Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCNCC1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f1) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1([C:7]2[C:16]([F:17])=[C:15]3[C:10]([C:11](=[O:24])[C:12]([C:21]([OH:23])=[O:22])=[CH:13][N:14]3[CH:18]3[CH2:20][CH2:19]3)=[C:9]([CH3:25])[C:8]=2[F:26])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].Cl>[OH-].[Na+]>[C:27]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:16]([F:17])=[C:15]3[C:10]([C:11](=[O:24])[C:12]([C:21]([OH:23])=[O:22])=[CH:13][N:14]3[CH:18]3[CH2:19][CH2:20]3)=[C:9]([CH3:25])[C:8]=2[F:26])[CH2:2][CH2:3]1)(=[O:29])[CH3:28]
Reactant: Cc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCN(c2c(F)c(C)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1

Procedure:
To a solution of 7-(1-piperazinyl)-1-cyclopropyl-6,8-difluoro-5-methyl-1, 4-dihydro-4-oxoquinoline-3carboxylic acid (42 mg) in 5% sodium hydroxide (2 ml) is added acetic anhydride (0.1 ml) at room temperature. After the mixture is made acidic with dilute hydrochloric acid, the resultant is extracted with dichloromethane and the extract is dried over magnesium sulfate. After concentrating, the obtained residue is recrystallized from ethanol to give 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-6,8-difluoro-5-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (30 mg), as white powder, m.p. 217°-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=O)[CH2:32]Br)=[CH:29][CH:28]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:32]=[C:31]([C:30]3[CH:35]=[CH:36][C:27]([Cl:26])=[CH:28][CH:29]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccc(Cl)cc3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 82.5 °C
Yield: 54.9 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (30 mL), 4-chlorophenacyl bromide (1.05 g, 4.48 mmol) was added. After heating the reaction mixture at 80-85° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2,4-bis-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (545 mg, 55%) as a pale yellow solid: mp 169-171° C. Anal. Calc'd. for C22H16N2SO2Cl2: C, 59.60, H, 3.64, N, 6.32, S, 7.23. Found: C, 59.86, H, 3.80, N, 6.10, S, 7.27.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:20][CH2:21][CH:22]([CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH2:23][CH2:24]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CCN(CC2CCNCC2)CC1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(CN4CCCCC4)CC3)cc2n1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 1-(piperidin-4-ylmethyl)piperidine using standard reductive amination conditions. The resulting crude solid was triturated with methanol to give 2-chloro-4-morpholin-4-yl-6-(4-piperidin-1-ylmethyl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine, which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with methanol to give 330 as an off white solid (23% yield). NMR (CDCl3, 400 MHz), 1.27-1.31 (3H, m), 1.42-1.46 (2H, m), 1.50-1.56 (4H, m), 1.77 (2H, d, J=13.1), 2.09 (2H, t, J=11.2), 2.15 (2H, d, J=7.1), 2.30-2.35 (4H, m), 2.97 (2H, d, J=10.9), 3.82 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.21 (1H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=509
Reaction SMILES: C1(C([NH:9][CH2:10][CH:11]2[CH2:15][O:14][C:13](=[O:16])[C:12]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C)C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].CO>[OH:14][CH2:15][CH:11]1[CH2:10][NH:9][C:13](=[O:16])[C:12]1([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: CC(NCC1COC(=O)C1(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1NCC(CO)C1(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
To 750 ml. of methanol and 80.0 g. (0.22 mole) of 4-(1-phenylethylaminomethyl)-4,5-dihydro-3,3-diphenylfuran-2(3H)one was added 3.0 g. of palladium hydroxide catalyst and the mixture was shaken in three atmospheres of hydrogen at 70° C. for 18 hrs. Upon filtering starting material was found to be present; fresh catalyst was added to the solution which was shaken in three atmospheres of hydrogen at 70° C. for three more hours. After filtering the filtrate was concentrated in vacuo. The residue was dissolved in 100 ml. of ethyl acetate, and 100 ml. of isopropyl ether was added. A portion of the crystallized material was recrystallized from the same solvent system to give product melting at 145°-148° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Br[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].O>CN(C=O)C>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:7])=[CH:10][CH:11]=1)[CH3:21]
Reactant: CCOC(CBr)OCC
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COc1ccc(CO)cc1)OCC
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Caesium carbonate (39.4 g) was added to a solution of 4-hydroxymethyl-phenol (10 g) and 2-bromo-1,1-diethoxyethane (12.73 mL) in DMF (200 mL) and the resulting mixture stirred at 90° C. for 16 h. The reaction was poured into water (500 mL) and extracted with ethyl acetate (3×250 mL). The combined organic solutions were washed with water (250 mL) and brine (250 mL), then dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with an isohexane to diethyl ether gradient to give the subtitled compound as a yellow oil. Yield 9.5 g.
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:8]([N:15]([CH3:40])[CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:36]=[CH:35][C:23]([C:24]([N:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])=[CH:22][C:21]=1[N+:37]([O-])=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:37][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][C:20]=1[NH:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:40])[C:24]([N:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:31][CH:32]([CH3:33])[CH3:34])=[O:25]
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)Cc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)Cc2ccccc2)c(N)c1
Temperature: 20 °C
Yield: 78 %

