Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>ClCCl.O1CCCC1.CO.C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)=[CH:12][CH:11]=2)[CH:9]=1)=[O:4]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)c1cnn(-c2ccc(C=O)cc2)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cnn(-c2ccc(CN3CCN(c4ccccc4)CC3)cc2)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 47.7 %

Procedure:
A mixture of 1-(4-formylphenyl)-1H-pyrazol-4-carboxylic acid methyl ester (5.0 g), 1-phenyl piperazine (4.21 g), acetic acid (3.7 ml), sodium cyanoborohydride (1.55 g), methanol (110 ml), tetrahydrofuran (75 ml) and dichloromethane (20 ml) was stirred for 15 minutes at 0° C. and for 14 hours at ambient temperature. The reaction mixture was poured into saturated NaHCO3 aqueous solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (1:1 hexane-ethyl acetate elution) and recrystallized from diisopropyl ether and acetone to give 1-[4-(4-phenylpiperazin-1-yl-methyl)phenyl]-1H-pyrazol-4-carboxylic acid methyl ester (3.90 g).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:32][C:22]1[CH:21]=[C:20]([O:19][CH2:18]/[CH:17]=[C:16](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)\[C:13]2[CH:14]=[CH:15][C:10]([C:3]#[C:2][CH2:1][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[CH:11][CH:12]=2)[CH:31]=[CH:30][C:23]=1[O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: C#CCN1CCCC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(I)cc2)c2ccc3oc(C)cc3c2)cc1C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCCC3)cc2)c2ccc3oc(C)cc3c2)cc1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
N-Propargylpyrrolidine (250 mg, 2.29 mmol) was added under nitrogen atmosphere to a degassed solution of the above ester (400 mg, 0.68 mmol) in a mixture of tetrahydrofuran (6 mL) and triethylamine (6 mL) The solution was cooled, tetrakis(triphenylphosphine)-palladium (71 mg, 0.061 mmol) and copper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixture was stirred at ambient temperature for 96 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[2-methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]allyloxy]phenoxy]acetate.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][N:7]1[C:11](I)=[C:10]([C:13]#[N:14])[N:9]=[CH:8]1.C([Sn](CCCC)(CCCC)[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)CCC>C(#N)C.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][N:7]1[C:11]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[C:10]([C:13]#[N:14])[N:9]=[CH:8]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: N#Cc1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1I
Agent: Cl[Pd]Cl
Solvent: N#Cc1ccccc1
Solvent: CC#N
Product: N#Cc1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Reaction time: 72 h

Procedure:
In a pressure vessel dissolve 1-(3,5-Bis-trifluoromethyl-benzyl)-5-iodo-1H-imidazole-4-carbonitrile (0.52 g, 1.2 mmol) in acetonitrile. Add 3-tributylstannanyl-pyridine (0.64 g, 1.7 mmol) and bis(benzonitrile)dichloropalladium(II) (22 mg, 0.06 mmol), and stir at 100° C. After 72 h, quench with sat. aq. NaHCO3, and extract with ether. Wash the organic layer with brine, dry over MgSO4, filter, and concentrate. Purify by radial chromatography on silica gel to give the title compound: MS (ES) 397.2 (M+1); 1H NMR (300 MHz, CDCl3) δ 8.75 (d, J=4.6 Hz, 1H), 8.60 (ap d, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.66 (m, 1H), 7.44 (m, 1H), 7.36 (s, 2H), 5.30 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[C:13]([O:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:14][CH:15]=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:44][CH:45]1[CH2:48][O:47][CH2:46]1>>[O:47]1[CH2:48][CH:45]([NH:44][C:2]2[CH:7]=[C:6]([C:8]3[C:12]4[C:13]([O:17][CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[N:14][CH:15]=[CH:16][C:11]=4[NH:10][N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:46]1
Reactant: Clc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccnc(OC4CCOCC4)c23)ccn1
Reactant: NC1COC1
Agent: Cl
Product: c1cc(-c2n[nH]c3ccnc(OC4CCOCC4)c23)cc(NC2COC2)n1
Yield: 19 %

