Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:11][CH2:12][NH:13][C:14](=O)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+].O>C(#N)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[C:14]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[N:13][CH2:12][CH2:11]2
Reactant: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc2c(cc1OC)C(CCc1ccc(C(F)(F)F)cc1)=NCC2
Temperature: 25 °C
Yield: 99.9 %

Procedure:
Phosphorous oxychloride (4.77 g, 2.9 mL, 31.0 mmol, 2.2 eq) was added to a suspension of 44a (5.37 g, 14.1 mmol, 1.0 eq) in acetonitrile (100 mL) resulting in the formation of a clear solution. The mixture was heated at reflux for 3.5 h. The resulting yellow solution was cooled to rt and concentrated under reduced pressure to a thick yellow oil. The oil was dissolved in methanol (10 mL) and water (100 mL) was added slowly with stirring. After several minutes, a thick suspension formed. The mixture was made alkaline by the slow addition of saturated sodium bicarbonate solution, adding water (˜100 mL) to facilitate stirring. The thick white suspension was extracted with ethyl acetate (1×200 mL, 1×100 mL). The combined organic solution was washed with brine (100 mL), dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give 5.12 g (100%) of 45a as an off-white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C[O:22][C:23](=O)[C:24]([CH3:26])=[CH2:25]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:23]([O:20][CH:18]([CH2:17][CH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=1)[CH3:19])(=[O:22])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)OC
Reactant: CC(O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: C=C(C)C(=O)OC(C)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A process as described in claim 2 where 4-(3,5-di-t-butyl-4-hydroxyphenyl)-butane-2-ol is esterified by reaction with methylmethacrylate in the presence of tetraisopropyl titanate to yield 4-(3,5-di-t-butyl-4-hydroxyphenyl)-2-butyl methacrylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:39]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51](O)=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)([O-:41])=[O:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:51]2[CH:50]=[CH:49][C:48]([C:45]3[CH:46]=[CH:47][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=3)=[CH:53][CH:52]=2)[N:15]=1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)cs1
Yield: 74.1 %

Procedure:
To a solution of 2-{[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (2.7 g) synthesized in Example 4 in tetrahydrofuran (15 ml) were added triphenylphosphine (2.5 g) and 4-(4-nitrophenyl)phenol (12.1 g), and the mixture was stirred under ice-cooling for 5 min. To the solution was added diisopropyl azodicarboxylate (40% toluene solution, 4.7 ml), and the mixture was stirred at room temperature overnight. To the solution were further added triphenylphosphine (1.2 g) and diisopropyl azodicarboxylate (40% toluene solution, 2.4 ml), and the mixture was stirred at room temperature for 3.5 hr. The reaction mixture was concentrated, extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (3.3 g) as a pale-brown solid.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[C:11]2[CH:12]=[N:13][C:14]([NH:17][C:18]([NH:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[O:19])=[C:15]([F:16])[C:10]=2[NH:9][N:8]=1)C(=O)C)[CH3:2].Cl>C1COCC1>[CH2:1]([NH:3][C:7]1[C:11]2[CH:12]=[N:13][C:14]([NH:17][C:18]([NH:20][C@@H:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH3:22])=[O:19])=[C:15]([F:16])[C:10]=2[NH:9][N:8]=1)[CH3:2]
Reactant: CCN(C(C)=O)c1n[nH]c2c(F)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: Cl
Solvent: C1CCOC1
Product: CCNc1n[nH]c2c(F)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 60 °C

Procedure:
(R)—N-Ethyl-N-(7-fluoro-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide (27 mg, 0.070 mmol) was dissolved in THF (3 mL), charged with HCl (300 μL, 3.65 mmol), and heated to 60° C. for 4 h. The solvents were removed in vacuo and the residue was taken up in DMF and purified by mass-triggered reverse phase HPLC. Fractions containing pure compound were filtered through a PS-HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)-1-(3-(ethylamino)-7-fluoro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C17H19FN6O [M+1]+ 343. found 343. 1H NMR (500 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.67 (s, 1H), 8.90 (br s, 1H), 8.49 (s, 1H), 7.39-7.27 (m, 4H), 7.26-7.18 (m, 1H), 4.90 (t, J=7.2 Hz, 1H), 3.25 (m, 2H), 1.42 (d, J=6.9 Hz, 3H), 1.20 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=1)=[O:15])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[S:44]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45]1>O1CCOCC1.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>[CH2:1]([O:8][CH2:9][CH:10]([NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:45]2[S:44][CH:48]=[CH:47][CH:46]=2)[CH:22]=1)=[O:15])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccsc1
Reactant: CCC(COCc1ccccc1)NC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1-c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCC(COCc1ccccc1)NC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1-c1cccc(-c2cccs2)c1
Temperature: 110 °C

