Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:31]=[CH:30][CH:29]=[CH:28][C:15]=1[NH:16][C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([OH:21])=O.Cl.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>>[F:13][C:14]1[CH:31]=[CH:30][CH:29]=[CH:28][C:15]=1[NH:16][C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([NH:41][O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:21]
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccccc1F
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccccc1F
Yield: 98.3 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (2.76 g, 16.8 mmol), 2-(2-fluoro-anilino)-4,5-difluorobenzoic acid (Example R, 4.08 g, 15.3 mmol), O-benzylhydroxylamine hydrochloride (2.44 g, 15.3 mmol), and triethylamine (2.3 mL, 16.8 mmol) provided 5.6 g of the crude title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14](Cl)(=[O:18])[CH2:15][CH2:16][CH3:17]>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 41, step 41.1, 1-Boc-piperazine replacing piperazine-1-carboxylic acid benzyl ester and butyryl chloride replacing benzoyl chloride.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)([OH:4])=[O:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Br:42][C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH:45]=O.O>C1COCC1.CCOCC>[Br:42][C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH:45]=[CH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:2]([OH:4])=[O:3])=[CH:31][CH:30]=1
Reactant: O=Cc1ccccc1Br
Reactant: O=C(O)c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1ccc(CC=Cc2ccccc2Br)cc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 4-carboxyphenethyl triphenylphosphonium bromide (11.2 g, 22.8 mmol) in THF (200 ml) under argon, was added a 1M solution of lithium hexamethyldisilazide (50 ml) in THF at 20° C., giving a deep red colour. After stirring for 30 minutes, the reaction was treated with a solution of 2-bromobenzaldehyde (4.0 g, 21.6 mmol) in THF (15 ml) and stirred for a further 30 minutes at 20° C. The solution was poured onto a stirred mixture of water (100 ml) and ether (100 ml). The layers were separated and the aqueous portion washed again with ether (100 ml), acidified with 1N HCl and extracted with ether (100 ml). The ether extracts were dried over anhydrous magnesium sulphate and "flashed" through a pad of silica to remove impurities, rinsing with further portions of ether. The filtrates were evaporated to give 4-[3-(2-bromophenyl)prop-2-en-1-yl]benzoic acid (6.1 g) as a yellow gum, which slowly solidified.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:22]=O)=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:24][NH2:25].[BH4-].[Na+].CO>O1CCCC1>[F:1][C:2]1[C:3]([CH2:22][NH:25][CH3:24])=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2)c1F
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
4-Fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0.27 g) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution (0.8 mL) of methylamine in tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hr. Sodium borohydride (91 mg) and methanol (7 mL) were added, and the mixture was stirred at the same temperature for further 30 min. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane-ethyl acetate=19:1→0:1). The above-mentioned operation was repeated to give the title compound (0.22 g, yield 39%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[O:11]1.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[NH:1][C:12](=[O:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:10]([O:11][CH3:21])[C:3]=2[CH:4]=1
Reactant: Cc1cc(C)c(N)c(C2OC(=O)c3ccccc32)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC1c2ccccc2C(=O)Nc2c(C)cc(C)cc21
Yield: 53.4 %

Procedure:
In 300 ml of methyl alcohol was dissolved 22.45 g of 3-(2-amino-3, 5-dimethylphenyl)-1, 3-dihydroisobenzofuran-1-one. The solution was heated at reflux for 10 hours in the presence of 20.23 g of p-toluenesulfonic acid monohydrate. The resulting solution was concentrated to dryness under reduced pressure. The obtained solid was dissolved in 200 ml of dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solution was filtered and the resulting filtrate was concentrated to dryness under reduced pressure. To the obtained solid was added to diisopropyl ether and the solid was ground into powders. Thus, 12.65 g of 2,4-dimethyl-11-methoxy-5, 11-dihydro-6H-dibenz[b,e]azepin-6-one was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH:31]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2ccccc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 2-naphthaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 376.02 g/mol.
Reaction SMILES: [O:1]=[C:2]1[C:13]2=[CH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([O:23]CC)=[O:22])=[CH:19][C:20]=3[N:12]2[CH2:11][C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][NH:3]1.[OH-].[Na+].O.C(O)(=O)C>C(O)C>[O:1]=[C:2]1[C:13]2=[CH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][C:20]=3[N:12]2[CH2:11][C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[CH2:4][NH:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CC1(CCOCC1)CNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2cc3n(c2c1)CC1(CCOCC1)CNC3=O
Temperature: 80 °C
Yield: 63.1 %

