Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C.Cl.C(N(CC)CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1>ClCCl>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](=[O:42])[NH:27][CH2:26][CH2:25][CH2:24][NH:23][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:2][CH2:3]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Yield: 92.1 %

Procedure:
A suspension of 2-[2-(3-aminopropylamino)-5-chloropyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (500 mg, 1.24 mmol) in dichloromethane (30 mL) is treated at room temperature with piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (340 mg, 1.48 mmol) in the presence of N,N-diisopropylethylamine (0.220 mL, 163 mg, 1.26 mmol), 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240 mg, 1.25 mmol), and 1-hydroxybenzotriazole (171 mg, 1.21 mmol) for 24 hours. The mixture is then diluted with dichloromethane (30 mL), filtered, washed with H2O (30 mL), and diethyl ether (30 mL), and dried to provide 4-{3-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propylcarbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (700 mg, 92%). A stirred mixture of this intermediate (695 mg, 1.13 mmol) in dichloromethane (25 mL) is treated at room temperature with TFA (2.5 mL) for 72 hours. The mixture is then concentrated under reduced pressure, and subjected to chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane: 16-40%, to provide the title compound (492 mg, 85% yield).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[B:30](OC(C)C)([O:35]C(C)C)[O:31]C(C)C.Cl>C1COCC1>[C:26]([O:25][C:23]([N:18]1[C:19]2[C:15](=[C:14]([F:13])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:17]1[B:30]([OH:35])[OH:31])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)n1ccc2c(F)cccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2c(F)cccc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 76.7 %

Procedure:
To a solution of diisopropylamine (7.5 mL, 0.11 mol) in THF (35 mL) at 0° C. was added n-BuLi (21 mL, 0.055 mol) dropwise. The mixture was stirred at 0° C. for 40 minutes. Then the mixture was cooled to −78° C. Tert-butyl 4-fluoro-1H-indole-1-carboxylate (5 g, 0.02 mol) in THF (13 mL) was added dropwise slowly. After addition, the mixture was stirred at −78° C. for 2 hours. Then triisopropyl borate (3.29 g, 0.03 mol) was added. The mixture was stirred at −78° C. for another 40 minutes. The reaction was monitored using TLC. When the reaction was completed, the mixture was adjusted to pH=6 with 1 N HCl. After extracted with EtOAc (25 mL×3), the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The obtained solid was recrystallized with EtOAc and petroleum ether to provide (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (4.5 g, yield: 76.7%, which might be unstable at high temp. work up, store in fridge). 1H-NMR (CDCl3, 400 MHz) δ 7.77 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)+: 280.
Reaction SMILES: CC([S@]([NH:7][C@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)C.[ClH:21].CC(S(OC)=O)(C)C>CO.O1CCOCC1>[ClH:21].[F:18][C:17]([F:19])([F:20])[C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:9][C@H:8]2[NH2:7])=[CH:12][CH:13]=1
Reactant: CC(C)(C)[S@@](=O)N[C@@H]1CCc2ccc(C(F)(F)F)cc21
Agent: COS(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H]1CCc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29 %

Procedure:
Intermediate 15B (370 mg, 1.21 mmol) was stirred in MeOH (5 mL) at rt. 4N HCl in dioxane (2 mL) was added. The resulting mixture was stirred at rt for 20 min. The solvents were evaporated and CH2Cl2 (3×) was added and evaporated. The resulting white solids were vacuum dried for 1 h to give Intermediate 15 (84 mg, 0.35 mmol, 29% yield) and methyl 2-methylpropane-2-sulfinate. The HCl salt was used directly in the next step. 1H NMR (400 MHz, MeOD) δ ppm 7.57 (1 H, d, J=7.8 Hz), 7.47 (1 H, d, J=7.6 Hz), 7.25 (1 H, t, J=7.8 Hz), 4.88 (1 H, dd, J=7.8, 4.8 Hz), 3.09-3.23 (1 H, m), 2.90-3.08 (1 H, m), 2.64 (1 H, dddd, J=14.1, 8.5, 8.3, 5.7 Hz), 2.01-2.23 (1 H, m, J=14.1, 8.7, 5.3, 5.3 Hz).
Reaction SMILES: CS([Cl:5])(=O)=O.C(N(CC)CC)C.[I:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:5][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[I:13]
Reactant: OCc1ccccc1I
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1ccccc1I
Temperature: 0 °C
Reaction time: 19 h
Yield: 100.7 %

