Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.O(N(C)[C:16](=[O:18])[CH3:17])C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:16]([C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: CON(C)C(C)=O
Reactant: Brc1cncnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1cncnc1
Temperature: -78 °C
Yield: 40.9 %

Procedure:
5-Bromopyrimidine (3.18 g, 20 mmol) was dissolved in 50 mL of tetrahydrofuran. While cooled to −78° C., 15 mL of 1.6 M n-butyllithium in hexane solution was added dropwise with stirring. After the solution was stirred for 30 minutes, a solution of N-methoxyl-N-methylacetamide (2.58 g, 25 mmol) in tetrahydrofuran solution (10 mL) was added slowly. The mixture was stirred at −78° C. for 1 hour and then allowed to be warmed slowly. When the temperature of the mixture was at 0° C., aqueous ammonium chloride solution was added. The solution obtained was extracted with ethyl acetate for 3 times. The pooled extracts were washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using 5% methanol/methylene chloride as eluent to obtain 1 g of the title compound (45% yield). MS (M+1)=123.05.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].B.CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCCc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
To a solution of 2-(3-fluoro-4-hydroxyphenyl)acetic acid (9.8 g, 57.6 mmol) in THF (500 mL) was added dropwise 57.6 mL of borane (10M in Me2S) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was added to CH3OH and was concentrated under reduced pressure. The residue was partitioned between EtOAc (800 mL) and water (100 mL). The organic layer was dried and concentrated to dryness to give the title product (8.5 g, 76%).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[CH2:60]([O:67][C:68]([NH:70][CH2:71][CH2:72][CH2:73][C@H:74]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C:75](OCC#N)=[O:76])=[O:69])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O.C(#N)C>[CH2:60]([O:67][C:68]([NH:70][CH2:71][CH2:72][CH2:73][C@@H:74]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C:75]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:76])=[O:69])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 28.6 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (67.9 mg, 0.107 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 5-(((benzyloxy) carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk66) (173 mg, 0.427 mmol) in acetonitrile (0.3 mL) were added to buffer A (18 mL), and the mixture was stirred at room temperature for 1.25 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk67) (30.1 mg, 29%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=5)[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Clc1cccc(-c2cncc(Br)c2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5cccc(Cl)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(3-chloro-phenyl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:22])[CH:17]=[N:18][C:19]=1[O:20][CH3:21].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8]([NH:22][C:16]2[CH:17]=[N:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(N)cnc1OC
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)c2cccnc2Cl)cnc1OC
Yield: 65.6 %

Procedure:
The title compound (542 mg, 1.64 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (530 mg, 2.5 mmol), 5,6-dimethoxypyridin-3-amine (424 mg, 2.8 mmol) and pyridine (0.6 mL, 7.5 mmol) in DCM (10 mL) using the methods of (IntC1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1.[CH3:15]O.S(Cl)(Cl)=O>O>[CH3:15][O:12][C:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=2[CH:8]=1)=[O:13]
Reactant: CO
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2cc(OC)ccc2o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Methoxybenzofuran-2-carboxylic acid (5.04 g, 26 mmol) was weighed into a 200 ml round bottom flask fitted with a stir bar, septum and nitrogen inlet. Anhydrous MeOH (50 ml) was added under nitrogen atmosphere. The solution was cooled in an ice bath and thionyl chloride (2.3 ml, 32 mmol) was added dropwise with vigorous stirring. After stirring for 72 h at room temperature, the reaction mixture was poured into water (150 ml) and the white solid was collected. The solid was dissolved in toluene (100 ml) and the solution was washed with 1M NaHCO3 and brine and dried over MgSO4. Removal of the organic layer provided 5-methoxybenzofuran-2-carboxylic acid methyl ester as a white solid (5.15 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([OH:22])=[N:10]2)=[CH:5][CH:4]=1.Br[CH2:24][C:25]#[C:26][CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([O:22][CH2:24][C:25]#[C:26][CH3:27])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CC#CCBr
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Product: CC#CCOc1nc(-c2ccc(OC)cc2)n(-c2ccc(OC)cc2)n1
Yield: 40.8 %