Procedure:
To a suspension of ethyl 1-oxo-2,2′,3,3′,5′,6′-hexahydro-1H-spiro[1,4-diazepino[1,2-a]indole-4,4′-pyran]-8-carboxylate (4.2 g, 12.2 mmol) in ethanol (120 mL) is added NaOH (1.22 g, 30.5 mmol) and water (30 mL). The reaction mixture is heated at 80° C. for 2 h. Acetic acid (19 mL) and water (180 mL) are added and the resulting solid is collected by filtration, washed with water and dried to afford the title compound (2.42 g, 64%) as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.C(OCC)(=O)C>[Si:18]([O:12][CH2:11][CH2:10][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[NH:9][CH:8]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1c[nH]c2ccccc12
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
A solution of tryptophol (5.0 g, 31 mmol) in DMF (30 ml) was treated with imidazole (4.64 g, 68 mmol) and cooled to 0° C. tert-Butyldimethylsilyl chloride (5.14 g, 34.1 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was then diluted with ethyl acetate (100 ml) and washed with water (2×100 ml) and the aqueous solutions were extracted with ethyl acetate (200 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatogaphy (30% ether/petroleum ether) yielded the title compound (8.43 g, 99% yield) as a colorless oil: IR (CCl4) 3910 (s), 3060 (w), 2960 (s), 2930 (s), 2850 (s), 1450 (m), 1370 (w), 1260 (s), 1100 (s), 900 (m), 840 (s), 780 (s), 750 (s) cm−1; 1H NMR (500 MHz, CDCl3) δ 8.26 (br s, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.64-7.50 (m, 4H), 4.28 (t, J=7.3 Hz, 2H), 3.38 (t, J=7.3 Hz, 2H), 1.29 (s, 2H), −0.43 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 136.08, 127.62, 122.08, 121.75, 119.12, 118.79, 112.84, 111.04, 63.89, 28.98, 25.98, 18.34, −5.29; high resolution mass spectrum (Cl, NH3) m/z 276.1750 [(M+H)+; calcd for C16H25NOSi: 276.1783].
Reaction SMILES: [CH:1]([N:3]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=O.CSC.B.Cl>O1CCCC1.C1(C)C=CC=CC=1.CO>[OH:15][C:8]1[C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:10][C:5]([CH2:4][N:3]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH3:1])=[CH:6][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(CN(C=O)n2ccnc2)cc(C(C)(C)C)c1O
Agent: B
Agent: Cl
Solvent: CSC
Solvent: CO
Solvent: Cc1ccccc1
Product: CN(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)n1ccnc1

Procedure:
3.30 g of 1-[N-formyl-N-(4-hydroxy-3,5-di-tert.-butylbenzyl)amino]imidazole are dissolved in 100 ml of absolute tetrahydrofuran. Into this solution there are injected at room temperature 20 ml of a 2 molar solution of borane-dimethyl sulfide complex [BH3.S(CH3)2 ] in toluene. The reaction mixture is subsequently heated to gentle reflux for 2 hours, cooled to 0°, treated with 20 ml of absolute methanol and heated for an additional 30 minutes. The solvent is removed completely by evaporation under reduced pressure on a rotary evaporator. The residual crystalline solid is triturated with n-hexane, removed by filtration and vacuum-dried for a short period. Thereupon, the solid obtained is suspended in 50 ml of absolute methanol and hydrogen chloride is introduced carefully while stirring up to saturation, whereby a clear solution results with strong warming. This solution is heated to gentle reflux for 1 hour and then evaporated under reduced pressure on a rotary evaporator. The residue is treated with 25 ml of ice-cold water, whereupon saturated sodium bicarbonate solution is added to a weakly alkaline reaction and the mixture is extracted three times with 25 ml of methylene chloride each time. The combined methylene chloride extracts are washed once with a small amount of water and subsequently with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is recrystallized from ethyl acetate/n-hexane and there is obtained 1-[N-(4-hydroxy-3,5-di-tert.-butylbenzyl)-N-methylamino]imidazole of m.p. 139°.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:14]=[N:15][C:16]([CH3:28])=[C:17]([O:24]C(=O)C)[C:18]=1[CH2:19][O:20]C(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:14]=[N:15][C:16]([CH3:28])=[C:17]([OH:24])[C:18]=1[CH2:19][OH:20]
Reactant: CC(=O)OCc1c(Cn2cnc3c(Cl)nc(N)nc32)cnc(C)c1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncc(Cn2cnc3c(Cl)nc(N)nc32)c(CO)c1O
Temperature: 50 °C