Procedure:
Tin chloride dihydrate (3.58 g, 5 eq) is added to a solution of 4-({3-[benzyl(methyl)amino]propyl}amino)-N,N-diisobutyl-3-nitrobenzamide (1.44 g, prepared according to the procedure described for Example A1), in ethyl acetate (40 ml). The mixture is heated under reflux for 7 hours then cooled down to a temperature of approximately 20° C. and poured into a saturated solution of NaHCO3. After decanting and extracting with ethyl acetate, the organic phases are combined, washed with salt water, dried over sodium sulphate and concentrated under reduced pressure at 40° C. Purification by flash chromatography on silica gel (eluent dichloromethane/methanol 95:5) produces the compound in the form of a foam (1.06 g, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[CH:15]1[CH:16]=[CH:17][N:18]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[NH:21][CH2:20][C:19]=12.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:21]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[CH2:24][N:18]3[CH:17]=[CH:16][CH:15]=[C:19]3[CH2:20]2)=[O:13])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cnc(Cl)nc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
2-Chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl chloride (2.57 g) was added gradually to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine, (1.84 g) and diisopropylethylamine (1.37 g) in dichloromethane (50 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (3.22 g), m.p. 221-223° C.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34]CC)=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH3:3].[OH-].[Na+]>CO>[CH2:1]([S:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH3:3]
Reactant: CCCSc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 89 %

Procedure:
A solution of ethyl 2-propylthio-1-[[2′-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.25 g) in methanol (5 ml) containing 1N-NaOH (1.5 ml) was heated under reflux for 2 Hours. After removal of the solvent, the aqueous residue was adjusted to about pH 3-4 with 1N-HCl to give crystals. The crystals were collected by filtration. Recrystallization from ethyl acetate-hexane gave colorless crystals (0.21 g, 91%), m.p. 222-223° C. (decomp.).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH3:22][N:23]1[CH:27]2[CH2:28][C:29]([CH2:31][CH:24]1[CH2:25][CH2:26]2)=O>[Zn].Cl[Ti](Cl)(Cl)Cl.C1COCC1>[CH2:1]([N:3]([CH2:20][CH3:21])[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:29]2[CH2:28][CH:27]3[N:23]([CH3:22])[CH:24]([CH2:25][CH2:26]3)[CH2:31]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CN1C2CCC1CC(=O)C2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(=C2CC3CCC(C2)N3C)c2ccccc2)cc1
Yield: 31 %

