Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]3)[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1.[OH-].[Na+].O>C(O)C>[F:28][C:2]([F:1])([F:27])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(OCC(F)(F)F)c3)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn(Cc2nc(-c3cccc(OCC(F)(F)F)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To a solution (2 mL) of the compound (24 mg, 0.058 mmol) obtained in Example 38d in ethanol was added 2N aqueous sodium hydroxide solution (0.12 ml, 0.24 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (11 mg, 49%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][CH3:20])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][N:19]([CH3:20])[C:7]([C:4]2[S:5][CH:6]=[C:2]([Br:1])[CH:3]=2)=[O:9])=[CH:15][CH:16]=1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: CNCCc1ccc(F)cc1
Product: CN(CCc1ccc(F)cc1)C(=O)c1cc(Br)cs1

Procedure:
From 4-bromo-thiophene-2-carboxylic acid and 1.47 g of [2-(4-fluorophenyl)-ethyl]-methyl-amine (the compound of Preparation Example 14) (1.98 g), a colorless solid (2.53 g) was obtained, in the same way as Preparation Example 118-b).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH:13]=[CH:17][CH:16]=[CH:15]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CC(C)c1ccc(N)cc1
Solvent: CC(=O)O
Product: CC(C)c1ccc(-n2cccc2)cc1
Yield: 99 %

Procedure:
Glacial acetic acid (100 ml) was added to a mixture of 4-isopropylaniline (10 ml, 72.4 mmol) and 2,5-dimethoxytetrahydrofuran (9.6 ml, 72.4 mmol) and the resulting mixture was refluxed for 1.5 h. The reaction mixture was allowed to cool and acetic acid was removed under reduced pressure. The resulting brown syrup was dissolved in ethyl acetate (200 ml) and washed with water (2×200 ml). The organic layer was dried over magnesium sulfate and filtered. Removal of the solvent gave 1-(4′-isopropylphenyl)pyrrole (13.28 g, 99% yield) as a brown syrup.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[C:5]([CH:9]([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH3:10])=[N:4][N:3]=1.[OH-].[Na+]>O=P(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]2=[C:9]([CH3:10])[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:4]2[N:3]=1
Reactant: CC(NC(=O)c1cccc(C(F)(F)F)c1)c1nnc(N)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Temperature: 110 °C
Yield: 21.8 %

Procedure:
Crude N-[1-(3-amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)ethyl]-3-(trifluoromethyl)benzamide (Intermediate 42) (8.34 g, 25.5 mmol) was suspended in POCl3 (30 mL) and heated in a sealed tube at 110° C. for 2h. After the reaction had cooled to rt, the solution was carefully poured onto ice, neutralized with NaOH(aq) and extracted into EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated. Purification of the residue by chromatography afforded 2-amino-5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-4(3H-one (1.63 g) as a pale yellow solid. 1H NMR (DMSO-d6): δ10.91 (s, 1H), 8.75-8.71 (m, 1H), 8.66 (s, 1H), 7.77-7.68 (m, 2H), 6.25 (bs, 2H), 2.48 (s, 3H). MS m/z 308 (M−1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=O)[CH3:17])[C:11]=3[OH:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:20]([C:22]([C:24]1[S:28][C:27]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)=[O:30])=[CH:26][CH:25]=1)=[O:23])[NH2:21]>CS(C)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=[N:21][NH:20][C:22]([C:24]4[S:28][C:27]([C:29]([NH:31][CH2:32][C:33]5[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=5)=[O:30])=[CH:26][CH:25]=4)=[O:23])[CH3:17])[C:11]=3[OH:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Reactant: NNC(=O)c1ccc(C(=O)NCc2ccncc2)s1
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2ccncc2)s1)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Yield: 73.1 %

