Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([CH:26]4[CH2:28][CH2:27]4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[C:34](F)[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:29][C:30]1[CH:35]=[C:34]([N:21]([C:19]2[C:18]([CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:11]3[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH:20]=2)[S:22]([CH3:25])(=[O:23])=[O:24])[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (2.00 g, 4.77 mmol), 2-choro-4-fluoronitrobenzene (1.68 g, 9.55 mmol), and potassium carbonate (1.98 g, 14.3 mmol) in 4:1 DME/water (20 mL) in a sealed vessel was heated to 100° C. with stirring. After 18 hours the mixture was treated with an additional 2.00 g portion of potassium carbonate, heated at 100° C. for another 15 hours, and then stirred at RT for 3 days. The mixture was partitioned between EtOAc and water. After separating the phases, the aqueous portion was extracted with two additional portions of EtOAc. The combined EtOAc solutions were washed with water (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from DCM to 7:3 DCM/EtOAc) to afford a tacky, yellow foam. This material was crystallized from hexane/EtOAc to give the title compound (1.78 g, 65%) as a light yellow solid. LCMS (m/z, ES+)=574 (M+H+).
Reaction SMILES: [CH2:1]([N:5]([CH2:49][CH2:50][C:51](O)=[O:52])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:17][C:16]=2[C:37]([N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:54][C:55]([CH2:60][OH:61])([CH2:58][OH:59])[CH2:56][OH:57]>>[CH2:1]([N:5]([CH2:49][CH2:50][C:51]([NH:54][C:55]([CH2:60][OH:61])([CH2:58][OH:59])[CH2:56][OH:57])=[O:52])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:17][C:16]=2[C:37]([N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NC(CO)(CO)CO
Reactant: CCCCN(CCC(=O)O)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Product: CCCCN(CCC(=O)NC(CO)(CO)CO)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 17.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 124, 3-(N-butyl-4-chloro-5-methyl-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazole-3-carboxamido)propanoic acid (Intermediate 158B, 20 mg, 0.026 mmol) and 2-amino-2-(hydroxymethyl) propane-1,3-diol (J. T. Baker, 10 mg, 0.083 mmol) were converted to the title compound (4 mg, 18%). 1H NMR (CD3OD, 1.5:1 mixture of amide rotamers) δ 8.73 (br s, 1H), 8.17-7.94 (m, 7H), 7.75-7.65 (m, 3H), 7.23-7.09 (m, 3.5H), 6.96-6.83 (m, 0.5H), 4.61-4.40 (m, 1H), 4.38-3.91 (m, 3H), 3.73-3.66 (m, 3H), 3.66-3.49 (m, 4H), 3.02-2.97 (m, 1H), 2.89-2.79 (m, 2H), 2.75-2.60 (m, 2H), 2.56 (t, J=6.9 Hz, 0.5H), 2.38-2.31 (m, 2H), 2.28-2.23 (m, 1.5H), 1.57-1.18 (m, 4H), 1.14-0.84 (m, 3H), 0.76 (t, J=7.3 Hz, 1H), 0.68 (t, J=7.3 Hz, 1H); MS(ESI+) m/z 859.4 (M+H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][CH2:12][NH2:13].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>CS(C)=O>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)[CH2:10][CH2:11][CH2:12][NH2:13])=[CH:17][CH:16]=1
Reactant: NCCCNc1ccccn1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Yield: 86.8 %

