Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][N:4]=[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([NH:8][CH3:9])=[O:7].[CH2:16]([O:20][C:21](=[O:31])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Cl)[N:24]=1)[CH2:17][C:18]#[CH:19].O>CN(C=O)C.CCOC(C)=O>[CH3:9][NH:8][C:6](=[O:7])[C:5](=[N:4][O:3][CH2:29][C:25]1[N:24]=[C:23]([NH:22][C:21](=[O:31])[O:20][CH2:16][CH2:17][C:18]#[CH:19])[CH:28]=[CH:27][CH:26]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CCCOC(=O)Nc1cccc(CCl)n1
Reactant: CNC(=O)C(=NO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCCOC(=O)Nc1cccc(CON=C(C(=O)NC)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
49 mg (1.22 mmol) of sodium hydride were added to a solution of 200 mg (1.12 mmol) of 2-(hydroxyimino)-N-methyl-2-phenylacetamide (only Z diastereoisomer in 5 ml of DMF, and the suspension was stirred for 30 minutes at room temperature. Then, a solution of 268 mg (1.12 mmol) of but-3-in-1-yl[6-(chloromethyl)pyridin-2-yl]carbamate in 5 ml was added. The mixture was stirred for 3.5 hours at room temperature and then poured into 70 ml of water and admixed with 50 ml of AcOEt. The organic phase was separated off and dried over MgSO4. After removing the solvent, this gave 388 mg (95% purity, 88:12 mixture of Z and E diastereoisomers) of but-3-yn-1-yl{6-[({[2-(methylamino)-2-oxo-1-phenylethylidene]amino}oxy)methyl]pyridin-2-yl}-carbamate.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Br:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1.C(#N)C>CC(C)=O>[Br-:9].[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N+:6]2[C:5]([CH3:7])=[C:4]([CH3:8])[O:3][C:2]=2[CH3:1])=[CH:12][CH:13]=1)([OH:19])=[O:18]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: Cc1nc(C)c(C)o1
Solvent: CC(C)=O
Solvent: CC#N
Product: Cc1oc(C)[n+](Cc2ccc(C(=O)O)cc2)c1C
Product: [Br-]
Temperature: 25 °C
Yield: 66.2 %

Procedure:
2,4,5-Trimethyloxazole (11.66 g), α-bromo-p-toluic acid (21.5 g), and dry acetonitrile (100 ml) were combined and refluxed for 14 hours under nitrogen with constant stirring. Upon cooling to room temperature, the reaction mixture solidified. The solid was diluted with 100 ml acetone and filtered. The collected solid was slurried in 400 ml refluxing acetone for 20 minutes and filtered while hot. The collected solid was again slurried in 400 ml refluxing acetone and filtered while hot. This solid was washed with 100 ml acetone, then 100 ml ligroin P950 and dried to yield 21.6 g 3-(4-carboxybenzyl)-2,4,5-trimethyloxazolium bromide (Intermediate F).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:17])[C:13]([NH2:16])([CH3:15])[CH3:14])=[N:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:17])[C:13]([NH:16][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([F:31])=[CH:33][CH:34]=2)([CH3:15])[CH3:14])=[N:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(NC(=O)C(C)(C)N)nc1-c1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc(NC(=O)C(C)(C)NC(=O)c2ccc(F)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-Amino-2-methyl-propionylamino)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (249 mg, 0.748 mmol), triethylamine (300 uL. 2.16 mmol) and 4-fluorobenzoyl chloride (135 uL, 1.13 mmol) in dichloromethane (3 mL) was stirred at RT for 2 h and partitioned between ethyl acetate and aq. K2CO3. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 456.1 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]([CH3:11])=[C:7]([CH3:10])[N+:8]=2[O-])[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:14].[CH2:17]([Cl:19])[Cl:18]>>[Cl:14][CH:1]([C:4]1[O:5][C:6]([CH3:11])=[C:7]([CH3:10])[N:8]=1)[CH2:2][CH2:17][Cl:19].[Cl:18][CH2:10][C:7]1[N:8]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[O:5][C:6]=1[CH3:11]
Reactant: ClCCl
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(C2CC2)[n+]([O-])c1C
Product: Cc1nc(C(Cl)CCCl)oc1C
Product: Cc1oc(C2CC2)nc1CCl