Procedure:
To a solution of 281A (27 mg, 50 umol) in 1 mL dioxane was added 2M solution of K3PO4 (100 uL), Pd(PPh3)4 (3 mg, 2 umol) and the contents were degassed and purged with nitrogen. To this solution was added 3-thiophene boronic acid (7 mg, 55 umol) and the resulting mixture was heated in a sealed 1 dram vial at 110° C. for 48 h. Contents were cooled to room temperature and passed through a waters HLB u elution plate to get rid of insoluble material and the filtrate was further purified via prep HPLC (Xterra 10×50 mm, S5 column, MeOH— Water gradient) to give the title compound. HPLC retention time (2.04 min). Observed mass 576.13.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)[OH:4])#[CH:2].[OH:17][C:18]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>O.C(OCC)C.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.[Cu](I)I>[OH:17][C:18]1[CH:27]=[C:26]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[C:13]3[C:8]([C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][S:12]3)=[CH:7][CH:6]=2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CC(O)c1ccc2c(c1)SCCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)SCCC3(C)C)cc1O
Reaction time: 4 h

Procedure:
2.5 g (10.8 mmol) of α-ethynyl-4,4-dimethyl-7-thiochromanmethanol, 3 g (10.8 mmol) of methyl 2-hydroxy-4-iodobenzoate and 50 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 30 min. and then 600 mg (0.86 mmol) of bis(triphenylphosphine)palladium(II) chloride and 240 mg (1.3 mmol) of copper iodide were successively added. Stirring was carried out at room temperature for four hours and the reaction mixture was evaporated to dryness and the residue obtained taken up in water and ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with dichloromethane. 3.2 g (80%) of methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl]benzoate, with a melting point of 101°-102° C., were recovered.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][C@H:13]([CH3:15])[CH2:12][CH2:11][C@H:10]1[CH:16]=[CH:17]C(=C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21]OS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+].CCOC(C)=O>CN(C=O)C.O=[Os](=O)(=O)=O>[CH2:1]([O:8][C@@H:9]1[CH2:14][C@H:13]([CH3:15])[CH2:12][CH2:11][C@H:10]1[C:16](=[O:21])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C=C[C@@H]1CC[C@@H](C)C[C@H]1OCc1ccccc1
Reactant: O=S([O-])OO
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)[C@@H]1CC[C@@H](C)C[C@H]1OCc1ccccc1
Reaction time: 0.08 h
Yield: 80 %

Procedure:
(1R, 2S, 5R)-(2-Isoprenyl-5-methyl-cyclohexyl) benzyl ether (120 mg) was dissolved in DMF (5 mL), and OsO4 (0.18 ML, 0.13M in toluene) was added and stirred for 5 min. OXONE (1.21 g) was added in one portion and the reaction had a final volume (7 mL). The reaction was stirred at room temperature for 3 hours or until the solution becomes colorless. This usually marks the completion of the reaction which was verified by TLC or GC. Na2SO3 (720 mg) was added, to reduce the remaining Os(VIII), and stirred for an additional hour or until solution became dark brown/black. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude product. (1R, 2R, 5R)-(2-Acetyl-5-methylcyclohexyl) benzyl ether was obtained in 80% yield after purification by silica gel column chromatography.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([OH:14])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][N:23]=1>CN(C)C=O>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[O:14][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][N:23]=1)[CH3:1]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: CC(C)Oc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
A mixture of 3-(1-methylethoxy)-4-nitrophenol (27.3 g), cesium carbonate (90.4 g), 2-bromo-5-(methylsulfonyl)pyridine (32.7 g) and N,N-dimethylformamide (250 mL) was stirred at 100° C. for 4 h. The mixture was concentrated under reduced pressure and water was added to the residue. The resulting brown suspension was filtered to collect a brown solid. The solid was washed with ethanol-hexane to give the title compound (38.82 g, 79%) as a brownish-yellow solid. MS 353 (MH+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:27]1([C:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[S:35][N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:30]3[CH2:31][CH2:32][N:27]([C:33]4[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[S:35][N:34]=4)[CH2:28][CH2:29]3)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl
Agent: Cl
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl)N1CCN(c2nsc3ccccc23)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid (example 49, step 2) was coupled with 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride to give the title compound as a colorless solid. MS: 581.6 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26][O:27][CH2:28][CH2:29]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:29][CH2:28][O:27][CH3:26])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCCBr
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Agent: [H-]
Agent: [Na+]
Product: COCCOCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to Example 15 intermediate c), from (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and 2-bromoethyl methyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(Br)c(OCC2CC2)n1
Reactant: C1CCNC1
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 32 a, using 2-[(5-bromo-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester (Example 265) and pyrrolidine (CAN 123-75-1) as starting materials. MS (EI): m/e=404.4 [M+H]+.
Reaction SMILES: [CH:1]1([C@H:4]([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH3:23])[N:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1.[C:24](OCC)(=[O:28])[C:25]([CH3:27])=O>C(O)C>[CH:1]1([C@H:4]([N:7]2[C:8]3[N:9]=[CH:10][N:11]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[C:13]=3[N:14]=[C:25]([CH3:27])[C:24]2=[O:28])[CH2:5][CH3:6])[CH2:3][CH2:2]1
Reactant: CC[C@@H](Nc1ncnc(-c2ccc(OC)cc2C)c1N)C1CC1
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Product: CC[C@H](C1CC1)n1c(=O)c(C)nc2c(-c3ccc(OC)cc3C)ncnc21
Reaction time: 18 h

