Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][NH:6][C@H:5]([C:8]([O:10]C)=[O:9])[CH2:4][O:3]1.[OH-].[Na+].[ClH:15]>CO.O>[ClH:15].[CH3:1][C:2]1([CH3:12])[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][O:3]1
Reactant: COC(=O)[C@@H]1COC(C)(C)CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CN[C@H](C(=O)O)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (S)-methyl 6,6-dimethylmorpholine-3-carboxylate (0.2 g, 1.2 mmol) (The compound was synthesized according to the procedure as described in WO2008024692) in anhydrous methanol (4 mL) was added a solution of sodium hydroxide (0.1 g, 2.4 mmol) in water (1 mL). The reaction mixture was stirred at 25° C. for 2 hours, and cooled to 0° C. The reaction mixture was adjusted to pH 1-2 with con. HCl. The mixture was concentrated in vacuo to give the title compound as a white solid (0.19 g, 100%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:8]([CH2:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:11])=[CH:7][N:6]=[CH:5]1>CO>[CH3:3][N:4]1[C:8]([CH2:9][CH:10]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[OH:11])=[CH:7][N:6]=[CH:5]1
Reactant: Cn1cncc1CC(=O)c1nccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cncc1CC(O)c1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Sodium borohydride (0.56 g, 14.9 mmol) was added to a solution of 2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethanone in methanol (150 ml) and the mixture stirred under a nitrogen atmosphere at ambient temperature for 2 hours. The reaction was evaporated to dryness and the resulting gum was treated with water (15 ml) and stirred for 30 minutes to give a solid precipitate which was filtered and dried to give 2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethanol (2.67 g, 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=1>CN(C)C=O>[C:27]([O:26][C:25](=[O:31])[NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:19]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])nc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.4 %

Procedure:
To a solution of 5-bromo-2-nitropyridine (20.0 g, 98.5 mmol) and cesium carbonate (48.1 g, 147 mmol) in N,N-dimethylformamide (150 mL) was added a solution of tert-butyl (3-hydroxyphenyl)carbamate (21.6 g, 103 mmol) in N,N-dimethylformamide (100 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, the obtained residue was diluted with water (300 mL), and extracted with ethyl acetate (500 mL). The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=90/10→60/40), and fractions containing the object product was concentrated under reduced pressure to give the title compound (19.4 g, 59%) as a pale-yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([O:25][CH2:26][CH3:27])[CH:17]=2)[S:9][C:10]=1[C:11](OCC)=[O:12])=O)C.O.[NH2:29][NH2:30]>C(O)C>[CH2:26]([O:25][C:18]1[CH:17]=[C:16]([C:8]2[S:9][C:10]3[C:11](=[O:12])[NH:30][NH:29][C:4](=[O:3])[C:6]=3[N:7]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][CH3:24])[CH3:27]
Reactant: NN
Reactant: CCOC(=O)c1nc(-c2ccc(OCC)c(OCC)c2)sc1C(=O)OCC
Solvent: O
Solvent: CCO
Product: CCOc1ccc(-c2nc3c(=O)[nH][nH]c(=O)c3s2)cc1OCC
Temperature: 130 °C

Procedure:
In 4 ml of ethanol was suspended 1 g of 4,5-diethoxycarbonyl-2-(3,4-diethoxyphenyl)thiazole. Thereto was added 2 ml of hydrazine hydrate. The mixture was sealed in a tube and heated at 130° C. for 48 hours. After cooling, the resulting crystals were collected by filtration, washed with ethanol, dried and recrystallized from dimethylformamide to obtain 220 mg of 2-(3,4-diethoxyphenyl)-5,6-dihydrothiazolo[4,5-d]pyridazine-4,7-dione.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])([CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccccc1F
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Reaction time: 20 h

Procedure:
2-(2-Fluorophenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladiun on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19](O)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=2)[NH2:33])[CH2:26][CH2:25]1>>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[C:30]([N:27]5[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]5)[CH:31]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCc1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cccc(COC(C)(C)C)c5)n4n3)c2)CC1
Yield: 44.8 %

Procedure:
Analogous to Example 1510b, 7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (109 mg, 0.37 mmol) and 3-(4-Methylpiperazin-1-yl)aniline (0.0878 g, 0.459 mmol) were reacted to afford [7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine (78 mg, 45%). LCMS: 471 (M+H); 1H-NMR (DMSO-d6): 9.26 (s, 1H), 9.26 (s, 1H), 8.97 (s, 1H), 8.08 (s, 1H), 7.99 (d, 1H, J=7.83 Hz), 7.46 (t, 1H, J=7.83 Hz), 7.35 (d, 1H, J=7.83 Hz), 7.27 (m, 2H), 7.13 (m, 2H), 6.95 (d, 1H, J=4.38 Hz), 6.57 (d, 1H, J=8.50 Hz), 4.48 (s, 2H), 3.01 (s, 4H), 2.40 (s, 4H), 2.22 (s, 3H), 1.22 (s, 9H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][O:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.Cl>CCO.C(OCC)C>[C:1]1([C:7](=[N:18][O:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)[C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(ON)CC1
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(ON=C(c2ccccc2)c2cc3ccncc3[nH]2)CC1
Reaction time: 3 h
Yield: 21.3 %

