Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.N[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH:5]1[CH3:15].[C:16]([BH3-])#[N:17].[Na+].[C:20](O)(=O)C>CO>[C:10]([N:7]1[CH2:8][CH2:9][CH:4]([N:17]([CH3:16])[CH3:20])[CH:5]([CH3:15])[CH2:6]1)([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: CCOC(=O)N1CCC(N)C(C)C1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(N(C)C)C(C)C1
Reaction time: 96 h

Procedure:
Paraformaldehyde (5.1 g) was added to the stirred solution of 4-amino-1-carbethoxy-3-methylpiperidine (3.5 g, 18.8 mmol) in methanol (100 ml) at 0° C. and sodium cyanoborohydride (1.7 g, 27.0 mmol) was added to it. Then, acetic acid (1 ml) was added to the resulting mixture and stirring was continued for 96 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to give 1-carbethoxy-4-dimethylamino-3-methylpiperidine. Yield 3.5 g (88%), C11H22N2O2, m/z 215 (M+1).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:3]1=2.[N+](C1C=CC(COC([NH:28][C:29]2C=[CH:40][C:32]3SC4C=C[CH:37]=[CH:36][C:35]=4[C:31]=3[CH:30]=2)=O)=CC=1)([O-])=O.CCN=C=NCCCN(C)C.CN(C=[O:59])C>>[O:1]=[S:2]1(=[O:16])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:37]([CH2:36][CH2:35][C:31]3[CH:30]=[CH:29][N:28]=[CH:40][CH:32]=3)=[O:59])[CH:13]=[CH:14][C:3]1=2
Reactant: O=C(Nc1ccc2sc3ccccc3c2c1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Reactant: Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Agent: CCN=C=NCCCN(C)C
Product: O=C(CCc1ccncc1)Nc1ccc2c(c1)-c1ccccc1S2(=O)=O

Procedure:
5,5-Dioxo-2-aminodibenzothiophene (J Med Chem, (1994), 37 (13), 2085-9; 115 mg, 0.5 mmol) was dissolved in DMF (2.0 ml) and 3-(pyridin-4-yl)propionic acid (Method 1; 75 mg, 0.5 mmol) was added in one portion followed by EDAC (115 mg, 0.5 mmol) and the resultant mixture was stirred for 72 hours at ambient temperature: It was then poured onto water (50 ml) and extracted with DCM (2-50 ml), dried and evaporated in vacuo. The residue thus obtained was purified by chromatography (Bond Elut column) eluted with 0-5.0% methanol in DCM to give the product as a colourless solid (31.8 mg). NMR 10.52 (brs, 1H), 8.46 (d, 2H), 8.32 (d, 1H), 7.97 (d, 1H), 7.94 (d, 1H), 7.88 (d, 1H), 7.76 (d, 1H), 7.70 (t, 1H), 7.64 (t, 1H), 7.26 (d, 2H), 2.93 (t, 2H), 2.75 (t, 2H); m/z 365.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]1([NH2:29])[CH2:28][CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([NH:29][CH:25]3[CH2:28][CH2:27][CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)NC3CCC3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), cyclobutylamine (43 uL, 36 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 35 mg (42% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.48-1.66 (m, 6 H), 1.68 (s, 9 H), 1.72-1.87 (m, 2 H), 1.95-2.08 (m, 2 H), 2.28-2.50 (m, 1 H), 3.31-3.41 (m, 2 H), 3.68-3.83 (m, 1 H), 3.90-3.99 (m, 2 H), 4.53 (d, J=7.62 Hz, 2 H), 7.96 (dd, J=8.80, 1.6 Hz, 1 H), 8.04 (d, J=9.0 Hz, 1 H), 8.19 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=406.0; Anal. Calcd for C21H31N3O3S+1.20 TFA+0.60 EtOAc+0.2H2O (598.86): C, 51.75; H, 6.29; N, 7.02. Found: C, 51.70; H, 6.25; N, 7.03.
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1.I[C:45]1[C:46]([O:54][CH3:55])=[N:47][N:48]([CH2:50][CH2:51][CH2:52][OH:53])[CH:49]=1>>[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28]([C:45]2[C:46]([O:54][CH3:55])=[N:47][N:48]([CH2:50][CH2:51][CH2:52][OH:53])[CH:49]=2)=[CH:29][CH:30]=1
Reactant: COc1nn(CCCO)cc1I
Reactant: CNC(=O)c1nc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cn(CCCO)nc2OC)ccc1N
Yield: 29 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Compound 48D, 500 mg, 2 mmol) and 3-(4-iodo-3-methoxy-pyrazol-1-yl)-propan-1-ol (Compound 48E, 600 mg, 2.18 mmol) to afford 177 mg of the title compound (30%). 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 4.11 (t, J=6.8 Hz, 2H), 3.98 (s, 3H), 3.57 (t, J=6.2 Hz, 2H), 2.93 (s, 3H), 2.05 (t, J=6.4 Hz, 2H). MS (ESI): m/z=306.24 [M+H]+. UPLC: tR=0.75 min (UPLC-TOF: polar—2 min).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([C:12]1[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:14]([C:18]([OH:20])=[O:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:8]([C:12]1[N:13]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[N:37]=[N:36][N:35]=3)=[CH:26][CH:27]=2)[C:14]([C:18]([O:20][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OCC(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl bromoacetate (263 μL, 2.37 mmol) was added to a solution of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (Intermediate 4, 1000 mg, 1.48 mmol), and potassium carbonate (347 mg, 2.51 mmol) in N,N-dimethylformamide (10 mL). The solution was stirred for 2 hours at room temperature. Water was added and the solution was extracted with diethyl ether (2×). The organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was used crude in the following step. LC-MS: m/z 787.1 (M+Na).
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=[O:4].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26](OC)[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH2:61]O)[CH:55]=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2([O:4][CH3:3])[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:61][CH2:60][C:56]4[CH:55]=[N:54][CH:59]=[CH:58][CH:57]=4)=[CH:26][CH:27]=3)[N:22]=[CH:21][NH:20]2)=[C:16]([F:34])[CH:15]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: OCCc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC1(Nc2ccc(Cl)cc2F)NC=Nc2cc(OCCc3cccnc3)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 132.9 %

