Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].C(Cl)(Cl)Cl.[CH3:40][CH:41]1[CH2:46][CH2:45][N:44]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:50]3[CH2:51][CH2:52][CH:47]([N:44]4[CH2:45][CH2:46][CH:41]([CH3:40])[CH2:42][CH2:43]4)[CH2:48][CH2:49]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CC1CCN(C2CCNCC2)CC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 69.7 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (36 mg, 0.072 mmol) in THF (2 mL)/CHCl3 (2 mL) were added 4-methyl-1,4′-bipiperidine (40 mg, 0.22 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.5 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (31 mg, 70%). LC-MS m/z 618 (M+H)+; 1H-NMR (MeOD) δ 1.00 (d, 3H), 1.22 (m, 2H), 1.27 (d, 6H), 1.38 (m, 3H), 1.68 (d, 2H), 1.81 (d, 2H), 2.19 (t, 2H), 2.30 (s, 3H), 2.50 (t, 1H), 2.71 (t, 2H), 2.93 (d, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 4.45 (m, 2H), 7.16 (t, 2H), 7.46 (d, 1H), 7.50 (m, 1H), 7.68 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[NH:14][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]2)=[C:2]([F:1])[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cn(-c2ccc(N)cc2F)nn1
Reactant: O=C(Cl)OCc1ccccc1
Product: Cc1cn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)nn1
Yield: 94.8 %

Procedure:
3-Fluoro-4-(4-methyl-[1,2,3]triazol-1-yl)-phenylamine (Intermediate 21) (34.8 g, 0.181 mol) and benzyl chloroformate (34 mL, 0.238 mol) were reacted following the procedure for Intermediate 26. The crude product obtained by filtration was dried in vacuo and triturated with chloroform/hexanes (250 ml/500 ml) to give the title compound as a colourless solid (56 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15](B(O)O)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:2]3[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11]1
Reactant: Oc1ccc(Br)cn1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ncc2cc(-c3ccc(=O)[nH]c3)ccc21
Temperature: 80 °C

Procedure:
The suspension of 5-bromo-2-hydroxypyridine (80 mg, 0.46 mmol), 1-methyl-1H-indazol-5-ylboronic acid (121 mg, 0.69 mmol) and 2N sodium carbonate solution (1.0 mL, 2 mmol) in DMF (2.1 mL) was degassed with N2 for 5 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.04 mmol), and the resulting mixture was heated at 80° C. overnight. The mixture was then diluted with CH2Cl2, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H12N3O: 226.25; Found: 226.3.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:31]=[C:32]1[NH:45][C:35]2=[N:36][CH:37]=[C:38](/[CH:40]=[CH:41]/[C:42](O)=[O:43])[CH:39]=[C:34]2[O:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH3:1][N:2]([CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:42](=[O:43])/[CH:41]=[CH:40]/[C:38]1[CH:39]=[C:34]2[O:33][C:32](=[O:31])[NH:45][C:35]2=[N:36][CH:37]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: O=C(O)/C=C/c1cnc2[nH]c(=O)oc2c1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2[nH]c(=O)oc2c1
Yield: 34 %