Procedure:
A mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (300 mg, 1.34 mmol) and tert-butyl 4-(aminooxy)piperidine-1-carboxylate (Reference Example 10) (289 mg, 1.34 mmol) in EtOH (30 mL) was adjusted to pH 4-5 with HCl (1.9 mL of a 1 N HCl solution in diethyl ether, 1.9 mmol). The reaction mixture was heated to reflux. After 3 h, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated NaHCO3. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 98:2 CH2Cl2/MeOH to 95:5 CH2Cl2/MeOH) gave tert-butyl 4-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]piperidine-1-carboxylate (120 mg, 23%) as a white amorphous solid (geometry of the oxime double bond undefined).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH:13]([OH:16])[CH:14]=[CH2:15])=[CH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13](=[O:16])[CH:14]=[CH2:15])=[CH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=CC(O)C(=C)c1ccc(OC)c(OC)c1
Agent: O=[Mn]=O
Product: C=CC(=O)C(=C)c1ccc(OC)c(OC)c1
Yield: 56.6 %

Procedure:
According to the General Procedure B, MnO2 (1.81 g, 20.79 mmol) and 2-(3,4-dimethoxyphenyl)-1,4-pentadien-3-ol (220 mg, 0.99 mmol) are converted to give after workup and chromatography (SiO2, PE/EE=2:1, Rf=0.40) the title compound (122 mg, 0.56 mmol, 56%) as a yellow oil; C14H16O3 (218.25).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][O:9][CH:10]=1)=[O:5])C.COC(=O)[C@@H](NC(C1C=NC(OCC2C(C3C=CC=CC=3)=NOC=2C)=CC=1)=O)CC1C=CC=CC=1>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=1
Reactant: CCOC(=O)c1conc1-c1ccccn1
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Product: O=C(O)c1conc1-c1ccccn1
Yield: 77.7 %

Procedure:
As described for example 231, 3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester (9.6 g, 44 mmol), instead of (S)-2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-3-phenyl-propionic acid methyl ester, was converted to the title compound (6.5 g, 79%) which was obtained as an off white solid. MS: m/e=189.3 [M−H]−.
Reaction SMILES: C([CH:6]([C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1)[CH:7]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[C:28]([O:36][CH:37]([F:39])[F:38])[CH:27]=1)[C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)(OCC)=O.C1COCC1.[Li+].[OH-].Cl>O.CO>[F:39][CH:37]([F:38])[O:36][C:28]1[CH:27]=[C:26]([CH:7]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[CH:12][CH:13]=2)[CH2:6][C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH:33]([F:35])[F:34]
Reactant: CCOC(=O)C(c1ccncc1)C(c1ccc(Oc2ccc(OC(F)(F)F)cc2)nc1)c1ccc(OC(F)F)c(OC(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: FC(F)Oc1ccc(C(Cc2ccncc2)c2ccc(Oc3ccc(OC(F)(F)F)cc3)nc2)cc1OC(F)F
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
To a solution of the crude ester from Step 4 above in 25 mL of a 3:1:1 mixture of THF:MeOH:water, was added 5.1 mL (10.3 mmol) of a 2 N solution of LiOH. The resulting solution was stirred at 65° C. for 1.5 h, cooled down to room temperature followed by the addition of 10 mL of a 1.0 N HCl solution. The resulting mixture was rotovaped down to evaporate MeOH and the aqueous residue was diluted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (50% Ethyl acetate/hexane) to afford the desired pyridine as an oil (380 mg, 68% from Step 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](F)[CH:20]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:26]([NH:30][C:21]1[CH:20]=[C:19]([C:18]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][N:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:24]=[CH:23][N:22]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: COc1cccc2c(-c3ccnc(F)c3)c(-c3ccc(F)cc3)nn12
Solvent: CCOC(C)=O
Product: CCCCNc1cc(-c2c(-c3ccc(F)cc3)nn3c(OC)cccc23)ccn1
Temperature: 130 °C

