Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OCc2ccccc23)c2ccc(Cl)cc21)N1CCOCC1

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (the preparation of which have been described in example 69) with commercially available 2-Chloro-1-morpholin-4-yl-ethanone as electrophile, the title compound was obtained as a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[O:4]C1C=CC([N+]([O-])=O)=CC=1.C(N(CC)C(C)C)(C)C.[Cl:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1>ClCCl>[Cl:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH:32][C:3]([NH:2][CH3:1])=[O:4])=[O:30])=[CH:27][CH:26]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: CNC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)NNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
575 mg (2.93 mmol) of 4-nitrophenyl methylcarbamate and 417 mg (3.22 mmol) of N,N-diisopropylethylamine are successively added to 500 mg (2.93 mmol) of 4-chlorobenzoic acid hydrazide in 15 ml dichloromethane and the mixture stirred overnight at room temperature. It is concentrated, the residue is purified by preparative HPLC [Method 9] and 410 mg (61% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[S:16](=[O:28])(=[O:27])[NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:10].CI>>[CH3:7][O:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[S:16](=[O:27])(=[O:28])[N:17]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH3:1])=[O:10]
Reactant: COC(=O)c1sccc1S(=O)(=O)NCCc1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)c1sccc1S(=O)(=O)N(C)CCc1ccc(F)cc1

Procedure:
In the presence of potassium carbonate (2.58 g), 3-[2-(4-fluorophenyl)-ethylsulfamoyl]-thiophene-2-carboxylic acid methylester (3.2 g) was reacted with methyl iodide (0.69 mL), and an oily substance (3.38 g) was obtained, in the same way as Preparation Example 52.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[N:4]1([C:8]2[C:13]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH3:31])[C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)=O)=[C:12](Cl)[N:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][CH2:5]1>O1CCOCC1>[N:4]1([C:8]2[N:9]=[CH:10][N:11]=[C:12]3[N:2]([CH3:1])[N:3]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:31])[C:20]=4[C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)[C:13]=23)[CH2:7][CH2:6][CH2:5]1
Reactant: CNN
Reactant: Cn1ncc(C(=O)c2c(Cl)ncnc2N2CCC2)c1-c1ccc(C(F)(F)F)cn1
Solvent: C1COCCO1
Product: Cn1ncc(-c2nn(C)c3ncnc(N4CCC4)c23)c1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methylhydrazine (98%, 0.254 mL, 4.73 mmol) was added to a solution of [4-(azetidin-1-yl)-6-chloropyrimidin-5-yl]{1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanone (C16) (200 mg, 0.473 mmol) in 1,4-dioxane (4 mL), and the reaction mixture was allowed to stir for 18 hours at room temperature. After removal of solvent in vacuo, the residue was chromatographed on silica gel to provide the product as a solid. Yield: 120 mg, 0.290 mmol, 61%. LCMS m/z 415.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.25-2.34 (m, 2H), 3.79-4.04 (br m, 4H), 3.94 (s, 3H), 3.98 (s, 3H), 7.80 (s, 1H), 7.85 (d, J=8.2 Hz, 1H), 8.12-8.16 (m, 1H), 8.17 (s, 1H), 8.77-8.79 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:24]=[CH:23][C:11]3[N:12]=[C:13]([C:15]4[O:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=4)[NH:14][C:10]=3[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1>CO.[Pd]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:24]=[CH:23][C:11]3[N:12]=[C:13]([C:15]4[O:16][C:17]([NH2:20])=[CH:18][CH:19]=4)[NH:14][C:10]=3[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc([N+](=O)[O-])o3)[nH]c2c1
Agent: [Pd]
Solvent: CO
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(N)o3)[nH]c2c1

Procedure:
A solution of 1 g of 5-methyl-6-[2-(5-nitro-2-furyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one in 30 ml of methanol is hydrogenated to completion on 0.2 g of 5% Pd-C at 20° and under 1 bar. The mixture is filtered, the filtrate is evaporated, and 5-methyl-6-[2-(5-amino-2-furyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one is obtained.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.[C:16]1([CH3:40])[CH:21]=[CH:20][C:19]([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)=[O:25])=[CH:18][CH:17]=1>>[C:16]1([CH3:40])[CH:17]=[CH:18][C:19]([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([N:7]3[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[C:10](=[O:11])[N:4]4[CH2:3][CH2:2][CH2:1][C@H:5]4[CH2:6]3)=[O:32])=[CH:29][CH:28]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)O)cc2)cc1
Reactant: O=C1c2ccccc2NC[C@@H]2CCCN12
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3C[C@@H]4CCCN4C(=O)c4ccccc43)cc2)cc1
Yield: 74.4 %