Procedure:
Diethyl azodicarboxylate (236 μl, 1.5 mmol) was added dropwise to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (393 mg, 1.5 mmol) and 2-(3-pyridyl)ethanol (86 mg, 0.7 mmol), (J. Heterocycl. Chem. 1992, 29, 1663), in methylene chloride (6 ml) and the mixture stirred for 4 hours at ambient temperature. The mixture was poured directly on to a silica column and eluted with methylene chloride/acetonitrile/methanol (60/35/5). The purified solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (1.5 ml of a 4.5M solution) was added. The volatiles were removed by evaporation, the solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)4-methoxy-7-(2-(3-pyridyl)ethoxy)quinazoline hydrochloride (154 mg, 52%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:34])=[N:13][C:14]2[N:15]([N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[CH:26]=2)[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:34])=[N:13][C:14]2[N:15]([N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[CH:26]=2)[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(-c4cccc(Cl)c4)nn23)cc1
Yield: 81 %

Procedure:
A solution of (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-5-methyl-7-(p-tolyl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.01 g, 0.021 mmol) and 1M NaOH (0.209 ml, 0.209 mmol) in MeOH (3 mL) was heated at reflux for h. Then, cooled, neutralized with 1M HCl (1 mL), concentrated and the residue was taken up in Et2O (25 mL), washed with water (5 mL), brine (5 mL), dried (MgSO4), filtered and concentrated to give (S)-2-(tert-butoxy)-2-(2-(3-chlorophenyl)-5-methyl-7-(p-tolyl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (0.0082 g, 0.017 mmol, 80% yield) as pale yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.85 (s, 1H), 7.76-7.72 (m, 1H), 7.69 (t, J=6.1 Hz, 2H), 7.42 (dd, J=14.3, 8.2 Hz, 2H), 7.32-7.28 (m, 2H), 6.91 (s, 1H), 5.28 (s, 1H), 2.68 (s, 3H), 2.51 (s, 3H), 1.01 (s, 9H). LCMS (M+H) calcd for C26H22ClN3O3: 464.17. found: 464.3.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]#[N:16])[CH:9]=1.Br[CH:18]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C=O)C>[C:15]([C:10]1[CH:9]=[C:8]([Cl:7])[CH:13]=[CH:12][C:11]=1[O:14][CH:18]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])#[N:16]
Reactant: O=C(c1ccccc1)C(Br)OCc1ccccc1
Reactant: N#Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1OC(OCc1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of potassium carbonate (0.06 g, 4.0 mmol), 4-chloro-2-cyanophenol (0.25 g, 1.6 mmol) and ω-bromo-2-benzyloxy-acetophenone (0.49 g, 1.6 mmol) in dry DMF (10 ml) is stirred at room temperature for 20 h. After evaporating the solvent under reduced pressure the residue is taken up in ethyl acetate. The solution is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by silical gel column chromatography to yield the title compound.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[F:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1>CO>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]3[C@@H:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[F:27])[C@@:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[C@@H:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])=[CH:8][CH:7]=2)=[N:1][N:2]=[N:3]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(-c3nnn[nH]3)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CO
Product: CC(C)(C)C[C@H]1N[C@H](C(=O)Nc2ccc(-c3nnn[nH]3)cc2)[C@@H](c2cccc(Cl)c2F)[C@]1(C#N)c1ccc(Cl)cc1F

