Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:17]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH3:20])=[O:18]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:20][O:19][C:17](=[O:18])/[CH:21]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC/C(=C\C=O)c1ccc(OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-2-heptenal (10 g) was treated with (carbomethoxymethylene)triphenylphosphorane (17 g) in carbon tetrachloride (70 mL) and dichloromethane (15 mL) for 4 days at room temperature. The ester was isolated in the normal way and purified by HPLC (ether-hexane; 1:9) to furnish 8 g of (E,E)-5-(4-methoxyphenyl)-2,4-nonadienoic acid methyl ester, as an oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](#[N:9])[CH3:8].[CH3:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>>[NH2:17][C:16]([C:15]1[CH:18]=[CH:19][C:12]([S:11][CH3:10])=[CH:13][CH:14]=1)=[CH:8][C:7]#[N:9]
Reactant: CC#N
Reactant: CSc1ccc(C#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CSc1ccc(C(N)=CC#N)cc1

Procedure:
Using a similar procedure to that of Preparation IX-2, but using 1.5 equivalents of potassium t-butoxide and 1.5 equivalents of acetonitrile per 1 equivalent of 4-(methylthio) benzonitrile, there is obtained 3-amino-3-[4-(methylthio)phenyl]acrylonitrile.
Reaction SMILES: C1(NC(=S)N[C@@H](CC2C=CC=CC=2)C([NH:13][C@H:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]([CH2:31][C:32]3[NH:36][N:35]=[N:34][N:33]=3)[C:15]2=[O:37])=O)C=CC=CC=1.[ClH:46]>O1CCCC1.C(OCC)(=O)C>[ClH:46].[NH2:13][C@H:14]1[N:20]=[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:15]1=[O:37]
Reactant: O=C(N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O)[C@H](Cc1ccccc1)NC(=S)Nc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O
Reaction time: 10 h

Procedure:
To a solution of (3S)-3-[[(2S)-2-[N'-(phenyl)thioureido]-3-phenylpropanoyl]amino]-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (14.10 g) in tetrahydrofuran (84.6 ml) was added dropwise 4N-hydrogen chloride in ethyl acetate (84.6 ml) below 6° C. After stirring under the-same conditions for 10 hours, the resultant precipitates were collected by filtration, and then the collected precipitate was suspended in chloroform and stirred for 1 hour at room temperature. The objective product was collected by filtration to give (3S)-3-amino-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one hydrochloride (7.15 g).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:13]2[C:14]([O:36][CH3:37])=[N:15][N:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=2[CH:11]=[C:10]([Cl:38])[N:9]=1)=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>O1CCOCC1.C(Cl)Cl.CO>[Cl:38][C:10]1[N:9]=[C:8]([C:6]2[S:48][C:1]([CH3:2])=[N:4][N:5]=2)[C:13]2[C:14]([O:36][CH3:37])=[N:15][N:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=2[CH:11]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)NNC(C)=O)c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(-c3nnc(C)s3)c12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N′-acetyl-6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbohydrazide (48 mg, 0.091 mmol, see synthesis of intermediate 43B) was taken up in 1,4-dioxane (1.0 ml) and Lawesson's Reagent (27.7 mg, 0.068 mmol) was added. The reaction mixture was stirred at 100° C. for 1 hr. Room temperature was attained. The reaction mixture was diluted with DCM and MeOH and was concentrated in vacuo while loading onto silica gel. The products were purified by MPLC 5-30% EtOAc/hexanes to give 2-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-5-methyl-1,3,4-thiadiazole (44B). MS: [M+H]+ m/z 524.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3N=N2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>P(=O)(O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[NH:8]2
Reactant: Brc1cccc(-n2nnc3cccnc32)c1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Brc1cccc2[nH]c3ncccc3c12
Temperature: 150 °C
Yield: 7.1 %