Procedure:
According to the procedure of Example 1 (a), except substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(2-oxo-2,3-dihydro-oxazolo[4,5-b]pyridine-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.23 g, 34%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 12.64 (br s, 1H), 8.37-8.12 (m, 2H), 7.64 (d, J=15.3 Hz, 1H), 7.51-7.26 (m, 3H), 7.17-7.07 (m, 1H), 7.04-6.94 (m, 1H), 6.42-6.17 (m, 1H), 5.06-4.85 (m, 2H), 3.73-3.68 (m, 3H), 3.12-2.99 (m, 3H); MS (ESI) m/e 363 (M+H)+.
Reaction SMILES: C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C.[CH2:18]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:50][CH3:51])=[C:27]([NH:29][C:30]2[O:31][C:32]([C:35]3[CH:36]=[C:37]([C:41]4[CH:46]=[CH:45][C:44]([C:47](O)=[O:48])=[CH:43][CH:42]=4)[CH:38]=[CH:39][CH:40]=3)=[CH:33][N:34]=2)[CH:28]=1)(=[O:22])=[O:21])[CH3:19].[CH2:52]1[N:57]([CH2:58][CH2:59][NH2:60])[CH2:56][CH2:55][O:54][CH2:53]1>CN(C=O)C>[CH2:18]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:50][CH3:51])=[C:27]([NH:29][C:30]2[O:31][C:32]([C:35]3[CH:36]=[C:37]([C:41]4[CH:42]=[CH:43][C:44]([C:47]([NH:60][CH2:59][CH2:58][N:57]5[CH2:52][CH2:53][O:54][CH2:55][CH2:56]5)=[O:48])=[CH:45][CH:46]=4)[CH:38]=[CH:39][CH:40]=3)=[CH:33][N:34]=2)[CH:28]=1)(=[O:22])=[O:21])[CH3:19]
Reactant: NCCN1CCOCC1
Reactant: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(-c4ccc(C(=O)O)cc4)c3)o2)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(-c4ccc(C(=O)NCCN5CCOCC5)cc4)c3)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
In succession, diethylcyanophosphonate (50.0 mg, 0.27 mmol) and triethylamine (65 mg, 0.65 mmol) were added to a solution of the title compound from Example 236 (104.0 mg, 0.22 mmol) and 2-(4-morpholino)ethylamine (54.0 mg, 0.42 mmol) in DMF (2 mL). After the reaction was allowed to stir for 1 h at RT, the reaction was quenched with water (10 mL). The resulting precipitate was filtered, washed with water (10 mL) and dried to afford the title compound (85 mg, 66%) as a tan solid. (In the event that a clean precipitate was not formed on quench, the aqueous solution was washed with 3:1 chloroform/i-propanol (3×20 mL). The combined organic layers were separated, dried by anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product purified by chromatography on silica gel using dichloromethane:methanol (up to 20% methanol gradient) as eluent to afford the title compound.) 1H NMR (400 MHz, d6-DMSO): δ 9.71 (bs, 1H), 8.74 (d, J=2.1, 1H), 8.45 (t, J=5.5, 1H), 7.88–7.93 (m, 3H), 7.78 (d, J=8.2, 2H), 7.58–7.64 (m, 3H), 7.52 (t, J=7.7, 1H), 7.44 (dd, J1=2.1, J1=8.5, 1H), 7.23 (d, J=8.6, 1H), 3.93 (s, 3H), 3.52 (t, J=4.5, 4H), 3.36 (q, J=6.4, 2H), 3.25 (s, 2H), 3.15 (q, J=7.3, 2H), 2.33–2.40 (m, 4H), 1.10 (t, J=7.3, 3H). MS (ES+, m/z)=591 (m+H)+.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].[SH:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH3:13]>>[CH3:8][C:7]1[N:6]=[CH:5][NH:4][C:3]=1[CH2:2][S:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH3:13]
Reactant: Cc1[nH]cnc1CO
Reactant: CCC(N)CS
Product: CCC(N)CSCc1[nH]cnc1C