Procedure:
To a mixture of sodium hydride (5.86 g, 60% dispersion in mineral oil, 0.1415 mol) in dry dimethylsulfoxide (250 ml) was slowly added a solution of N-(pyridin-2-yl)propane-1,3-diamine (20 g, 0.1323 mol) in dry dimethylsulfoxide (50 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred until gas evolution was ceased. A solution of 4-bromobenzylbromide (36.09 g, 0.1415 mol) in dry dimethylsulfoxide (100 ml) was slowly added at room temperature. The reaction mixture was stirred for 48 h at room temperature. The reaction mixture was poured onto ice water (500 ml) and extracted with ethyl acetate (3×250 ml). The combined organic extracts were washed with water (3×150 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue (40.56 g) was washed with n-heptane (30 ml) which afforded 36.77 g of crude N-(4-bromobenzyl)-N-(pyridin-2-yl)propane-1,3-diamine. 20 g crude product was purified by column chromatography on silica gel (900 ml) using dichloremethane/methanol/triethylamine 9:0.5:0.5 as eluent affording 13.75 g (70%) of N-(4-bromobenzyl)-N-(pyridin-2-yl)propane-1,3-diamine as an oil.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH:4]([NH2:9])[CH2:5][CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[CH2:17]([O:19][C:20]1[N:21]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[NH:49][N:48]=[N:47][N:46]=3)=[CH:35][CH:34]=2)[C:22]2[C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Cl:2][CH2:3][CH:4]([NH:9][C:29]([C:28]1[C:22]2[N:21]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[C:45]4[NH:49][N:48]=[N:47][N:46]=4)=[CH:35][CH:34]=3)[C:20]([O:19][CH2:17][CH3:18])=[N:24][C:23]=2[CH:25]=[CH:26][CH:27]=1)=[O:30])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CC(C)CC(N)CCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1nc2cccc(C(=O)NC(CCl)CC(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
1-Chloromethyl-3-methylbutylamine hydrochloride (39 mg, 230 μmol) and triethylamine (31.6 μL, 1 equiv) were dissolved in DCM (2.00 mL). 2-Ethoxy-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzimidazole-4-carboxylic acid (100 mg, 1 equiv) was added, followed by HOBt (31 mg, 1 equiv) and EDC HCl (51 mg, 1.1 equiv). The reaction was stirred overnight at room temperature, then diluted with DCM (10 mL), washed (H2O, 10 mL), dried over NaSO4, decanted, and the solvent evaporated. The residue was purified by flash chromatography (5% MeOH/DCM) to afford the title compound as a white solid (19 mg, 15%). ESMS [M+H]+ calcd for C30H32ClN7O2 557.3. found 558.3.
Reaction SMILES: Cl.[CH3:2][C@H:3]([O:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([O:28]C)[N:14]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:10]([NH2:30])[N:9]=1)[CH2:4][CH2:5][CH3:6]>O1CCOCC1.CO>[NH2:30][C:10]1[N:9]=[C:8]([O:7][C@@H:3]([CH3:2])[CH2:4][CH2:5][CH3:6])[N:16]=[C:15]2[C:11]=1[NH:12][C:13](=[O:28])[N:14]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCCCN3CCCCC3)c2n1
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A solution of hydrogen chloride in dioxane (4M, 0.71 mL) was added to a solution of 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[5-(1-piperidinyl)pentyl]-9H-purin-6-amine (for example, as prepared for Intermediate 9) (0.046 g, 0.126 mmol) in methanol (3 mL). The resultant mixture was allowed to stand overnight at room temperature and then blown down under nitrogen. The residue was dissolved in methanol and loaded onto a 2 g aminopropyl SPE cartridge (pre-conditioned with methanol), eluted with methanol and the resultant solution blown down under nitrogen to give the title compound as a yellow solid (40.97 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16]2)[CH:12]=[CH:11][C:10]=1[N:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25](=[O:30])[C:24]([C:31]2[N:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:34]=[CH:33][CH:32]=2)=[N:23]1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[F:21][C:17]1[C:18]([F:20])=[CH:19][N:15]([C:13]2[CH:12]=[CH:11][C:10]([N:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25](=[O:30])[C:24]([C:31]4[N:35]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:34]=[CH:33][CH:32]=4)=[N:23]3)=[C:9]([OH:8])[CH:14]=2)[CH:16]=1
Reactant: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OCc2ccccc2)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2O)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
A suspension of 1-[2-(benzyloxy)-4-(3,4-difluoro-1H-pyrrol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (3.20 g) and 10% palladium on carbon (containing water (50%), 3.20 g) in acetic acid (100 mL) was stirred at room temperature for 3 hr under a hydrogen atmosphere. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by SFC (column: CHIRALPAK ADH (trade name), 20 mmID×250 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD., mobile phase: carbon dioxide/2-propanol/acetonitrile=700/150/150 (v/v/v)), and the obtained fraction was concentrated under reduced pressure. The residue was recrystallized from acetone to give the title compound (1.24 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].[CH2:22]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH2:23][CH2:24][CH3:25].CC#N>CCOC(C)=O>[CH2:22]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:15])[CH2:28][CH2:27]1)[CH2:23][CH2:24][CH3:25]
Reactant: O=c1ccc2ccccc2n1CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCC1CCN(CCCn2c(=O)ccc3ccccc32)CC1
Temperature: 50 °C
Reaction time: 60 h
Yield: 49 %