Procedure:
Compound 3 (2.8 g, 10.2 mmol) was dissolved in ortho-phosphoric acid (40 ml). The mixture was heated to 150° C. for 18 hours, and the intended product confirmed by LC-MS. The mixture was cooled to 0° C. and the acid neutralized with concentrated NaOH. Extraction with methylene chloride afforded a mixture of Compounds 4 and 4′, which was then purified by HPLC to provide Compound 4 (180 mg, 9%). 1H NMR (400 MHz, CD3OD) δ 9.16 (d, J=7.8 Hz 1H) 8.48 (s, 1H) 7.62 (d, J=7.8 Hz 1H) 7.52 (d, J=6.8 Hz 1H) 7.44 (m, 2H). [M+H] calc'd for C17H12N2, 245; found 245.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][C:18]([CH3:25])=[C:19]([CH2:21][C:22]([OH:24])=[O:23])[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][CH2:27]O.S(=O)(=O)(O)O>O>[CH2:26]([O:23][C:22](=[O:24])[CH2:21][C:19]1[N:20]=[C:16]([C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)[O:17][C:18]=1[CH3:25])[CH3:27]
Reactant: CCO
Reactant: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Cc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)oc1C
Yield: 83 %

Procedure:
A mixture of [2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyloxazol-4-yl]-acetic acid (1.5 g, 4.35 mmol), EtOH (50 mL), and concentrated sulfuric acid (0.5 mL) was refluxed for 10 hours. The mixture poured into water, and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from ethyl ether/hexane gave a light brown solid (1.35g, 83% yield), m.p. 103°-105° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25](C(F)(F)F)[CH:24]=1)[N:19]([CH3:33])[C:18]2=[O:34]>N1C=CC=CC=1>[CH3:33][N:19]1[C:18](=[O:34])[C:17]2[C:22](=[C:13]([NH:12][S:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)(=[O:10])=[O:9])[CH:14]=[CH:15][CH:16]=2)[N:21]=[C:20]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(N)cccc2c1=O
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c(-c2ccccc2)nc2c(NS(=O)(=O)c3cccnc3)cccc2c1=O
Temperature: 80 °C
Yield: 62.7 %

Procedure:
Pyridine-3-sulfonyl chloride hydrochloride 7 (280 mg, 1.3 mmol) was added to a solution of 8-amino-3-methyl-2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one 5 (100 mg, 0.313 mmol) in pyridine (5 mL). The reaction mixture was heated at 80° C. for 12 h. The pyridine was removed in vacuo. The residue was taken up in CH2Cl2, washed with sat. aq NaHCO3, dried (MgSO4) and concentrated. The crude residue was purified by MPLC eluting with CH2Cl2/MeOH (0-10%) followed by recrystallization from CH3CN to give Compound 361 (77 mg, 53% yield). MS (ESI) calcd for C21H15F3N4O3S: 460.08. found: 461 [M+H].
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[N:16]([CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1)=[N+:17]=[N-:18]
Reactant: O=C1O[C@@H](CCl)CN1c1ccc(Cl)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(Cl)cn2)C(=O)O1
Yield: 93.2 %

Procedure:
A mixture of (5R)-5-(chloromethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (2.32 g, INTERMEDIATE 7) and sodium azide (1.22 g) was heated to 100° C. in 75 ml of dimethylformamide for 15 h. The mixture was then diluted with 500 ml of water and extracted with 500 ml of ethyl acetate (3×). The combined organic layers were washed with water (250 ml) and brine (250 ml). They were then dried over sodium sulfate and concentrated in vacuo to provide 2.22 g (93%) of the title compound in >95% purity via LC/MS. Mass spectrum (ESI) 254.1 (M+1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[O:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:38]C(C1C=CC2CCCCC=2C=1)=O>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:15]2[C:16](=[O:17])[C@H:13]([S:12][CH2:11][C:10](=[O:36])[C:6]3[CH:7]=[CH:8][C:9]4[CH2:38][CH2:1][CH2:2][CH2:3][C:4]=4[CH:5]=3)[C@H:14]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)CCC4)C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(CBr)c1ccc2c(c1)CCCC2
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)CCCC4)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
The titled compound above was prepared using the same procedure as that used for the synthesis of {4-[(2R,3R)-3-{[2-(2,3-dihydro-1H-inden-5-yl)-2-oxoethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid but using 2-bromo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanone instead of 2-bromo-1-(2,3-dihydro-1H-inden-5-yl)ethanone. 1H NMR [(CD3)2SO), 400 MHz]δ 1.66-1.75 (m, 4H), 2.66-2.77 (m, 4H), 4.22-4.31 (m, 3H), 4.62 (s, 2H), 5.11 (d, 1H), 6.86-7.61 (m, 11H).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C([O:7][C@H:8]1[CH2:25][C@@:23]2([CH3:24])[C@@H:19]([CH2:20][CH2:21][C@@H:22]2OS(C)(=O)=O)[C@H:18]2[C@@:9]1([F:33])[C@:10]1([CH3:32])[C:15]([CH2:16][CH2:17]2)=[CH:14][C:13](=[O:31])[CH:12]=[CH:11]1)(=O)C.O>CN(C)C=O>[CH2:1]([S:3][C@@H:22]1[CH2:21][CH2:20][C@H:19]2[C@H:18]3[C@:9]([F:33])([C@@H:8]([OH:7])[CH2:25][C@:23]12[CH3:24])[C@:10]1([CH3:32])[C:15](=[CH:14][C:13](=[O:31])[CH:12]=[CH:11]1)[CH2:16][CH2:17]3)[CH3:2]
Reactant: CCS
Reactant: CC(=O)O[C@H]1C[C@]2(C)[C@@H](OS(C)(=O)=O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Solvent: CN(C)C=O
Solvent: O
Product: CCS[C@@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 25 °C