Procedure:
Prepared according to the procedure described in Example 111, by reacting 3-(2-chloropyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine with 3-aminooxetane hydrochloride for 70 minutes in Step 1 to give the title compound (13.3 mg, 19% over two steps). LC-MS (Method G): m/z=368.1 [M+H]+; 2.93 min. 1H-NMR (400 MHz, DMSO): δ 13.68 (s, 1H), 8.24 (d, J=7.1, 1H), 7.96-7.91 (m, 1H), 7.63 (s, 1H), 7.54 (d, J=7.1, 1H), 7.24 (d, J=5.4, 1H), 5.55-5.40 (m, 2H), 3.91-3.81 (m, 2H), 3.68-3.46 (m, 5H), 2.18-1.99 (m, 2H), 1.91-1.78 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([NH:14][CH3:15])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[S:38](Cl)(=[O:40])=[O:39].CC(O)=O>C(#N)C>[CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([N:14]([CH3:15])[S:38]([C:34]4[S:33][CH:37]=[CH:36][CH:35]=4)(=[O:40])=[O:39])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc(NC)cnc3n2CC2CC2)cc1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1ccc(Cc2nc3cc(N(C)S(=O)(=O)c4cccs4)cnc3n2CC2CC2)cc1
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-6-amine (250.0 mg, 0.74 mmol) in acetonitrile (5 mL) at room temperature was added triethylamine (207 mL, 1.49 mmol) followed by 2-thiophenesulfonyl chloride (176 μL, 0.96 mmol). The mixture was stirred overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved into EtOAc (10 ml) and Na2CO3 saturated aqueous solution (10 mL). The phases were separated and the aqueous phase was back-extracted with additional EtOAc (10 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using preparative HPLC (C-18 column, 20 to 80% [0.1% AcOH in AcCN solution] in 0.1% AcOH aqueous solution) to provide 72 mg of the AcOH salt of the title compound N-[3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-3H-imidazo[4,5-b]pyridin-6-yl]-N-methyl-2-thiophenesulfonamide (18% yield from 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-6-amine). 1H-NMR (400 MHz, d3-MeOD): δ 0.37 (m, 2H), 0.43 (m, 2H), 1.10 (m, 1H), 1.35 (t, J=7.0 Hz, 3H), 3.32 (s, 3H), 3.99 (t, J=7.0 Hz, 2H), 4.10 (d, J=7.2 Hz, 2H), 4.32 (s, 2H), 6.86 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 7.20 (m, 1H), 7.44 (d, J=5.3 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.85 (d, J=5.1 Hz, 1H), 8.15 (d, J=2.3 Hz, 1H). MS (ESI) (M+H)+: 483.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7](OC)=[O:8].CC(C[AlH]CC(C)C)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=[CH:12][N:13]=1
Reactant: COC(=O)c1ccnc(OC(F)F)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1ccnc(OC(F)F)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of methyl 2-(difluoromethoxy)isonicotinate (2.690 g; 13.24 mmol) in anh. toluene (60 ml) was treated dropwise with a solution of 1 M DIBAH in toluene (40.00 ml; 40.00 mmol), and the resulting mixture was further stirred at −78° C., under nitrogen, for 5 min., and then at 0° C. for 1.5 h. The obtained mixture was treated successively with water (55 ml), 1 M aq. NaOH (12 ml), and aq. sat. NaHCO3 (100 ml). The separated aq. layer was further extracted with Et2O (2×100 ml). The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording (2-(difluoromethoxy)pyridin-4-yl)methanol as a yellow oil. LC-MS (conditions A): tR=0.49 min.; [M+H]+: 176.37 g/mol.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[C:22]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30])(=[O:24])[CH3:23]>>[C:22]([O:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:28]([C:29](=[O:30])[NH:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[CH2:8][CH2:7]2)=[O:5])[CH:27]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Product: CC(=O)Oc1cccc(C(=O)N[C@@H](C(=O)N2CCC(c3ccc(Cl)cc3)CC2)C(C)C)c1
Yield: 50 %