Procedure:
A suspension of 6-chloro-9-(5-acetoxy-4-acetoxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-purin-2-ylamine and K2CO3 (excess) in MeOH was heated to 50° C. for 15 min. Filtration, work-up (EtOAc) and purification by preparative TLC gave the title compound. HPLC Rt: 4.498 min. 1H-NMR (d6-DMSO) δ 8.08 (s, 1H), 7.74 (s, 1H), 6.95 (s, 1H), 5.31 (s, 2H), 4.74 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)[S:5]([CH3:8])(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:26]([O:30][C:31]([N:33]1[CH2:40][CH:39]2[O:41][CH:35]([CH2:36][NH:37][CH2:38]2)[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(#N)C>[C:26]([O:30][C:31]([N:33]1[CH2:34][CH:35]2[O:41][CH:39]([CH2:38][N:37]([CH2:2][CH2:3][N:4]([CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)[S:5]([CH3:8])(=[O:7])=[O:6])[CH2:36]2)[CH2:40]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: CS(=O)(=O)N(CCBr)CCOc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCN(CCOc3ccc(C#N)cc3)S(C)(=O)=O)CC(C1)O2

Procedure:
To a suspension of N-(2-bromoethyl)-N-[2-(4-cyanophenoxy)ethyl]methane-sulfonamide (6 g, 0.019 mol; see Preparation C above) and anhydrous potassium carbonate (3.6 g, 0.026 mol) in dry acetonitrile (100 mL) was added 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4.35 g, 0.019 mol; see WO 01/28992), and the resultant mixture was then stirred at 50-55° C. overnight. After completion of the reaction (as determined by TLC), the mixture was filtered and concentrated. The crude product was further purified by column chromatography (silica gel: 60-120 mesh, eluent: chloroform-methanol, 99:1). Yield: 4.2 g (46%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]>CO.[Pd]>[CH3:1][N:2]([CH3:19])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)N1CCc2ccc(N)cc2CC1
Reaction time: 1 h

Procedure:
7-Nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-carboxylic acid dimethylamide (82 mg, 0.312 mmol) was placed in methanol (5 mL) and 10% palladium on carbon (8.2 mg) was added. The reaction was hydrogenated at 40 psi for 1 hour. The mixture was then filtered through celite and concentrated under reduced pressure to obtain 7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-carboxylic acid dimethylamide as a clear thin film (72 mg, 100%). LCMS (m/e) 234 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 6.91 (d, 1H, J=7.6 Hz), 6.58-6.49 (m, 2H), 3.75 (bs, 2H), 3.42-3.34 (m, 4H), 2.93-2.82 (m, 4H), 2.85 (s, 3H), 2.84 (s, 3H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[C:6]1[CH:11]=[C:10]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CCC[Si](C)(C)C)=[O:22])=[C:16]([F:31])[CH:15]=2)[CH:9]=[C:8]([C:32]#[CH:33])[CH:7]=1)([CH3:3])[CH3:2].O>CS(C)=O>[CH:1]([O:4][C:5](=[O:34])[C:6]1[CH:7]=[C:8]([C:32]#[CH:33])[CH:9]=[C:10]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[C:16]([F:31])[CH:15]=2)[CH:11]=1)([CH3:3])[CH3:2]
Reactant: C#Cc1cc(C#Cc2ccc(CC(=O)OCCC[Si](C)(C)C)c(F)c2)cc(C(=O)OC(C)C)c1
Solvent: O
Solvent: CS(C)=O
Product: C#Cc1cc(C#Cc2ccc(CC(=O)O)c(F)c2)cc(C(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.6 %