Procedure:
In a sealed-tube was combined 2-(4Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-7-methoxypyrazolo[1,5-a]pyridine (from Example 30, 20 mg, 0.06 mmol) and n-butylamine (2.0 mL, 1.5 g, 20 mmol), and the reaction was placed in a pre-heated oil bath at 130° C. The reaction was stirred at 130° C. until consumption of starting material was indicated by TLC analysis (50% ethyl acetate in hexanes). The contents of the sealed-tube was transferred to a flask and concentrated to dryness at 50° C. under high vacuum. The residue was purified by silica gel chromatography to yield the title compound, 2.0 mg (0.005 mmol, 80%). 1H NMR (d6-acetone): δ 8.04(d, 1H, J=5.1 Hz), 7.74(dd, 2H, J=5.7, 9.0 Hz), 7.33–7.38(m, 2H), 7.22(t, 2H, J=9.0 Hz), 6.45–6.54(m, 3H), 4.25(s, 3H), 3.30–3.40(m, 2H), 1.60(quint, 2H, J=7.2 Hz), 1.45(sext, 2H, J=7.2 Hz), 0.9(t, 3H, J=7.2 Hz). MS (ES+ve): 391.1 (100, M+), 376.3 (100).
Reaction SMILES: Cl[CH:2]([C:7]1[O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]=1[CH2:12][CH3:13])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=1>>[CH2:12]([C:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C:7]=1[CH:2]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=1)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH3:13]
Reactant: CCc1c(C(Cl)CC(C)C)oc2ccccc12
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: CCc1c(C(CC(C)C)Nc2ccc(C(=O)NCCC(=O)O)cc2)oc2ccccc12
Yield: 32 %

Procedure:
Using 2-(1-chloro-3-methylbutyl)-3-ethyl-1-benzofuran (300 mg) synthesized in Example A31(4) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (283 mg) synthesized in Example 1(2) and in the same manner as in Example A22(4), the title object compound (162 mg, 32%) was obtained as a pale-brown solid.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([OH:10])[N:2]=1.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([O:10][C:13](=[O:14])[N:12]([CH3:11])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:2]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1nnc2cccnc21
Product: CN(C(=O)On1nnc2cccnc21)c1ccccc1

Procedure:
The title compound was prepared from [1,2,3]Triazolo[4,5-b]pyridin-3-ol and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (99%, oil).
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:17])=O.Cl.S(=O)=O>NCC(OC(=O)CCCCCCCCCCC)=O.[Na]>[C:1]([Cl:17])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Agent: CCCCCCCCCCCC(=O)OC(=O)CN
Agent: Cl
Agent: O=S=O
Product: CCCCCCCCCCCC(=O)Cl
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a stirred mass of lauric acid (200 g, 1.0 gmol) and sodium lauroyl glycinate (0.6 g, 0.002 gmol) at 25° C. under nitrogen blanket, thionyl chloride (123 g, 1.03 gmol) was added slowly at 25° C. and atmospheric pressure over a period of 2 hours maintaining temperature below 25° C. The hydrochloric acid and sulfur dioxide generated during the process was continuously scrubbed in a gas scrubber containing caustic lye. The reaction mixture was stirred for additional 4 hours at the reaction temperature. The progress of reaction was monitored by measuring alkoyl chloride formation. Nitrogen gas was purged through the reaction mass for 3 hours to remove the residual traces of sulfur dioxide, hydrogen chloride gas and unreacted thionyl chloride. At the end of this procedure lauroyl chloride (218 g, 99.8%) was obtained as practically colorless product. The detailed analysis is given in the Table 11.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].Cl.[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:14]=3[N:13]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:27]([CH3:41])[CH:26]=3)=[O:24])[CH2:12][C:11]=2[CH:10]=[N:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:7][N:8]1[C:17]2[NH:16][C:15]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:14]=3[N:13]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH:35]4[CH2:36][CH2:37][N:38]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:39][CH2:40]4)=[C:27]([CH3:41])[CH:26]=3)=[O:24])[CH2:12][C:11]=2[CH:10]=[N:9]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(OCCCC2CCNCC2)c(C)c1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(OCCCC2CCN(CC(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of isobutyraldehyde (0.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of (3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[3-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-methanone hydrochloride (2.6 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and DIEA (0.0026 ml). The mixture was stirred at room temperature for 1 h then a solution of sodium triacetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=530.5
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.[CH:18]([N:21]=[C:22]=[O:23])([CH3:20])[CH3:19]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:22]([NH:21][CH:18]([CH3:20])[CH3:19])=[O:23])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC(C)N=C=O
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: ClCCl
Product: CC(C)NC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Reaction time: 6 h
Yield: 44.1 %