Procedure:
(R)-2-Amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride was coupled with 3-acetoxy benzoic acid in a similar manner as described for the preparation of Example 75 to give (R)-3-((1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamoyl)phenyl acetate (115 mg, 50% yield). MS found: 457.3 (M+).
Reaction SMILES: [CH3:1][C:2]1[O:16][C:5]2=[CH:6][C:7]3[CH2:8][C:9](=[O:15])[N:10]([CH2:13][CH3:14])[C:11]=3[CH:12]=[C:4]2[CH:3]=1.[C:17](=O)([O:21]CC)[O:18][CH2:19][CH3:20]>>[CH3:1][C:2]1[O:16][C:5]2=[CH:6][C:7]3[CH:8]([C:17]([O:18][CH2:19][CH3:20])=[O:21])[C:9](=[O:15])[N:10]([CH2:13][CH3:14])[C:11]=3[CH:12]=[C:4]2[CH:3]=1
Reactant: CCN1C(=O)Cc2cc3oc(C)cc3cc21
Reactant: CCOC(=O)OCC
Product: CCOC(=O)C1C(=O)N(CC)c2cc3cc(C)oc3cc21
Yield: 85 %

Procedure:
Starting with 1.5 g. (6.98 mmoles) of 2-methyl-5-ethyl-6-oxo-6,7-dihydro-furo[2,3-f]indole and 2.47 g. (20.9 mmoles) of diethyl carbonate, and following the procedure of Preparation C, 1.7 g. (85% yield) of the desired intermediate was obtained, m.p. 82°-90° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=O.[BH4-].[Na+].CO.[ClH:15]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH2:7][Cl:15]
Reactant: Cl
Reactant: Cc1ccc(Br)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Br)cc1CCl
Temperature: 2.5 °C
Reaction time: 5 h

Procedure:
To a mixture of 80.9 g (0.406 mol) of 5-bromo-2-methylbenzaldehyde and 7.80 g (0.206 mol) of NaBH4 in 300 ml of THF 200 ml of methanol was added dropwise by vigorous stirring for 5 h at 0-5° C. This mixture was stirred overnight at room temperature and then added to 1 liter of cold water. The resulting mixture was acidified by 2 M HCl to pH˜1, and the formed (5-bromo-2-methylphenyl)methanol was extracted with 3×250 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. To the residue dissolved in 450 ml of dichloromethane 37 ml of SOCl2 was added dropwise at +5° C. The resulting solution was stirred overnight at room temperature, evaporated to dryness, the residue was dissolved in 500 ml CH2Cl2, and the obtained solution was washed with 500 ml of water. The organic layer was separated, the aqueous layer was additionally extracted with 2×100 ml of dichloromethane. The combined organic extract was passed through a short pad of silica gel 60 (40-63 um), the filtrate was evaporated to dryness, and the residue was dried in vacuum to yield 5-bromo-2-methylbenzyl chloride as a slightly yellowish liquid which was further used without an additional purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:38])[CH:9]([CH3:37])[C:10]([NH:12][CH:13]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:14]([N:16]1[CH:23]2[CH:19]([N:20]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:21][CH:22]2[C:24]([OH:26])=O)[CH2:18][CH2:17]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C@H:72]1([NH2:82])[C:81]2[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=2)[CH2:75][CH2:74][CH2:73]1>CN1C(=O)CCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[N:8]([CH:9]([C:10](=[O:11])[NH:12][CH:13]([CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:14]([N:16]1[CH2:17][CH2:18][CH:19]2[N:20]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:21][CH:22]([C:24](=[O:26])[NH:82][CH:72]3[C:81]4[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=4)[CH2:75][CH2:74][CH2:73]3)[CH:23]12)=[O:15])[CH3:37])[CH3:38])([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)O)CN2S(C)(=O)=O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2S(C)(=O)=O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of crude 21 (106 mg, 0.19 mmol) in NMP (5 mL) was cooled to 0° C. and treated with HATU (73 mg, 0.19 mmol) and DIPEA (0.1 mL, 0.57 mmol). After 10 min, (1R)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (0.05 mL, 0.35 mmol) in NMP (3 mL) was added. The reaction was allowed to warm to ambient temperature. After 16 h, the solution was diluted with EtOAc, washed successively with 1M HCl, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 22 which was used without further purification. Mass spectrum, m/z [688.5] (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([O:11]C)=O)[CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:18][CH2:19][NH:20][CH3:21].[H-].[Na+].COCCOCCOC>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:18][CH2:19][N:20]([CH3:21])[C:9](=[O:11])/[CH:8]=[CH:7]/[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: COC(=O)/C=C/c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: COc1ccc(CCN(C)C(=O)/C=C/c2cccnc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.6 %