Procedure:
1-[5-(2,3-Dihydro-1H-inden-5-yl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (30 mg, 0.117 mmol) and 5-(hydrazinecarbonyl)-N-(pyridine-4-ylmethyl)thiophene-2-carboxamide (32 mg, 0.117 mmol, synthesized in accordance with WO2007010954) in dimethyl sulfoxide (0.9 mL) was heated at 100° C. for 3 days with stirring. After the reaction, the reaction solution was concentrated under reduced pressure. After addition of chloroform and ethyl acetate, the resulting crystals were collected by filtration and dried under reduced pressure to obtain the desired product (44 mg, 73% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[C:24]([C:31]([OH:33])=O)[CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:39][C:31]([C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:23]=2[N:22]=[C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:16]=2)[CH:30]=[CH:29]3)=[O:33])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(-c3ccc4cccc(C(=O)O)c4n3)c2)CC1
Product: O=C(NC1CCCC1)c1cccc2ccc(-c3cccc(OC4CCNCC4)c3)nc12

Procedure:
The same general amide coupling procedure outlined above was employed using 2-(3-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)phenyl)quinoline-8-carboxylic acid and cyclopentylamine. Purification by column chromatography (1:5 ethyl acetate/pentane), followed by treatment with 4N HCl/MeOH and concentration produced the product as a yellow solid. MS (ESI) calcd for C26H29N3O2 (m/z): 415.23. found: 416 [M+1].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:26]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:35](=[O:36])[C:34]2[CH:33]=[CH:32][C:31]([O:30][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:39][CH:38]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)N[C@@H]2CCc3cccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.41 mmol) and triethylamine (95 μL, 0.69 mmol) in methylene chloride (20 mL) was added dropwise 4-butoxybenzoyl chloride (103 mg, 0.48 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent. Yield: 150 mg (75%) of the title compound as white crystals: mp 190-191° C.; [α]21D -49° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 421 (0.6, M+).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[NH:7])=[CH:4][CH:3]=1.C([Li])CCC.Cl[P:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][P:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:16]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(=N)Nc2ccccc2)cc1
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(c2ccccc2)c2ccccc2)Nc2ccccc2)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.05 g of 4-methyl-N1-phenylbenzamidine (Amidine IX, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, the residue was treated with 20 mL of pentane. The yellow solid was collected and dried (1.85 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH2:32][CH3:33]>>[CH2:32]([N:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:15][CH:16]=1)=[O:21])[CH3:33]
Reactant: Cc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Reactant: CCI
Product: CCN(Cc1ccc(C)cc1)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-Ethyl-2′-methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-N-(4-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.88,(1H, d), 7.76,(1H, s), 7.56-7.45,(5H, m), 7.25-7.13,(4H,m), 4.66-4.48,(2H, m), 3.37-3.18,(2H, m), 2.55,(3H, s), 2.31-2.28,(6H, m), 1.05,(3H, b). LCMS; retention time 3.70 min, MH+ 426.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[CH:3]1[CH2:4][C@H:5]([CH3:23])[C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:22].N1C=CC=CC=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:30]([O:22][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:15]([CH2:14][CH2:13][C@:11]12[CH3:12])[C@:16]1([CH3:21])[CH:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]1)[CH2:4][C@@H:5]3[CH3:23])(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@H]1CC2N(C)C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CC2N(C)C(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](OC(=O)C(C)(C)C)CC[C@H]3[C@H]12
Reaction time: 24 h

Procedure:
To a solution of 70 from Example 69, being 60.2 mg in 4 ml methylene chloride and 200 ml pyridine was added 15 mg DMAP (4-dimethylaminopyridine) followed by 68.66 mg pivaloyl chloride, i.e., trimethyl acetyl chloride. After stirring for 24 hours, the reaction mixture was diluted with ethyl acetate, washed with water, then aqueous sodium carbonate and brine. The organic layer was dried, concentrated to a residue, which was purified by preparative chromatography on silica gel using 3:1 chloroform/acetone as eluant to yield pure title compound 71 Proton NMR confirmed the assigned structure.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6](=[O:12])[C:5]2[CH:13]=[C:14]([CH3:16])[S:15][C:4]1=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:27][CH3:28])(=O)=O>>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:27][CH3:28])=[O:10])[C:6](=[O:12])[C:5]2[CH:13]=[C:14]([CH3:16])[S:15][C:4]1=2)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(C)sc21
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cn(CC)c2sc(C)cc2c1=O
Temperature: 100 °C