Procedure:
Methanesulfonyl chloride (2.0 ml, 29 mmol) and triethylamine (3.6 ml, 26 mmol) were added to a solution of o-iodobenzyl alcohol (5.0 g, 21 mmol) in methylene chloride (50 ml) cooled to 0° C., and the mixture was stirred at that temperature for 19 hours. A 5% aqueous sodium hydrogencarbonate solution was added, and the resulting mixture was extracted with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (5.34 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCCOC)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][C:15](I)=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.O=C1C2C(=CC(C3C=CC=CC=3)=CC=2)N=C(N2C=C(C(O)=O)C=N2)N1.[Cl:54][C:55]1[CH:56]=[C:57](B(O)O)[CH:58]=[CH:59][CH:60]=1>>[Cl:54][C:55]1[CH:60]=[C:59]([C:15]2[CH:14]=[C:13]3[C:18]([C:19](=[O:27])[NH:20][C:11]([N:9]4[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]4)=[N:12]3)=[CH:17][CH:16]=2)[CH:58]=[CH:57][CH:56]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)n2COCCOC)c1
Agent: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc3cc(-c4cccc(Cl)c4)ccc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 184, steps C-E using 1-[7-iodo-3-(2-methoxy-ethoxymethyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 184, product from step B) and 3-chlorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11ClN4O3, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.04 (br s, 1H), 12.94 (br s, 1H), 8.97 (s, 1H), 8.28 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.00 (s, 1H), 7.91 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.82 (d, J=6.7 Hz, 1H), 7.60-7.52 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([NH+](CCCC)CCCC)CCC.[NH:41]([CH2:45][CH2:46][N:47]1[C:51]([SH:52])=[N:50][N:49]=[N:48]1)[C:42]([NH2:44])=[NH:43]>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][S:52][C:51]4[N:47]([CH2:46][CH2:45][NH:41][C:42]([NH2:44])=[NH:43])[N:48]=[N:49][N:50]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1csc(N)n1
Reactant: N=C(N)NCCn1nnnc1S
Agent: CCCC[NH+](CCCC)CCCC
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=N)N)CS[C@H]12)c1csc(N)n1
Temperature: -20 °C
Yield: 45 %

Procedure:
To a solution of 559 mg of tributylammonium 7β-[2 -(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3 -hydroxymethyl-3-cephem-4-carboxylate and 374 mg of 1-(2-guanidinoethyl)-5-mercapto-1H-tetrazole in 10 ml of DMF was added 500 mg of ethyl o-phenylenephosphate under stirring at -20° C. The reaction mixture was stirred at -20° C. to 0° C. for 90 minutes and subjected to a column chromatography on silica gel (100 g), being washed with acetonitrile and eluted with a (5:1) mixture of acetonitrile and water. The eluate was concentrated under reduced pressure, and the concentrate was subjected to a column chromatography on XAD-II (150 ml), being washed with water and eluted with 10% aqueous ethanol. The eluate was concentrated under reduced pressure and then lyophilized to give 245 mg of the title compound as a colorless powder.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>ClCCl>[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]2[CH2:6]1)=[O:29]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(Br)c1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (5.0 g, 27 mmol) and N,N-diisopropylethylamine (7.5 mL, 43 mmol) in dry dichloromethane (135 mL) was added 3-bromobenzoyl chloride (2.9 mL, 22 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was then washed with 1 M hydrochloric acid (5×200 mL), 1 M sodium hydroxide (200 mL), and brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow solid (7.2 g). Recrystallization from ethyl acetate gave the title compound (5.8 g, 72%) as a white crystalline solid.
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH2:37]([N:40]([CH2:45]CC)[CH2:41][C:42](=O)[CH3:43])[CH2:38][CH3:39].[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([CH2:45][N:40]([CH2:41][CH2:42][CH3:43])[CH2:37][CH2:38][CH3:39])[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCCN(CCC)CC(C)=O
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)Cc1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 58 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-dipropylamino-propan-2-one (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (70 mg, 58% yield). MS: 485.34 (M+H+); HPLC Procedure A, retention time=9.20 min.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]([F:20])[C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24].[BH4-].[Na+]>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:26][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:15]=[C:14]([F:20])[C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1ccc(Oc2c(F)cc(C=O)cc2F)nc1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)CCNCc1cc(F)c(Oc2ccc(C(N)=O)cn2)c(F)c1
Yield: 84.7 %

