Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH2:27][CH3:28])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.OC1CCN(S(C2C=CC(OCC)=C(C3NC(=O)C4=CN=C(CCC)N4N=3)C=2)(=O)=O)CC1>ClCCl.CO>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:14]3[NH:19][C:18](=[O:20])[C:17]4=[C:21]([CH2:27][CH3:28])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]4[N:15]=3)[CH:6]=2)(=[O:12])=[O:11])[CH2:32][CH2:31]1
Reactant: CCCc1nc(CC)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Reactant: OC1CCNCC1
Agent: CCCc1ncc2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCC(O)CC4)ccc3OCC)nn12
Solvent: CO
Solvent: ClCCl
Product: CCCc1nc(CC)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCC(O)CC4)ccc3OCC)nn12

Procedure:
By the same method, starting with 640 mg (1.5 mmol) of 4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 460 mg (45 mmol) of 4-hydroxypiperidine, 485 mg (66%) of 2-[5-(4-hydroxy-piperidine-1-sulphonyl)-2-ethoxyphenyl]-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained. Rf=0.37 (dichloromethane/methanol=19:1)
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:36][CH3:37])[CH2:23][CH2:24][CH2:25][N:26]([CH3:35])[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1)[CH3:21].O.[ClH:39].Cl>>[OH2:3].[ClH:1].[ClH:39].[CH2:36]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][N:26]([CH3:35])[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH3:37]
Reactant: CCN(CC)CCCN(C)CCC1CCCCN1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Agent: Cl
Solvent: O
Product: CCN(CC)CCCN(C)CCC1CCCCN1C(=O)N1c2ccccc2NC(=O)c2cccnc21
Yield: 48 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 2-[2-[[3-(diethylamino)propyl]methylamino]ethyl]piperidine in a yield of 48% of theory. The colourless dihydrochloride-hydrate melted at 145°-150° C. (D.).
Reaction SMILES: [C:1]1([CH2:7][C:8]2([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:34](Cl)=[O:35]>C(OCC)(=O)C>[CH3:43][O:42][C:38]1[CH:37]=[C:33]([CH:32]=[C:31]([O:30][CH3:29])[C:39]=1[O:40][CH3:41])[C:34]([N:10]1[CH2:11][CH2:12][C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:35]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(Cc2ccccc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCO)(Cc3ccccc3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine 3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidine (3.94 mmol) and sodium carbonate (0.21 g, 2.00 mmol) in 1/1 ethyl acetate/water (50 mL). Cool the reaction mixture to 0° C. with an ice bath. Add 3,4,5-trimethoxybenzoyl chloride (0.83 g, 3.58 mmol). Warm to ambient temperature. After 18 hours, separate the layers and extract the aqueous layer three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf=0.09 (silica gel, ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[CH:11]=[C:4]2[N:3]=1>CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nc(C3CC3)cc2n1
Agent: [Zn]
Solvent: CC(=O)O
Product: Clc1ccn2nc(C3CC3)cc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a solution of 5,7-dichloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine x272 (26.7 mmol, 1 eq., 6.08 g) in 125 ml of AcOH is added Zn powder (0.107 mol, 4 eq, 6.97 g). The mixture is then stirred for 48 hours at room temperature. After this time, the solvent is evaporated under reduce pressure and the reaction mixture poured on water, quenched with NaHCO3, and extracted with dichloromethane. The organic layer is dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product is purified by chromatography on silicagel (CH2Cl2/hexane: 50/50) to afford 5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine x274 as a solid (3.60 g).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[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][CH2:17][CH3:18].[OH-].[Mg+2:22].[OH-]>C(O)C>[C:1]([O-:20])(=[O:19])[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][CH2:17][CH3:18].[Mg+2:22].[C:1]([O-:20])(=[O:19])[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][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Mg+2]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
1,422 parts of stearic acid is added to 10,000 parts of ethanol, and mixed together at 75° C. 298 parts of magnesium hydroxide is gradually added to the mixture, and mixed for one hour after completion of the addition. The resultant mixture is cooled to 20° C., and the reaction product is filtered to remove ethanol and reaction residue. The obtained reaction solid product is dried at 150° C. for 3 hours using a heating vacuum drier. The product is taken out from the drier, and is allowed to stand for cooling, as a result of which a solid product of magnesium stearate is obtained. The obtained solid product is milled and classified in a similar manner to the production of zinc stearate particles 1, and further classified in a similar manner to the production of zinc stearate particles 6, as a result of which magnesium stearate particles 1 are obtained. The particle size distribution of the obtained magnesium stearate particles 1 is shown in Table 1.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12](=[O:29])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[C:18]([C:38]4[CH:37]=[CH:36][CH:35]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:39]=4)[CH:19]=[CH:20][CH:21]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12](=[O:29])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CN(S(=O)(=O)c2ccccc2)CC(c2cccc(Br)c2)N1c1ccccc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CS(=O)(=O)c1cccc(-c2cccc(C3CN(S(=O)(=O)c4ccccc4)CC(=O)N3c3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 4-benzenesulfonyl-6-(3-bromo-phenyl)-1-phenyl-piperazin-2-one (100 mg), (3-methylsulfonylphenyl) boronic acid (46.7 mg) and tetrakis(triphenylphosphine)palladium(0) (24.5 mg) in 1,2-dimethoxyethane (2mL) was added potassium carbonate (73.3 mg). The reaction mixture was stirred at 80° C. overnight. Additional amounts of (3-methylsulfonylphenyl) boronic acid (21 mg), potassium carbonate (58.6 mg) and tetrakis(triphenylphosphine)palladium(0) (24.5 mg) were added and stirring was continued at 80° C. for 3 h. To the reaction mixture water and ethyl acetate were added, the phases were separated, and the inorganic one was extracted with ethyl acetate (×2). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, n-heptane/ethyl acetate 1:3, followed by ISOLUTE Flash NH2, n-heptane/ethyl acetate 1:1) to yield 58 mg (50%) of 4-benzenesulfonyl-6-(3′-methanesulfonyl-biphenyl-3-yl)-1-phenyl-piperazin-2-one as a white foam, MS: 547.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][S:17][C:3]1=2.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C)C=O.O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][S:17][C:3]1=2
Reactant: NC(=O)c1ccc2nc3c(c(=O)n2c1)SCC3
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc2nc3c(c(=O)n2c1)SCC3
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide(1.7 g., 0.007 mol),p-toluenesulfonyl chloride (2.0 g., 0.01 mol) and pyridine (1.7 ml, 0.021 mol) in dimethylformamide (30 ml) is heated at 100° C. under nitrogen for 40 minutes. The reaction mixture is cooled and diluted with water (15 ml). The resulting aqueous solution is stirred for one hour. The precipitate is filtered off, washed with water and sucked dry. Recrystallization from methanol gives the product (1.1 g.), mp 261°-263° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[NH:10]2)=[CH:5][CH:4]=1.I[CH2:24][CH3:25]>CN(C)C=O.ClCCl>[CH2:24]([N:10]1[C:11]2[C@@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:25]
Reactant: CCI
Reactant: COc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1c2c(c(=O)n1-c1ccc(OC)cc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 46.6 %