Procedure:
A 100 mL dry THF slurry of 18.6 g (284 mmol) zinc powder and 15.6 mL (142 mmol) TiCl4 was stirred and allowed to reflux for 2 h under Ar. The reaction was allowed to cool then a 20 mL THF solution of 10 g (35.5 mmol) N,N-diethyl-4-benzoylbenzamide and 5 g (35.5 mmol) tropinone was added slowly. Once the addition was complete, the reaction was allowed to reflux for 3 h, cooled, then quenched with 10% K2CO3 in H2O. The resulting slurry was partitioned between water and Et2O. The organic fraction was washed with brine, dried over MgSO4, filtered, and concentrated. The remaining yellow oil was absorbed onto silica gel then purified by flash chromatography eluted with 10% 0.5 M NH3 in MeOH 90% CH2Cl2 to produce the product N,N-diethyl-4-[(8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenyl methyl] benzamide (4.27 g, 11 mmol). The HCl salt was precipitated from Et2O after the addition of ethereal HCl; mp 145-147° C. MS m/z (MH+) 389. 1H NMR 300 MHz (DMSO-d6) δ 7.2-7.45 (m, 9H), 3.8-3.9 (m, 2H), 3.15-3.25 (m, 2H), 2.75-2.95 (m, 4H), 2.65 (s, 3H), 2.25-2.4 (m, 2H), 2.15-2.25 (m, 2H), 1.75-1.9 (m, 2H), 0.95-1.2 (m, 6H). Anal calc C26H32N2O.HCl (3% H2O): C, 71.21; H, 7.93; N, 6.39. Found: C, 71.16; H, 7.95; N, 6.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:39][CH2:38][N:37]=[C:36]1[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][NH:48][CH3:49])=[CH:42][CH:41]=1.Cl>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([N:48]([CH2:47][CH2:46][C:43]2[CH:42]=[CH:41][C:40]([C:36]3[NH:37][CH2:38][CH2:39][N:35]=3)=[CH:45][CH:44]=2)[CH3:49])=[O:21])[CH:16]=1)[CH3:13])(=[O:10])=[O:11]
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CN(CCc1ccc(C2=NCCN2)cc1)C(=O)c1coc(CN(C)S(=O)(=O)c2ccc(Cl)cc2Cl)c1
Reaction time: 2 h

Procedure:
5-({[(2,4-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (34 mg, 0.08 mmol) was dissolved in DCE (1 mL) and CDI (26 mg, 0.16 mmol) was added. The reaction was stirred for 2 h. The activated acid solution in DCE was added to a vial containing 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine.HCl (43 mg, 0.16 mmol) and TEA (0.022 mL, 0.16 mmol). The reaction was stirred at ambient temperature for 18 h, then partitioned between saturated aqueous NaHCO3 (1 mL) and DCE (3×1 mL)). The organic layer was dried over MgSO4 and solvents were removed in vacuo. A portion of the crude product was purified by prep method A.
Reaction SMILES: [O-2].[Zn+2:2].[C:3]1([P:9](=[O:12])([OH:11])[OH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C.O>[C:3]1([P:9](=[O:10])([O-:12])[O-:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Zn+2:2]
Reactant: O=P(O)(O)c1ccccc1
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Solvent: CCO
Product: O=P([O-])([O-])c1ccccc1

Procedure:
A slurry in ethanol-water of zinc oxide was prepared by charging a 300 mL reaction flask equipped with a stirrer with 10.0 g (123 mmol) of zinc oxide (JIS grade 2, available from HakusuiTech Ltd.) and 90.0 g of 50% by mass ethanol-water. A solution of 1.9 g (12 mmol) of phenylphosphonic acid (Nissan Chemical Industries, Ltd.) dissolved in 11.0 g of 50% by mass ethanol-water was gradually added dropwise at room temperature (about 25° C.) to this slurry with stirring, thereby effecting a reaction for one hour. The slurry was then filtered and the wet cake was thoroughly rinsed with ethanol. The wet cake was subsequently dried at 120° C. for at least 12 hours, yielding a white powder of zinc phenylphosphonate-containing zinc oxide.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23]>>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]3=[O:23])=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCCN1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Product: O=C1CCCCN1Cc1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, brown oil, MS: m/e=291.2 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and piperidin-2-one.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][S:6]([O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16](O)[C:15]([CH3:20])([CH3:19])[C:14]=2[CH:21]=1)(=[O:8])=[O:7].N1C=CC=CC=1>C(Cl)Cl>[CH3:5][S:6]([O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16]([Cl:3])[C:15]([CH3:20])([CH3:19])[C:14]=2[CH:21]=1)(=[O:8])=[O:7]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1Cl
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of thionyl chloride (72 parts) in methylene chloride (270 parts) was added dropwise over a period of 30 minutes to a mixture of 2,3-dihydro-2-hydroxy-3,3-dimethyl-5-benzofuranyl methanesulphonate (130 parts) and pyridine (48 parts) in methylene chloride (1,300 parts) cooled in an ice bath. After stirring for three hours, the solution was washed twice with water, dried over sodium sulphate and the solvent distilled off under reduced pressure. The brown liquid which remained solidified to form 2-chloro-2,3-dihydro-3,3-dimethyl-5-benzofuranyl methanesulphonate (135 parts, 97% yield), melting point 59°-61° C, confirmed by its elemental analysis:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:10]([CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:12]3[S:11][CH:15]=[CH:14][CH:13]=3)=[CH:23][CH:22]=2)[C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[CH:18][CH:17]=1
Reactant: BrCc1ccc(-c2cccs2)cc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1csc(-c2ccc(CN(Cc3ccc(-c4cccs4)cc3)c3ccc4[nH]cnc4c3)cc2)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 4-(thiophen-2-yl)benzylbromide (557 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.09 g (18.9%); MS m/z: 478.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.70 (s, 4H); 6.73 (br s, 1H); 6.78 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 7.10-7.11 (m, 2H); 7.33-7.36 (m, 5H); 7.45 (dd, 2H); 7.49 (dd, 2H); 7.59-7.60 (m, 4H); 7.91 (s, 1H); 11.99 (br s, 1H); HPLC (METHOD [A]): rt 19.76 min (100%)
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](Cl)=[O:24]>N1C=CC=CC=1>[C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)=[O:24])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccccc1OC1CN(C(=O)c2ccccn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.1 %