Procedure:
1,5-bis(4-methoxyphenyl)-3-(2-butynyloxy)-1H-1,2,4-triazole (96 mg, 40.8% yield) was prepared from 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol and 1-bromo-2-butyne by the similar manner described for Example 18.
Reaction SMILES: [NH2:1][C:2]1[N:30]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>CN(C)C(=O)C.C(OCC)(=O)C>[CH:31]1([C:34]([NH:1][C:2]2[N:30]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2n1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (100 mg, 0.24 mmol) in N,N-dimethylacetamide (2.0 mL) was added cyclopropanecarbonyl chloride (33 μL, 0.36 mmol), and the mixture was stirred at room temperature for 4 hr. Cyclopropanecarbonyl chloride (15 μL, 0.17 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (150 mL), washed with 1N hydrochloric acid (15 mL), 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and fractions containing the desired product were concentrated under reduced pressure and the residue was recrystallized from ethyl acetate, hexane and diisopropyl ether to give the title compound (108 mg, 92%) as a colorless powder.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]([CH:28]3[CH2:30][CH2:29]3)[C:24](=[O:27])[NH:25][N:26]=2)=[CH:18][CH:17]=1>C(#N)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]([CH:28]3[CH2:29][CH2:30]3)[C:24](=[O:27])[N:25]([CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:26]=2)=[CH:20][CH:21]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 85 °C

Procedure:
384 mg (2.12 mmol) of ethyl 2-bromopropionate and 1.38 g (4.24 mmol) of caesium carbonate are added to 500 mg (2.12 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 36A in 5 ml acetonitrile and the reaction mixture is heated at 85° C. overnight. It is then concentrated in vacuo, the residue is partitioned between water and dichloromethane, and the separated organic phase is dried over sodium sulphate and again evaporated. After purification of the residue by flash chromatography over silica gel (eluent: first dichloromethane, then dichloromethane/methanol 200:1), 729 mg (97% of theory) of the target compound are obtained.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:13](Cl)(=[O:15])[CH3:14]>[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>[C:13]([NH:12][C@@H:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:9]([OH:11])=[O:10])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.5 %