Procedure:
Reaction of 4-hydroxymethyl-5-methylimidazole and 1-mercapto-2-aminobutane in the procedure of Example 1(i) yields 4-methyl-5-[(2-aminobutyl)thiomethyl]imidazole and, when this is reacted with S-methyl-N'-[2-((4-methyl 5-imidazolyl)methylthio)ethyl]thiouronium sulphate in the procedure of Example 1(iii), the title compound is produced.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].C[O:7][C:8]1[C:13]2=[CH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N+:20]=3[CH:21]=[C:12]2[CH:11]=[CH:10][CH:9]=1.Cl([O-])(=O)(=O)=O.[Na+]>Br>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[OH:7][C:8]1[C:13]2=[CH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N+:20]=3[CH:21]=[C:12]2[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc2c[n+]3ccccc3cc12
Agent: Br
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: Oc1cccc2c[n+]3ccccc3cc12
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4 g of 10-methoxybenzo[b]quinolizinium perchlorate in 50 mL of 48% HBr was heated at 100° C. for 20 h, cooled to room temperature, and the resulting mixture was poured into 100 mL of 50% sodium perchlorate solution and stirred for 5 min. The precipitate was filtered, washed with ice-water, ether, ethyl acetate and air dried to afford 2.9 g of 10-hydroxybenzo[b]quinolizinium perchlorate, (Formula II: R1 =R2 =H; R7 =10--OH; X- =ClO4-) m.p. 218°-229° C. (d).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=[O:19].[CH3:21][C:22]([S:25]([N:27]=[C:28]1[CH2:31][O:30][CH2:29]1)=[O:26])([CH3:24])[CH3:23]>O1CCCC1>[CH3:23][C:22]([CH3:24])([S:25]([NH:27][C:28]1([C:17]2[S:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[CH2:31][O:30][CH2:29]1)=[O:26])[CH3:21]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: O=C(O)c1cccs1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(c2ccc(C(=O)O)s2)COC1
Temperature: 25 °C

Procedure:
Butyllithium (6.16 ml, 15.41 mmol) was added dropwise to a stirred solution of diisopropylamine (1.919 ml, 13.69 mmol) in tetrahydrofuran (10 ml) at −78° C. The solution was allowed to warm to room temperature and then added dropwise by syringe to a stirred −78° C. solution of thiophene-2-carboxylic acid (0.877 g, 6.85 mmol) in tetrahydrofuran (30 ml). The resulting suspension was stirred for 40 minutes at −78° C. when a solution of 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1 g, 5.71 mmol) in tetrahydrofuran (10 ml) was added dropwise. After the addition was complete, the reaction mixture was allowed to warm to room temperature, quenched with saturated ammonium chloride and diluted with a water to dissolve the remaining solids. The aqueous solution was extracted with ethyl acetate, adjusted to pH 2 by addition of 1N aqueous hydrochloric acid and re-extracted with ethyl acetate and methylene chloride. The organic extracts were dried with magnesium sulfate, filtered, concentrated and purified by normal phase chromatography to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Yield: 27.2 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and morpholine (0.34 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-[(4-bromophenyl)sulfonyl]morpholine (0.13 g, 28%) was provided after purification. MS (ESI) m/z 306. HPLC purity 100.0% at 210-370 nm, 8.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([OH:17])=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[C:18]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH2:26])=[CH:22][CH:21]=1)#[N:19]>>[C:18]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH:26][C:15](=[O:17])[CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)=[CH:22][CH:21]=1)#[N:19]
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Reactant: N#Cc1ccc(CCN)cc1
Product: Cn1c(=O)c2c(ncn2CC(=O)NCCc2ccc(C#N)cc2)n(C)c1=O
Yield: 21.2 %

Procedure:
Compound 409 (93 mg, 21%) was prepared from 101 (300 mg, 1.3 mmol) and 115 (175 mg, 1.2 mmol) according to General Procedure B. MS (APCI): m/z 367 [M+H]+. Anal. Calcd. for C18H18N6O3.0.04EtOAc.0.1H2O: C, 58.68; H, 5.02; N, 22.61. Found: C, 58.75; H, 5.01; N, 22.46.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[OH:10])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([CH2:8][CH:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[OH:10])([OH:7])=[O:5]
Reactant: COC(=O)c1ccc(C(O)CC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C(O)CC(=O)O)cc1
Reaction time: 3 h
Yield: 100.8 %