Procedure:
To an ice-cold stirred solution of 3-(2-tert-butylphenoxy)azetidine (2.00 g, 9.74 mmol) in pyridine (20.0 ml) was added picolinoyl chloride hydrochloride (2.08 g, 11.7 mmol). After stirring for 16 h at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 10% aqueous Na2CO3 and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered by a pad of silica gel and concentrated under reduced pressure. The residue was purified with flash column chromatography (silica gel, 90:10 to 50:50 heptane/ethyl acetate) to provide a yellow solid. The solid was recrystallized from heptane/ethyl acetate to provide (3-(2-tert-butylphenoxy)azetidin-1-yl)(pyridin-2-yl)methanone (0.94 g, 31%) as a off-white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH2:21])[CH:15]=2)[CH:10]([CH3:23])[CH2:9]1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].B.C[N+]([O-:29])(C)C.[Cl-].[Na+]>COCCOCCOC.C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][OH:29])[CH:15]=2)[CH:10]([CH3:23])[CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=Cc1cccc(C2(C)CCN(C(=O)CCCCC)CC2C)c1
Reactant: C[N+](C)(C)[O-]
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: CCCCCCN1CCC(C)(c2cccc(CCO)c2)C(C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a stirred solution of 1-hexanoyl-3,4-dimethyl-4-(3-vinylphenyl)-piperidine (Preparation 8, 50 mg, 0.16 mmol) in bis(2-methoxyethyl)ether (1.5 mL) at 0° C. under nitrogen was added dropwise borane (1.0 M in tetrahydrofuran, 0.35 mL, 0.35 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then for 2 hours at room temperature. Trimethylamine N-oxide (48 mg, 0.64 mmol) was subsequently added and the reaction mixture heated at reflux under a nitrogen atmosphere for 2 hours. To the cooled reaction was then added diethyl ether (10 mL) and saturated aqueous sodium chloride solution (10 mL). The phases were separated and the aqueous layer was further extracted with diethyl ether (10 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1.5 g) eluted with ethyl acetate:hexane (50:50) to give the title compound as an oil (30 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12](Br)[C:13]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][C:30]=3[Cl:32])[C:13]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cnc2cc(CNC(=O)OC(C)(C)C)c(Br)cn12
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: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(CNC(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3Cl)cn12
Temperature: 150 °C
Yield: 79.8 %

Procedure:
In a sealed tube, a mixture of 6-bromo-7-(tert-butoxycarbonylamino-methyl)-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (1.4 g, 3.52 mmol), 2,4-dichloro-benzeneboronic acid (1.01 g, 5.29 mmol), Pd(PPh3)4 (203 mg, 0.18 mmol) and Na2CO3 (2.0 M solution in water, 6.2 mL) in DME (20 mL) was heated at 150° C. for 17 min under microwave irradiation. The reaction mixture was cooled to RT, diluted in AcOEt (400 mL) and washed with a 2.0 M aqueous Na2CO3 solution (2×200 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→2:8) to yield the title compound (1.39 g, 2.81 mmol, 80%). MS: 464 [M+1]+; HPLC: AtRet=2.31; TLC: RF 0.47 (hexane/DCM/TBME 1:1:2).