Procedure:
A solution of 3-ethynyl-5-[3-fluoro-4-(3-trimethylsilanyl-propoxycarbonylmethyl)-phenylethynyl]-benzoic acid isopropyl ester (Intermediate 207, 0.15 g, 0.32 mmol) in anhydrous dimethysulfoxide (4 mL) was treated with tetra-n-ethyl ammonium fluoride (0.19 mL, 1.3 mmol) and the resulting reaction mixture was stirred at ambient temperature for 5 min. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil that was purified by recrystallization from ethyl acetate/hexane to afford the title compound as a white solid (0.045 g, 38%).
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:14])[C:5]2[N:6]([CH2:11][CH:12]=[CH2:13])[CH:7]=[N:8][C:9]=2[N:10]=1.N([O-])=[O:16].[Na+]>CC(O)=O.O>[CH2:11]([N:6]1[C:5]2[C:4](=[O:14])[NH:3][C:2](=[O:16])[NH:10][C:9]=2[N:8]=[CH:7]1)[CH:12]=[CH2:13]
Reactant: C=CCn1cnc2nc(N)[nH]c(=O)c21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Temperature: 55 °C
Yield: 42.8 %

Procedure:
A mixture of 2-amino-7-(2-propen-1-yl)-1,7-dihydro-6H-purin-6-one (40 g, 0.209 mol) in AcOH (900 ml) and water (100 ml) was heated at 55° C. Sodium nitrite (57.74 g, 0.837 mol) in water (100 ml) was added dropwise. Care; toxic fumes. After the addition was complete (approximately 25 minutes) the reaction mixture was allowed to cool to ambient temperature and then concentrated to approximately ⅓ of its original volume. Water (500 ml) was added and the resulting precipitate collected by filtration. The residue was washed with water then dried at 50° C. over P2O5 and under vacuum for 2 hours to give the title compound (17.20 g). The aqueous fraction was concentrated and water added (100 ml). Again the resulting solid was filtered and dried. This gave more of the title compound (2.31 g). Combined product (19.52 g, 49%). m/z 193.2[MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:17][CH3:18])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([CH3:22])([O-:21])=[O:20].C([O-])(=O)C.[NH4+]>CC(O)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11]([CH:12]=[CH:22][N+:19]([O-:21])=[O:20])[C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(C=O)cccc1OCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1c(C=C[N+](=O)[O-])cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.46 g (18.4 mmol) 3-Benzyloxy-2-methoxy-benzaldehyde (see CN 102451178), 2.96 mL (55.2 mmol) nitromethane and 1.42 g (18.4 mmol) ammonium acetate in 30 mL AcOH are stirred at 100° C. over night. The reaction mixture is cooled to r.t. and quenched by the addition of 20 mL MeOH and 6 mL water. After stirring at r.t. for 1 h, the precipitate is filtered off and dried at 40° C.
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(=O)[C:22]1[CH:27]=[C:26]([C:28]2[CH:33]=[C:32]([S:34][CH2:35][CH2:36][C:37](=[O:52])[NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47]C(C)(C)C)=O)[N:31]=[C:30]([NH2:53])[N:29]=2)[C:25]([CH3:54])=[CH:24][C:23]=1[CH3:55])(C)(C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:53][C:30]1[N:31]=[C:32]2[CH:33]=[C:28]([C:26]3[CH:27]=[C:22]([C:45](=[O:47])[NH:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:37](=[O:52])[CH2:36][CH2:35][S:34]2)[C:23]([CH3:55])=[CH:24][C:25]=3[CH3:54])[N:29]=1
Reactant: Cc1cc(C)c(-c2cc(SCCC(=O)NCCCCCNC(=O)OC(C)(C)C)nc(N)n2)cc1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c2cc1C(=O)NCCCCCNC(=O)CCSc1cc-2nc(N)n1
Reaction time: 6 h
Yield: 45.8 %