Procedure:
Rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1H-tetrazol-5-yl)-phenyl]-amide (522 mg) was resolved on a Berger SFC machine under 1000 bar, 30° C. with 35% of methanol on an O.D. column gave two separated peaks. Peak 1, 186 mg (undesired), peak 2, 185 mg (desired).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:20])(=O)=O>O>[NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[N:5]([CH3:20])[C:4](=[O:13])[CH:3]=1
Reactant: C=C(C)Cn1c(N)cc(=O)[nH]c1=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)Cn1c(N)cc(=O)n(C)c1=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Methallylamine (211 g, 2.97 mol) is added to a solution of concentrated hydrochloric acid (250 ml) in water (1.9 l), followed by portionwise addition of potassium cyanate (240 g, 2.97 mol). The reaction is then heated for 2 hours at 80° C., prior to cooling and evaporation to afford (2-methyl-allyl)-urea (2445 g), mp 114-115° C. The urea (268 g, 2.35 mol) is added to a solution of cyanoacetic acid (220 g, 2.59 mol) in acetic anhydride, (536 ml) and the reaction is heated at 70° C. for 1 hour, cooled to 0° C. and diluted with ether. The resultant solid is collected by filtration, washed with ether, suspended in water (2.2 l) and heated to 75° C. 2M aqueous sodium hydroxide solution is then added portionwise over 30 min to maintain pH between 8 and 9.5. The reaction is cooled to room temperature, treated with acetic acid (12 ml), further cooled to 10° C. and the resultant solid is collected by filtration, washed with cold water and dried to afford 6-amino-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 267-269° C. The uracil (253 g, 1.40 mol) is added to a solution of sodium hydroxide (123 g, 3.07 mol) in water (2.5 l) and allowed to exotherm then cooled to 20° C. Dimethyl sulfate (196 ml, 2.06 mol) is added portionwise over 1 hour. After standing overnight, the reaction is cooled to 5° C. and the solid collected by filtration to give 6-amino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4dione, mp 162-163° C. The methyluracil (165 g, 0.85 mol) is suspended in water (1.55 l) and concentrated hydrochloric acid (72 ml). A solution of sodium nitrite (58.4 g, 0.85 mol) in water (117 ml) is then added dropwise over 30 minutes and the reaction is stirred at 20° C. for 3 hours. The solid is collected by filtration, washed successively with water, methanol and ether to afford 6-amino-3-methyl-1-(2-methyl-allyl)-5-nitroso-1H-pyrimidine-2,4dione, mp 213° C. (dec). The nitrosouracil (190 g, 0.85 mol) is suspended in water (950 ml), heated to 85° C. and sodium dithionite (85%, 347.2 g, 1.69 mol) is added portionwise. After cooling to room temperature, the solid is collected by filtration to afford 5,6-diamino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine2,4-dione, mp 152-153° C.
Reaction SMILES: C([O:5][C:6]1[CH:36]=[CH:35][C:9]([O:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][N:18]=[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=4)[C:16]=3[CH:15]=[C:14]2[C:31]([O:33][CH3:34])=[O:32])=[CH:8][CH:7]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH2:29]([O:28][C:24]1[CH:23]=[C:22]([C:17]2[C:16]3[CH:15]=[C:14]([C:31]([O:33][CH3:34])=[O:32])[N:13]([CH2:12][CH2:11][O:10][C:9]4[CH:8]=[CH:7][C:6]([OH:5])=[CH:36][CH:35]=4)[C:21]=3[CH:20]=[CH:19][N:18]=2)[CH:27]=[CH:26][CH:25]=1)[CH3:30]
Reactant: CCOc1cccc(-c2nccc3c2cc(C(=O)OC)n3CCOc2ccc(OC(C)(C)C)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cccc(-c2nccc3c2cc(C(=O)OC)n3CCOc2ccc(O)cc2)c1
Yield: 80 %