Procedure:
Methyl 4-(2-tert-butoxycarbonyl-1-hydroxyethyl)benzoate (140 mg, 0.50 mmol) was dissolved in trifluoroacetic acid (2.0 mL), and the resulting solution was left to stand at room temperature for 3 hours and concentrated to dryness under reduced pressure to give 113 mg of the desired product (stoichiometric yield).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].[CH:12]1[C:22]2[CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:18][N:17]([C:27]([C:29]3[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=3)=[O:28])[C:16]=2[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH:12]1[C:22]2[CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:18][N:17]([C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:33]([O:5][CH2:4][C:3]4[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=4[CH3:1])=[O:34])=[CH:36][CH:37]=3)=[O:28])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccccc1CO
Reactant: O=C(Cl)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1COC(=O)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reaction time: 1 h
Yield: 32 %

Procedure:
To a mixture of 248 mg of 2-methylbenzyl alcohol in 4 ml of anhydrous tetrahydrofuran is added 80 mg of sodium hydride (60% in mineral oil) and the mixture stirred for 1 hour. To the mixture is added 430 mg of 4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]benzoyl chloride and the mixture is stirred for 18 hours. The tetrahydrofuran is evaporated in vacuo to a residue which is partitioned between methylene chloride and water. The organic layer is separated and washed with 1N HCl, water, 1M NaHCO3, and brine. The organic layer is dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate and hexane added at the boil to give 170 mg of the desired product, m.p. 140°-142° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CN.C([O:8][C:9]([C:11]1[N:32]=[C:14]2[CH2:15][N:16]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[N:13]2[N:12]=1)=O)C>CO>[CH3:1][N:2]([CH3:3])[C:9]([C:11]1[N:32]=[C:14]2[CH2:15][N:16]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[N:13]2[N:12]=1)=[O:8]
Reactant: CCOC(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: CNC
Agent: CN
Solvent: CO
Product: CN(C)C(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
Pure gaseous dimethylamine free, in particular, from methylamine, is fed for 2 hours at room temperature, with stirring, into a suspension of 3.85 (0.01 mole) of 6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic acid ethyl ester [cp. Example 2 (a)-(c)] in 200 ml of methanol. The clear reaction mixture is concentrated in vacuo to dryness. After recrystallisation from isopropanol, the residue yields pure N,N-dimethyl-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide, M.P. 180°-182°.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[CH:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:30]=[CH:29][N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: CCOC(=O)C(=O)C=CN(C)C
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: CCOC(=O)c1ccnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 170 °C
Yield: 34 %