Procedure:
A mixture of (4S,7R)-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 40; 300 mg, 1.0 mmol) and iodoethane (405 μL, 5.0 mmol) in dimethylformamide (9 mL) was heated in a sealed tube at ˜100° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane (100 mL), transferred to a round-bottomed flask and evaporated. Ethyl acetate (100 mL) was added and the solution was washed with water, concentrated aqueous sodium thiosulfate (50 mL; 50% w/v), saturated aqueous sodium hydrogen carbonate (50 mL) and brine (50 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified using a Biotage 40S system, eluting with 3% methanol/dichloromethane. Fractions homogeneous for the product were evaporated, co-evaporated with ethanol and dried under high vacuum to give (4S,7R)-1-ethyl-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (152 mg, 46%) as a light yellow solid. APCI(+)-MS (M+H) 327.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)[CH3:2].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:19])([C:11]([F:13])([F:14])[F:12])[C:15]([F:16])([F:18])[F:17])=[CH:8][CH:9]=1)[S:29]([C:26]1[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=1)(=[O:30])=[O:31])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CCN(c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 75.4 %

Procedure:
To a solution of 104 mg 2-(4-Ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 3 ml of pyridine was added 104 mg 4-Nitro-benzenesulfonyl chloride and 10 mg of dimethylaminopyridine. The mixture was stirred for 16 hrs and then concentrated in vacuo. After chromatography (1:3 Ethyl Acetate:Hexane), 129 mg of the named product was obtained. 1H NMR was consistent with the structure.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([NH:13][CH:14]2[CH2:17]C[CH2:15]2)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]2[N:23]=[CH:24][S:25][C:21]=2[CH:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[S:25]1[C:21]2[CH:20]=[C:19]([NH:18][C:2]3[CH:12]=[C:11]([NH:13][CH:14]([CH3:15])[CH3:17])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=3)[CH:27]=[CH:26][C:22]=2[N:23]=[CH:24]1
Reactant: Nc1ccc2ncsc2c1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC1CCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnc(Nc2ccc3ncsc3c2)cc1NC(C)C
Temperature: 115 °C

