Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]=[C:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24].O>N1C=CC=CC=1>[C:1]([O:10][CH:11]=[C:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CCC(=CO)C2=O
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CCC(=COC(=O)c1ccccc1)C2=O
Reaction time: 2 h
Yield: 80 %

Procedure:
Benzoyl chloride (11.4 ml, 0.1 mole) was added to a stirred solution of 2-hydroxymethylene-6-methoxy-1-tetralone 2 (10 g, 0.05 mole) in about 60 mL of pyridine at about 0°. After the addition was complete, the mixture was stirred at about 23° for about 2 hours then poured into water. The solid was filtered and washed with water. The pure product was obtained by recrystallization from methanol to yield 2-benzoyloxymethylene-6-methoxy-1-Tetralone (12.1 g, 0.04 mole, 80% yield), mp 128.5°-129.5°, [Lit. Kieboom et al., Synthesis, 476-478, (1970), mp 130°-130.5°].
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[N:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1>C(O)C.[Pt].O>[CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][CH:4]([NH:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: CC1(C)CC(=NNC(=O)OC(C)(C)C)CC(C)(C)C1
Agent: [Pt]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(NNC(=O)OC(C)(C)C)CC(C)(C)C1
Reaction time: 8 h
Yield: 83.3 %

Procedure:
t-Butyl N′-(3,3,5,5-Tetramethylcyclohexylidene)hydrazine carboxylate (10.0 g, 0.0373 moles) was dissolved in ethanol (600 ml) and 5% Platinum on carbon (0.4 g) was added in water (2 mL). Stirred overnight under a hydrogen atmosphere (balloon). Filtered through HyFlo to remove the catalyst and evaporated the solvents to give a grey solid. Triturated with water and filtered off the grey solid. Dried in a desiccator to give the product as a grey solid (8.4 g, 83%). 1H NMR (300 MHz DMSO-d6) 8.1 (brm, 1H), 4.1 (brm, 1H), 2.95 (m, 1H), 1.45 (m, 2H), 1.35 (s, 9H), 1.15 (m, 1H), 0.95 (m, 1H), 0.95 (s, 6H), 0.9 (s, 6H).
Reaction SMILES: O=C(C)CCCC[N:7]1[C:16](=[O:17])[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[N:10]([CH3:18])[C:8]1=[O:9].CN1C2N=CNC=2C(=O)NC1=O.[H-].[Na+].Cl[CH2:35][CH2:36][C:37]([CH3:42])([CH3:41])[C:38]([O-])=[O:39]>CS(C)=O.O>[CH3:18][N:10]1[C:11]2[N:12]=[CH:13][N:14]([C:38](=[O:39])[C:37]([CH3:42])([CH3:41])[CH2:36][CH3:35])[C:15]=2[C:16](=[O:17])[NH:7][C:8]1=[O:9]
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: CC(=O)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)(C)C(=O)n1cnc2c1c(=O)[nH]c(=O)n2C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
This example illustrates a method for synthesis of CT1505 (1-(5-oxohexyl)-3-methylxanthine). A mixture of 3-methylxanthine (1.00 g, 6.0 mmol) and NaH (145 mg, 6.0 mmol) in DMSO (dimethyl sulfoxide) (20 ml) was stirred until homogeneous (about 30 min). Chloromethylpivalate (865 μl, 904 mg, 6.0 mmol) was added and the reaction mixture was stirred for 18 hrs. The reaction mixture was poured into 70 ml of water and extracted with 25% ethanol/dichloromethane (4×60 ml). The combined organic extracts were combined, dried with sodium sulfate, and then evaporated in a rotoevaporator to a volume of 40 ml. The solution was cooled in ice water and it formed a thick, white precipitate. The solid was filtered off under suction and dried under vacuum to give the 3-methyl-7-(methylpivaloyl)xanthine (1.43 g, 5.4 mmol, 90% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Pd]>[C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NN=Cc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNCc1ccccc1
Yield: 96.2 %