Procedure:
(R)-N4-(1-Cyclopropyl-propyl)-6-(4-methoxy-2-methyl-phenyl)-pyrimidine-4,5-diamine (0.21 g, 0.67 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.75 ml, 6.7 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 2.0 mg of (R)-8-(1-Cyclopropyl-propyl)-4-(4-methoxy-2-methyl-phenyl)-6-methyl-8H-pteridin-7-one (Example 612a). 1H NMR (300 MHz, CDCl3) δ ppm 8.86 (s, 1 H), 7.33 (d, J=9.15 Hz, 1 H), 6.80 (d, J=2.20 Hz, 1 H), 6.78 (d, J=2.20 Hz, 1 H), 4.56 (m, 1 H), 3.80 (s, 3 H), 2.45 (s, 3 H), 2.30 (m, 1 H), 2.20 (s, 3 H), 2.12 (m, 1 H), 0.81 (t, J=7.51 Hz, 3 H), 0.76 (m, 1 H), 0.68 (m, 1 H), 0.42 (m, 1 H), 0.29 (m, 1 H), 0.12 (m, 1 H). MS (EI) 377.3 [(M+H)+, 100].
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([CH2:20][NH2:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.C[O:27][C:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1.[OH-].[Na+]>>[CH3:40][N:35]([S:36]([CH3:39])(=[O:38])=[O:37])[C:32]1[CH:31]=[CH:30][C:29]([C:28]([NH:21][CH2:20][CH:9]2[CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:27])=[CH:34][CH:33]=1
Reactant: NCC1CN(c2ccccc2)CCN1Cc1ccccc1
Reactant: COC(=O)c1ccc(N(C)S(C)(=O)=O)cc1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Product: CN(c1ccc(C(=O)NCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1)S(C)(=O)=O
Temperature: 25 °C

Procedure:
To 4-phenyl-1-(phenylmethyl)-2-piperazinemethanamine (6.95 g, 24.7 mmol) intoluene (130 mL) at 0° C. add trimethylaluminum (2.0M in toluene, 16.2 mL, 32.4 mmol). Allow the reaction to warm to room temperature and add 4-[(methyl)(methylsulfonyl)amino]benzoic acid methyl ester (6.91 g, 28.4 mmol). Heat the reaction and monitor the progress by thin-layer chromatography. Upon completion make the solution basic with aqueous NaOH and extract with EtOAc. Remove the solvent in vacuo. Flash chromatograph the residue on silica gel with EtOAc/hexane (2/1) to obtain the title compound.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[NH2:10][C:11](=[O:26])[C@@H:12]([NH:18]C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:15]([OH:17])=O.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.CN>C(#N)C>[NH2:18][C@@H:12]([CH2:13][CH2:14][C:15]([NH:4][CH3:1])=[O:17])[C:11]([NH2:10])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(N)=O
Reactant: CCN(C(C)C)C(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CNC(=O)CC[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (2.0 ml) was added to a solution of (4S)-5-amino-4-[[(1,1-dimethylethoxy)carbonyl]amino]-5-oxo-pentanoic acid (0.49 g), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.20 g) and methylamine (0.16 g) in acetonitrile (20 ml). The reaction mixture was stirred at room temperature for 2 hours then concentrated. The residue was taken into 4M HCl in 1,4-dioxane (20 ml), stirred for 4 hours then concentrated. Purification (Preparative C18 125 Å bulk packing material, water:methanol, gradient elution 0:100 to 100:0) gave the sub-title compound (0.48 g).
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]([OH:5])=[O:4].[N+](=[CH2:19])=[N-].C(Cl)(Cl)Cl>CCOCC>[CH3:19][O:4][C:3](=[O:5])[C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: C=[N+]=[N-]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)C(=O)O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](C)CCC[C@H](C)CCCC(C)C

