Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@H:10]([CH:34]([CH3:39])[C:35]([O:37]C)=[O:36])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:28][CH2:29]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@H:10]([CH:34]([CH3:39])[C:35]([OH:37])=[O:36])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@H](C(C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@H](C(C)C(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of methyl 2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoate (56 mg, 0.094 mmol; Example 127, Step F) in MeOH/THF/H2O (1 mL/1 mL/2 mL) was added LiOH (3 M in water) (157 μL, 0.470 mmol) at room temperature. The slurry was heated to ˜100° C. for 3 h. The mixture was cooled to room temperature, acidified with 1 M HCl and extracted with EtOAc (2×). The organic layers were combined, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The colorless film was purified by reverse phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes) to give the title compound.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[C:16](=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[CH:11][CH:10]=1
Reactant: c1ccncc1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: [K+]
Solvent: CCC(C)=O
Product: Brc1ccc(OCc2cccnc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
A mixture of 12.75 g (77.73 mmol) of 3-chloromethyl)pyridine hydrochloride, 13.45 g (77.73 mmol) of 4-bromophenol and 27.6 g (200 mmol) of potassium carbonate in 100 ml of methyl ethyl ketone is stirred at room temperature for 24 hr and at 60° C. for 4 hr. The solids are filtered and the filtrate is concentrated. The residue is partitioned between water and diethyl ether. The ethereal layer is washed with 2N NaOH and water, and is dried and concentrated. The resulting oil (12.9 g, 49% yield) solidifies on cooling.
Reaction SMILES: [CH:1]1([CH2:9][CH2:10][C:11](O)=O)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.[O:14]1[C:20]2[CH:21]=[CH:22][C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH:17]=[CH:16][CH2:15]1.C([O-])(=O)/C=C/C([O-])=O>>[CH:1]1([CH2:9][CH2:10][CH2:11][N:28]2[CH2:29][CH2:30][N:25]([C:23]3[CH:22]=[CH:21][C:20]4[O:14][CH2:15][CH:16]=[CH:17][O:18][C:19]=4[CH:24]=3)[CH2:26][CH2:27]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1
Reactant: O=C(O)CCC1Cc2ccccc21
Reactant: C1=COc2cc(N3CCNCC3)ccc2OC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: C1=COc2cc(N3CCN(CCCC4Cc5ccccc54)CC3)ccc2OC1

Procedure:
Prepared as described in Example 9, starting from 3-(benzocyclobutan-1-yl)propionic acid and 4-(benzo-1,5-dioxepin-7-yl)piperazine. The fumarate of the title compound melts at 168°-170° C. (ethanol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:11]F.C(=O)([O-])O.[Na+].C(OCC)(=O)C>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][C:5]([F:11])=[CH:6][N:7]=1
Reactant: FF
Reactant: NC(=O)c1nccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nc(F)cnc1N
Temperature: 0 °C

Procedure:
In 9 mL of trifluoroacetic acid was dissolved 0.3 g of 3-amino-2-pyrazinecarboxamide. At an ice-cooled temperature, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced into the solution at a rate of 45 ml per minute for a period of 22 minutes. After stirring the mixture at an ice-cooled temperature for 17 minutes, the temperature was elevated to room temperature. The reaction mixture was added to a mixture of 30 mL of saturated aqueous solution of sodium hydrogen carbonate and 30 mL of ethyl acetate, and the organic layer was separated. The remaining aqueous layer was acidified with 6 mol/L hydrochloric acid and then extracted with 20 ml of ethyl acetate. The organic layers thus obtained were united, washed successively with 10 mL of water and 10 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=2:1] to obtain 0.015 g of 3-amino-6-fluoro-2-pyrazinecarboxamide as a light yellow-colored solid product.