Procedure:
Using a method similar to Example 712, using 6-(2,6-difluoro-4-formyl-phenoxy)-nicotinamide (Example 712, Step 1) (139 mg, 0.500 mmol), isoamylamine (52 mg, 0.600 mmol), and NaBH4 (28 mg, 0.750 mmol) gave the title compound (148 mg) as a white solid. Mass spectrum (ion spray): m/z=350 (M+1); 1HNMR (CDCl3): 8.51 (s, 1H), 8.21 (d, 1H), 7.14 (d, 1H), 7.03 (d, 2H), 5.74 (br. s, 9H), 3.79 (s, 2H), 2.65 (t, 2H), 1.66 (m, 1H), 1.41 (m, 2H), 0.91 (d, 6H).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].C(O)(=O)C.[CH3:22][C:23](=O)[CH2:24][CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:23]([N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH3:2])(=[O:5])=[O:4])[CH:7]=2)[CH2:13][CH2:14]1)([CH2:24][CH3:25])[CH3:22]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Reactant: CCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCC(C)N1CCC(c2cccc(S(C)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-(3-methanesulfonyl-phenyl)-piperidine hydrochloride (20 mg), glacial acetic acid (4.4 mg) and 2-butanone (5.1 mg) were mixed in 1,2-dichloroethane (5 mL). Sodium triacetoxyborohydride (23.5 mg) was added to the solution and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 5 h (G.L.C. analysis indicated a complete reaction). The reaction was quenched with saturated aqueous NaHCO3 and the product was extracted with CH2Cl2. The combined organic phases were dried (MgSO4), filtered, and the solvent was evaporated to afford 1-sec-butyl-4-(3-methanesulfonyl-phenyl)-piperidine as an oily residue. The product was chromatographed on a silica column with CH2Cl2:MeOH (9:1 (v/v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure amine (15 mg, 71%); MS m/z (relative intensity, 70 eV) 295 (M+, 1), 280 (7), 266 (bp), 187 (4), 129 (4).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[O:4]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>ClCCl.N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH:5]2[O:4][CH:3]([CH2:2][O:1][S:16]([C:13]3[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=3)(=[O:18])=[O:17])[CH2:7][CH2:6]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OCC1CCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC(COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
34.0 g (261 mmol) of 2,5-bis(hydroxymethyl)tetrahydrofuran are dissolved in 260 ml of dichloromethane. A solution of 99.0 g (521 mmol) of p-toluenesulfonyl chloride in 52 ml of pyridine and 130 ml of dichloromethane is added dropwise thereto. After stirring at room temperature for 24 hours, the precipitate is filtered off with suction and washed with dichloromethane. The filtrate and the washing phases are combined, washed with dilute hydrochloric acid and then with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness. The crude product is recrystallized from ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15].CC(=CC)C.P([O-])([O-])(O)=[O:22].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([CH3:12])([CH3:10])[CH3:11])[N:5]=[C:4]([C:13]([OH:22])=[O:14])[C:3]=1[Cl:15]
Reactant: O=P([O-])([O-])O
Reactant: CC(C)(C)c1nc(C=O)c(Cl)c(N)c1F
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)c1nc(C(=O)O)c(Cl)c(N)c1F
Temperature: 70 °C