Procedure:
In step b], both products were isolated and characterized as follows: 36.27 g of 2-cyclopropyl-4,5-dimethyl-oxazole 3-oxide (152 mmol, prepared from cyclohexanecarboxaldehyde and diacetyl monooxime as described above) was dissolved in 555 ml of CH2Cl2 and treated dropwise with 16.75 ml of POCl3 (1.2 eq.). The reaction mixture was refluxed over night and then quenched by carefully pouring onto crashed ice/3N NaOH. Separation of the layers, additional extraction of the aqueous phase with CH2Cl2, washing with Na2CO3 and water, drying of the combined organic phase over sodium sulfate, evaporation of the solvents, and, finally, flash chromatography (SiO2, hexane/AcOEt=9/1) yielded in the less polar fractions 6.53 g of 2-(1,3-dichloro-propyl)-4,5-dimethyl-oxazole (MS: 207.1, 209.1 (M+)) and in the more polar ones 10.33 g of 4-chloromethyl-2-cyclopropyl-5-methyl-oxazole as colorless liquid, exhibiting in the 1H-NMR the typical signals at 4.42 ppm (s, 2H), 2.27 (s, 3H), 1.97–2.03 ppm (m, 1H), 0.98–1.04 ppm (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([CH2:15][CH3:16])[CH2:9]2)[C:3](O)=[O:4].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[CH3:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([CH2:15][CH3:16])[CH2:9]2)[C:3]([Cl:19])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CCC1Cc2ccc(C(C)C(=O)O)cc2C1
Solvent: c1ccccc1
Product: CCC1Cc2ccc(C(C)C(=O)Cl)cc2C1

Procedure:
A solution of 57 g of 2-methyl-(2-ethylindan-5-yl)acetic acid and 40 ml of thionyl chloride in 200 ml of benzene is heated under reflux for 2 hours. The solvent and the excess thionyl chloride are then evaporated off in vacuo. The resulting oil is then distilled in vacuo. 56 g of 2-methyl-(2-ethylindan-5-yl)-acetic acid chloride are thus recovered in the form of a liquid:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19]C(=O)C)=[CH:15][CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1>[OH-].[Na+].CO>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1ccc(Nc2ncnc3cc(N)ncc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(Nc2ncnc3cc(N)ncc23)cc1
Yield: 33.4 %

Procedure:
A solution of 7-amino-4-(4-acetamidoanilino)pyrido[4,3-d]pyrimidine (0.30 g, 1.02 mmole) in aqueous NaOH (2 M, 10 mL) and MeOH (10 mL) is stirred at 100° C. for 7 h. The resulting product is chromatographed over alumina (3-4% EtOH/CHCl3) to give 7-amino-4-(4-aminoanilino)pyrido[4,3-d]pyrimidine (86 mg, 33%) as an orange solid. 1H NMR (DMSO) δ 9.58 (1H, brs), 9.24 (1H, s), 8.25 (1H, s), 7.31 (2H d, J=8.6 Hz), 6.58 (2H, d, J=8.6 Hz), 6.48 (2H, brs), 6.39 (1H, s), 5.00 (2H, brs).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[OH-:9].[Na+].N#N>O>[C:1]([OH:8])(=[O:7])[C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:9]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: [OH-]
Agent: N#N
Agent: [Na+]
Solvent: O
Product: O=C(O)C[C@H](O)C(=O)O

Procedure:
A reaction solution containing maleic acid (116 g) and 5N sodium hydroxide (200 ml) (having a total volume of 1,000 ml by adding water), which had been previously subjected to N2 substitution by carrying out agitation while blowing N2 gas in it for 30 minutes, was transferred into a jar fermenter having a volume of 3 L. The microbial cells of the both species (IFO 12669 strain: 20 g, AB-41 strain: 50 g), which had been recovered in Example 1 and in the item (1) described above, were added thereto, followed by agitation while supplying N2 at a velocity of 0.02 vvm to carry out a reaction at 30° C. for 36 hours with sealing. L-Malic acid was obtained in an amount of 104 g/L. Calcium chloride was added to the obtained solution of sodium L-malate to precipitate calcium malate, followed by washing with water. After that, L-malic acid was separated by using an ion exchange resin, and dried. Thus crystals of L-malic acid were obtained. The obtained crystals had an amount of 90 g.
Reaction SMILES: C[Si](I)(C)C.[OH:6][NH:7][C:8](=[O:42])[C@H:9]([NH:25][S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)(=[O:28])=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OCC1C=CC=CC=1)=O.CO>C(#N)C>[OH:6][NH:7][C:8](=[O:42])[C@H:9]([NH:25][S:26]([N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)(=[O:28])=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: O=C(NCCCC[C@@H](NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1)C(=O)NO)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: NCCCC[C@@H](NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1)C(=O)NO
Temperature: 25 °C
Yield: 43.5 %