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][C:11]([CH2:18][NH:19][C:20]([C:22]3[C:23]([CH3:33])=[N:24][C:25](S(C)(=O)=O)=[N:26][C:27]=3C)=[O:21])([CH2:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[C-:34]#N.[Na+].[CH3:37][N:38](C=O)C>>[CH:1]1([CH2:4][S:5]([CH:8]2[CH2:9][CH2:10][C:11]([CH2:18][NH:19][C:20]([C:22]3[CH:27]=[N:26][C:25]([C:37]#[N:38])([CH3:34])[NH:24][C:23]=3[CH3:33])=[O:21])([CH2:14][CH:15]3[CH2:17][CH2:16]3)[CH2:12][CH2:13]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: [C-]#N
Reactant: Cc1nc(S(C)(=O)=O)nc(C)c1C(=O)NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Agent: [Na+]
Product: CC1=C(C(=O)NCC2(CC3CC3)CCC(S(=O)(=O)CC3CC3)CC2)C=NC(C)(C#N)N1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-methanesulfonyl-4,6-dimethyl-pyrimidine-5-carboxylic acid (4-cyclopropylmethanesulfonyl-1-cyclopropylmethyl-cyclohexylmethyl)-amide (82 mg; 0.165 mmol) in DMF (2 ml) was added sodium cyanide (12 mg; 0.247 mmol) and the mixture was stirred at room temperature for 90 minutes. The mixture was evaporated in vacuo, coevaporating with toluene, to give an orange oil. The oil was partitioned between EtOAc (20 ml) and water (20 ml). The organic phase was separated, washed with water (20 ml) and brine (20 ml), dried (MgSO4) and evaporated in vacuo to give a yellow oil. The crude product was purified by prep. TLC eluted with 50% EtOAc in hexane to give the product as a white foam (43 mg). 1H NMR (400 MHz, CDCl3): δ 5.96 (1H, t, J 6.2), 3.64 (2H, d, J 6.4), 2.99-2.93 (1H, m), 2.87 (2H, d, J 7.1), 2.57 (6H, s), 2.04-1.84 (6H, m), 1.47-1.39 (2H, m), 1.27-1.23 (2H, m), 1.16-1.08 (1H, m), 0.79-0.67 (3H, m), 0.55-0.51 (2H, m), 0.42-0.38 (2H, m), 0.05-0.03 (2H, m). m/z=445 (M+H+).
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH:21]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[C:30]([Cl:39])[CH:29]=3)[N:24]=2)[CH3:22])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O.O>>[Cl:39][C:30]1[CH:29]=[C:28]([C:25]2[N:24]=[C:23]([C@H:21]([NH:20][C:16]3[N:15]=[C:14]([N:9]4[C@@H:8]([CH:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]4=[O:13])[CH:19]=[CH:18][N:17]=3)[CH3:22])[O:27][N:26]=2)[CH:33]=[CH:32][C:31]=1[O:34][C:35]([F:36])([F:38])[F:37]
Reactant: CC(Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1nc(-c2ccc(OC(F)(F)F)c(Cl)c2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(O)[C@H]1COC(=O)N1c1ccnc(N[C@H](C)c2nc(-c3ccc(OC(F)(F)F)c(Cl)c3)no2)n1
Yield: 66.3 %

Procedure:
(4R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-((1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (97 mg, 0.17 mmol) was treated with 90% TFA/water for 2 hours. Concentrate in vacuo and neutralized by passing through a column of MP-carbonate resin (2.0 g, 0.55 mmol/g eluting with MeOH/DCM/MeOH afforded 58 mg of (R)-3-(2-(((R)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-(1-hydroxyethyl)oxazolidin-2-one as a waxy off-white foam. Separated the diastereomers via chiral SFC chromatography on an AD-H column (75 g/min, 120 bar, 21×250 mm) eluting 25% IPA/CO2 (v/v) to give (R)-3-(2-(((R)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one and (R)-3-(2-(((S)-1-(3-(3-chloro-4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)=[CH:4][C:3]=1[N:20]=[C:21]=[O:22].C[O:24][C:25](=O)[CH:26]([NH:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH3:27]>C(Cl)Cl>[C:33]([O:32][C:30](=[O:31])[CH2:29][N:28]1[CH:26]([CH3:27])[C:25](=[O:24])[N:20]([C:3]2[CH:4]=[C:5]([CH2:6][C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10](=[O:17])[NH:9][N:8]=3)[CH:18]=[CH:19][C:2]=2[F:1])[C:21]1=[O:22])([CH3:35])([CH3:34])[CH3:36]