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-6-(tert-butyl)-3-chloro-5-fluoropicolinaldehyde (316 mg, 1.370 mmol) and t-butanol (6.85 mL). The mixture was treated with H2O (2.283 mL), 2-methylbut-2-ene (1.1 mL, 1.370 mmol), sodium hydrogenphosphate (389 mg, 2.74 mmol). Finally, sodium chlorite (372 mg, 4.11 mmol) was added in one portion. The mixture was heated to 70° C. in the microwave for 2 h. An aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was diluted with EtOAc (15 mL) and washed with 1 M HCl (1×5 mL), H2O (1×5 mL) and saturated NaCl (1×5 mL). HPLC analysis of the combined aqueous washes showed only trace amounts of the desired product. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give 414 mg of a cream colored solid. The crude material was stirred with Et2O (˜5 mL). After stiffing for ˜3 h the solid was removed by vacuum filtration washing with Et2O. The solid was air-dried for several hours and then dried under vacuum. The title compound (348 mg, >99%) was isolated as a white solid: mp 149-151° C.; 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 4.97 (s, 2H), 1.41 (d, J=1.5 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −132.92; 13C NMR (101 MHz, CDCl3) δ 161.62, 151.12, 149.21, 146.63, 141.58, 117.18, 36.69, 28.37.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=O)[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:5][CH:4]=1.[CH2:19]([SH:22])[CH2:20][SH:21]>>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2([CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)[S:22][CH2:19][CH2:20][S:21]2)=[CH:5][CH:4]=1
Reactant: SCCS
Reactant: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Agent: Cl
Product: Clc1ccc(CCC2(Cn3ccnc3)SCCS2)cc1
Yield: 32 %

Procedure:
The title compound was synthesized from ketone 5e (Vlahakis, J. Z.; Kinobe, R. T.; Bowers, R. J.; Brien, J. F.; Nakatsu, K.; Szarek, W. A. Bioorg. Med. Chem. Lett. 2005, 15, 1457-1461) by the procedure employed for the synthesis of QC-15, except using 1,2-ethanedithiol instead of ethylene glycol, to afford a beige solid in 32% yield after recrystallization (2-propanol): mp 204-205° C.; Rf=0.21 (EtOAc); 1H NMR (400 MHz, CD3OD): δ 2.17-2.25 (m, 2H), 2.94-3.06 (m, 4H), 3.28-3.38 (m, 2H), 4.65 (s, 2H), 7.21 (d, 8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.56 (s, 1H), 7.81 (s, 1H), 9.11 (s, 1H); 13C NMR (100 MHz, D2O): δ 32.6, 41.6, 43.4, 59.8, 71.2, 119.9, 125.5, 129.6, 131.1, 133.0, 138.2, 141.3; HRMS (ES) [M−Cl]+ Calcd. for C15H18ClN2S2: 325.0600. Found: 325.0587.
Reaction SMILES: CI.[Mg].Br[CH2:5][C@@H:6]([CH3:16])[CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1.[CH3:17][CH:18]([CH3:22])[CH2:19][CH2:20]O.C1(C)C=CC(S([O-])(=O)=O)=CC=1>O1CCCC1>[CH3:16][C@H:6]([CH2:5][CH2:20][CH2:19][CH:18]([CH3:22])[CH3:17])[CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: CC(C)CCO
Reactant: C[C@H](CBr)CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)CCC[C@@H](C)CCOC1CCCCO1
Reaction time: 0.08 h

