2H), 2.27 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[NH:15]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:14][C:4]1[N:3]=[C:2]([N:15]2[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16]2)[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=1
Reactant: OC[C@H]1CCNC1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cnc2cc(Cl)nc(N3CC[C@H](CO)C3)c2c1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (270 mg, 1.17 mmol), (S)-pyrrolidin-3-ylmethanol (1.40 mmol), Hunig's base (1.02 mL, 5.85 mmol) and dioxane (4 mL) was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and worked-up. The residue was purified using slilica gel flash column chromatography (eluent: 0-10% methanol in dichloromethane) to afford (S)-7-chloro-5-(3-(hydroxymethyl)pyrrolidin-1-yl)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one as a white solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][CH3:20])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2].C(O)(=O)C.[Br:25]Br>C(Cl)(Cl)Cl>[Br:25][C:6]1[C:7](=[O:8])[C:3]([CH2:1][CH3:2])([CH2:19][CH3:20])[O:4][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: BrBr
Reactant: CCC1(CC)OC(c2ccc(S(C)(=O)=O)cc2)=CC1=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCC1(CC)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2,2-diethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (4.5 g) in 200 ml chloroform with 3 ml acetic acid, was added dropwise 1.5 ml bromine at 0° C. The solution was then allowed to warm to room temperature and was stirred for another 4 hours. The reaction was quenched by adding saturated aqueous sodium thiosulfate until the characteristic color of bromine disappeared. The reaction mixture was then extracted with dichloromethane (100 ml×2) and the organic layer was dried over anhydrous magnesium sulfate. After the magnesium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by recrystallization from hexane and ethylacetate to afford 4.5 g of 4-bromo-2,2-diethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone. mp: 130-131° C. NMR: δ0.88 (t, J=7.5 Hz, 6H), 1.95 (q, J=7.5 Hz, 4H), 3.11 (s, 3H), 8.12 (d, J=8.7 Hz, 2H), 8.42 (d, J=8.7 Hz, 2H). IR (cm−1): 2973, 1705, 1583, 1558, 1315, 1160, 1084.
Reaction SMILES: [P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Na+:6].[Na+].[Na+].[O:9]=[P:10]12[O:21]P3(O[P:12]([O:14]P(O3)([O:17]1)=O)(=[O:13])[O:11]2)=O>>[O-:2][P:1]([O:5][P:12]([O:11][P:10]([O-:21])([O-:17])=[O:9])([O-:14])=[O:13])([O-:4])=[O:3].[Na+:6].[Na+:6].[Na+:6].[Na+:6].[Na+:6]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]

Procedure:
The loaded organic extract fed to stripping column 20 was treated with water countercurrently to extract P2O5 values and yielded a purified acid stream containing the equivalent of 8,978 pounds per hour of P2O5 and 5.6 pounds per hour of fluoride ion. This purified acid was passed through line 22 into make up reactor 24 along with enough sodium carbonate to yield 7,497 pounds per hour of sodium ion. The resulting reaction yielded an ortho liquor containing a sodium orthophosphate solution having a Na:P of about 1.67, a P2O5 content of 9,127 pounds per hour and fluoride ion in amounts of 9.2 pounds per hour. The ortho liquor was removed from reactor 24 through line 28 and introduced into a spray dryer 30. The ortho liquor was heated by downwardly directed burners to yield 8,829 pounds per hour of sodium tripolyphosphate containing not more than about 1 pound per hour of fluoride ion. The sodium tripolyphosphate product was removed through line 34 and contained about 100 ppm of fluoride, which is considered acceptable for all but food grade purposes.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:12]=[C:13]([C:24]2[C:29](F)=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[S:14][C:15]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:10].F[C:33]1(C2N(C)N=CC=2[N+]([O-])=O)[CH2:39][CH2:38][CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH:36]([OH:48])[CH2:35][CH2:34]1>>[C:19]([O:18][C:17]([NH:16][C:15]1[S:14][C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:12][C:11]=1[C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[C:33]12[O:48][CH:36]([CH2:35][CH2:34]1)[CH:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:38][CH2:39]2)=[O:10])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cn1ncc([N+](=O)[O-])c1C1(F)CCC(O)C(NC(=O)OC(C)(C)C)CC1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1Cl
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2NC(=O)OC(C)(C)C)c1C12CCC(NC(=O)OC(C)(C)C)C(CC1)O2