Procedure:
Trimethylsilyl iodide (0.026 ml, 0.19 mmol) was added to a solution of N-hydroxy-6-(benzyloxycarbonyl)amino-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-hexanoamide (103 mg, 0.19 mmol) [prepared as described in Example 17, Step 3] in acetonitrile (2 ml) at 0° C. The reaction mixture was allowed to warm to RT, and additional trimethylsilyl iodide (0.47 mmol, 0.065 ml) was added in 0.5 equiv. portions over 2.5 h. Methanol (1.0 ml) was added and the reaction mixture was concentrated in vacuo. The residue was chromatographed (SiO2, 2%-10% methanol/methylene chloride) to give N-hydroxy-6-amino-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}hexanoamide (43.5%) as tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH:25]=[CH2:26])(=[O:24])=[O:23])=[CH:17][CH:16]=3)=[CH:10][C:9]=2[CH3:27])=[O:7])=[CH:4][CH:3]=1.[CH2:30]([N:32](CC)[CH2:33]C)C.Cl.CNC.CN(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH2:25][CH2:26][N:32]([CH3:33])[CH3:30])(=[O:23])=[O:24])=[CH:17][CH:16]=3)=[CH:10][C:9]=2[CH3:27])=[O:7])=[CH:28][CH:29]=1
Reactant: CCN(CC)CC
Reactant: C=CS(=O)(=O)Nc1ccc(Cc2cc(C)c(C(=O)c3ccc(Cl)cc3)n2C)cc1
Agent: CN(C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(Cc2ccc(NS(=O)(=O)CCN(C)C)cc2)n(C)c1C(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 93 %

Procedure:
N-{4-[5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]phenyl}-ethenesulfonamide (250 mg, 0.583 mmol) [prepared as in Example 19], was dissolved in DMF (1.1 ml). Triethylamine (0.11 ml, 0.8 mmol), followed by dimethylamine hydrochloride (36 mg, 0.69 mmol), was added and the reaction mixture was stirred for 1 h. A second batch of trimethylamine and dimethyamine hydrochloride was added and the stirring was continued overnight. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was separated and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was then dissolved in ethyl acetate, after which ethanolic HCl was added to give N-{4-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]phenyl}-2-(dimethyl-amino)ethanesulfonamide (257 mg, 86%) as the hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:37]=[CH:38][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:25][CH:24]=3)[S:9][C:10]=2[N:11]=1
Reactant: Cc1ccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)cc1
Reactant: COc1ccc(OCC(=O)O)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(CCc5ccc(C)cc5)nc34)CC2)cc1
Yield: 68 %

Procedure:
This compound was prepared from 2-(4-methylphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 68%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][C:44]1[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=1[CH3:50]>O.ClCCl.C(N(CC)CC)C>[OH:52][C:45]1[C:44]([CH2:43][NH:42][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:12])=[C:2]([CH3:1])[CH:3]=2)=[C:49]([CH3:50])[CH:48]=[C:47]([CH3:51])[N:46]=1
Reactant: Cc1cc(C(=O)O)ccc1C(C)Oc1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)c(C)c2)c(O)n1
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 3-methyl-4-(1-phenoxyethyl)benzoic acid (95 mg, 0.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1 mmol), N-hydroxybenzotriazole (135 mg, 1 mmol), triethylamine (0.2 mL) and dichloromethane (5 mL) were stirred at 25° C. for half an hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-3-methyl-4-(1-phenoxyethyl)benzamide as a white solid (100 mg, 51%). LRMS (M+H+) m/z: calcd. 390.19. found 390. 1H NMR (300 MHz, d6-DMSO): δ 11.47 (s, 1H), 8.23 (t, J=4.8 Hz, 1H), 7.65-7.58 (m, 2H), 7.35 (d, J=8.1 Hz, 1H), 7.18 (t, J=8.1 Hz, 2H), 6.86-6.73 (m, 3H), 5.84 (s, 1H), 5.60 (q, J=6.3 Hz, 1H), 4.27 (d, J=4.8 Hz, 2H), 2.41 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.51 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:18][CH2:19][CH2:20]Br.O>CS(C)=O>[CH2:18]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[CH2:19][CH3:20]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCOc1ccc(OCc2ccccc2)cc1
Yield: 97.1 %