Procedure:
200 mg (0.850 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole and 20 ml of dichloromethane were stirred at room temperature, and 92 μl (0.935 mmol) of isopropyl isocyanate were added thereto and stirred for 6 hours. The crystals precipitated were filtered off to obtain 120 mg of the intended compound as colorless crystals. (yield: 44%)
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3([OH:22])[CH2:21][CH2:20][O:19][CH2:18]3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3([OH:22])[CH2:21][CH2:20][O:19][CH2:18]3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: [H][H]
Reactant: OC1(c2ccc3c(c2)CN(Cc2ccccc2)C3)CCOC1
Product: OC1(c2ccc3c(c2)CNC3)CCOC1

Procedure:
Prepared in analogy to Example A62(c) from 3-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-tetrahydro-furan-3-ol and hydrogen. Brown oil. MS (m/e): 206.1 ([M+H]+, 100%).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][N:40]([CH2:43][C:44]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][C:47]=3[CH3:54])=[O:45])[C:39](=[O:55])[CH:38]=2)=[N:33][CH:34]=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>>[Br:25][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:44](=[O:45])[CH2:43][N:40]2[C:39](=[O:55])[CH:38]=[C:37]([O:36][CH2:35][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][N:33]=3)[CH:42]=[N:41]2)=[C:47]([CH3:54])[CH:48]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccc(F)cn2)cc1=O
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccc(F)cn2)cc1=O
Yield: 92 %

Procedure:
2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-fluoro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 1d employing 5-(5-fluoro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 6a) instead of preparation 1c.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)C.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[C:16]([O:15][C:13](=[O:14])[NH:12][C@H:9]1[CH2:8][CH2:7][C@H:6]([CH2:5][CH:4]=[O:3])[CH2:11][CH2:10]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-(4-tert-butoxycarbonylamino-cyclohexyl)-acetic acid ethyl ester (1.04 g, 4 mmol), in toluene (10 mL) at −78° C. a 1.2 M solution of diisobutylaluminium hydride (DIBAL-H) (5.1 mL, 6 mmol) in toluene was added. The mixture was stirred at −78° C. until TLC after 0.5 h indicated completion of the reaction. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was used without purification on the next step. MS (m/e): 242.3 (M+H+).
Reaction SMILES: C(C([NH:7][C:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]2[O:18][CH2:19][C:20]3[CH:21]=[N:22][S:23][C:24]=3[C:11]2=[CH:10][CH:9]=1)=O)(C)(C)C.S(=O)(=O)(O)O>CO.C(OCC)(=O)C>[NH2:7][C:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]2[O:18][CH2:19][C:20]3[CH:21]=[N:22][S:23][C:24]=3[C:11]2=[CH:10][CH:9]=1
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCc1cnsc1-2
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1c(N)ccc2c1OCc1cnsc1-2
Yield: 66 %

Procedure:
A suspension of methyl 7-tert-butylcarbonylamino-4H-chromeno[3,4-d]isothiazole-6-carboxylate (Intermediate 75, 0.690 g) in methanol (30 mL) was treated with concentrated sulfuric acid (1.2 mL) and the resultant mixture was heated at 75° C. in a sealed vessel overnight. The mixture was cooled, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was saturated with sodium chloride then extracted with ethyl acetate again. The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 15-45% to give methyl 7-amino-4H-chromeno[3,4-d]isothiazole-6-carboxylate (0.345 g) as a yellow solid.
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[CH2:38]2)=[CH:33][CH:32]=1.[Cl-].[NH4+]>C(OCC)C.C(Cl)Cl>[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)([OH:46])[CH2:38]2)=[CH:35][CH:36]=1
Reactant: O=C1CC(c2ccc(F)cc2)c2ccccc21
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOCC
Product: OC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CC(c2ccc(F)cc2)c2ccccc21
Reaction time: 1 h

Procedure:
A 3.0 M solution of ethylmagnesium bromide (5.9 ml, 0.0177 mol) in diethyl ether was added to a solution of 4-iodo-1-trityl-1H-imidazole (7.22 g, 0.0165 mol, prepared according to K. L. Kirk J. Heterocycl. Chem. 22 (1985) 57) in 70 ml of dry methylene chloride at ambient temperature. After one hour, a solution of 3-(4-fluorophenyl)indan-1-one (2.00 g, 0.00884 mol) in 6 ml of dry methylene chloride was added and stirring was continued for 45 hr. Saturated ammonium chloride solution was added to quench the reaction. The methylene chloride phase was separated and the aqueous phase was extracted twice with methylene chloride. The combined organic extracts were washed with brine, dried and concentrated. The crude 3-(4-fluorophenyl)-1-(1-trityl-1H-imidazol-4-yl)indan-1-ol was purified by flash chromatography using methylene chloride as an eluent.