Procedure:
A mixture of N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]guanidine dinitrate (298 mg, 0.80 mmol), ethyl 4-dimethylamino-2-oxo-but-3-enoate (171 mg, 1.0 mmol) and potassium carbonate (69 mg, 0.5 mmol) in ethanol (2 mL) was heated in a sealed tube in a microwave oven to 170° C. for 0.5 h. The mixture was cooled, diluted with ethyl acetate (30 mL), and then washed with saturated sodium carbonate solution (10 mL) and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-20% methanol as eluent to give the title compound (96 mg, 34%) as a pale-yellow solid. MS ISP (m/e): 354.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.67 (d, 1H), 7.91 (d, 1H), 7.64 (s, 1H), 7.45 (s, 1H), 7.44 (d, 1H), 7.19 (d, 1H), 7.02 (dd, 1H), 6.88 (s, 1H), 4.47 (q, 2H), 3.91 (s, 3H), 2.30 (s, 3H), 1.44 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=2)=[C:4]([CH3:16])[CH:3]=1.[OH-].[Na+].[C:19](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH3:19])=[CH:9][N:8]=2)=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Oc1ccc(N)cn1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: CNc1ccc(Oc2ccc(Cl)cc2C)nc1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
2-(4-Chloro-2-methyl-phenoxy)-5-aminopyridine (2.15 g, 9.16 mmol) was combined with powdered sodium hydroxide (1.46 g, 36.6 mmol), potassium carbonate (1.27 g, 9.16 mmol), tetrabutyl ammonium bromide (60 mg, 0.18 mmol) and toluene (10 mL) was stirred for 1 hour at 35° C. A solution of dimethyl sulfate (0.91 mL, 9.6 mmol) dissolved in toluene (5 mL) was added slowly. The mixture was heated at 35° C. for 20 hours. After cooling, the solids were removed by filtration and the solvent was concentrated in vacuo. The desired material was purified by chromatography on SiO2 using 30% ethyl acetate / hexanes as eluent. MS (m/z): 248/250 (M+H)+; C13H13N2OCl requires 249.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.[Li]C(C)(C)C.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>O1CCCC1>[CH3:14][Sn:15]([CH3:17])([CH3:16])[C:5]1[S:1][C:2]2[CH:8]=[C:7]([Sn:15]([CH3:17])([CH3:16])[CH3:14])[S:6][C:3]=2[CH:4]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1cc2sccc2s1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2sc([Sn](C)(C)C)cc2s1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In a 3-neck round bottom flask equipped with an argon inlet and an addition flannel, thieno[3,2-b]thiophene (7.5 g, 54 mmol) was dissolved in tetrahydrofuran (1 L). After the solution was cooled to −78° C. using an isopropanol/dry ice bath, t-BuLi (100 mL, 170 mmol) was transferred by cannula to the addition funnel. The organolithium reagent was then added dropwise. After completion of the addition, the mixture was stirred for 20 min at −78° C. then warmed up with an isopropanol bath at room temperature for 30 minutes during which a yellow precipitate formed. The solution was cooled back at −78° C., and after cannula transfer to the addition funnel, trimethyltin chloride (200 mL of 1 M solution in THF, 200 mmol) was added dropwise. During addition of trimethyltin chloride, the precipitate disappeared and the solution turned light brown. After warming to room temperature the solution was stirred for 30 minutes then was poured into ice-cold water. The aqueous phase was further extracted with hexane. The combined organic phase were washed with cold water then dried with magnesium sulfate. After filtration, the solvent is evaporated under vacuum to yield a grey-brown solid. The product was purified by precipitation of a chloroform solution into methanol followed by filtration (13.2 g, 53%).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])=[O:3].[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:1][C:2]([CH2:4][C@@H:5]([C@@H:7]([CH2:9][O:10][S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[OH:8])[OH:6])=[O:3]
Reactant: CC(=O)C[C@H](O)[C@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)C[C@H](O)[C@H](O)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 14 h
Yield: 83.3 %

Procedure:
Methyl-2-deoxy-D-ribose (8 g, 54 mmol) was dissolved in pyridine (60 mL). To this solution was added tosylchloride (10.86 g, 57 mmol) over 1 hour at 0° C. After 14 hours at room temperature, the solution was concentrated, quenched with ice water (250 mL), and extracted with ethyl acetate. The extract was washed with saturated NaHCO3, water, dried, filtered, and concentrated. The residue (13.6 g, 83.5% yield) was used directly. NMR
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]1([C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:15](O)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:7]1([C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:15]([Cl:2])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)C=C(c1ccccc1)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.164 g of phosphorus pentachloride were added to 90 ml of a methylene chloride solution containing 4.485 g of 3,3-diphenylacrylic acid, which had previously been cooled at 0°-5° C. The reaction mixture was then stirred for one hour at room temperature, after which the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 50 ml of toluene, and then the solvent was once again distilled off under reduced pressure. This procedure comprising dissolution and distillation was repeated once more. 3,3-Diphenylacryloyl chloride was obtained as a white solid. This crude product was immediately used in the next reaction.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]1.N12CCCN=C1CCCCC2>O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: OCC1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(CO)CC2)nn1

Procedure:
To a stirred solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide (0.200 g, 0.90 mmol) in 1,4-dioxane (10 mL) was added 4-piperidine methanol (0.155 g, 1.40 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 mL, 2.700 mmol) and tetrabutyl ammonium bromide (0.032 g, 0.10 mmol). The resulting mixture was stirred at reflux for 18 hours. 1,4-Dioxane was removed in vacuo and the obtained crude product was used without further purification.