Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:16]=2[CH:17]=[CH:18][CH:19]=1)=O.O>O1CCCC1>[OH:8][CH2:9][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=1)(=[O:22])=[O:21]
Reactant: COC(=O)c1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CO)cccc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.4 %

Procedure:
2nd stage: The suspension of 1.9 g of lithium-aluminum hydride in 165 ml of tetrahydrofuran cooled to 0° C. is proportionately mixed with 16.45 g of 1-tosylindole-4-carboxylic-acid-methylester. After 30 minutes 1.9 ml of water, 1.9 ml of 15% soda lye and 5.7 ml of water are carefully and sequentially dripped in. After 20 minutes, the precipitate is filtered off, washed out with acetic-acid-ethylester and the filtrates are concentrated. The raw product (15.97 g) is crystallized out of diisopropylether. 13.15 g of 4-hydroxymethyl-1-tosylindole with a m.p. of 125°-126° C. is obtained.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[N:24]=[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[CH:21][N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[N:24]=[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[CH:21][N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2ncc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cnc(COc3cc(C(CC(=O)O)C4CC4)ncn3)nc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyrimidin-2-yl)methoxy)pyrimidin-4-yl)propanoate (111 mg) in THF (2.0 mL) and methanol (1.0 ml) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added 1N hydrochloric acid (2.0 mL) at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (105 mg) as a white amorphous solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]([CH3:18])([CH3:17])[CH2:3]1.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([O:10][N:5]2[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([NH:1][C:19](=[O:22])[CH:20]=[CH2:21])[CH2:3][C:4]2([CH3:18])[CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1

Procedure:
The procedure of Example 3 is repeated using 3.0 grams of 4-amino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine, 0.92 ml of acryloyl chloride and 1.8 ml of triethylamine in methylene chloride. The title compound is isolated as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>O>[C:23]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1)(=[O:25])[CH3:24]
Reactant: Nc1ccc(N2CCCCC2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(4-aminophenyl)piperidine dihydrochloride (2.49 g) and triethylamine (5.6 g) in dichloroform (30 ml) was ice-cooled and to this was added dropwise acetyl chloride (1.42 ml). After stirred at room temperature for 30 minutes, water (10 ml) was added to the mixture and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and then the residue was recrystallized from ethyl ether to obtain N(4-acetylaminophenyl)piperidine (2 g) as colorless crystals, m.p. 150°-152° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:14])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][CH2:16][C:17](Br)=[O:18].N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[Br:15][CH2:16][C:17]([NH:1][C:2]1[N:3]=[C:4]([CH3:14])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:18]
Reactant: Cc1nnc(-c2ccccc2)c(N)n1
Reactant: O=C(Br)CBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nnc(-c2ccccc2)c(NC(=O)CBr)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-3-methyl-6-phenyl-[1,2,4]triazine (Example 25, step b); 550 mg, 2.96 mmol) in dichloromethane was added bromoacetyl bromide (0.308 ml, 3.55 mmol), pyridine (0.357 ml, 4.44 mmol) and 4-dimethylaminopyridine (10 mg). The reaction mixture was stirred under nitrogen at room temperature for 2 h, then evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 40% ethyl acetate in hexanes) to yield 5-(bromoacetamido)-3-methyl-6-phenyl-[1,2,4]triazine (475 mg), m/z (ES+) 307/309 (M++H). To a solution of this product (470 mg, 1.53 mmol) in 1,2-dichloroethane was added triethylamine (0.235 ml, 1.68 mmol) and sodium iodide (10 mg), and the mixture was heated at reflux for 4 h. On cooling the title compound crystallised out of solution and was collected by filtration to yield 220 mg. δH (400 MHz; d6-DMSO) 2.80 (3H, s), 7.34 (1H, s), 7.56 (3H, m), 8.54 (2H, m), 11.35 (1H, bs); m/z (ES+) 227 (M++H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)[CH3:12]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(c1cc2cccnc2cc1F)c1nnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc2nnc(C(C)c3cc4cccnc4cc3F)n2n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (100 mg, 0.305 mmol), PdCl2(PPh3)2 (21.4 mg, 0.031 mmol) and tributyl(1-ethoxyvinyl)stannane (220 mg, 0.61 mmol) in 5 mL of 1,4-dioxane was heated at 90° C. for 5 h under nitrogen. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in HOAc and 3 N HCl, and stirred at rt for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/MeOH gradient to afford the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.87 (d, 1H), 8.16 (d, 1H), 8.03 (d, 1H), 7.80 (d, 1H), 7.73 (d, 2H), 34 (dd, 1H), 5.39 (q, 1H), 2.62 (s, 3H), 2.09 (d, 3H). LCMS (method A): [MH]+=336, tR=4.95 min.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>CC#N>[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:22][CH2:21]1
Reactant: NC1CCC(F)(F)CC1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)N1C(=O)C(NC2CCC(F)(F)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 68.4 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.155 g, 0.54 mmol), 4,4-difluorocyclohexylamine (0.11 g, 0.81 mmol) and TEA (0.082 g, 0.81 mmol) was dissolved in dry MeCN (3 ml) and heated in a microwave reactor at 130° C. for 10 mins. The reaction mixture was purified by silica gel column chromatography using a 85:15 mixture of hexane and EtOAc as eluant, to give the title compound (0.142 g, 68%); 1H NMR (500 MHz, CDCl3): δ 7.54-7.49 (m, 2H), 7.49-7.42 (m, 3H), 5.23-5.16 (m, 1H), 4.41 (hep, 1H), 3.10-3.00 (m, 1H), 1.97-1.86 (m, 2H), 1.77-1.68 (m, 2H), 1.57 (d, 6H), 1.49-1.37 (m, 2H), 1.37-1.21 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 158.6, 134.5, 131.8, 130.3, 129.0, 125.1, 123.9, 122.0, 120.0, 107.3, 49.9, 47.9, 32.1, 31.9, 31.7, 29.0, 28.9, 20.4; Mass Spectrum: M−H+ 385.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:15])C2C=CC=CC=2)=[N:6][CH:7]=1.Cl[C:17]1[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:15][C:17]2[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=2)=[N:6][CH:7]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OC(c1ccccc1)c1ccc(F)cn1
Product: [O-][n+]1ccc(OCc2ccc(F)cn2)cc1
Yield: 50.9 %