Procedure:
Anisole (0.051 ml, 0.47 mmol) and trifluoroacetic acid (1.0 ml) were added to a dichloromethane (3.2 ml) solution of 5-{2-amino-6-[2-(5-tert-butoxycarbonylaminopentylcarbamoyl)ethylsulfanyl]pyrimidin-4-yl}-2,4-dimethyl benzoic acid tert-butyl ester (111 mg, 0.19 mmol) obtained in Step 2 above. The reaction solution was stirred for 6 hours while gradually warming from 0° C. up to room temperature. The reaction solution was concentrated under reduced pressure, and then benzene (1.5 ml) was added to the residue. The resulting solution was concentrated under reduced pressure. This treatment was repeated three times, and then the obtained pale yellow oily material was dissolved in N,N-dimethylformamide (94.5 ml). N-Hydroxybenzotriazole (128 mg, 0.95 mmol), diisopropylethylamine (0.33 ml, 1.9 mmol), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (362 mg, 1.9 mmol) were sequentially added to the solution. The resulting reaction solution was reacted at room temperature for 14 hours, and then concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (100 ml), and sequentially washed twice with water (50 ml), and with a saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml), and a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography with diol-silica gel (developing solvent: ethyl acetate to ethyl acetate:methanol=20:1) and amino-silica gel (ethyl acetate to ethyl acetate:methanol=15:1) to yield 4-amino-20,22-dimethyl-7-thia-3,5,11,17-tetraazatricyclo[17.3.1.12,6]tetracosa-1(22),2(24),3,5,19(23),20-hexaene-10,18-dione (Compound 1) (36 mg) as a white solid material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=1.P(Br)(Br)[Br:16]>C1COCC1>[Br:16][CH2:13][C:9]1[CH:8]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: BrP(Br)Br
Reactant: OCc1cccc(-c2cnccn2)c1
Solvent: C1CCOC1
Product: BrCc1cccc(-c2cnccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
To a stirred solution of (3-(pyrazin-2-yl)phenyl)methanol (200 mg, 1.08 mmol) in THF (5 mL), PBr3 (349 mg, 1.29 mmol) was added dropwise at 0° C. and stirred for 10 min. Then, the reaction mixture was refluxed for 3 h. The mixture was cooled to rt, poured into ice-cold saturated aqueous NaHCO3 solution (5 mL) and extracted with ethyl acetate (2×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (200 mg, 75%). [TLC Rf=0.54 (ethyl acetate/hexane 50:50)].
Reaction SMILES: Cl.Cl[CH:3]([C:9]1[N:16]2[C:12]([S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=32)=[N:11][C:10]=1[C:21]1[CH:25]=[C:24]([CH3:26])[S:23][C:22]=1[CH3:27])[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(S([O-])=O)O.[Na+]>ClCCl>[CH3:8][N:6]([CH3:7])[C:4](=[O:5])[CH2:3][C:9]1[N:16]2[C:12]([S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=32)=[N:11][C:10]=1[C:21]1[CH:25]=[C:24]([CH3:26])[S:23][C:22]=1[CH3:27]
Reactant: Cc1cc(-c2nc3sc4ccccc4n3c2C(Cl)C(=O)N(C)C)c(C)s1
Agent: Cl
Agent: O=S([O-])CO
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2nc3sc4ccccc4n3c2CC(=O)N(C)C)c(C)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
34 g (0.077 mole) of α-chloro-N,N-dimethyl-2-(2,5-dimethylthien-3-yl)imidazo[2,1-b]benzothiazole-3-acetamide hydrochloride in solution in 500 ml of dichloromethane are treated with 36.9 g (0.24 mole) of Rongalite®, while stirring the mixture at room temperature for 24 h. The organic phase is separated after settling has taken place, the solid residue is washed with dichloromethane, the organic phase is washed with a saturated sodium hydrogen carbonate solution and then with water, it is dried over sodium sulphate, the solvent is evaporated under reduced pressure and 22 g of solid are obtained. After recrystallization from ethanol and treatment with vegetable black, 17 g of pale yellow crystals are finally obtained. Melting point: 194°-195° C.