Procedure:
To a solution of N'-benzylidenehydrazinecarboxylic acid tert-butyl ester (2.7 g, 12.3 mmol) in tetrahydrofuran (100 ml) was added 10% palladium on carbon (0.3 g) and the mixture was hydrogenated with 280 ml of hydrogen for 40 min at atmospheric pressure. The mixture was filtered through a plug of celite and the filtrate was concentrated in vacuo to give 2.63 g of N'-benzylhydrazinecarboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44]>CC(C)=O>[CH3:46][O:45][C:43](=[O:44])[CH2:42][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:10]3[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:19]=1
Reactant: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(O)cc3)cc12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(OCC(=O)OC)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1-benzyl-3-pentyl-2-phenyl-1H-indol-5-yl)-phenol (0.300 g, 0.673 mmol) was reacted with K2CO3 (0.121 g, 0.875 mmol) and methyl bromoacetate (0.134 g, 0.875 mmol) in acetone (10 ml) to give the product (0.296 g, 0.572 mmol, 85%) as a white, waxy solid, mp 106-109° C. 1H NMR (DMSO-d6) δ 0.72 (t, J=7.0 Hz, 3H), 1.09-1.19 (m, 4H), 1.49-1.56 (m, 2H), 2.64 (t, J=7.5 Hz, 2H), 3.68 (s, 3H), 4.79 (s, 2H), 5.23 (s, 2H), 6.79-6.81 (m, 2H), 6.97 (d, J=8.9 Hz, 2H), 7.09-7.18 (m, 3H), 7.29-7.34 (m, 4H), 7.37-7.47 (m, 3H), 7.55 (d, J=8.9 Hz, 2H), 7.72 (d, J=0.7 Hz, 1H); [ESI(+)], m/z 519 (M+H)+.
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:10])[CH2:4][C:5](=[O:9])[C:6]([OH:8])=[O:7].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH3:2][CH:3]([CH3:10])[CH2:4][C:5](=[O:9])[C:6]([O:8][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: BrCc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)CC(=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 92 %

Procedure:
With reference to reaction Scheme 2, a slurry of 25 g (0.164 mol) of the sodium salt of 4-methyl-2-oxopentanoic acid, sodium salt in anhydrous N,N-dimethylformamide (50 ml) containing 19.6 ml (0.164 mol) of benzyl bromide was agitated at room temperature for 4 days. The solvent was removed in vacuo. The residue was dissolved in 250 ml of hexane and washed with water (3×50 ml) and brine (50 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to give 33.2 g (92% yield) of benzyl 4-methyl-2-oxopentanoate (1a) as a viscous, colorless oil. TLC: Rf 0.70 (ethyl acetate-hexane 1:4); 1H NMR(CDCl3) δ 0.94(d, 6H), 2.18(m, 1H), 2.71(d, 2H), 5.26(s, 2H), 7.37(m, 5H); 13C NMR (CDCl3) δ 22.5, 24.2, 48.1, 67.9, 128.7, 128.8, 128.9, 134.7, 161.3, 194.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>[Cl-].[Cl-].[Cl-].[Ti+3]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]([C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[CH3:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2CCN(C(C)c3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Cc1ccc(N2CCN(C(C)c3ccc(N)cc3)CC2)cc1

Procedure:
In the manner given in Example 1B, 1-(p-methylphenyl)-4-[1-(p-nitrophenyl)ethyl]piperazine is reduced with aqueous titanium trichloride to give 1-(p-methylphenyl)-4-[1-(p-aminophenyl)ethyl]piperazine.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.Cl.[NH:12]([CH2:14][CH2:15][CH2:16][OH:17])[NH2:13].Cl>C(O)C>[NH2:6][C:5]1[N:12]([CH2:14][CH2:15][CH2:16][OH:17])[N:13]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: NNCCCO
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(CCCO)n1
Yield: 85.4 %