Procedure:
In 75 ml of dimethylsulfoxide (DMSO) was dissolved 7.5 g (37.5 mmol) of 4-(benzyloxy)phenol, and an aqueous solution of sodium hydroxide (NaOH/H2O: 1.65 g/15 ml) was added thereto. The mixture was stirred until dissolving homogeneously. Next, 5.0 g (40.7 mmol) of n-propyl bromide was added to the mixture, and the resultant mixture was subjected to a reaction at a room temperature for 24 hours. The reaction mixture was poured into 1 L of an iced water, and a solid was formed by stirring. The resultant solid was collected by filtration, dried, and recrystallized from methanol to give 8.82 g (36.4 mmol) of 1-(n-propyloxy)-4-benzyloxybenzene.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Reactant: C1CCNC1
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCCC1
Yield: 17.1 %

Procedure:
To the intermediate 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea (225 mg, 0.426 mmol) from Example 79A was added pyrrolidine (0.105 mL, 1.278 mmol) in the manner described in Example 80 to yield 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea (41 mg, 18%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 7.65-7.50 (m, 2H), 7.35-7.05 (m, 4H), 6.50 (s, 1H), 4.30 (m, 2H), 4.00-3.75 (m, 7H), 2.55 (m, 2H), 1.98 (m, 4H), 1.30 (s, 9H); LC-MS (ESI)m/z 563 (M+H)+.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]1[CH2:26][CH:25]([C:27]([NH2:29])=O)[CH2:24][CH2:23][N:18]12.N1C=CC=CC=1>O1CCOCC1>[CH:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]1[CH2:26][CH:25]([C:27]#[N:29])[CH2:24][CH2:23][N:18]12
Reactant: NC(=O)C1CCn2c(cc3ccccc32)C1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: N#CC1CCn2c(cc3ccccc32)C1
Yield: 53.9 %

Procedure:
25.7 g (126 mmol) of trifluoroacetic anhydride were added dropwise to a stirred suspension of 26.5 g (123 mmol) of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxamide and 23.4 g (300 mmol) of pyridine in 500 ml of dry dioxane at 10° C. After completion of the addition, the solvent was removed under reduced pressure and the residue was crystallized from methanol to give 13 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8(RS)-carbonitrile, as a light tan solid of melting point 106°-109° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.CC[O-].[Na+].[CH3:17][N:18]([CH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26]N)=O)[CH3:19].Cl.CCOCC>C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[NH:10][N:26]=[C:24]([C:23]3[CH:22]=[C:21]([CH:30]=[CH:29][CH:28]=3)[CH2:20][N:18]([CH3:19])[CH3:17])[N:9]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C(=N)N)cc1
Reactant: CN(C)Cc1cccc(C(=O)NN)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2nc(-c3cccc(CN(C)C)c3)n[nH]2)cc1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a stirred ethanolic suspension of 4-methoxybenzamidine hydrochloride salt (280 mg, 1.5 mmol, 1.5 eq.) was added over 3 minutes 1.2N NaOEt in ethanol (1.7 ml, 2 eq.) and stirring was continued for 30 min. at r.t. 3-Dimethylaminomethyl-benzoic acid hydrazide (193 mg, 1 mmol) in ethanol was then added at 20° C. and the mixture heated at reflux for 24 hrs. Upon cooling the product mixture was filtered, the solvent was evaporated and the residue subjected to preparative reversed phase-HPLC purification using a YMC ODS-AQ column (20×50 mm) and a (0.1% trifluoroacetic acid) water-acetonitrile gradient (25 ml/min.). The pure fractions were concentrated and the product obtained was converted to the hydrochloride salt by addition of excess 2N HCl/ether solution. Solvent evaporation and high vacuum drying afforded the title compound (86 mg, 0.25 mmol, 25% yield) as a white foam. MS: m/e=309.4 (M+H+).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1C=CN=C1)=[O:2].[F:13][C:14]([F:34])([F:33])[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][CH:28]([O:31]N)[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[CH2:35](N(CC)CC)[CH3:36].C1(CN)CC1>C(Cl)Cl>[CH:11]1([CH2:12][NH:8][C:1]([NH:3][O:31][CH:28]2[CH2:29][CH2:30][N:25]([S:22]([C:19]3[CH:20]=[CH:21][C:16]([O:15][C:14]([F:34])([F:33])[F:13])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[CH2:26][CH2:27]2)=[O:2])[CH2:36][CH2:35]1
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reactant: CCN(CC)CC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: NCC1CC1
Solvent: ClCCl
Product: O=C(NCC1CC1)NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 39.2 %