Reactant: O=C=Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: COC(=O)C(C)NCC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)N1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4-(3-isocyanato-benzyl)-2H-phthalazin-1-one (2)(3.12 mmol) in dry DCM (80 ml) in the presence of activated 4 Å molecular sieves (ca 5 g) was added 2-(tert-butoxycarbonylmethyl-amino)-propionic acid methyl ester (33A)(1.07 g, 4.7 mmol). The reaction was then stirred for 48 hours at ambient temperature. HPLC analysis showed there to a mixture of cyclised and uncyclised ureas 1:1 ratio. The mixture was filtered and concentrated in vacuo. The crude oil was then subjected to flash chromatography eluent: 1:1 hexane ethyl acetate, Rf=0.09. Single peak in LC-MS analysis, (1.3 g, 95% purity) and required no further purification; m/z (LC-MS, ESP), RT=3.66 mins (M+H) 481—compound cyclised on column
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.BrCC1C(Cl)=NC(Cl)=CC=1.[CH3:21][C:22]1[N:27]=[C:26]([SH:28])[N:25]=[C:24]([OH:29])[CH:23]=1>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([CH2:8][S:28][C:26]2[N:25]=[C:24]([OH:29])[CH:23]=[C:22]([CH3:21])[N:27]=2)=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: OCc1ccc(Cl)nc1Cl
Agent: Clc1ccc(CBr)c(Cl)n1
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ccc(Cl)nc2Cl)n1
Yield: 82 %

Procedure:
The crude (2,6-dichloropyridin-3-yl)methanol was converted to 3-(bromomethyl)-2,6-dichloropyridine, which was then reacted with 6-methyl-2-sulfanylpyrimidin-4-ol in the presence of triethylamine to provide 2-{[(2,6-dichloropyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.822 g, 82% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 4.36 (s, 2H), 5.95 (bs, 1H), 7.40 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H); M+ 302.5.
Reaction SMILES: Cl[N:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:10]=3[CH:9]=2)[CH2:4][C@@H:3]1[CH3:19].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:18][O:17][C:16]1[C:10]2[CH:9]=[C:8]([CH:5]3[CH2:6][CH2:7][N:2]=[C:3]([CH3:19])[CH2:4]3)[S:12][C:11]=2[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc2sc([C@H]3CCN(Cl)[C@@H](C)C3)cc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cccc2sc(C3CCN=C(C)C3)cc12
Reaction time: 17 h
Yield: 111.8 %

Procedure:
A solution of the crude cis-(±)-N-chloro-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (2.348 g, 7.93 mmol) in THF (80 mL) was treated with DBU (1.18 mL, 7.93 mmol). After stirring 17 h, the DBU salt was filtered off through a sintered funnel, rinsed with Et2O, and the filtrate was concentrated under reduced pressure to give 4-(4-methoxybenzo[b]thiophen-2-yl)-2-methyl-3,4,5,6-tetrahydropyridine as a golden oil (2.3 g, 99%) that was immediately used in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[CH3:33])[NH2:29])(=[O:24])[CH3:23]>CC(O)C>[C:22]([O:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[CH3:33])[NH:29][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][N:14]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Oc1cc(N)ccc1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (20.8 g, 7.25 mmol), 3-acetoxy-4-methylaniline (1.32 g, 8 mmol) and 2-propanol (50 ml) was stirred and heated to reflux for 1 hour. The mixture was cooled to ambient temperature. The precipitate was collected by filtration, washed with 2-propanol and ether to give 4-(3-acetoxy-4methylanilino)-7-benzyloxy-6-methoxyquinazoline. A mixture of 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline (2.68 g, 5.75 mmol), 10% palladium-on-charcoal catalyst (0.27 g) in methanol (50 ml), DMF (12 ml) and trichloromethane (50 ml) was stirred at ambient temperature under 1.5 atmospheres of hydrogen for 30 minutes. The catalyst was removed by filtration and the filtrate evaporated. The residual solid was triturated in ether, collected by filtration and dried under vacuum at 50° C. to give 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (2.1 g, 100%).