Procedure:
5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) and 4-chloropyridine-N-oxide (2.03 g, 15.7 mmol) were reacted according to Example 34 (step a) to provide the title compound (1.76 g, 50%) as a tan solid: 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 8.12 (d, J=7.7 Hz, 2H), 7.48-7.46 (m, 2H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N([C:16]1[NH:17][CH2:18][CH2:19][CH2:20][N:21]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>O>[NH:21]1[CH2:20][CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCCC(O)c1ccccc1
Reactant: O=[N+]([O-])NC1=NCCCN1
Solvent: O
Solvent: Cc1ccccc1C
Product: OC(CCNC1=NCCCN1)c1ccccc1

Procedure:
A mixture of 8 parts of α-(2-aminoethyl)benzylalcohol, 7.2 parts of 2-(nitramino)-1,4,5,6-tetrahydropyrimidine and 40 parts of xylene is stirred and refluxed for 48 hours with water-separator. Upon cooling the reaction mixture, the product is separated as an oil. The xylene is decanted and the oily product is triturated in diisopropylether. The solid product is filtered off and crystallized from acetone, yielding α-[2-(1,4,5,6-tetrahydro-2-pyrimidinylamino)ethyl]benzylalcohol; m.p. 130°-135°C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH:10]([F:12])[F:11])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][NH2:23])=[N:19][CH:20]=1>>[F:11][CH:10]([F:12])[O:9][C:4]1[CH:3]=[C:2]([NH:23][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:25])([F:13])[F:24])=[CH:20][N:19]=2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(I)cc1OC(F)F
Product: Cc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1OC(F)F

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (3-difluoromethoxy-4-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 347.1 [M+H]+) was prepared from 4-iodo-2-difluoromethoxy-toluene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:2]=[CH2:3].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.[OH-].[K+]>C(O)C>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)[CH:2]=[CH2:3]
Reactant: C=CCOCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOCCCCOc1ccc(C=O)cc1