Procedure:
The same procedures used in Example 25 were repeated using (11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one prepared in Reference Example 24 and 4-[[2-(4-tolyl)benzoyl]amino]benzoic acid to give the title compound. Yield 74.4%.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]([CH2:16]Cl)=[CH2:15].[OH-].[Na+]>>[O:12]=[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:16][C:14]([Cl:13])=[CH2:15])[C:9]([OH:11])=[O:10]
Reactant: C=C(Cl)CCl
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C=C(Cl)CC(C(=O)C(=O)O)c1ccccc1

Procedure:
By the same operation as in Example 45, 1.64 g (10 mmoles) of phenylpyruvic acid was reacted with 0.11 g (10 mmoles) of 2,3-dichloropropene in a 1N aqueous solution of sodium hydroxide (20 ml, 20 mmoles) to give 2-oxo-3-phenyl-5-chloro-5-hexenoic acid as a pale yellowish white solid. It was converted to a methyl ester by using diazomethane, and then the methyl ester was purified by silica gel column chromatography. Methyl 2-oxo-3-phenyl-5-chloro-5-hexenoate as a pure product (1.87 g; yield 74 %) was obtained.
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1.[Cl:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[S:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[C:56](=[O:60])[N:55]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[CH2:54]4)=[CH:47][CH:46]=2)[CH:39]=[CH:40][CH:41]=1>>[Cl:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[S:69])[NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[C:56](=[O:60])[N:55]([C@@H:61]([CH:66]([CH3:67])[CH3:68])[C:62]([OH:64])=[O:63])[CH2:54]4)=[CH:49][CH:50]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(Cl)c4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(Cl)c4)cc3)ccc2C1=O
Yield: 92 %

Procedure:
The compound of example 267 was prepared analogous to compound of example 257 by hydrolysis of compound of example 266.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:12]=1)=[O:7])C>CO>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][C:11]2[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[NH:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc(CCc2ccc(Cl)cc2)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(CCc2ccc(Cl)cc2)c[nH]1

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 4.84 mmol) was added to a stirring, room temperature solution of 38 (0.2689 g, 0.968 mmol) in MeOH (2.42 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC (30 min): The product was concentrated and then dissolved in 5 mL H2O. The product was extracted with EtOAc, then the aqueous layer was made acidic (pH=2) with the dropwise addition of 10% aq. HCl. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 39 as a pale pink solid (Note: An undesired impurity has a retention time of 10.956 min by HPLC. 1H (CD3OD, 400 MHz): δ 10.89 (1H, broad s), 7.22 (2H, d, J=8.3 Hz), 7.13 (2H, d, J=8.3 Hz), 6.69 (1H, s), 6.66 (1H, s), 2.82 (2H, t, J=7.1 Hz), 2.73 (2H, t, J=7.1 Hz) ppm. 13C (CD3OD, 100 MHz): δ 164.48, 142.15, 132.49, 131.15, 129.21, 125.97, 123.60, 122.88, 116.44, 37.92, 29.70 ppm. DEPT (CDCl3, 100 MHz): CH2 carbons: 37.92, 29.70; CH carbons: 131.15, 129.21, 122.88, 116.44 ppm. HPLC: 9.996 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CC=C(F)C=2)=NOC=1C)=O)C>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)noc1C
Agent: CCOC(=O)c1c(-c2cccc(F)c2)noc1C
Product: Cc1onc(-c2ccc(F)cc2)c1CO
Yield: 72.4 %

Procedure:
As described for example 88d, 3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (3.0 g, 12 mmol) was converted, instead of 3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (1.8 g, 71%) which was obtained as a white solid. MS: m/e=208.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:6](=[O:13])[NH:5][C:4](=[O:14])[CH:3]=1.Cl.[N:16]([O-])=[O:17].[Na+]>CS(C)=O.O>[NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])([CH3:10])[CH3:12])[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:16]=[O:17]
Reactant: CC(C)(C)Cn1c(N)cc(=O)[nH]c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)Cn1c(N)c(N=O)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7.0 g of XXVI in 50 ml of DMSO was added 8 ml of 5N HCl and 2.7 g of NaNO2 dissolved in 5 ml of water. The reaction mixture was stirred 10 minutes at 50° C. and then 100 ml of water was added. The red crystals were filtered off. Yield 6 g (XXVII).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[CH2:5]2.N1CCCCC1.Cl[C:20]([C:22]([O:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])=[O:21]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:20]([C:22]([O:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])=[O:21])[NH:7][C:6](=[O:12])[CH2:5]2
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CC(=O)OC(C)(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -40 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A stirred solution of 5-fluoro-6-amino-1,3-dihydro-indol-2-one (410 mg, 2.46 mmol) in 10 ml of tetrahydrofuran was added with piperidine (0.3 ml). The mixture was cooled to −40° C. in an acetone-dry ice bath and added with acetic acid 1-chlorocarbonyl-1-methyl-ethyl ester (405 mg, 2.46 mmol) in 10 ml of tetrahydrofuran dropwise. Upon the completion of the addition, the resulting mixture was stirred at the room temperature overnight until the precipitate was formed. The solid was filtered, washed with water and recrystallized from methanol to give acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-1-methyl-ethyl ester (720 mg, 99.5%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1Br)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:31]=[N:32]O.N1C(C)=CC=CC=1C.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1[C:31]#[N:32])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Reactant: C=NO
Agent: [Cu]I
Solvent: Cc1cccc(C)n1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 95 °C