Procedure:
A solution of 4,4-dimethyl-3-oxo-pentanenitrile (0.7 g, 5.58 mmol) in ethanol (IMS grade, 5 mL) was treated with 3-hydrazino-propan-1-ol dihydrochloride (1 g, 6.13 mmol), followed by conc. HCl (0.05 mL), and the reaction mixture was heated at reflux for 18 h. The mixture was concentrated in vacuo and the residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM to afford the title compound as a white gummy solid (0.94 g, 85%). LCMS (Method 3): Rt 0.42 min, m/z 198 [MH+].
Reaction SMILES: C([O:5][C:6]([N:8]([CH2:42][CH3:43])[C:9]1[C:10]([CH2:37]OC(=O)C)=[N:11][CH:12]=[C:13]([C:15]2[CH:24]=[CH:23][C:22]3[N:21]=[CH:20][C:19]4[N:25]([CH3:36])[C:26](=[O:35])[N:27]([C:28]5[C:29]([CH3:34])=[N:30][N:31]([CH3:33])[CH:32]=5)[C:18]=4[C:17]=3[CH:16]=2)[CH:14]=1)=[O:7])(C)(C)C.[C-]#N.[K+]>CCO.CCOC(C)=O>[CH3:33][N:31]1[CH:32]=[C:28]([N:27]2[C:18]3[C:17]4[CH:16]=[C:15]([C:13]5[CH:12]=[N:11][C:10]6[CH2:37][O:7][C:6](=[O:5])[N:8]([CH2:42][CH3:43])[C:9]=6[CH:14]=5)[CH:24]=[CH:23][C:22]=4[N:21]=[CH:20][C:19]=3[N:25]([CH3:36])[C:26]2=[O:35])[C:29]([CH3:34])=[N:30]1
Reactant: CCN(C(=O)OC(C)(C)C)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1COC(C)=O
Agent: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN1C(=O)OCc2ncc(-c3ccc4ncc5c(c4c3)n(-c3cn(C)nc3C)c(=O)n5C)cc21
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of acetic acid 3-(tert-butoxycarbonyl-ethyl-amino)-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-2-ylmethyl ester (stage 155.1.1, 0.107 mmol) and KCN (0.16 mmol) in EtOH (0.6 ml) was stirred for 17 h at 80° C. The RM was diluted with EtOAc and washed with water, with brine, dried over Na2SO4, filtered and evaporated. The residue The residue was absorbed on silica gel and purified by flash chromatography (CH2Cl2/MeOH 0% to 8%). The fractions containing product were evaporated together to give the title compound as an off-white solid. (HPLC: tR 2.42 min (Method A); M+H=470 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.35-8.32 (m, 1H), 8.17-8.13 (m, 1H), 8.11 (s, 1H), 8.04-8.00 (m, 1H), 7.62-7.59 (m, 1H), 7.49-7.47 (m, 1H), 5.40-5.31 (m, 2H), 4.04-3.85 (m, 2H), 3.87 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H), 1.24 (t, 3H))
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20]O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2Cn2cncn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 1-Boc-4-(hydroxymethyl-phenyl)-piperazine (300 mg, 1.02 mmol, 1.0 eq.), 1,2,4 triazole (104 mg, 1.53 mmol, 1.5 eq.), triphenylphosphine (535 mg, 2.04 mmol, 2.0 eq.) and THF at 0° C. under nitrogen was added DEAD (0.321 mL, 2.04 mmol, 2.0 eq.) slowly so that temperature of reaction does not rise above 10° C. After addition was completed, the ice bath was removed and the reaction mixture was stirred at r.t. overnight. Methanol was added and the mixture was stirred for about 15 minutes. The mixture was then concentrated. Purification by flash chromatography (35 g SiO2, linear gradient 50-70% EtOAc/Hexane for 15 minutes and 70% EtOAc for 18 minutes) afforded Boc protected title compound (200 mg, 0.5 mmol, 57%). LRMS (ESI+): 344.1 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH:20]([N:22]([CH3:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)=[O:21]>>[CH:20]([N:22]([CH3:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:19][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH:10]([N:13]4[CH2:17][CH2:16][CH2:15][CH:14]4[CH3:18])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:28])=[CH:25][CH:24]=1)=[O:21]
Reactant: CN(C=O)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(N(C)C=O)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(formyl-methyl-amino)-benzoic acid. MS: 421.3 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:10][C:11]([C@@H:13]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([N:44]2[CH2:48][CH2:47][C@@H:46]([NH2:49])[CH2:45]2)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:14]1)=[O:12])[CH3:9].[CH3:50][O:51][C:52]1[C:53](=O)[C:54](=[O:58])[C:55]=1[O:56]C>CCO.CN(C1C=CN=CC=1)C>[CH2:8]([NH:10][C:11]([C@@H:13]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([N:44]2[CH2:48][CH2:47][C@@H:46]([NH:49][C:53]4[C:54](=[O:58])[C:55](=[O:56])[C:52]=4[O:51][CH3:50])[CH2:45]2)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:14]1)=[O:12])[CH3:9]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](Nc5c(OC)c(=O)c5=O)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A mixture comprising (2S,3S,4R,5R)-5-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid ethylamide trifluoroacetate (Intermediate E) and 3,4-dimethoxy-3-cyclobutene-1,2-dione in absolute EtOH and cat.DMAP is heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 120° C. for 1 hour. The solvent is removed in vacuo and the resulting crude product partitioned between ethyl acetate and water. The organic portion is separated, dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography on silica gel eluting with EtOAc/iso-hexane (30-100% EtOAc) affords the titled compound.
Reaction SMILES: [F:1][C:2]1([F:22])[CH:6](OS(C(F)(F)F)(=O)=O)[CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[N-:23]=[N+:24]=[N-:25].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.CC(OC)(C)C>[N:23]([CH:6]1[CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][C:2]1([F:22])[F:1])=[N+:24]=[N-:25]
Reactant: CC(C)(C)OC(=O)N1CC(OS(=O)(=O)C(F)(F)F)C(F)(F)C1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC(N=[N+]=[N-])C(F)(F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
tert-Butyl 3,3-difluoro-4-{[(trifluoromethyl)sulfonyl]oxy}pyrrolidine-1-carboxylate (5.56 g, 15.2 mmol) was dissolved in DMF (20 mL) and cooled in an ice bath under nitrogen atmosphere. Tetrabutylammonium azide (TBA-N3, 4.8 g, 17 mmol, 1.1 mol eq) in DMF (15 mL) was added slowly over 15 min via an addition funnel. The reaction mixture was stirred in the cold bath and was allowed to warm to ambient temperature gradually. After 16 hr, the reaction was diluted with MTBE (300 mL), washed with sat. aq. NaHCO3 (2×30 mL), and brine (2×30 mL), dried over Na2SO4 and evaporated to give a residue. This crude material was purified on silica (40 g) with gradients from 100% heptane to 20% ethyl acetate-80% heptane to give the title product as a colorless oil (3.02 g, 80% yield, >95% purity). 1H NMR (400 MHz, chloroform-d) δ ppm 4.06 (dtd, J=8.86, 5.41, 5.41, 3.91 Hz, 1 H) 3.65-3.83 (m, 3 H) 3.36-3.57 (m, 1 H) 1.47 (s, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −106.10-−102.44 (m, 1 F) −120.14-−116.68 (m, 1 F). m/z (ESI+) for C9H14F2N4O2 149 (small)/123 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([CH:9]([C:11]2[N:12]=[C:13](OS(C(F)(F)F)(=O)=O)[C:14]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16][C:15]=3[N:28]=2)[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC#N>[CH3:1][NH:2][C:13]1[C:14]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16][C:15]=2[N:28]=[C:11]([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:10])[N:12]=1
Reactant: CN
Reactant: CC(c1ccccc1)c1nc2c(c(OS(=O)(=O)C(F)(F)F)n1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: CC#N
Product: CNc1nc(C(C)c2ccccc2)nc2c1CCN(C(=O)OC(C)(C)C)CC2
Yield: 90 %