Procedure:
4.7 g (0.202 mol) of magnesium shavings in a 3-necked flask under an argon atmosphere and provided with a calcium chloride tube are activated by addition of 2.0 ml of methyl iodide. After 5 minutes, the methyl iodide is removed and the magnesium washed several times with absolute tetrahydrofuran. To the activated magnesium is added dropwise a solution of 44 g (0.175 mol) of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran in 50 ml of absolute tetrahydrofuran at such a rate that the solvent just boils. Where the Grignard reaction does not start itself, it is warmed to 85° with the oil bath. After completed addition of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran, the mixture is stirred at 85° for so long (0-15 min.) until only traces of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran are still present in accordance with gas-chromatographical analysis. The solution obtained is cooled to -78° and treated dropwise with 21.2 g (0.0875 mol) of 3-methyl-1-butanol-p-toluenesulphonate followed by 3.6 ml of a 0.1 molar solution of Li2CuCl4 in absolute tetrahydrofuran. This reaction mixture is stirred at -78° during 10 min. then at 0° for 2 hours and subsequently at room temperature for a further 14 hours. For the working up of the 2-[(R)-3,7-dimethyloctanoxy]-tetrahydro-2H-pyran obtained the mixture is poured on to ice and brought to pH 5-6 with 2-N sulphuric acid. By three-fold extraction with ether and removal of the solvent on the rotary evaporator there is obtained a mixture of (R)-3,7-dimethyl-1-octanol and 2-[(R)-3,7-dimethyloctanoxy]-tetrahydro-2H-pyran. This mixture is treated portionwise in 100 ml of methanol at 0° with a total of 100 ml of 7-N aqueous hydrochloric acid. After 2-hours stirring at room temperature, the mixture is neutralised with dilute aqueous caustic soda and extracted with ether. After chromatography on silicagel, deactivated with 0.5% ammonia, with pentane/ether (4:1), there are obtained 10.6 g (76% based on 3-methyl-1-butanol-p-toluenesulphonate employed) of pure (R)-3,7-dimethyl-1-octanol. B.p. 58°-59°/0.05 Torr; [α]D20 = +4.0 (c = 1.03, CHCl3).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]([NH:16][NH2:17])=O)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>C(O)CCC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]2[N:16]([C:14]([C:11]3([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH2:13][CH2:12]3)=[N:20][N:21]=2)[N:17]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NNC(=O)C1(c2ccc3ncccc3c2)CC1
Solvent: CCCCO
Product: Clc1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Temperature: 140 °C
Yield: 27 %

Procedure:
A sealed tube was charged with 1-(quinolin-6-yl)cyclopropanecarbohydrazide (513 mg, 2.26 mmol), 3,6-dichloro-pyridazine (437 mg, 2.93 mmol) and 5 mL of n-butanol. The mixture was heated at 140° C. for 12 h. After cooling, solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound (196 mg, 41%). LCMS (method A): [MH]+=322, tR=4.38 min.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1)C1C=CC=CC=1.C(N(CC)CC)C.C(OC([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=O)(C)(C)C.[Na]>C(Cl)Cl>[N:30]1([CH:11]2[CH2:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C1CNCC(N2CCNCC2)C1
Temperature: 50 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
1-Benzyl-3-piperidone hydrochloride (700 mg, 2.7 mmol), triethylamine (270 mg, 2.7 mmol) and 1-(tert-butoxycarbonyl)-piperizine (500 mg, 2.7 mmol) in DCM, was stirred at rt for 1 h, then heated to 50° C. for 40 min. Sodium triacetoxyborahydride (1.12 g, 5.3 mmol) was added and the reaction mixture allowed to cool, with stirring, over 12 h then concentrated to dryness in vacuo. The residue was partioned between DCM/water, the organics dried (MgSO4) and concentrated to dryness in vacuo. The resulting residue in EtOH (10 ml) was hydrogenated with 10% w/w palladium on carbon (200 mg) under hydrogen at rt for 18 h. The reaction was filtered through celite and concentrated to dryness in vacuo to give 3-piperazine-1-yl-piperidine as a pale yellow gum (700 mg, 2.6 mmol, 97%). 8H (CDCl3, 300K) 3.43-3.37 (4H, m br), 3.21 (1H, d br, J=11.6 Hz), 3.01 (1H, d br, J=12.2 Hz), 2.59-2.47 (6H, m br), 2.45-2.38 (1H, m), 1.99-1.92 (1H, m br), 1.82-1.75 (1H, m), 1.58-1.48 (1H, m), 1.45 (9H, s), 1.42-1.33 (1H, m). m/z (ES+, 70V) 270.3 (MH+).