Procedure:
Methyl 1-[2-(4-tert-butoxyphenoxy)ethyl]-4-(3-ethoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (900 mg, 1.842 mmole) was taken up in TFA (10 mL) at RT. After 3 hr the mixture was concentrated. The residue was taken up in saturated NaHCO3 and extracted with EtOAc (3 x). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (Biotage-SNAP-25 g SiO2, 50% EtOAc/hexanes) gave the title compound (637 mg, 80%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.49 (d, J=6.0 Hz, 1 H); 7.60 (s, 1 H); 7.52-7.38 (m, 4 H); 7.01 (dd, J=8.2, 2.5 Hz, 1 H); 6.68-6.60 (m, 3 H); 5.72 (s, 1 H); 4.97-4.91 (m, 2 H); 4.33-4.27 (m, 2 H); 4.12 (dd, J=13.9, 7.0 Hz, 2 H); 3.93 (s, 3 H); 1.43 (t, J=7.0 Hz, 3 H).
Reaction SMILES: [C:1]1([C:7]([N:20]=[N+:21]=[N-:22])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([OH:27])[CH2:24][C:25]#[CH:26]>C1(C)C=CC=CC=1>[C:1]1([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:20]2[CH:26]=[C:25]([CH2:24][CH2:23][OH:27])[N:22]=[N:21]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CCCO
Solvent: Cc1ccccc1
Product: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1

Procedure:
In toluene (90 ml) were dissolved triphenylmethyl azide (8.23 g) and 3-butyn-1-ol (2.2 ml). The solution was heated for 60 hours under reflux. The reaction mixture was concentrated under reduced pressure. The concentrate was purified by means of a column chromatography (carrier: silica gel, 150 g, developing solvent: ethyl acetate). The resulting crystalline product was washed with isopropyl ether to give the title compound (3.06 g).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)[OH:6].[CH2:14]([CH2:16]N)[OH:15].C(#[N:20])C>>[C:11]([C:9]1[CH:10]=[C:4]([C:3]([NH2:20])=[O:13])[C:5]([O:6][CH2:16][CH2:14][OH:15])=[CH:7][CH:8]=1)#[N:12]
Reactant: NCCO
Reactant: CC#N
Reactant: COC(=O)c1cc(C#N)ccc1O
Product: N#Cc1ccc(OCCO)c(C(N)=O)c1