Procedure:
Following the procedure for Intermediate 1 starting from tert-butyl N-(5-fluoro-2-hydroxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptyl)carbamate gave tert-butyl N-(5-[4-((5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carbonyl)amino)-2-methyl-pyrazol-3-yl]-8-oxabicyclo[3.2.1]octan-2-yl]carbamate as a pale pink solid (310 mg, 31% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.50 (br s, 1H), 10.48 (s, 1H), 8.39-8.29 (m, 2H), 7.60-7.51 (m, 1H), 7.38-7.31 (m, 1H), 7.18 (dd, J=11.4, 8.3 Hz, 1H), 4.86 (br s, 1H), 4.36 (br s, 1H), 4.07 (br s, 1H), 3.86 (s, 3H), 2.43-2.35 (m, 1H), 2.22-1.92 (m, 7H), 1.55 (s, 9H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[O:10][CH:9]([CH3:26])[CH2:8]2)(=[O:3])[CH3:2].[OH-:27].[Na+].Cl>CS(C)=O.CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C:11]([OH:27])([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[O:10][CH:9]([CH3:26])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: COc1cc2c(cc1NC(C)=O)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1cc2c(cc1NC(C)=O)CC(C)OC2(O)c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h

Procedure:
A solution of 14 (1.8 g) in 5 ml of DMSO and 30 ml of DMF was cooled to 8-12° C. and air was passed through the mixture. To the solution was added 1.2 ml of 50% aqueous sodium hydroxide in one portion and the resulting mixture was stirred for 5 hours. HCl (1 N) was added, and extracted with ethyl acetate three times. The combined organic phase was washed with water, dried over Na2SO4. Removal of the solvent afforded 22 (1.9 g) as a syrup, which was used directly for the next step.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[CH:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([CH3:13])[CH:7]=1.S(=O)(=O)(O)O.[OH-].[Na+]>COC(C)(C)C>[CH3:4][C:3]1([CH3:5])[C:10]2[CH:9]=[C:8]([CH3:13])[CH:7]=[CH:6][C:11]=2[O:12][CH2:2]1
Reactant: C=C(C)CCl
Reactant: Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: Cc1ccc2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Chloro-2-methylpropene (9.7 mL) was added dropwise to a mixed solution of p-cresol (CAS #106-44-5, 10.8 g) and concentrated sulfuric acid (2.5 g), and the mixture was stirred at room temperature for one hour and 20 minutes. The reaction solution was ice-cooled and a 5 N sodium hydroxide aqueous solution (20 mL) was added, followed by stirring at 90° C. for 45 minutes. A 5 N sodium hydroxide aqueous solution (10 mL) was added to the reaction solution, and the mixture was stirred at 90° C. for two hours and 45 minutes. The reaction solution was left to cool to room temperature. tert-Butyl methyl ether was added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with water (three times) and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Merck silica gel 60 (230-400 mesh); elution solvent:heptane:ethyl acetate=1:0→49:1). The target fraction was concentrated and the resulting residue was purified again by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane). The target fraction was concentrated and the resulting residue was distilled under reduced pressure to obtain 1.87 g of the target compound (bp. 102° C./20 mmHg). The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[CH:5]=[N:6][C:7]=1Cl.[CH3:11][S-:12].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5]([S:12][CH3:11])=[N:6][CH:7]=1
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ncc(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
5,6-Dichloro-3-pyridinecarbonitrile (1.73 g, 0.01 mol) was dissolved with stirring in dimethyl sulphoxide (25 mL) and sodium methanethiolate (0.77 g, 0.011 mol) added. The reaction mixture was stirred at room temperature for two hours and poured onto ice (100 g). The mixture was extracted with dichloromethane (50 mL), and the organic extract washed with water (100 mL), and brine, and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and recrystallisation of the residue from ethyl acetate:hexane gave the desired product (1.3 g, 71%) as a cream solid, MP 147-9° C.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33].[C:34]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C(=O)C>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:13]([C:4]3[C:3](=[O:33])[N:2]([N:1]=[C:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[C:11]4[C:6]([C:5]=3[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:14][S:15](=[O:32])(=[O:31])[C:16]=2[CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CCCC1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1N=C1CCCC1
Temperature: 165 °C
Yield: 65.1 %