Procedure:
A solution of methylamine (2.0M, 0.65 mL, 1.30 mmol) was added to a solution of Tert-butyl 2-(1-phenylethyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate of preparation 2, step B (130 mg, 0.26 mmol) in MeCN (4.0 mL) at room temperature with stirring. The mixture was stirred at room temperature for 20 h. The solvent was evaporated in vacuo to provide the crude title compound as a yellow gum. The crude material was purified by flash column chromatography eluting with CH2Cl2:ethyl acetate (100:0 to 50:50) to yield the desired product as a white crystalline solid (89 mg, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[N:11]=[C:10]2[O:23][CH3:24])=[C:4]([F:25])[CH:3]=1.[CH2:26](Br)[CH:27]=[CH2:28].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:28]([O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:25])=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:21])([F:22])[C:17]([F:20])([F:18])[F:19])[N:11]=[C:10]2[O:23][CH3:24])[CH:6]=1)[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOc1cc(-n2c(OC)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone and allyl bromide with sodium carbonate in acetone there is obtained 1-(5-allyloxy-4-chloro-2-fluorophenyl)-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone, m.p. 82°-83° C.;
Reaction SMILES: COC[O:4][C:5]1[C:6]([C:19]#[C:20][C:21]2[CH:22]=[C:23]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=2[O:36][CH3:37])[CH2:24][C:25]2[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=2)=[CH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15]COC)[CH:11]=[CH:10][CH:9]=2.O.Cl>C1COCC1>[NH2:31][C:28]1[N:27]=[C:26]([NH2:32])[C:25]([CH2:24][C:23]2[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:21]([C:20]#[C:19][C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][C:5]=3[OH:4])[C:12]([OH:15])=[CH:11][CH:10]=[CH:9]4)[CH:22]=2)=[CH:30][N:29]=1
Reactant: COCOc1cc2c(OCOC)cccc2cc1C#Cc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cc2cnc(N)nc2N)cc(C#Cc2cc3cccc(O)c3cc2O)c1OC
Yield: 48.5 %