Procedure:
1,1′-Carbonyldiimidazole (227 mg, 1.4 mmol) was added to a solution of O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl) hydroxylamine (238 mg, 0.70 mmol) and triethylamine (141 mg, 1.4 mmol) in CH2Cl2 (6 ml) and stirred at room temperature for 17 hours. Cyclopropylmethanamine (75 mg, 1.05 mmol) was added to the reaction mixture and stirred at room temperature for another 7 hours. The reaction mixture was quenched with H2O (10 ml) and aqueous 1 N HCl solution (pH=3) and extracted with CH2Cl2 (70 ml×3). The combined organic phase was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/n-hexane: 33/67) to give 1-(cyclopropylmethyl)-3-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)urea (120 mg, 39%) as a white solid: LCMS: 438 [M+1]+. 1H NMR (DMSO-d6) δ: 0.14 (m, 2H), 0.35 (m, 2H), 0.90 (m, 1H), 1.74 (m, 2H), 1.86 (m, 2H), 2.85 (m, 4H), 3.20 (m, 2H), 3.65 (m, 1H), 6.71 (m, 1H), 7.65 (m, 2H), 7.90 (m, 2H), 8.86 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([F:8])[CH:7]=1.CN([CH:19]=[O:20])C1C=CC=CC=1>C(OCC)C.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH:19]=[O:20]
Reactant: CN(C=O)c1ccccc1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc(F)c1

Procedure:
The 3,5-difluorobenzaledehyde used as a starting compound can be prepared as follows: 3,5-difluorophenylmagnesiumbromide can be prepared as described by A. Roe and W. F. Little: J.Org.Chem. 20 (1955) 1577. A solution of 3,5-difluorophenylmagnesiumbromide in diethylether is added dropwise to a solution of N-methylformanilide in tetrahydrofuran. By working up this reaction mixture, 3,5-difluorobenzaldehyde is obtained. b55 =86°-88° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C.[CH:26]([C:29]1[NH:30][CH:31]=[CH:32][N:33]=1)([CH3:28])[CH3:27]>CN(C=O)C.O>[CH:26]([C:29]1[N:30]([CH2:2][CH2:3][O:4][C:5](=[O:18])[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=2[CH:15]([CH3:17])[CH3:16])[CH:31]=[CH:32][N:33]=1)([CH3:28])[CH3:27]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1C(=O)OCCBr
Reactant: CC(C)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1cc([N+](=O)[O-])ccc1C(=O)OCCn1ccnc1C(C)C
Yield: 43.4 %

Procedure:
2-Isopropyl-4-nitro-benzoic acid 2-bromo-ethyl ester (0.19 g, 0.6 mmol) was dissolved in DMF (5 mL), then triethylamine (0.5 mL, 3.6 mmol) and 2-isopropylimidazole (0.2 g, 1.8 mmol) were added. The mixture was heated at reflux for 15 h then allowed to cool, diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (60-120 mesh), eluting with ethyl acetate, to afford 2-isopropyl-4-nitro-benzoic acid 2-(2-isopropyl-imidazol-1-yl)-ethyl ester (90 mg, 43%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[C:5]([CH3:12])=[CH:4][N+:3]=1[O-:13].C([Cl:17])(=O)C>>[Cl:17][C:6]1[C:5]([CH3:12])=[CH:4][N+:3]([O-:13])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: CC(=O)Cl
Reactant: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Product: Cc1c[n+]([O-])c(C)c(C)c1Cl
Reaction time: 0.33 h

Procedure:
The 2,3,5-trimethyl-4-nitropyridine 1-oxide (13.4 g, 73.6 mmol) obtained in the step (11c) was added to acetyl chloride (80 ml, 1.125 mmol) at −30° C. in a nitrogen atmosphere. The mixture was stirred at −30° C. to room temperature for 4 hours and 20 minutes. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography (NH silica gel: 300 g, elution solvent: heptane, heptane/ethyl acetate=50/50, ethyl acetate, ethyl acetate/methanol=10/1) to obtain fractions containing a pure product of the title compound and fractions containing a crude product of the title compound.