Procedure:
To a solution of L-diphenylalanine (100 mg, 0.4 mmol) (Peptech Corp.) in 5 mL 1N NaOH and 0.5 mL saturated Na2CO3 (resulting solution at pH 10) was added acetyl chloride (0.5 mmol) dissolved in 5 mL. Afterwards, the reaction mixture was stirred at room temperature for 2 h. The alkaline solution was extracted once with ether (10 mL) and the aqueous phase was acidified with 1N HCl. This was extracted twice with 20 mL EtOAc, and the combined organic phases were washed with 50 mL 1N HCl. The organic phase was dried over Na2SO4, filtered and evaporated to an oil, which solidifies to yields 70 mg (60%) of the desired material. This crude intermediate was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[N:18]=[C:17]([C:19](=O)[CH3:20])[CH:16]=[CH:15][CH:14]=1)[CH3:12].[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:19](=[N:27][C:26]2[C:28]([CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=[CH:31][C:25]=2[CH:22]([CH3:24])[CH3:23])[CH3:20])[N:18]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: C1CCOC1
Product: CC(=Nc1c(C)cc(C)cc1Cl)c1cccc(C(C)=Nc2c(C(C)C)cccc2C(C)C)n1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
18.80 g of 1-{6-[1-(2-chloro-4,6-dimethylphenylimino)-ethyl]pyridin-2-yl}ethanone (0.0625 mol), 22.16 g of 2,6-diisopropylaniline (0.125 mol) and 20.0 g of Sicapent were heated under reflux under argon in 300 ml of tetrahydrofuran for 17 h. A further portion of Sicapent (10.0 g) was added and the mixture was heated under argon for a further 4 h and then cooled to room temperature. It was filtered and the residue on the filter was washed with 50 ml of tetrahydrofuran. The solvent was distilled off completely from the combined filtrates and the residue was stirred with 50 ml of methanol. The precipitate formed was filtered off, washed twice with methanol, stirred with 100 ml of hot methanol and then filtered. 17.84 g (0.0388 mol) of 2-[1-(2-chloro-4,6-dimethylphenylimino)ethyl]-6-[1-(2,6-diisopropylphenylimino)ethyl]pyridine were obtained in a yield of 62%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26]>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:26]#[C:25][C:24]([CH3:28])([CH3:27])[CH3:23])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-Iodo-phenyl)-carbamic acid tert-butyl ester (37a, 1.0 g, 3.13 g) was dissolved in THF (30 mL) and treated with Et3N (2.2 mL, 15.7 mmol), 3,3-dimethyl- 1-butyne (0.58 mL, 4.70 mmol), bis(triphenylphosphine) palladium (II) chloride (0.218 g, 0.31 mmol), and copper (I) iodide (0.03 g, 0.16 mmol). The reaction was stirred overnight at room temperature, then filtered and concentrated. The residue was chromatographed on silica gel eluting with 8:1 hexanes/EtOAc to give 0.7 g (82%) of the mostly clean desired product which was carried on without further purification.
Reaction SMILES: C([O:4][C@H:5]([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[C:16]([Br:22])=[N:15][C:14]=2[N:13]([CH3:23])[C:11]1=[O:12])(=O)C.Cl>CO.CCOCC>[Br:22][C:16]1[N:17]([CH3:21])[C:18]2[C:19](=[O:20])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:24])[C:11](=[O:12])[N:13]([CH3:23])[C:14]=2[N:15]=1
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2C)n(C)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc(Br)n2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.9 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-8-bromo-3,7-dimethylxanthine (5.88 g, 14.7 mmol) in methanol (200 ml) was added a solution of hydrogen chloride in ether (1.0 M, 20 ml). The reaction mixture was stirred at room temperature for 24 hours. Evaporation of the solvent under reduced pressure provided (R)-8-bromo-3,7-dimethyl-1-(5-hydroxyhexyl)xanthine (4.8 g, 91% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=3)[NH:15][N:14]=1)[CH:7]=[CH:6]2.[OH:24]O.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH2:23])=[O:24])[CH:20]=3)[NH:15][N:14]=1)[CH:7]=[CH:6]2
Reactant: OO
Reactant: COc1ccc2cc(-c3n[nH]c4ccc(C#N)cc34)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2cc(-c3n[nH]c4ccc(C(N)=O)cc34)ccc2c1
Temperature: 45 °C
Yield: 20 %

Procedure:
A mixture of 3-(6-methoxy-2-naphthyl)-1H-indazole-5-carbonitrile (0.230 g, 0.77 mmol), 95% ethanol (6 mL), aqueous 30% hydrogen peroxide (3 mL), and 6.0 N aqueous sodium hydroxide (1 mL, mmol) was heated at 45° C. for 3 h. The reaction mixture was diluted with water (30 mL) and acidified to pH 6 with 3 N hydrochloric acid. The solid was filtered and dried in a vacuum oven to give product (0.050 g, 20% yield): 1H NMR (DMSO-d6) δ 13.45 (s, 1H), 8.72 (s, 1H), 8.50 (s, 1H), 8.18 (s, 1H), 8.15 (d, 1H), 8.02 (d, 1H), 7.95 (d, 1H), 7.61 (d, 1H), 7.37 (m, 2H), 7.22 (dd, 1H); ES-MS (m/z) 318 [M+1]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH2:11][C:12]#[N:13].[NH2:14][C:15]1[C:20]([CH:21]=O)=[CH:19][N:18]=[C:17]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=1.O>C(OCCO)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:12]([NH2:13])=[N:14][C:15]2[N:16]=[C:17]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:18]=[CH:19][C:20]=2[CH:21]=1
Reactant: N#CCc1c(Cl)cccc1Cl
Reactant: Nc1nc(Nc2ccccc2)ncc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Product: Nc1nc2nc(Nc3ccccc3)ncc2cc1-c1c(Cl)cccc1Cl
Yield: 68.4 %