Procedure:
A stirred mixture of 3-acetylamino-4-(2'-bromo-4',6'-dinitrophenylazo)-N,N-diethylaniline(4.8 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.75 parts), 2,6-lutidine (2.15 parts), and nitrobenzene (150 parts) was heated to 95° C. for 10 hours when thin layer chromatography showed reaction to be complete. Isolation by the method of Example 1 gave 3-acetylamino-4-(2'-cyano-4',6'-dinitrophenylazo)-N,N-diethylaniline (infra red spectrum identical with that of authentic material). Similar results were obtained when the 2,6-lutidine was replaced by 2,4-lutidine (2.15 parts) and 2,4,6-collidine (2.4 parts).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:8]([OH:10])=[O:9])[S:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>ClCCl.CO>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=[O:9])[S:6][CH:7]=1)=[O:16]
Reactant: CSc1csc(C(=O)O)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1csc(C(=O)O)c1
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A stirred solution of 2.46 g (14.1 mmoles) of 4-methylthio-2-thiophenecarboxylic acid (prepared as described in Example 28 below) in 150 ml dichloromethane and 10 ml methanol was cooled to icebath temperature. A 120 ml dichloromethane solution of 2.82 g (13.9 mmoles) of m-chloroperoxybenzoic acid (technical grade, 80-85%) was slowly added to the cooled reaction solution. After 1 hour the reaction was essentially complete with a colorless precipitate forming. The precipitate was filtered and dried to give 1.18 g (6.20 mmoles) of desired compound as a colorless solid, m.p. 188-190° C. The concentrated mother liquor was chromatographed (silica gel) to give an additional 0.83 g (4.36 mmoles) of desired 4-methylsulfinyl-2-thiophenecarboxylic acid, total yield 75% (10.56 mmoles).
Reaction SMILES: [C:1]([C:4]1[C:5]([F:25])=[C:6]([N:10]([CH2:22][O:23][CH3:24])[S:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:26][Si:27](OS(C(F)(F)F)(=O)=O)([CH3:29])[CH3:28]>C(Cl)Cl>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[S:11]([N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([O:3][Si:27]([CH3:29])([CH3:28])[CH3:26])=[CH2:2])[C:5]=1[F:25])[CH2:22][O:23][CH3:24])(=[O:13])=[O:12]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COCN(c1cccc(C(C)=O)c1F)S(=O)(=O)c1cc(F)ccc1F
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C)c1cccc(N(COC)S(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
100 mg (0.27 mmol) of N-(3-acetyl-2-fluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide were dissolved in 4 mL of dry DCM under nitrogen atmosphere. The solution was cooled to 0° C. and 94 μL (0.65 mmol) of TEA and 106 μL (0.54 mmol) of trimethylsilyl-trifluoromethansulfonate were added. The solution was stirred 15 min at the same temperature and then diluted with DCM and washed rapidly with brine. The organic layer was dried over Na2SO4 and evaporated giving 2,5-difluoro-N-(2-fluoro-3-{1-[(trimethylsilyl)oxy]ethenyl}phenyl)-N-(methoxymethyl)benzenesulfonamide as a clear oil. The latter was re-dissolved in 4 mL of dry DCM under nitrogen atmosphere and 58 mg (0.32 mmol) of N-bromosuccinimide were added at 0° C. After 30 min the reaction was complete. The mixture was diluted with DCM and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated to give the title compound, which was used without any further purification.
Reaction SMILES: [C:1](Cl)(=[O:8])C1C=CC=CC=1.CO.C(N(CC)CC)C.[C:19]([N:27]1[CH2:32][CH:31]([OH:33])[CH:30]([OH:34])[CH:29]([OH:35])[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.O>[C:19]([N:27]1[CH2:28][CH:29]([OH:35])[CH:30]([OH:34])[CH:31]([OH:33])[CH:32]1[CH2:1][OH:8])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(c1ccccc1)N1CC(O)C(O)C(O)C1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CC(O)C(O)C(O)C1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27 ml of benzoyl chloride in 300 ml of ethyl acetate were added dropwise to a solution of 30 g of 1-desoxynojirimicin in 120 ml of H2O, 350 ml of CH3OH and 30 ml of triethylamine at 30°-35° C. The mixture was subsequently stirred at room temperature for 1 hour and a further 15 ml of triethylamine and 13.5 ml of benzoyl chloride in 150 ml of ethyl acetate were then added dropwise at 30°-35° C. After stirring for 1 hour, the reaction mixture was evaporated to dryness in vacuo. The residue was taken up in water and the aqueous mixture was extracted with ether. The aqueous phase was again concentrated to dryness in vacuo and the residue was stirred with acetone. The triethylamine hydrochloride which has precipitated was filtered off. Residual triethylamine hydrochloride was separated off by again concentrating the acetone solution and taking up the residue in a little acetone. After removal of the solvent, the product was obtained as a resin. After thorough drying, this resin could be employed in the next stage. Yield: 56 g of crude N-benzoyl-3,4,5-trihydroxypiperidine. After standing for a relatively long period, the compound crystallised from acetone. Melting point: 159° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([S:11][CH3:12])[C:5]2=[N:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[N:6]3[CH:7]=[CH:8][N:9]=[C:10]([S:11][CH3:12])[C:5]3=[N:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CSc1nccn2c(Br)cnc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cnc3c(SC)nccn23)cc1
Temperature: 88 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
A mixture of 3-Bromo-8-methylsulfanyl-imidazo[1,2-a]pyrazine (1.06 g, 4.33 mmol), 4-methoxybenzeneboronic acid (0.79 g, 5.2 mmol), Pd(OAc)2 (0.05 g, 0.22 mmol), (oxidi-2,1-phenylene)bis(diphenylphosphine) (233 mg, 0.43 mmol), 1.5M K2CO3 in water (5.8 mL, 8.66 mmol) and DMF (12.8 mL) is stirred at 88° C. for 16 h. Then allowed to cool, filtered through cotton, diluted with EtOAc and washed with water and brine. The organic layer is dried with MgSO4 anh., filtered and evaporated. The crude is purified by column chromatography using a gradient of (Pet. Ether 40-60/AcOEt: 7/3 to 1/1) to give 3-(4-Methoxy-phenyl)-8-methylsulfanyl-imidazo[1,2-a]pyrazine as a pale yellow solid (1.0 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26]#[C:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:18]=1)[CH2:7]2
Reactant: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(Oc4ccccc4)cc2)C3=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CCN(CCCc2cc(Cl)c3c(c2)CN(Cc2ccc(Oc4ccccc4)cc2)C3=O)CC1
Yield: 47.6 %