Procedure:
4-allyloxybutyl-p-toluene sulfonate is reacted with p-hydroxybenzaldehyde in the presence of KOH and C2H5OH to form 4-(4-allyloxybutoxy)benzaldehyde which is reacted with malonic acid in the presence of pyridine to form p-(4-allyloxybutoxy)cinnamic acid. The acid is esterified with CH3OH and sulfuric acid to yield the methyl ester, namely methyl p-(4-allyloxybutoxy)cinnamic carboxylate. This methyl ester is then reacted with TosMIC in Et2O/DMSO in the presence of sodium hydride or other strong base to form the substituted pyrrole, represented as follows: ##STR7##
Reaction SMILES: [CH3:1][C:2]([CH3:22])([C@H:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[N:16]=[CH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[F:34][C:35]([F:41])([F:40])[CH2:36][C:37](O)=[O:38]>C1COCC1>[CH3:1][C:2]([CH3:22])([C@H:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[N:16]=[CH:15]2)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][NH:4][C:37](=[O:38])[CH2:36][C:35]([F:41])([F:40])[F:34]
Reactant: Cn1ncc2cc([C@H](c3ccccc3)C(C)(C)C#N)ccc21
Reactant: O=C(O)CC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1ncc2cc([C@H](c3ccccc3)C(C)(C)CNC(=O)CC(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
(b)(c) To a stirred solution of (S)-2,2-dimethyl-3-(1-methyl-1H-indazol-5-yl)-3-phenylpropanenitrile (54 mg, 0.193 mmol) in anhydrous THF (10 mL) was added 1.0M lithium aluminum hydride in diethyl ether (0.5 mL, 0.5 mmol) portionwise at RT under nitrogen. After stirring at RT for 3 hr, the mixture was carefully quenched with MeOH, poured into brine, extracted with ethyl acetate (2×100 mL), dried (MgSO4) and concentrated. The crude product was coupled with 3,3,3-trifluoropropanoic acid (29 mg, 0.226 mmol) using General Coupling Method A to give 40 mg (51% yield) of (S)—N-(2,2-dimethyl-3-(1-methyl-1H-indazol-5-yl)-3-phenylpropyl)-3,3,3-trifluoropropanamide. MS found: (M+H)+=404.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:51])([F:50])[C:17]1[CH:18]=[C:19]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][C@H:23]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1)=[O:21].[CH3:52][N:53]1[CH:57]=[C:56]([CH:58]=O)[CH:55]=[N:54]1>ClCCl>[F:51][C:16]([F:15])([F:50])[C:17]1[CH:18]=[C:19]([CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=1)[C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:58][C:56]2[CH:55]=[N:54][N:53]([CH3:52])[CH:57]=2)[CH2:24][C@H:23]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1)=[O:21]
Reactant: Cn1cc(C=O)cn1
Reactant: COCCOCOc1cc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCOCOc1cc(C[C@@H]2CN(Cc3cnn(C)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Sodium triacetoxyborohydride (0.3 g) was added in portions to a mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]-piperazine (0.5 g) and 1-methyl-1H-pyrazole-4-carboxaldehyde (0.12 g) in dichloromethane (10 ml) and the whole was stirred at room temperature for 1 hour. The mixture was washed with sodium hydrogen carbonate aqueous solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as an eluent. The fractions containing the objective compound were collected and evaporated in vacuo to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]-4-[(1-methyl-1H-pyrazol-4-yl)methyl]piperazine (0.54 g) as an oil.
Reaction SMILES: [CH:1]1([C:13]2[C:14](=[O:29])[NH:15][C:16](=[O:28])[C:17]=2[C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][N:4]3[CH:3]=[N:2]1)[CH:7]=[CH:8][CH:9]=2.[CH2:30]=O.[OH-].[Na+]>CN(C)C=O.C(O)(=O)C>[CH3:30][CH:12]1[N:4]2[C:5]3[C:10]([CH:1]([C:13]4[C:14](=[O:29])[NH:15][C:16](=[O:28])[C:17]=4[C:18]4[CH:27]=[CH:26][CH:25]=[C:24]5[C:19]=4[CH:20]=[CH:21][N:22]=[CH:23]5)[N:2]=[CH:3]2)=[CH:9][CH:8]=[CH:7][C:6]=3[CH2:11]1
Reactant: O=C1NC(=O)C(C2N=CN3CCc4cccc2c43)=C1c1cccc2cnccc12
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1Cc2cccc3c2N1C=NC3C1=C(c2cccc3cnccc23)C(=O)NC1=O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Add a solution of 3-(5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinazolin-1-yl)-4-(isoquinolin-5-yl)-2,5-dioxopyrrole (0.300 g, 0.7853 mmol) in anhydrous dimethylformamide (1.5 mL) to formalin (37% solution in water, 0.750 ml) in 2 ml glacial acetic acid and stir at 65° C. for 2 hours. Pour into ice water and neutralize with 5.0N sodium hydroxide. Extract with 200 mL ethyl acetate, wash sequentially with water (1×75 mL), and saturated aqueous sodium chloride (1×75 mL), dry over anhydrous magnesium sulfate, and concentration under reduced pressure. Dissolve the residue in 150 ml 2.0 M ammonia in methanol stir at room temperature for 2 hours, concentrate and purify by column chromatography to give the title compound as an orange solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:8]([N+:22]([O-:24])=[O:23])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(O)(=O)C>[C:25]([N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:8]([N+:22]([O-:24])=[O:23])=[CH:7][CH:6]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)N1CCN(c2nc(NC3CC3)ccc2[N+](=O)[O-])CC1
Solvent: CC(=O)O
Product: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2[N+](=O)[O-])CC1