Procedure:
A mixture of methyl trans-3-(3-pyridyl)acrylate (326 mg), 3,4-dimethoxy-N-methylphenethylamine (390 mg), 60% sodium hydride (80 mg) and diethylene glycol dimethyl ether (2 ml) was stirred at room temperature for 24 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. After the solvent was distilled out under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=50:1) and recrystallized to yield the titled compound (278 mg, 43%).
Reaction SMILES: C[Si]([CH2:5][C:6]([O-:8])=[O:7])(C)C.[CH3:9][CH:10]([CH3:12])[O-].[Al+3].[CH3:14][CH:15]([CH3:17])[O-].[CH3:18][CH:19]([CH3:21])[O-]>C1CCCCC1>[CH2:10]1[CH2:12][CH2:17][CH2:15][CH2:14][CH2:9]1.[CH:19]([O:8][C:6](=[O:7])[CH3:5])([CH3:21])[CH3:18]
Reactant: C[Si](C)(C)CC(=O)[O-]
Reactant: CC(C)[O-]
Agent: [Al+3]
Solvent: C1CCCCC1
Product: CC(=O)OC(C)C

Procedure:
In connection with the aluminosiloxane compound additive, the preparation thereof may be accomplished according to K. Folting, W. E. Streib, K. G. Caulton, O. Poncelet and L. G. Hubert-Pfalzgraf, Polyhedron, 10 (14), 1639-1646 (1991). A mixture of trimethylsilylacetate and cyclohexane may be added to aluminum isopropoxide in the desired ratio so as to provide the desired relation of Si:Al of 1:1, 2:1 or 3:1. The mixtures so formed are then subjected to azeotropic distillation so as to obtain cyclohexane/isopropylacetate, and the solution can then be concentrated and distilled so as to provide the desired additive. Azeotropic distillation may be carried out at a temperature of approximately 80° C. and for a time period of between about 8 to about 24 hours. Of course, the time and temperature of the procedure may be adjusted to particular conditions and ingredients. The resulting additive product may suitably be identified and confirmed to possess the desired structure through IR and 1H NMR spectroscopies.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:15]=3[CH:24]=2)=[CH:7][CH:6]=1)(=O)C.Cl>C(O)C>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:15]=3[CH:24]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(NC(C)=O)cc3)ccc2o1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc2cc(-c3ccc(N)cc3)ccc2o1
Reaction time: 8 h