Procedure:
A suspension of 50% sodium hydride-paraffin (300 mg, 6.5 mmole) in dry dimethylformamide (20 ml) was cooled and stirred in an ice-water bath and ethanethiol (0.67 ml, 9.0 mmole) was added. The ice bath was then removed and the mixture was stirred at room temperature until a clear solution resulted. Then, (11β,17β)-11-(acetyloxy)-9-fluoro-17-(methanesulfonyloxy)androsta-1,4-dien-3-one (540 mg, 1.21 mmole) was added. The resulting solution was heated in a bath at 110°-120° C. under an atmosphere of nitrogen for 5.0 hours. After cooling to room temperature, water (1.0 ml) was added and the mixture was stirred for 20 minutes. The mixture was then added into water (150 ml) and was extracted with chloroform (3×50 ml). The extracts were combined, washed with water, dried (anhydrous magnesium sulfate) and evaporated to afford the title compound as a solid contaminated with paraffin. It was dissolved in chloroform-hexane (7:3; 20 ml) and absorbed on a column of silica gel (15 g). The column was then successively eluted with chloroform and chloroform:ethyl acetate (85:15) to afford the homogeneous (tlc) title compound as a solid (380 mg) from the later fractions. One crystallization from ethyl acetate-hexane followed by drying (110° C., 0.3 mm of Hg, 6 hours) gave the analytical specimen (362 mg), melting point 196°-197° C. with consistent spectral data.
Reaction SMILES: [N:1]1([C:7]2[C:12]3[O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[C:10](=O)[C:9](=[O:21])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:23][OH:24].N1CCCCC1>CO>[OH:21][C:9]1[CH:8]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:12]2[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:11]=2[C:10]=1[N:23]=[O:24]
Reactant: NO
Reactant: O=C1C=C(N2CCCCC2)c2oc3ccccc3c2C1=O
Agent: Cl
Solvent: CO
Solvent: C1CCNCC1
Product: O=Nc1c(O)cc(N2CCCCC2)c2oc3ccccc3c12

Procedure:
4-Piperidinodibenzofuran-1,2-dione (18.4; 0.062 mol) was added in one portion to a vigorously stirred solution of hydroxylamine hydrochloride (22.9 g; 0.33 mol) and piperidine (28 g; 0.33 mol) in methanol (230 ml) at room temperature. After 1.75 hours the mixture was filtered and the resulting solid washed with water and dried to yield 2-hydroxy-1-nitroso-4-piperidinodibenzofuran as a red-brown solid (3.48 g; 19%), m.pt. 181°-185° C. (decomp 207° C.). ##STR12##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>CN1C(=O)CCC1>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:2]2[CH:7]=[C:6]([N:8]3[CH:12]=[N:11][C:10]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:9]3)[CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1cc(-n2cnc(Nc3ccccc3)n2)ccn1
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2cc(-n3cnc(Nc4ccccc4)n3)ccn2)cc1
Reaction time: 0.25 h