Procedure:
To a solution of ethyl 6-chloro-4-(isopropylamino)nicotinate (2) (5 g, 20.66 mmol) in dioxane (30 mL): H2O (5 mL), 6-amino benzothiazole (20.66 mmol, 1 equiv.), xanthphos (8.2 mmol, 0.4 equiv.) and Na2CO3 (82.6 mmol, 4 equiv.) were added and degassed for 10 min. To the reaction mixture Pd2(dba)3 (8.2 mmol, 0.4 equiv.) was added and degassed again for 10 min. It was then heated at 115° C., overnight. The reaction was cooled and filtered through small pad of celite. The filtrate obtained was concentrated to provide crude material. The crude material was purified by column chromatography through silica gel and EtOAC: pet. Ether as eluent to afford ethyl 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinate (3). LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.78 min; LCMS (ES-API), m/z 357.8 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[CH2:39][C:29]3([C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:28][C:25]2=[N:26][CH:27]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([NH:21][C:22]2[CH:23]=[C:24]3[CH2:39][C:29]4([C:37]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:38])[CH2:28][C:25]3=[N:26][CH:27]=2)=[O:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1c(=O)n(-c2ccccn2)c2ccccc21)Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (15 mg, 0.055 mmol, described in Intermediate 7), (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (14 mg, 0.055 mmol, described in Intermediate 4), PyClu (26 mg, 0.072 mmol), and N,N-diisopropylethylamine (0.048 mL, 0.277 mmol) in THF (1 mL) was stirred at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×10 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=504 (M+1). HRMS: m/z=504.1787; calculated m/z=504.1779 for C28H22N7O3.
Reaction SMILES: Br[C:2]1[CH:17]=[C:16]([S:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:15]=[CH:14][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1.C[C:27]12CC3(C)P(C4C=CC=CC=4)[C:33](C)([CH2:35][C:29]([CH3:45])(O3)O1)[O:34]2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:27][O:34][C:33]1[N:11]=[CH:8][CH:7]=[C:29]2[C:45]([C:2]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:3]=3[O:4][C@H:5]3[CH2:10][CH2:9][C@H:8]([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]3)=[CH:22][N:21]([CH3:25])[C:35]=12
Reactant: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Reactant: CN(C)[C@H]1CC[C@H](Oc2ccc(S(=O)(=O)N3CCCC3)cc2Br)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1nccc2c(-c3cc(S(=O)(=O)N4CCCC4)ccc3O[C@H]3CC[C@H](N(C)C)CC3)cn(C)c12
Temperature: 100 °C

Procedure:
A mixture of Example 144B (60 mg, 0.14 mmol) and Example 59A (40.1 mg, 0.14 mmol) was degassed under argon. To this mixture was added dioxane (8 mL) followed by degassing with argon. To this mixture was added potassium phosphate, dibasic (109 mg, 0.626 mmol) and water (2.000 mL) followed by degassing with argon. To this mixture was added 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (6.91 mg, 0.024 mmol) and then immediately tris(dibenzylideneacetone)dipalladium (0) (8.92 mg, 9.74 μmol) followed by degassing with argon. The reaction mixture was heated at 100° C. for 1 hour. The mixture was cooled to ambient temperature and partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to provide the title compound (0.042 g, 59% yield)
Reaction SMILES: [OH:1][C@H:2]([CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][O:19][CH2:20][CH3:21])[C:13]([SH:22])=[N:12][C:11]=2[N:10]([CH3:23])[C:8]1=[O:9].[C:25](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH2:20]([O:19][CH2:18][N:14]1[C:15]2[C:16](=[O:17])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([OH:1])[CH3:24])[C:8](=[O:9])[N:10]([CH3:23])[C:11]=2[N:12]=[C:13]1[S:22][CH3:25])[CH3:21]
Reactant: CCOCn1c(S)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOCn1c(SC)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a stirring suspension of (R)-1-(5-hydroxyhexyl)-7-ethoxymethyl-8-mercapto-3-methylxanthine (62.0 mg, 0.174 mmol) and potassium carbonate (42 mg, 0.30 mmol) in acetonitrile (3.4 ml) was added methyl iodide (44 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 3 hours. After evaporation of the solvent under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (3:1) to provide (R)-7-ethoxymethyl-1-(5-hydroxyhexyl)-3-methyl-8-methylsulfanylxanthine (58 mg, 89% yield) as a white solid.
Reaction SMILES: [N:1]([N:3]([CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)C(N)=O)=O.[OH-].[Na+]>CCOCC.CCCCC>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH2:8][CH:7]=[N+:3]=[N-:1]
Reactant: NC(=O)N(CCOC1CCCCO1)N=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: CCOCC
Product: [N-]=[N+]=CCOC1CCCCO1
Reaction time: 0.5 h