Procedure:
A mixture of 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.073 g, 0.15 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.035 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79 (m, 2H), 2.22-2.60 (m, 13H), 2.66 (t, 2H), 4.22 (s, 2H), 4.74 (s, 2H), 6.86-7.38 (m, 11H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C[O-].[Mg+2].C[O-].O1CCCC1.[CH2:20]([O:38][C:39]1[S:43][C:42](C(N2C=CN=C2)=O)=[CH:41][CH:40]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH:31]=[CH:32][CH2:33][CH:34]=[CH:35][CH2:36][CH3:37]>CO>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([C:42]1[S:43][C:39]([O:38][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH2:30][CH:31]=[CH:32][CH2:33][CH:34]=[CH:35][CH2:36][CH3:37])=[CH:40][CH:41]=1)=[O:8])[CH3:2]
Reactant: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)n2ccnc2)s1
Reactant: CCOC(=O)CC(=O)O
Agent: C[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CO
Product: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)CC(=O)OCC)s1

Procedure:
A mixture of 14.5 g (0.110 mole) of malonic acid mono ethyl ester, 19.0 g (0.220 mole) of magnesium methoxide and anhydrous tetrahydrofuran is heated with stirring under nitrogen allowing the methanol produced to distill off. To this mixture is added 45.0 g (0.105 mole) of N-[5-(9,12,15-octadecatrien-1-yloxy)-2-thenoyl]imidazole with stirring and cooling on an ice bath for four hours. The solvent is removed and the residue diluted with ice-concentrated HCl (1:1) solution to give 5-(9,12,15-octadecatrien-1-yloxy)then-2-oylacetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH3:13][N:14]([O:15][CH3:16])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[NH2:1]
Reactant: CNOC
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Cl)cc1N
Temperature: 25 °C

Procedure:
2-Amino-4-chlorobenzoic acid (3 g) and N,O-dimethylhydroxylamine hydrochloride (1.9 g) were dissolved in a mixture of methylene chloride (40 ml) and N,N-dimethylformamide (4 ml). To the solution were added, while stirring at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-hydrochloride (3.6 g) and triethylamine (1.4 g). The mixture was stirred for 90 minutes, which was then concentrated under reduced pressure. To the concentrate were added ethyl acetate (100 ml) and-water (100 ml). The mixture was shaken, The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was purified by means of a silica gel chromatography to give N-methyl-N-methyloxy-2-amino-4-chlorobenzamide as a yellow oily product (3.0 g).