Procedure:
A suspension of 0.237 part of 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylic acid and 0.83 part of pulverized potassium carbonate in 6 parts by volume of dry dimethylformmide is stirred under heating at 100°C for 1 hour. To the mixture is then added 0.3 part by volume of diethyl sulfate. The mixture is stirred under heating at 100°C for 1 hour and filtered to remove insoluble material. The filtrate is concentrated to dryness under reduced pressure and the residue is extracted with chloroform. Evaporation of the solvent from the extract gives ethyl 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylate as crystals. Recrystallization from ethyl acetate yields colorless plates melting at 140°-142°C.
Reaction SMILES: [I:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[I:1][C:2]1[N:3]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
The starting material can be prepared in the following manner. A mixture of 2-iodo-4-hydroxymethyl-1-(triphenylmethyl)imidazole (3.264 g, 7.0 mmol) and manganese dioxide (12.17 g, 140 mmol) in methylene chloride (100 mL) was stirred overnight at room temperature and filtered though Celite. The filtrate was concentrated in vacuo to give 2-iodo-4-formyl-1-triphenylmethylimidazole as a white foamy solid (3.05 g, 94%), mp 173-75° C. which was sufficiently pure to be used in the next step without further purification. 1H NMR (CDCl3) δ 9.77 (s, 1H), 7.55 (s, 1H), 7.38-7.30 (m, 9H), 7.16-7.09 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:8]=1[CH3:9]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:5][C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:8]=1[CH3:9])=[O:1]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C=O
Yield: 50.3 %

Procedure:
To a solution of 5-hydroxymethyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (0.3 g) in ethyl acetate (10 ml) was added activated manganese dioxide (2.4 g) and the mixture was refluxed for 2 hours under stirring vigorously. After allowing to stand to room temperature, manganese dioxide was filtered off. The filtrate was evaporated in vacuo, and the residual precipitate was recrystallized from diethyl ether to give 5-formyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (0.15 g).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:9][C:10]#[N:11])(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C>C1COCC1>[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:9][CH2:10][NH2:11])[CH3:2]
Reactant: CC(=O)N1CCC[C@H]1CC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN1CCC[C@H]1CCN
Temperature: 0 °C
Yield: 64.2 %

Procedure:
((S)-1-Acetylpyrrolidin-2-yl)acetonitrile (Intermediate 137, 1.0 g) was added portionwise to a stirred, cooled solution of lithium aluminium hydride (0.36 g) in THF (30 mL) under an atmosphere of nitrogen while maintaining the temperature at 0° C. The mixture was allowed to warm to room temperature then heated at reflux for 2 hours. After cooling, ethanol (4 mL) was added dropwise and the resultant solid was filtered off. The filtrate was evaporated to dryness to give 2((S)-1-ethylpyrrolidin-2-yl)ethylamine (0.6 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:24][OH:25]>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:24][OH:25])[CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(=NO)c1ncc(Cl)cc1Cl
Yield: 79.3 %

Procedure:
To 0.32 g of N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]phthalimide in 15 ml of ethanol, 0.66 g of hydroxylamine hydrochloride was added and refluxed with heating for 4 hours with stirring. After completion of the reaction, the solvent was evaporated under reduced pressure, and the reaction mixture was mixed with 30 ml of water and 50 ml of ethyl acetate, and the resulting organic layer was collected. The organic layer was washed with water (30 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was washed with 10 ml of hexane to obtain 265 mg of the desired product as yellow crystals.
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].SCCO>C1(C)C=CC=CC=1>[CH2:1]([Sn:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Agent: OCCS
Solvent: Cc1ccccc1
Product: CCCC[Sn]CCCC
Yield: 154.5 %

Procedure:
Following the procedure of Example 1, 24.9 g (0.10 mole) dibutyltin oxide was reacted with 15.6 g (0.20 mole) 2-mercaptoethanol in toluene to give 36 g of dibutyltin-bis-(2-hydroxyethylmercaptide), a light yellow liquid.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=3[CH3:19])[CH2:28][CH2:29]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(C(C)(C)C)n3)CC2)c(C)c1