Procedure:
To a solution of 0.022 g 60% sodium hydride suspension in 2.00 mL of 2-ethoxyethanol was added 0.46 g of 2,6-dichlorophenylacetonitrile and 0.50 g of 4-amino-2-phenylamino-pyrimidine-5-carboxaldehyde from Example 72. The reaction was refluxed for 4 hours, cooled, poured into water, and extracted several times with dichloromethane. The dichloromethane washes were combined, washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The residue was washed with diethyl ether to give 0.61 g of the title compound, CIMS (1% NH3 in CH4): 410=M+ +C2H5, 382=M+ +H, 381=M+.
Reaction SMILES: [CH2:1]([O:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:22].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-:22])=[CH:8][C:7]=2[N:6]=[CH:5]1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOn1cnc2cnc3ccccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOn1cnc2c[n+]([O-])c3ccccc3c21
Temperature: 0 °C
Yield: 91 %

Procedure:
A solution of 1-ethoxy-1H-imidazo[4,5-c]quinoline (2.45 g, 11.5 mmol) in dichloromethane (100 mL) was cooled to approximately 0° C., and 3-chloroperoxybenzoic acid (3.85 g of approximately 77% pure material, 17 mmol) was added. The reaction was stirred for ten minutes at 0° C., stirred for three hours at room temperature, and then stirred with saturated aqueous sodium bicarbonate (35 mL) for 15 minutes. The aqueous layer was separated and extracted with dichloromethane (5×50 mL), and the combined organic fractions were dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 2.4 g of 1-ethoxy-5-oxido-1H-imidazo[4,5-c]quinoline as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[NH:7][C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[H-].[Na+].[Na].[Br:19][CH2:20][CH2:21][CH2:22]Br>CN(C=O)C>[Br:19][CH2:20][CH2:21][CH2:22][N:9]1[C:8](=[O:13])[NH:7][C:6]2[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[S:10]1(=[O:12])=[O:11]
Reactant: COc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)S(=O)(=O)N(CCCBr)C(=O)N2
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
0.03 mol of 7-methoxy-1,2,4-benzothiadiazin-3(4H)one 1,1-dioxide is dissolved in 50 ml of absolute DMF, and 0.03 mol of sodium hydride is added. After 15 minutes, formation of the sodium salt was complete. Then 0.06 mol of 1,3-dibromopropane is added dropwise and the mixture is heated at 80° C. for 2 hours. The solvent is then distilled out and the residue is purified by column chromatography on silica gel. The eluting agent used was a mixture of CH2Cl2CH3OH (98:2).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29]>C(O)(C)C>[OH:32][C:27]1([C:28]([F:31])([F:30])[F:29])[CH2:26][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:13]1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccccn2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccccn2)cc1
Temperature: 77.5 °C
Yield: 17.8 %

Procedure:
To a mixture of the amidine of step 1 (4.4 g, 16 mmol) and sodium bicarbonate (2.7 g, 32 mmol) in isopropanol (400 ml), 3-bromo-1,1,1-trifluoroacetone (2.5 ml, 24 mmol) was added. After heating at 75-80° C. for 24 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude product (16.2 g) was purified by chromatography (silica gel, ethyl acetate/toluene 1/1) to give 2-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine (1.1 g, 18%) as a white solid: mp 195-198° C. Anal. Calc'd. for C16H14N3SO3F3: C, 49.87, H, 3.66, N, 10.90. Found: C, 50.13, H, 3.66, N, 10.30.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>C(O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:26][CH:22]([CH2:24][CH3:25])[CH3:23])#[N:2]
Reactant: CCC(C)N
Reactant: CCCCCC(=O)Nc1ccc(OCC2CO2)c(C#N)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCC(=O)Nc1ccc(OCC(O)CNC(C)CC)c(C#N)c1
Yield: 19 %

Procedure:
Ten grams (0.035 mol) of 1-(2-cyano-4-n-hexanoylamino-phenoxy)-2,3-epoxypropane were dissolved in 100 ml of ethanol, 7.3 gm (0.1 mol) of sec.butylamine were added, and the mixture was refluxed for one hour. After the solvent was distilled off in vacuo, the residue was purified by column chromatography in the manner described in Example 6. The base thus obtained was dissolved in ethyl acetate, washed with dilute NaOH and water, dried, and evaporated to dryness. The test substance remaining was recrystallized from ethyl acetate with the addition of petroleum ether. Subsequent recrystallization from acetonitrile yielded 2.4 gm of pure white crystalline base. M.p.: 72°-74° C.