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH:27]1([C:33]2[CH:38]=[CH:37][C:36]([C:39]([NH:41][C:42]3[CH:51]=[CH:50][C:49]([C:52]#[C:53][Si](C)(C)C)=[CH:48][C:43]=3[C:44]([O:46][CH3:47])=[O:45])=[O:40])=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(OCC)(=O)C>[CH:27]1([C:33]2[CH:34]=[CH:35][C:36]([C:39]([NH:41][C:42]3[CH:51]=[CH:50][C:49]([C:52]#[CH:53])=[CH:48][C:43]=3[C:44]([O:46][CH3:47])=[O:45])=[O:40])=[CH:37][CH:38]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)ccc1NC(=O)c1ccc(C2CCCCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(NC(=O)c2ccc(C3CCCCC3)cc2)c(C(=O)OC)c1
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
351 mg (1.1 mmol) of tetrabutyl ammonium fluoride trihydrate was added to a THF (9 mL) solution comprising 322 mg (0.74 mmol) of methyl 2-{[(4-cyclohexylphenyl)carbonyl]amino}-5-[(trimethylsilyl)ethynyl]benzoate at 0° C., and the mixture was stirred for 1.5 hours. Thereafter, the reaction mixture was diluted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography, thereby giving 208 mg of methyl 2-{[(4-cyclohexylphenyl)carbonyl]amino}-5-ethynylbenzoate (yield: 78%).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][C@@H:5]([N:11]1[C:17](=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:6]([N:8]([CH3:10])[CH3:9])=[O:7].[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)/[CH:23]=[CH:24]/[C:25](O)=[O:26].C(N(CC)CC)C>>[Cl:19][C:20]1[CH:21]=[C:22](/[CH:23]=[CH:24]/[C:25]([N:14]2[CH2:15][CH2:16][C:17](=[O:18])[N:11]([C@H:5]([CH2:4][CH2:3][OH:2])[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])[CH2:12][CH2:13]2)=[O:26])[CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)C(=O)[C@@H](CCO)N1CCNCCC1=O
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H](CCO)N1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O
Yield: 72 %

Procedure:
In analogy to the procedure described in example 1, (R)-4-hydroxy-N,N-dimethyl-2-(7-oxo-[1,4]diazepan-1-yl)-butyramide hydrochloride and (E)-3-chlorocinnamic acid with 1.1 eq. of triethylamine gave the titled compound in 72% yield as white foam. MS: 408.1 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:30](Cl)(Cl)=[O:31].C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:7]=[C:30]=[O:31]
Reactant: O=C(Cl)Cl
Reactant: NCc1ccccc1OC(F)(F)F
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C=NCc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a methylene chloride solution of commercially available 2-(trifluoromethoxy)benzyl amine (2.81 mmol) at 0° C. was added solid Proton sponge (2.81 mmol) then a 20% solution of phosgene in toluene (2.81 mmol). The solution was stirred at 25° C. for 1 hour and then washed with 1N HCl (40 mL). The methylene chloride was then dried with sodium sulfate and evaporated. 1H-NMR (CDCl3): 7.5 ppm (d, 1H); 7.4 ppm (m, 2H); 7.3 ppm (d, 1H); 4.6 ppm (s, 2H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:20]=[C:21]([C:25]2[N:33]=[C:32]3[C:28]([NH:29][C:30](=[O:41])[N:31]3[CH2:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:27]([C:42](OC)=[O:43])[N:26]=2)[CH:22]=[CH:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:46]C1C(C(OC)=O)=NC(C2C=CC=C(O[Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)C=2)=NC=1NCC1CCOCC1>ClCCl>[OH:18][C:19]1[CH:20]=[C:21]([C:25]2[N:33]=[C:32]3[C:28]([NH:29][C:30](=[O:41])[N:31]3[CH2:34][CH:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[C:27]([C:42]([NH2:46])=[O:43])[N:26]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)nc(NCC2CCOCC2)c1N
Reactant: COC(=O)c1nc(-c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)nc2c1[nH]c(=O)n2CC1CCOCC1
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2CC1CCOCC1
Yield: 70 %

Procedure:
Methyl 2-(3-(tert-butyldiphenylsilyloxy)phenyl)-8-oxo-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9-dihydro-7H-purine-6-carboxylate. Methyl 5-amino-2-(3-(tert-butyldiphenyl-silyloxy)phenyl)-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyrimidine-4-carboxylate (0.276 g, 0.536 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.522 g, 3.22 mmol) in dichloromethane (15 mL) were reacted according to General Procedure F and purified via biotage chromatography (0-75% EtOAc in hexanes) to afford the title compound (0.202 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.40 (t, J=8.39, 1H), 7.00 (d, J=7.99, 1H), 3.94 (s, 3H), 3.8 (m, 4H), 3.24 (t, J=10.79, 3H), 2.15 (m, 1H), 1.57 (d, J=12.39, 2H), 1.31 (m, 5H), 1.11 (d, J=7.59, 18H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=O)[CH2:2][CH:3]=[CH2:4].C([O-])(=O)C.[Na+].Cl.[NH2:15][OH:16]>C(O)C.O>[CH2:1]([O:5][CH2:6][CH:7]=[N:15][OH:16])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOCC=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCCOCC=NO