Procedure:
A solution of 9.7 g (0.547 mole) of 5-cyanosalicylic acid methyl ester (prepared as described in Chem. Pharm. Bull., 1984, 38, 4466-4477) in 15 ml of acetonitrile, was combined with 4.01 g (0.65 mole) of ethanolamine, and then heated at reflux for 24 hours. At the end of the 4th and 7th hours, two further portions of 1 g (0.016 mole) each of ethanolamine were added. At the end of the heating, the solution was evaporated to dryness under vacuum, taken up with ethyl acetate and washed with hydrochloric acid 1N and then with water. The organic layer was dried over sodium sulphate and concentrated to small volume. The formed solid was filtered and dried under vacuum yielding 9.2 g of 5-cyano-(2-hydroxyethyl)salicylamide. m.p. 144°-146° C. (acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC(C)C(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (35 mg) was reacted with 27 μL of isobutyryl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)isobutyramide.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[NH2:30][C:31]1[C:36]([F:37])=[CH:35][N:34]([CH2:38][CH2:39][CH2:40][CH2:41]I)[C:33](=[O:43])[N:32]=1>CC#N>[NH2:30][C:31]1[C:36]([F:37])=[CH:35][N:34]([CH2:38][CH2:39][CH2:40][CH2:41][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:33](=[O:43])[N:32]=1
Reactant: Nc1nc(=O)n(CCCCI)cc1F
Reactant: c1nc[nH]n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1nc(=O)n(CCCCn2cncn2)cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
To a mixture of 1,2,4-triazole (0.044 g, 0.64 mmol), potassium tbutoxide (KOtBu; 0.072 g, 0.64 mmol), and 18-crown-6 (18C6; 0.008 g, 0.03 mmol) in CH3CN (3.5 mL) was added 4-amino-5-fluoro-1-(4-iodobutyl)-1H-pyrimidin-2-one (0.10 g, 0.32 mmol), and the mixture was warmed to 70° C. and stirred for 16 h. The resulting homogeneous solution was concentrated in vacuo to give the crude product as a white solid. Purification by reverse phase chromatography (13 g C18; gradient, 0 to 20% CH3CN/water) afforded 4-amino-5-fluoro-1-(4-[1,2,4]triazol-1-yl-butyl)-1H-pyrimidin-2-one (0.023 g, 28%) as a white solid: mp 197-200° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.94 (m, 2H), 7.56 (s, 1H), 7.35 (s, 1H), 4.19 (t, J=6.9 Hz, 2H), 3.61 (t, J=7.0 Hz, 2H), 1.73 (m, 2H), 1.51 (m, 2H); ESIMS m/z 253 ([M+H]+), m/z 251 ([M−H]−).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][N:21]=1)[C:18]([N:22]1[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]1=[O:32])=[N:17][CH:16]=[CH:15]2>C(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[C:18]1[N:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[N:21][C:12]([NH:11][CH:8]=[O:10])=[CH:13]2
Reactant: O=CO
Reactant: Nc1cc2ccnc(N3C(=O)c4ccccc4C3=O)c2cn1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CNc1cc2ccnc(N3C(=O)c4ccccc4C3=O)c2cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Acetic anhydride (2.01 mL, 20.6 mmol) was added to formic acid (0.75 mL, 20.6 mmol) at 0° C. The mixture was heated to 60° C. for 30 minutes. After that 2-(6-amino-2,7-naphthyridin-1-yl)isoindoline-1,3-dione 4-7 (300 mg, 1.03 mmol) dissolved in CH2Cl2 (10 mL) was added at 0° C. The mixture was stirred for 1 h at room temperature. The mixture was concentrated and the residue was triturated with CH2Cl2/hexane (1:1) to give 240 mg (73%) of 4-8 as a pale yellow solid: 1H NMR (300 MHz, CDCl3)1H NMR (rotamer ratio: s-cis/s-trans=4:1) δ 9.46 (0.2H, br d, J=10.3 Hz), 9.01 (0.8H, br s), 8.75 (0.2H, br d, J=10.3 Hz), 8.68 (1H, br d, J=5.4 Hz), 8.60 (1H, br s), 8.56 (1H, br s), 8.48 (0.8H, br s), 8.03 (2H, m), 7.86 (2H, m), 7.77 (0.8H, br d, J=5.4 Hz), 7.67 (0.2H, br d, J=5.4 Hz); ESI-MS m/z 319 [C17H10N4O3+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([Cl:16])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCc1ccc(F)cc1
Yield: 101.4 %

Procedure:
A mixture of 4-(4-fluorophenyl)butyric acid (68.2 g, 0.37 mol) and thionyl chloride (155 g, 1.3 mol) was refluxed for 1.25 h. The mixture was concentrated in vacuo to give 75.3 g (100%) of 4-(4-fluorophenyl)butyryl chloride).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C([O-])([O-])=O.[K+].[K+].[CH2:18]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCCCCCNCCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 86 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (1.59 g, 10 mmol) in DMSO (15 mL) were added K2CO3 (3.04 g, 22 mmol) and di-n-hexylamine (2.04 g, 11 mmol). The mixture was heated at 90° C. overnight, then cooled to rt, diluted with water (50 mL) and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=10:1) to give the title compound as pale yellow oil (2.79 g, 86%).