Procedure:
79 mg (87%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(2,4-dimethylphenyl)piperazine (36 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:5][C:4]=1[CH3:12])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Product: Cc1cc(C(C)(C)C)cc(C)c1[N+](=O)[O-]

Procedure:
contacting the 1,3-dimethyl-5-tertiary-butylbenzene with nitric acid in the presence of a mercuric acetate catalyst at a temperature of from about 0° C. to about 100° C. to form 2-nitro-1,3-dimethyl-5-tertiary-butylbenzene;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12]C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[K+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(=O)Oc1ccc(OC(C)C)c(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc(O)cc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of acetic acid 3-bromo-4-isopropoxy-phenyl ester (1.44 g, 4.98 mmol, 1.00 eq.) in MeOH (20 mL), a solution of KOH (303 mg, 5.39 mmol, 1.08 eq.) in H2O (3 mL) was added. The resulting mixture was stirred at r.t. for 45 min. Water (5 mL) was added and the mixture was acidified with 2N aq. HCl soln. then extracted with DCM (3×). The comb. org. layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a brown oil. The product was used without purification.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)(C)C.[CH2:33]([O:35][C:36](=[O:45])[C:37]#[C:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:34].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:33]([O:35][C:36](=[O:45])[CH:37]=[C:38]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:34]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Reactant: CCOC(=O)C#Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Reaction time: 24 h
Yield: 64 %

Procedure:
A mixture of 2-[3-(1-triisopropylsilanyl-1H-indol-5-yl)-propyl]-[1,8]naphthyridine (125 mg, 0.282 mmol), phenyl-propynoic acid ethyl ester (98.0 mg, 0.563 mmol), and tetrabutylammonium fluoride [1.0 M] 0.85 mL, 0.85 mmol) in THF (3 mL) was stirred for 24 h. After removal of the solvent, the crude reaction mixture was purified via column chromatography on silica gel with ethyl acetate/hexane (2:1) to give the title product as an E/Z isomeric mixture in 64% yield. Mass Spectrum (LCMS, ESI) calculated for C30H28N3O2 462.2 (M+H); found 462.3.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C.O>[Br:20][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:12])[C:3]2([CH2:1][CH3:2])[CH2:13][CH3:14]
Reactant: CCC1(CC)C(=O)Nc2ccccc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1(CC)C(=O)Nc2ccc(Br)cc21

Procedure:
A solution of 3,3-diethylindol-2-one (8 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in acetic acid (100 ml) was treated with bromine (6.4 g, 40 mmol). After 30 min. the mixture was diluted with water and extracted with EtOAc (2×); the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, then brine, dried (MgSO4) and evaporated to afford the crude product (7.6 g, 75%). A sample was recrystallized from EtOAc/hexane to obtain 5-bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one, m.p. 164–165° C.; 1H-NMR (DMSO-d6) δ 10.45 (s, 1H), 7.41–7.40 (d, 1H, J=2.2 Hz), 7.34–7.31 (m, 1H), 6.78–6.76 (d, 1H, J=8.2 Hz), 1.78–1.65 (m, 4H), 0.50–0.46 (m, 6H); MS (−ESI) m/z 266/268 (M−H).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:12][C@H:11]1[C@H:13]([O:22][CH2:23][O:24][CH3:25])[CH2:14][C:15](=[CH2:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C@H:10]1[O:12][C@H:11]1[C@H:13]([O:22][CH2:23][O:24][CH3:25])[CH2:14][C:15](=[CH2:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=C(C[C@@H](OCOC)[C@@H]1O[C@@H]1CO[Si](C)(C)C(C)(C)C)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C=C(C[C@@H](OCOC)[C@@H]1O[C@@H]1CO)C(=O)OCC
Reaction time: 2 h
Yield: 88 %

Procedure:
To a well stirred solution of silyl ether 11 (1.1 g, 2.94 mmol) was added 1 M solution of tetrabutylammonium fluoride (6.2 mL, 5.87 mmol) at 0° C. The reaction mixture was stirred at this temperature for 2 h after which the solvent was removed under reduced pressure and the residue was subjected to column chromatography with petroleum ether/ethyl acetate (5:5 v/v) to afford free alcohol 12 oily liquid.