Procedure:
146 mg of 5-[3-(3,5-bis-methoxymethoxy-naphthalen-2-ylethynyl)-4,5-dimethoxybenzyl]-pyrimidin-2,4-diamine (Example 12ap)) in 2.5 ml of THF, 2.5 ml of water and 2.5 ml of 6N hydrochloric acid are held at 50° for 7.5 hrs. The mixture is concentrated and the residue is chromatographed on silica gel with methylene chloride/methanol 9:1. 59 mg of 6-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-naphthalene-1,7-diol are isolated as a yellowish solid. Yield: 48%. Mass spectrum: peaks inter alia at 443 (M++H, 100%).
Reaction SMILES: O[CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[I:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[NH:16][N:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4])[N:15]=[C:14]([I:13])[C:22]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](Cn1nc(I)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.2 %

Procedure:
To a solution of tert-butyl N-[(1R)-2-hydroxy-1-methyl-ethyl]carbamate (1.9 g, 10.8 mmol), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.0 g, 7.7 mmol), and PPh3 (6.1 g, 23.2 mmol) in THF (80 mL) cooled with an ice bath was added DIAD (3.0 mL, 15.5 mmol; in 28 mL of THF) dropwise over a 1 hour period. The reaction was then stirred for 24 h at room temperature. The mixture was diluted into ethyl acetate (50 mL) and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated. The resulting material was suspended in 20% ethyl acetate in dioxane (1000 mL) and sonicate for 1 hr. The solid was collected by filtration to obtain 2.1 g (66%) of tert-butyl N-[(1R)-2-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)-1-methyl-ethyl]carbamate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].CC(C)([O:36][C:37](=[O:68])[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][C:59]1[CH:60]=[C:61]([CH:65]=[CH:66][CH:67]=1)[C:62](O)=[O:63])C>>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:62]([C:61]2[CH:60]=[C:59]([CH2:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][C:37]([OH:68])=[O:36])[CH:67]=[CH:66][CH:65]=2)=[O:63])=[C:3]([C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[CH:30]=[CH:31][N:32]=2)[CH:4]=1)[CH3:10]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCOCCOCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared from 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 25b using the procedures described in Example 251 using 3-(2,2-dimethyl-4-oxo-3,7,10,13,16,19,22-heptaoxapentacosan-25-yl)benzoic acid 299d as the protected acid component in the coupling. MS (ES, m/z) 897.9 [M+H]+; 1H NMR (400 MHz, d6 DMSO) δ 11.77 (s, 1H), 10.60 (t, J=5.9 Hz, 1H), 8.78 (d, J=5.2 Hz, 1H), 8.50 (s, 1H), 7.81 (d, J=5.1 Hz, 1H), 7.76 (s, 2H), 7.73 (s, 1H), 7.68 (s, 1H), 7.65-7.58 (m, 3H), 7.58-7.53 (m, 2H), 7.49 (t, J=7.9 Hz, 1H), 7.36-7.26 (m, 2H), 6.99 (d, J=3.0 Hz, 1H), 6.79 (dd, J=9.0, 3.0 Hz, 1H), 4.57 (d, J=6.0 Hz, 2H), 3.56-3.30 (m, 43H), 2.68-2.58 (m, 2H), 2.07 (t, J=7.5 Hz, 2H), 1.77 (p, J=6.1 Hz, 2H), 1.09 (t, J=7.0 Hz, 6H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].CN([CH:23]=[O:24])C>>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:23]=[O:24])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1cc2ccccc2[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1[nH]c2ccccc2c1C=O
Temperature: 40 °C

Procedure:
2-Ethylindole (0.5 g, 3.4 mmol) dissolved in DMF (2 mL) was added to a cold (0° C.) premixed (30 minutes) mixture of DMF (1.15 mL) and phosphorous oxychloride (0.64 g, 4.16 mmol). After addition of 2-ethylindole, the mixture was heated to 40° C. for 1 h, water (5 mL) was added and the pH adjusted to 5 by means of 1 N sodium hydroxide. The mixture was subsequently extracted with diethyl ether, the organic phase isolated, dried with MgSO4 and evaporated to dryness affording 2-ethylindole-3-carbaldehyde (300 mg).