Procedure:
2(R),6(R),10-trimethylundecanoic acid (270 mg., [α]D25 -8.64°) was dissolved in ether and treated with an excess of etheral solution of diazomethane at 23° C. for 2.0 hour. The crude product was subjected to evaporative distillation at 98°-101°/0.15 mm Hg to give 247 mg. of 2(R), 6(R),10-trimethylundecanoic acid methyl ester as a colorless oil, [α]D25 -11.30° (c1.1065, CHCl3).
Reaction SMILES: [CH2:1]([N:4]([CH:10]([CH3:13])[CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].O.[CH2:15]([NH:22][CH2:23]C(O)=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:23][CH2:3][CH:2]2[CH:11]1[CH:10]([CH3:13])[N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCN(C(=O)OCC)C(C)C=O
Reactant: O=C(O)CNCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1C

Procedure:
37 g (0.2 mol) of ethyl N-allyl-N-(1-oxo-2-propyl)-carbamate are heated under reflux overnight in a water separator with 33 g (0.2 mol) of N-benzylglycine in 500 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][N:3]=1.[PH2](O)=O.N(OCC(C)C)=O>C(O)C>[Br:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[CH:2]2
Reactant: Nc1n[nH]c2ccc(Br)cc12
Agent: CC(C)CON=O
Agent: O=[PH2]O
Solvent: CCO
Product: Brc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
A mixture of 3-amino-5-bromo-indazole, (4.60 g, 22 mmol) and ethanol (50 mL) was treated with hypophosphorous acid (50% aqueous solution, 9.6 ml, 87 mmol) and cooled to 0° C. To the reaction mixture was added isobutyl nitrite (2.6 mL, 22 mmol). The mixture was warmed to room temperature and the yellow suspension was stirred for two hours. The resulting brown suspension was treated with isobutyl nitrite (1 mL) and stirred at room temperature for one hour. The reaction was quenched with brine (100 mL) and the mixture extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to a brown oil which was purified by chromatography using silica gel and hexane/ethyl acetate to give 5-bromo-indazole as a tan solid (1.74 g, 40%): mp 122-124° C.; MS [M+H]+ 195, 197.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]I)=[CH:4][C:3]=2[O:2]1.[Li].[CH3:18][CH2:19][C:20](=[O:26])[CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>CN(C)C=O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH:21]([C:20](=[O:26])[CH2:19][CH3:18])[C:22](=[O:25])[CH2:23][CH3:24])=[CH:4][C:3]=2[O:2]1
Reactant: ICCC=CCCc1ccc2c(c1)OCO2
Reactant: CCC(=O)CC(=O)CC
Agent: [Li]
Solvent: CN(C)C=O
Product: CCC(=O)C(CCC=CCCc1ccc2c(c1)OCO2)C(=O)CC

Procedure:
[I; Ar is 3,4-methylenedioxyphenyl, R0 is H, R' and R" are CH3CH2CO, Y is CH=CHCH2CH2 ] was prepared from 12.5 g. of 6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D2) and 12.5 g. of the lithium salt of 3,5-heptanedione in 175 ml. of dimethylformamide. The product was chromatographed on silica gel and eluted with pentane-benzene (1:1) and then with chloroform-benzene (7:3). The latter brought out 7.0 g. of 4-[6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione as a light amber oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1)=O.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21].B(O)(O)O.O>C1(C)C(C)=CC=CC=1>[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[N:21]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2nc3ccccn3n2)cc1
Reactant: Nc1ccccc1Cl
Agent: OB(O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: Clc1ccccc1N=Cc1ccc(-c2nc3ccccn3n2)cc1
Temperature: 60 °C

Procedure:
22.32 g of 2-(p-formylphenyl)-s-triazolo[1,5-a]pyridine (II), 14.03 g of o-chloroaniline and 1 g of boric acid in 350 ml of xylene are refluxed for 2 hours, the water formed being distilled off. The mixture is cooled to 60° C., 450 ml of methanol are added and the resulting mixture is further cooled to -10° C. The product which has precipitated is filtered off with suction, washed with 100 ml of cold methanol and dried. This gives 26.3 g (79.1% of theory) of compound (101) in the form of a pale beige powder with a melting point of 135° to 136° C. After recrystallising twice from methanol, 22.2 g (66.7% of theory) of small, pale yellow, glossy needles with a melting point of 135° to 136° C. are obtained.