Procedure:
[1 g, 3.68 mMol] of [1-(2-Chloro-pyridin-4-yl)-1H-[1,2,4]triazol-3-yl]-phenyl-amine was dissolved in 14 mL of NMP with [2.4 mL, 2.52 g, 18.4 mMol] of p-methoxybenzylamine and heated 250 C. for 15 min (MW, 150 W). The solvent was removed in vacuo (Kugel-Rohr style) and the residue was treated with MTBE. The ether was decanted away from the dark residue and was replaced with fresh MTBE and mass broken up with vigorous stirring. The ether was again decanted away and replaced with methanol and vigorously stirred for 1 hour. The tan solid was isolated via suction filtration and washed sequentially with methanol and MTBE. The resulting powder was boiled in hot acetonitrile for several minutes, allowed to cool, isolated via suction filtration, and washed with more acetonitrile and finally MTBE. Yield: 0.5g (38.5%). 1H NMR 500 MHz (DMSO-d6) ∂ 3.7(s, 3H), 4.45(d, 2H), 6.85(m, 3H), 6.93(s, 1H), 6.98(d, 1H), 0.3(m, 5H), 7.64(d, 2H), 8.05(d, 1H), 9.1(s, 1H), 9.5(s ex, H). LC/MS [M+H+]=373.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.[Si]([O:31][CH2:32][CH2:33][NH:34][C:35]1[CH:44]=[C:43]2[C:38]([CH:39]=[C:40]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]([F:55])([F:54])[F:53])[NH:41][C:42]2=[O:45])=[CH:37][CH:36]=1)(C(C)(C)C)(C)C.[Cl-].[NH4+]>C(OCC)(=O)C>[OH:31][CH2:32][CH2:33][NH:34][C:35]1[CH:44]=[C:43]2[C:38]([CH:39]=[C:40]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]([F:55])([F:53])[F:54])[NH:41][C:42]2=[O:45])=[CH:37][CH:36]=1
Reactant: CC(C)(C)[Si](C)(C)OCCNc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NCCO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
TBAF (1 M THF solution, 88.2 μL, 0.882 mmol) was added to a THF solution (4 mL) that contained the 7-[2-(tert-butyldimethylsilanyloxy)ethylamino]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (204 mg, 0.441 mmol) obtained in step A, and the obtained mixture was then stirred at a room temperature for 1 hour. Thereafter, the reaction solution was poured into a mixed solution of ethyl acetate and a saturated ammonium chloride aqueous solution. An organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=40:1 to 10:1), so as to obtain 7-(2-hydroxyethylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (173 mg, quant).
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:18]1([CH2:24][C:25](OCC)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:25]([CH2:24][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccc3)nc(=O)c1-2
Temperature: 25 °C
Yield: 191.4 %