Procedure:
A mixture of 3.0 g of 12B, 50 ml of 6 N hydrochloric acid and 50 ml of ethanol was stirred and refluxed for 5 hours. The solution was concentrated to about half its volume, the solid that formed was collected, and dissolved in chloroform containing some triethylamine. The solution was washed with water, dried (MgSO4) and filtered. The solvent was evaporated from the filtrate under reduced pressure. The residue was dry column chromatographed over silica gel, using a 1/9 v/v mixture of tetrahydrofuran and chloroform as eluent. The solvents were evaporated, the appropriate sections were combined and extracted with chloroform. The extract was filtered and the solvent was evaporated under reduced pressure. The residue was refluxed in petroleum ether for 8 hours. The mixture was filtered and the filtrate placed in a freezer overnight. The solid that formed was collected and dried to give ethyl 5-(4-aminophenyl)benzofuran-2-carboxylate (12C), mp: 95°-97° C.
Reaction SMILES: [OH-].[K+].[C:3](=[N:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:5])[CH3:4].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:6]=[C:3]([CH3:5])[CH3:4]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)=NNC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)=NN(Cc1ccccc1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 105.1 %

Procedure:
Powdered KOH (4.24 g, 75.48 mmol) and tetrabutylammonium hydrogen sulfate (1.97 g, 5.81 mmol) were added to a solution of tert-butyl 2-isopropylidenehydrazinecarboxylate (10 g, 58.05 mmol) in toluene (150 mL). The mixture was stirred vigorously and heated to 50° C. and 1-(bromomethyl)-2-fluorobenzene (13.17 g, 69.68 mmol) was added slowly. The temperature was increased to 80° C. and maintained for 3 h and cooled to room temperature. The mixture was washed with water until the pH of the aqueous wash was neutral. The organic layer was washed with brine and dried over MgSO4 and concentrated to give a yellow oil (17.11 g) used for the next step without further purification). LC-MS [M+H]+=280.9, RT=3.41 min.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH3:35][C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:37](=[O:38])[C:36]([CH3:41])([CH3:40])[CH3:35])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)C(C)(C)C)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure K using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 2,2-dimethylpropanoyl chloride as a colorless oil (88%). 1H NMR (CDCl3, 300 MHz) δ 7.72 (d, J=2.5 Hz, 1H), 7.43 (m, 4H), 7.15 (m, 4H), 7.06 (dd, J=8.7, 2.5 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 4.84 (s, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.75 (s, 6H), 1.61 (m, 2H), 1.36 (m, 2H), 1.07 (s, 9H), 0.94 (t, J=7.4 Hz, 3H). M+ (ESI): 524.2. HPLC, Rt: 5.85 min (Purity: 99.5
Reaction SMILES: O1[C:5]2[NH:6][CH2:7][C:8]3[N:9]([CH:11]=[CH:12][CH:13]=3)[CH2:10][C:4]=2C=C1.C(N(CC)CC)C.[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O>C(Cl)Cl.C(OCC)(=O)C>[CH:7]1[C:8]2[N:9]([CH:11]=[CH:12][CH:13]=2)[CH2:10][CH:4]=[CH:5][N:6]=1
Reactant: c1cc2n(c1)Cc1ccoc1NC2
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C1=CN=Cc2cccn2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 mmol of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine in 10 ml of methylene chloride under argon is added 1.5 mmol of triethylamine followed by ice bath cooling. A solution of 1.1 mmol of 4-nitrobenzoyl chloride in 5 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture is stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C(Cl)Cl.S(Cl)(Cl)=O.[NH4+:19].[OH-]>CCOC(C)=O>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([NH2:19])=[O:7])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(F)ncc1C(=O)O
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc(F)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
A round bottom flask was charged with 6-fluoro-4-methylnicotinic acid (1.13 g, 7.28 mmol, Frontier) and DCM (73 mL) to give a clear solution. Thionyl chloride (5.32 mL, 72.8 mmol) was added drop-wise and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in EtOAc (10 mL) and added drop-wise to a rapidly stirred mixture of EtOAc (40 mL) and concentrated aqueous NH4OH (36.9 ml, 947 mmol). The mixture was stirred for about 1 h, and the layers were separated. The aqueous layer was further extracted with EtOAc (50 mL) and the combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give 6-fluoro-4-methylnicotinamide (0.69 g, 61%) as white solid: LC/MS (Table 2, Method d) Rt=1.03 min; MS m/z 153 (M−H)−.