Procedure:
A solution of 64.0 g (0.19 mole) of 4-[6-(cyclo- propylamino)-3-nitro-2-pyridinyl]-1-piperazinecarboxylic acid, ethyl ester, 115 ml of acetic anhydride and 115 ml of acetic acid was heated on a steam bath for 36 hours. The solvents were removed in vacuo, the residue was triturated with a mixture of ethanol and toluene which was also evaporated in vacuo to give 68.3 g of the title compound, mp 90°-93° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[O:16]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(Oc2ccccc2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluorobenzaldehyde and phenol.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:29])/[CH:21]([OH:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:30][CH3:31])[C:15]([CH3:32])=[C:14]2[C:10]=1[C:11](=[O:33])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:34]I>CC#N.[Ag]=O>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:29])/[CH:21]([O:28][CH3:34])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:30][CH3:31])[C:15]([CH3:32])=[C:14]2[C:10]=1[C:11](=[O:33])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)CC(O)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Agent: O=[Ag]
Solvent: CC#N
Product: CCOC(=O)CC(OC)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Temperature: 25 °C
Yield: 60 %

Procedure:
Ethyl (E) 6-(1,3-dihydro-4-tert-butyldimethylsilyloxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-hydroxy-4-methyl-4-hexenoate (974 mg) was dissolved in a 6:1 mixture of methyl iodide in CH3CN (25 ml). Silver oxide was then added (5.1 g) and the mixture heated at reflux for 24 hr. The mixture was cooled to room temperature and filtered through a bed of celite. The celite was washed with CHICl2 (80 ml) and ethyl acetate (80 ml). The combined organic layers were evaporated to dryness and the residue passed through a flash column (silica gel, hexanes-EtOAc 8:2) to afford 601 mg (60%) of ethyl (E) 6-(1,3-dihydro-4-tert-butyldimethylsilyloxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5yl)-3-methoxy-4-methyl-4-hexenoate the product as a colorless oil.
Reaction SMILES: Br[C:2]([CH:5]1[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[OH:12]/[N:13]=[C:14](/[C:20](=[O:22])[CH3:21])\[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(Cl)Cl>O1CCOCC1.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:2]([CH3:4])([O:12]/[N:13]=[C:14](/[C:20](=[O:22])[CH3:21])\[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:3])[CH2:6][CH2:7]1
Reactant: CC1CCC(C(C)(C)Br)CC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)/C(=N\OC(C)(C)[C@H]1CC[C@H](C)CC1)C(C)=O