Procedure:
The product of Example 304F (0.284 g, 0.61 mmol) and cyclopentanone (0.80 mL, 9.04 mmol) in N,N-dimethylacetamide (2 mL) were reacted at 130° C. for 40 minutes in a microwave reactor in a sealed tube. The reaction was concentrated under a stream of nitrogen warmed through a manifold heated to 165° C. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.210 g, 65%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.72 (m, 2 H) 1.87 (m, 2 H) 2.16 (m, 2 H) 2.71 (m, 2 H) 5.18 (s, 2 H) 7.31 (m, 11 H) 8.10 (d, J=8.46 Hz, 1 H) 16.22 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH2:29][CH3:30]>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:28][CH2:29][CH3:30])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[O:14][CH2:13]2
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(OC)ccc(-c2ccc3c(c2)COC3=O)c1OC
Temperature: 80 °C
Yield: 32.7 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and propyl bromide (103 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (30 mg, 32.8%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:18]4[CH2:27][CH2:28][CH2:29][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[I-].[Na+].[CH3:32][NH:33][CH3:34].O1CCCC1>CN(C)C=O>[CH3:32][N:33]([CH3:34])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:18]4[CH2:27][CH2:28][CH2:29][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: CNC
Reactant: ClCCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1

Procedure:
A solution of 7-(3-chloro-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (54 mg, 0.13 mmol), sodium iodide (5 mg, 0.03 mmol), and 2 N dimethylamine in tetrahydrofuran (3 mL, 6 mmol) in N,N-dimethylformamide (5 mL) is heated at 100° C. for 48 h. The mixture is cooled and concentrated in vacuo. The residue is chromatographed on SiO2 (100% ethyl acetate to 10% methanol in ethyl acetate) to yield the title compound, 41 mg (74%), as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([O:20]C)=O)=[N:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[NH3:22]>CO>[NH2:1][C:2]1[C:3]([C:18]([NH2:22])=[O:20])=[N:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: N
Reactant: COC(=O)c1nc(-c2cccc3ccccc23)cnc1N
Solvent: CO
Product: NC(=O)c1nc(-c2cccc3ccccc23)cnc1N
Temperature: 85 °C
Yield: 79 %

Procedure:
A solution of methyl 3-amino-6-naphthalen-1-ylpyrazine-2-carboxylate (80 mg, 0.29 mmol) in methanol (30 mL) was saturated with ammonia gas at 0° C. in a high-pressure test tube. The reaction tube was tightly sealed and heated to 80-90° C. for 4h. Reaction cooled to room temperature and evaporated at reduced pressure to afford 3-amino-6-naphthalen-1-ylpyrazine-2-carboxamide (59 mg, 79% yield) as yellow product: 1H NMR (400 MHz, CDCl3): δ 8.80 (s, 1H), 8.10 (d, 1H), 7.90 (d, 2H), 7.58 (m, 6H); MS (EI) for C15H12N4O: 265 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@@H:7]1[C@@H:27]([N:28]2[CH2:33][CH2:32][O:31][C:30]([CH3:35])([CH3:34])[CH2:29]2)[CH2:26][C@@:25]2([CH3:36])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:37])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:20])[CH2:18][OH:19])[CH2:8]1.O.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[OH:6][C@@H:7]1[C@@H:27]([N:28]2[CH2:33][CH2:32][O:31][C:30]([CH3:35])([CH3:34])[CH2:29]2)[CH2:26][C@@:25]2([CH3:36])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:37])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:20])[CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:8]1
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](C(=O)CO)CC[C@@H]43)C[C@@H]2O)CCO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](C(=O)COS(C)(=O)=O)CC[C@@H]43)C[C@@H]2O)CCO1
Temperature: -25 °C
Reaction time: 1.5 h