Procedure:
A solution of 41.8 g of N-nitroso-N-[2-(tetrahydropyran-2-yloxy)ethyl]urea in 200 ml of ether and 100 ml of pentane is added to 450 ml of 1N sodium hydroxide solution at 1°-4°C over a 25 minute period. The solution is stirred for an additional 30 minutes and the layers are separated. The organic layer is dried over sodium hydroxide pellets at 20°C for 5 minutes, and then filtered.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[Cl:12]N1C(=O)CCC1=O>>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Cl:12])=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Product: Cc1c(Cl)cnc(N)c1[N+](=O)[O-]
Yield: 75.1 %

Procedure:
2-Amino-3-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methyl propionitrile (26 mg) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (78 mg). 1-(6-Chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 105 part a to d except using 5-chloro-4-methyl-3-nitropyridine-2-carboxaldehyde (1.3 g) in part a to yield [2-(tert-butyldimethylsilanyloxy)propyl]-(5-chloro-4-methyl-3-nitropyridin-2-yl-methyl)amine (1.4 g, 57%). 5-Chloro-4-methyl-3-nitro-pyridine-2-carboxaldehyde was prepared using a procedure similar to that described in Example 136 part a to c except starting from 2-amino-5-chloro-4-methyl-3-nitropyridine (32 g) in part a to generate 2-bromo-5-chloro-4-methyl-3-nitropyridine (25.2 g, 59%). Oxidative cleavage using a 4% solution of osmium tetroxide in water (1.5 mL) and sodium periodate (2.5 g) was carried out in a mixture of THF and water (10:1, 60 mL) in part c instead of ozonolysis following a procedure similar to that described in Example 61 to afford 5-chloro-4-methyl-3-nitropyridine-2-carboxaldehyde (1.3 g, 56%) from 5-chloro-4-methyl-3-nitro-2-vinylpyridine (2.3 g). 2-Amino-5-chloro-4-methyl-3-nitropyridine (4.6 g, 75%) was prepared using a procedure similar to that described in Example 38 part a except starting from 2-amino-4-methyl-3-nitropyridine (5 g) and using N-chlorosuccinimide (5.8 g) instead of N-bromosuccinimide.
Reaction SMILES: C([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([O:15]C(=O)C)=[CH:5]1)(=O)C.O=O.[OH-].[Na+]>CO>[OH:15][C:6]1[CH:7]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][CH:5]=1
Reactant: CC(=O)Oc1cc(-c2ccccc2)n(C(C)=O)c1
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1c[nH]c(-c2ccccc2)c1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
A finely divided portion of N-acetyl-3-acetoxy-5-phenylpyrrole (2) (36.8 g; 0.15 mol) was freed of oxygen by stirring in a flowing argon stream for 10 minutes, then suspended in deoxygenated methanol (MeOH) (379 mL), cooled to -6° C. (in a -15° C. methanol (MeOH)/dry-ice bath) under an inert gas atmosphere and rapidly treated with an ice cold deoxygenated solution of 2N NaOH (300 mL). The reaction temperature rose immediately upon addition of base to 18° C., and after ~3 minutes the reaction mixture became homogeneous. As the reaction mixture cooled, compound 3 separated as fine crystals. After 15 minutes a solution of cold deoxygenated 2M citric acid (150 mL) was added, the resulting mixture was stirred for 10 minutes, and then filtered. The solid was washed thoroughly with deoxygenated water (200 mL), taking care to minimize exposure of the product to air, then dried under vacuum overnight to yield the title compound (22.3 g; 93.6%) as light pink tiny needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])=[CH:11][CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]([CH2:13][Br:21])=[CH:11][CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnn1C(=O)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nccc1CBr
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 5-methyl-pyrazole-1-carboxylic acid tert-butyl ester in CCl4 (40 mL) was added NBS (3.3 g, 18.5 mmol) and benzoylperoxide (450 mg, 1.86 mmol). The reaction mixture was heated to reflux for 4 h and cooled to rt. The insoluble material was filtered off and the solution was diluted with EtOAc. The organics were washed with saturated NaHCO3 and H2O, dried with Na2SO4, and concentrated. The crude product was purified by combi-flash to give 1.67 g of 5-bromomethyl-pyrazole-1-carboxylic acid tert-butyl ester in 52% yield.