Procedure:
2-Bromo-2-(4-methylcyclohex-1-yl)propane (1.99 g, 9.06 mmol), ethyl (Z)-2-hydroxyimino-3-oxobutyrate (1.44 g, 9.06 mmol) and silver trifluoromethanesulphonate (2.33 g) were reacted together in dry dioxane (8 ml) using a similar method to Example 9a. The title compound was obtained as an oil (1.31 g, 51%), νmax (CH2Cl2) 2920, 2860, 1740, 1685, 1370, 1320, 1235, 1070, and 1000 cm-1. δ13C (100 MHz, CDCl3) 14.14 (CH3), 22.55 (CH3), 23.24 (2×CH3), 25.11 (CH3), 26.8 (2×CH2), 32.76 (CH), 35.36 (2×CH2), 46.25 (CH), 61.7 (CH2) 87.6, 149.7, 161.6 (C=O), 193.1 (C=O); δH (400 MHz, CDCl3), 0.86 (3H, d, J 6.5 Hz), 0.8-0.95 (2H, m), 0.95-1.15 (2H, m), 1.29 (6H, s), 1.32 (3H, t, J 7.1 Hz), 1.2-1.35 (1H, m), 1.45-1.65 (2H, m), 1.65-1.80 (3H, m), 2.40 (3H, s), and 4.34 (2H, q, J 7.1 Hz).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][O:20][CH2:21][C:22]#[CH:23].O>C(#N)C>[CH3:1][O:2][N:3]([CH2:19][O:20][CH2:21][C:22]#[CH:23])[C:4](=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C#CCOCCl
Reactant: CONC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCOCN(OC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
0.6 g of N-methoxybenzamide was dissolved in 10 ml of acetonitrile, and 0.55 g of potassium carbonate and 0.42 g of chloromethylpropargyl ether were added thereto in this order. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 0.8 g of N-methoxy-N-propargyloxymethylbenzamide.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8](N(C(C)C)C2C=C(C(C)C)C3OCC(C)(C)C=3C=2)=[CH:7][CH:6]=1)C.[CH3:30][C:31]1([CH3:47])[C:35]2[CH:36]=[C:37]([NH:43][CH:44]([CH3:46])[CH3:45])[CH:38]=[C:39]([CH:40]([CH3:42])[CH3:41])[C:34]=2[O:33][CH2:32]1.[OH-].[Na+]>C(O)C>[CH:44]([N:43]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([OH:29])=[O:3])[C:37]1[CH:38]=[C:39]([CH:40]([CH3:42])[CH3:41])[C:34]2[O:33][CH2:32][C:31]([CH3:30])([CH3:47])[C:35]=2[CH:36]=1)([CH3:46])[CH3:45]
Reactant: CC(C)Nc1cc(C(C)C)c2c(c1)C(C)(C)CO2
Reactant: CCOC(=O)c1ccc(N(c2cc(C(C)C)c3c(c2)C(C)(C)CO3)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cc(N(c2ccccc2C(=O)O)C(C)C)cc2c1OCC2(C)C
Yield: 13.4 %

Procedure:
Following general procedure I and using 4-[isopropyl-(3,3-dimethyl-7-isopropyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester [(Compound 39, 0.15 g, contaminated with 3,3-dimethyl-7-isopropyl-5-(isopropyl)amino-2,3-dihydro-benzofuran (Compound 35)] and 2 mL of 5M sodium hydroxide in 10 mL of ethanol, the title compound (0.043 g, 13.4% for 2 steps) was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.86 (d, 2H, J=9.0 Hz), 6.71 (d, 1H, J=2.0 Hz), 6.64 (d, 1H, J=2.0 Hz), 6.51 (d, 2H, J=9.0 Hz), 4.36 (heptet, 1H, J=6.4 Hz), 4.30 (s, 2H), 3.09 (heptet, 1H, J=6.9 Hz), 1.33 (s, 6H), 1.23 (d, 6H, J=6.9 Hz), 1.15 (d, 6H, J=6.4 Hz).