Procedure:
A solution of methanesulfonyl chloride (2.48 ml) in dry pyridine (9.6 ml) was added to a solution of the 3,21-dihydroxy compound of Example 9 (3.26 g) in dry pyridine (33 ml) at -25° C. over ca. 5 min. The solution was stirred at -25° C. for 1.5 h and poured into water (400 ml). Aqueous sodium carbonate was added until the pH exceeded 9 and the precipitated solid was filtered off and dissolved in dichloromethane. The solution was dried over sodium sulfate and the solvent was removed under reduced pressure to give (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-21-[(methylsulfonyl)oxy]pregnan-20-one (3.80 g). δ (CDCl3) 0.65 (s,3H), 0.86 (s,3H), 3.22 (s,3H) and 4.79 (m,2H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:26])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23]C)=[CH:18][CH:19]=4)[C:14]3=[O:25])[CH:7]=2)[CH2:3][CH2:2]1.[I-].[Li+].[OH-].[Na+].Cl>N1C(C)=CC(C)=CC=1C>[CH:1]1([NH:4][C:5](=[O:26])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][CH:19]=4)[C:14]3=[O:25])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc2ccn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(O)cc2c1=O
Temperature: 200 °C
Yield: 69.3 %

Procedure:
A stirred suspension of N-cyclopropyl-3-(7-methoxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (845 mg) and lithium iodide (585 mg) in 2,4,6 collidine (10 ml) was heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 200° C. for 90 minutes. The mixture was dissolved using 2N NaOH and re-acidified using 2N HCl. The aqueous phase was extracted with ethyl acetate (×4) and the combined organic layers concentrated. The residue was triturated with 2N HCl and the solid collected by filtration, washed with diethyl ether and air dried to yield N-cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide as a brown solid (562 mg); NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.69 (m, 2H), 2.10 (s, 3H), 2.85 (m, 1H), 6.66 (d, 1H), 7.11 (d, 1H), 7.24 (d, 1H), 7.49 (d, 1H), 7.60 (s, 1H), 7.61 (d, 1H), 7.73 (s, 1H), 7.88 (d, 1H), 8.43 (d, 1H), 10.00 (s, 1H); Mass Spectrum: M+Na+ 357.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>[I-].[K+]>[CH2:35]([O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[O:27][CH2:26][CH2:25][CH2:24][N:13]1[CH2:12][CH2:11][CH:10]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:9])[CH2:15][CH2:14]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: ClCCCOc1ccccc1OCc1ccccc1
Agent: [I-]
Agent: [K+]
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(CCCOc2ccccc2OCc2ccccc2)CC1

Procedure:
Following the procedure of Example 2 and using potassium iodide catalyst, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 2-(3-chloropropoxy)-1-benzyloxybenzene are reacted to give 1-[3-(2-benzyloxyphenoxy)propyl]-α,α-bis(4-fluorophenyl)-4-piperidinemethanol which is reacted with hydrogen over palladium on carbon catalyst to give the title compound.
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.C(C1CC=CCCC=CCC(C(C)C)N=N1)(C)C.[CH3:37][CH2:38][CH2:39][CH:40]([CH:45]1[CH2:56][CH:55]=[CH:54][CH2:53][CH2:52][CH:51]=[CH:50][CH2:49][CH:48]([CH:57]([CH2:61][CH2:62][CH2:63][CH3:64])[CH2:58][CH2:59][CH3:60])[N:47]=[N:46]1)[CH2:41][CH2:42][CH2:43][CH3:44]>>[NH2:46][CH:45]([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH:48]([NH2:47])[CH:57]([CH2:58][CH2:59][CH3:60])[CH2:61][CH2:62][CH2:63][CH3:64])[CH:40]([CH2:39][CH2:38][CH3:37])[CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCC(CCC)C1CC=CCCC=CCC(C(CCC)CCCC)N=N1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Agent: CC(C)C1CC=CCCC=CCC(C(C)C)N=N1
Product: CCCCC(CCC)C(N)CCCCCCCCC(N)C(CCC)CCCC

Procedure:
If there are used in the manner described under (a), instead of 250 g (1 mol) of 3,12-diisopropyl-1,2-diaza-1,5,9-cyclododecatriene, 35.9 g (0.09 mol) of crude 3,12-di-(4-octyl)-1,2-diaza-1,5,9-cyclododecatriene and correspondingly reduced amounts of catalyst and solvent, with otherwise the same procedure, there is obtained, after chromatographical purification and bulb-tube distillation, 8.8 g (24% of theory) of 6,15-diamino-5,16-dipropyleicosane in the form of colourless oil [nD20 =1.4655; IR (liquid) inter alia bands at 3380, 3300 and 1623 cm-1 ].