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
(But-3-en-1-yloxy)acetaldehyde (C6) (40 g from the preceding step, ≦312 mmol) was dissolved in a 2:1 mixture of ethanol and water (700 mL). Sodium acetate (128 g, 1560 mmol) was added, and the mixture was stirred for 20 minutes. Hydroxylamine hydrochloride (98%, 66.4 g, 936 mmol) was then added, and the reaction mixture was heated to 60° C. for 18 hours, at which point it was cooled to room temperature and concentrated under reduced pressure to remove ethanol. The aqueous residue was poured into water (500 mL) and extracted four times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 40% ethyl acetate in heptane) afforded the product as an oil, presumed from the 1H NMR spectrum to be a mixture of E and Z oximes. Yield: 24 g, 0.19 mmol, 60% over three steps. 1H NMR (400 MHz, CDCl3) δ 2.33-2.41 (m, 2H), 3.51-3.57 (m, 2H), [4.11 (d, J=5.7 Hz) and 4.36 (d, J=3.7 Hz), total 2H], 5.04-5.16 (m, 2H), 5.76-5.89 (m, 1H), [6.92 (t, J=3.7 Hz) and 7.51 (t, J=5.6 Hz), total 1H].
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[CH2:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCCCO
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6 g (0.2 mol) of a sodium hydride dispersion (80% in white oil) are placed at room temperature in 120 ml of absolute dimethylformamide, and 22.2 ml (0.25 mol) of 1,4-butanediol are added dropwise. When the addition is complete, the mixture is stirred for a further 30 minutes at room temperature. 23.1 ml (0.2 mol) of benzyl chloride are then slowly added dropwise, a slight exothermic reaction being observed. The reaction mixture is stirred overnight at room temperature, water/ice is added, and the mixture is extracted twice with ether. The organic phases are washed with water and with saturated sodium chloride solution, combined, dried over MgSO4, filtered and concentrated by evaporation. The residue is subjected to fractional distillation under a water-jet vacuum over a 10 cm Vigreux column. 4-benzyloxybutanol is obtained, b.p.22= 161°-162°.
Reaction SMILES: [Na+].[NH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(#N)C>[NH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)([O-])CCCCCCNc1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: O=S(=O)(O)CCCCCCNc1ccccc1

Procedure:
6-Anilino 1-hexanesulfonic acid sodium salt (11.2 g, 0.5 mol) is dissolved in aqueous 0.5 M HCLO4 solution (30 mL) and acetonitrile (400 mL) is added to the solution. The solution is filtered and the filtrate is kept in a refrigerator overnight to obtain 6-anilino-1-hexanesulfonic acid as a precipitate.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[NH2:55][C@@H:56]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH:70]([CH3:72])[CH3:71])=[CH:65][CH:64]=1)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:55][C@@H:56]([CH2:62][C:63]3[CH:64]=[CH:65][C:66]([O:69][CH:70]([CH3:72])[CH3:71])=[CH:67][CH:68]=3)[C:57]([N:59]([CH3:60])[CH3:61])=[O:58])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CC(C)Oc1ccc(C[C@H](N)C(=O)N(C)C)cc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C[C@H](NC(=O)c2ccc3c(N4CCN(C)CC4)nc(N)nc3c2)C(=O)N(C)C)cc1
Reaction time: 0.17 h
Yield: 19.2 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (42 mg, 0.11 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (20 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) and N,N-diisopropylethylamine (24 uL, 0.14 mmol). The reaction was stirred for 10 min, and the (2S)-2-amino-3-(4-isopropoxyphenyl)-N,N-dimethylpropanamide (35 mg, 0.14 mmol) was added. The reaction was stirred for 2 h. at r.t., and was purified by RP-HPLC (pH=2) to afford the desired product (7 mg, 20%) as a white solid TFA salt. Analytical LCMS (M+H)+: m/z=520.0.