Procedure:
Alternatively, the product can be prepared as follows: sodium (2.12 g) was dissolved in ethanol (145 ml) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (10 g, 45 mmol), followed by ethyl phenylacetate (2.8 g) were added and the reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature, stripped and then water, followed by 2 N HCl were added to the residue. The product was collected by filtration and recrystallized from ethyl acetate to afford 10.52 g (73%) of 1-cyclopentyl-3-ethyl-6-(phenylmethyl)-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[N+:8]([C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][OH:11])=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Product: O=[N+]([O-])c1cccc(-c2ccc(CO)cc2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 2 using 1-bromo-3-nitrobenzene instead of tert-butyl N-(4-bromobenzyl) carbamate and 4-hydroxymethylphenylboronic acid instead of 3-benzyloxyphenylboronic acid.
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[N:15]2)[O:10][N:9]=1)=O)C.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.C1(C)C=CC=CC=1>[N+:19]([C:17]1[CH:16]=[N:15][N:14]([CH2:13][C:11]2[O:10][N:9]=[C:8]([CH2:6][OH:5])[CH:12]=2)[CH:18]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)c1cc(Cn2cc([N+](=O)[O-])cn2)on1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(Cc2cc(CO)no2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(4-nitro-pyrazol-1-ylmethyl)-isoxazole-3-carboxylic acid ethyl ester (3.477 g, 13.061 mmol) in THF (130.0 mL) was treated dropwise, at −78° C. with DiBAL (44.4 mL of a 1M solution in toluene, 44.41 mmol). The reaction mixture was stirred at −78° C. for 1 h followed by 1 h at rt. Sat. aq. Rochelle's salt (300 mL) was added and the reaction mixture was stirred for 2 h at rt. The aq. layer was extracted with EA (2×300 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (20:80 hept-EA) gave the title compound as a yellow oil. TLC: rf (20:80 hept-EA)=0.33. LC-MS-conditions 02: tR=0.68 min.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]1[C:16]([S:17][CH3:18])=[CH:15][C:14]([C:19]2[C:24]([CH2:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:27][CH3:28])=[N:13][C:12]=1[CH3:29])C.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:27]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25][CH3:26])[C:19]=1[C:14]1[N:13]=[C:12]([CH3:29])[C:11]([CH2:10][OH:9])=[C:16]([S:17][CH3:18])[CH:15]=1)[CH3:28]
Reactant: CCOC(=O)c1c(SC)cc(-c2c(CC)cccc2CC)nc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1-c1cc(SC)c(CO)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of LiAlH4 (1 M in THF, 1 ml, 1 mmol) is added to a solution of 6-(2,6-diethyl-phenyl)-2-methyl-4-methylsulfanyl-nicotinic acid ethyl ester (125 mg) in THF (5 mL) at 0° C. The mixture is warmed to room temperature and stirred for 1 hour, cooled to 0° C. and Na2SO4. 10H2O is added to quench the reaction. The mixture is filtered through Celite and the filtrate is concentrated in vacuo to give [6-(2,6-diethylphenyl)-2-methyl-4-methylsulfanyl-pyridin-3-yl]-methanol.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[N:13]O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:17][CH3:18])=[C:7]([O:15][CH3:16])[CH:8]=2)[N:3]=1>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:17][CH3:18])=[C:7]([O:15][CH3:16])[CH:8]=2)[N:3]=1
Reactant: COc1cc2cc(C=NO)c(Cl)nc2cc1OC
Solvent: CC(=O)OC(C)=O
Product: COc1cc2cc(C#N)c(Cl)nc2cc1OC
Temperature: 25 °C

Procedure:
To 112 g of 2-chloro-6,7-dimethoxy-3-quinolinecarboxaldehyde oxime was added 1000 ml of acetic anhydride. The mixture was stirred at reflux for 3 hours and then cooled to room temperature. The precipitate which formed was separated by filtration, washed with hot ethanol, and then dried to give 2-chloro-6,7-dimethoxy-3-quinolinecarbonitrile melting at about 223.5°-224.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1.C1C=C([O:35]O)C(C(O)=O)=C(C(O)=O)C=1>CO>[F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@@H:21]([CH2:23][NH+:24]([O-:35])[C:25](=[O:27])[CH3:26])[O:20][C:19]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (VIII-A, R1═COCH3, R2═H, X1═F, X2═H) (11.8 g) is dissolved in 200 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure, 18.5 g) is added and the resulting suspension is stirred at 25° C. for two hours. The reaction is filtered and the filtrate is concentrated to afford a white solid. This solid is chromatographed on silica gel using 20% methanol in chloroform as eluent to afford the N-oxide. Lyophilization of this material affords the purified product as a hydrate (9.5 g).
Reaction SMILES: Cl[CH2:2][CH:3]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(O)(CC)C.[OH-].[K+]>COC(C)(C)C>[CH2:10]([O:9][C:3]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH2:2])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOC(CCl)OCCCC
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)(C)O
Solvent: COC(C)(C)C
Product: C=C(OCCCC)OCCCC
Reaction time: 6 h

Procedure:
209 g (1 mol) of 1-chloro-2,2-dibutoxyethane, 300 ml of tert.-butyl methyl ether, 13.2 g (0.13 mol) of 2-methyl-2-butanol, 8 g of polyethylene glycol 1000 dimethyl ether and 200 g (3 mol) of technical grade potassium hydroxide were heated under reflux while stirring for six hours. The reaction mixture was worked up as described above. The conversion was 77.1% of theoretical, the yield of pure material was 60.8% of theoretical (b.p. 87°-88° C., 1.5 kPa).