Procedure:
A 7 mL vial was charged with 1-(3-chloropropyl)-1H-quinolin-2-one (0.450 g, 2.0 mmol), K2CO3 (0.34 g, 2.5 mmol), KI (0.42 g, 2.5 mmol), 4-butylpiperidine (0.30 g, 2.1 mmol) and dry CH3CN (3 mL). The mixture was shaken at 50° C. for 60 h and thereafter diluted with EtOAc (50 mL) and washed with water (50 mL). The water phase was extracted with EtOAc (2×50 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 4:1) followed by prep RP-HPLC to give the title compound (0.32 g, 49%). 1H NMR (CD3OD) δ 7.88 (d, J=9.6 Hz), 7.68 (brd, J=8.0 Hz), 7.65-7.61 (m, 2H), 7.33-7.25 (m, 1H), 6.64 (d, 9.6 Hz), 4.39-4.32 (m, 2H), 2.95-2.86 (m, 2H), 2.50-2.43 (m, 2H), 2.01-1.86 (m, 4H), 1.71-1.62 (m, 2H), 1.35-1.12 (m, 9H), 0.89 (t, J=6.6 Hz); 13C NMR (CD3OD) δ 163.1, 140.4, 139.0, 131.1, 129.2, 122.6, 121.4, 120.3, 114.7, 55.8, 53.9, 40.6, 36.2, 35.7, 32.0, 28.9, 24.7, 22.8, 13.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].Br[CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: Oc1ccc(F)cc1F
Reactant: CC(Br)c1ccnc2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(F)cc1F)c1ccnc2ncnn12
Reaction time: 0.5 h

Procedure:
A solution of 2,4-difluorophenol (1.30 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue was dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of dichloromethane and ethanol (in the ratio 97:3 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-[1-(2,4-difluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 1.8 g, (m.p. 96°-97° C.).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][N:3]=1.[CH3:10][NH:11][CH2:12][CH:13]=[O:14]>C1C=CC=CC=1>[CH3:10][N:11]([CH2:12][CH:13]=[O:14])[C:8]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)=[O:9]
Reactant: Cc1nnc(N=C=O)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: Cc1nnc(NC(=O)N(C)CC=O)s1

Procedure:
A mixture of 5-methyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)-ureido]acetaldehyde.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(O)=[O:2].C[CH2:21][N:22]=C=NCCCN(C)C.Cl.CN>C(Cl)Cl.[Ni].CN1CCOCC1>[CH3:21][NH:22][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Ni]
Agent: CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 72 h
Yield: 48.2 %

Procedure:
A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCI.HCl (3.63 g, 18.6 mmol), Ni-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF 8 mL, 16 mmol) in CH2Cl2 (45 mL) was stirred at room temp. for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organic phases were washed with a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).
Reaction SMILES: [N:1](=[C:3]1[CH:8]([CH3:9])[N:7]([CH3:10])[C:6](=[O:11])[CH2:5][S:4]1)[OH:2].[CH3:12][N:13]=[C:14]=[O:15]>C(N(CC)CC)C>[CH3:12][NH:13][C:14]([O:2][N:1]=[C:3]1[CH:8]([CH3:9])[N:7]([CH3:10])[C:6](=[O:11])[CH2:5][S:4]1)=[O:15]
Reactant: CN=C=O
Reactant: CC1C(=NO)SCC(=O)N1C
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C1SCC(=O)N(C)C1C

Procedure:
Utilizing the procedure of Example V, 2-oximino-3,4-dimethyltetrahydro-1,4-thiazin-5-one was reacted with methyl isocyanate in the presence of triethylamine to yield 3 g of 2-[O-(methylcarbamoyl)oximino]-3,4-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 161°-163° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42]>CN(C=O)C>[NH2:24][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42]
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reaction time: 8 h
Yield: 44.7 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (1.834 g, 5.22 mmol) was heated at 60° C. with potassium carbonate (2.89 g, 20.88 mmol) in DMF (23 ml) for 1 hour. Phenylmethyl 2-(3-bromopropyl)-1-piperidinecarboxylate (2.131 g, 6.26 mmol) was added and heating continued at 50° C. overnight (20 hours). The reaction mixture was partitioned between water (250 mL) and ethyl acetate (150 mL). The aqueous was further extracted with ethyl acetate (100 ml). The combined organic layers were washed with brine (100 ml) and passed through a hydrophobic frit to dry, then stripped to dryness (rotary evaporator) to give an orange liquid. The material was loaded onto 2×70 g aminopropyl cartridge and eluted on the Flashmaster system in gradient of 0-100% ethylacetate in cyclohexane over 40 mins. Appropriate product fractions were combined and evaporated in vacuo to give the title compound as a clear oil (1.16 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18].I[CH2:21][CH2:22][CH3:23]>>[CH:14]([C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:21][CH2:22][CH3:23])=[C:3]([C:17](=[O:19])[CH3:18])[CH:4]=2)[O:9][C:8]([CH3:13])([CH3:12])[CH:7]=1)([CH3:15])[CH3:16]
Reactant: CC(=O)c1cc2c(cc1O)OC(C)(C)C=C2C(C)C
Reactant: CCCI
Product: CCCOc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure A, 1-(7-hydroxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)ethanone (Compound 62, 400 mg, 1.38 mmol) and 1-iodopropane (0.70 mL, 6.90 mmol) were reacted to produce the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:17])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>CCO.O>[CH2:15]([N:12]1[C:9]2=[N:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]([OH:17])=[C:8]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1ncc2c(O)c(C(=O)O)cnc21

Procedure:
1-Ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (10.0 g, 42.6 mmol) was suspended in 50 mL EtOH. To this suspension was added 6 N NaOH (21.3 mL, 3 eq). The resulting light brown solution was heated at reflux for 3 hr before being diluted with 100 mL water. The aqueous solution was extracted with diethyl ether (50 mL×3) and the organic layer was discarded. The aqueous layer was acidified with 1 N HCl and a white precipitate formed. The title compound was collected by filtration and rinsed with water and diethyl ether affording a white solid (7.9 g, 90%): mp 218° C. (decomposed); LRMS (m/z) 208 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:6]=2)[CH2:3][CH2:2]1.[NH:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[O:27].N1CCCCC1>CCO>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:31]4\[NH:25][C:26](=[O:27])[NH:28][C:29]\4=[O:30])=[C:9]3[N:8]=[C:7]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(Nc2cc(NC3CC3)n3ncc(C=O)c3n2)cc1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1ccc(Nc2cc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 79.1 %

Procedure:
4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (75 mg, 0.24 mmol) was suspended in EtOH (2.4 mL). Hydantoin (36 mg, 0.35 mmol) and piperidine (36 μL, 0.35 mmol) were added and the reaction was heated to 80° C. After 15 h, the solution was filtered while warm and the filter cake was washed with warm EtOH (3 mL) to give (Z)-4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (76 mg, 80%) as a bright yellow solid. LCMS (ES): >90% pure, m/z 401 [M+1]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([NH:13]C(=O)OC(C)(C)C)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Cl>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N2CCOCC2)c1
Agent: Cl
Product: Nc1cccc(N2CCOCC2)c1
Yield: 90.5 %

Procedure:
A solution of tert-butyl (3-morpholinophenyl)carbamate (5.91 g, 21.20 mmol) in a solution of HCl (106 mL, 106.0 mmol, 1 M in MeOH) was stirred at rt overnight, then concentrated in vacuo. The residue was dissolved in water (100 mL). The soltution was basified with saturated Na2CO3 aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a light brown solid (3.42 g, 91%).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH2:13])=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[NH2:2].[CH:14]1([CH2:17][C:18]([CH:20]2[C:25](=[O:26])[CH2:24][C:23]([CH3:28])([CH3:27])[CH2:22][C:21]2=O)=O)[CH2:16][CH2:15]1>CCO>[NH2:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([N:1]3[C:21]4[CH2:22][C:23]([CH3:28])([CH3:27])[CH2:24][C:25](=[O:26])[C:20]=4[C:18]([CH2:17][CH:14]4[CH2:16][CH2:15]4)=[N:2]3)=[CH:4][CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: NNc1ccc2c(N)ncnc2c1
Reactant: CC1(C)CC(=O)C(C(=O)CC2CC2)C(=O)C1
Solvent: CCO
Product: CC1(C)CC(=O)c2c(CC3CC3)nn(-c3ccc4c(N)ncnc4c3)c2C1
Temperature: 50 °C
Reaction time: 22 h

Procedure:
7-Hydrazino-quinazolin-4-ylamine (0.092, 16 mg) is dissolved in 1 mL EtOH and 2-(2-Cyclopropyl-acetyl)-5,5-dimethyl-cyclohexane-1,3-dione (0.092 mmol, 20.4 mg) is added. The reaction is stirred at 50° C. for 22 h. The reaction is cooled and quenched by pouring into 20 mL H2O and extracted 3 times with 5 mL CH2Cl2. The combined organics are dried with Na2SO4, concentrated, and purified by silica gel chromatography on Biotage using a gradient of 0-15% MeOH in DCM. 1-(4-Amino-quinazolin-7-yl)-3-cyclopropylmethyl-6,6-dimethyl-1,5,6,7-tetrahydro-indazol-4-one is isolated (1 mg, LC/MS m/z=362 [M+H]+)) as a white powder.