Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].F[CH:29](F)[C:30](O)=O>>[CH2:29]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH:23]([CH3:25])[CH3:24])[CH3:30]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C(C)C)CO3
Reactant: O=C(O)C(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
Compound 125 was prepared according to General Method 6 (EXAMPLE 3) from (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (30 mg, 0.1 mmol) and NaBH4 pellets (large excess, >10 equiv) in 5 mL difluoroacetic acid (0.02 M) stirred at rt for 12 h, to afford 28 mg (79%) of (3R)-4-ethyl-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. 1H NMR (500 MHz, CDCl3) 7.44 (d, J=9.3, 1H), 7.30 (d, J=9.3, 1H), 7.21 (s, 1H), 5.98 (m, 1H), 5.49 (m, 1H), 4.55 (dd, J=10.7, 2.4, 1H), 3.84 (dd, J=10.7, 2.4, 1H), 3.79 (m, 1H), 3.54 (m, 1H), 2.93 (m, 1H), 1.84 (m, 1H), 1.39 (d, J=6.3, 3H), 1.38 (d, J=6.3, 3H), 1.00 (d, J=9.8, 3H), 0.99 (d, J=9.8, 3H). This material (13 mg, 0.03 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 3 mL acetic acid and 3 mL concentrated HCl heated at 90° C. for 4 h to afford 8 mg (70%) of Compound 125, after purification by column chromatography (3:1 hexanes: EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 11.59 (bs, 1H), 7.15 (d, J=8.8, 1H), 7.13 (s, 1H), 6.94 (d, J=8.8, 1H), 5.96 (m, 1H), 4.55 (dd, J=10.7, 1.3, 1H), 3.87 (dd, J=10.7, 2.4, 1H), 3.74 (m, 1H), 3.50 (m, 1H), 2.91 (bd, J=8.8, 1H), 1.80 (m, 1H), 1.00 (d, J=11.7, 3H), 0.97 (d, J=11.7, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[NH2:2].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClC1C=CC=CC=1>[CH3:5][N:2]=[C:1]=[O:3].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:5]1([O:11][C:1](=[O:3])[NH2:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(=O)Cl
Solvent: Clc1ccccc1
Solvent: Oc1ccccc1
Product: CN=C=O
Product: NC(=O)Oc1ccccc1

Procedure:
Example 2 is modified to the effect that the N-methyl-carbamic acid chloride solution described in Example 2 as solution 302 is freed by distillation from free methylisocyanate 411 prior to the reaction with phenol, so that 523 g per hour of a 50% by weight solution of carbamic acid chloride in chlorobenzene, corresponding to 2.8 mol of carbamic acid chloride, are produced in the side stream 404 and 1495 g per hour of pure chlorobenzene are produced in the sump 403. The concentrated carbamic acid chloride solution 404 was mixed with 400 g of a circulated 80% by weight solution 405 of phenol in chlorobenzene, corresponding to 3.4 mol of phenol, and was converted into the carbamic acid aryl ester solution 406 or 106 to be split up with separation of hydrogen chloride 412. 172 g of a 90% by weight chlorobenzolic methyl isocyanate solution 108 or 408 and 664 g of a 50% by weight chlorobenzolic phenol solution 107 or 407 containing a further 1.9% by weight of unmodified carbamic acid phenyl ester are obtained per hour during the decomposition of this solution 106 or 406. The methyl-isocyanate solution 108 or 408 is introduced into the upper section of the distillation column D and there separated into pure product 411 and solvent in 404 and 403 respectively. A total of 222 g per hour, corresponding to a 97% yield of methyl-isocyanate, are obtained. The phenol solution 107 or 407 is concentrated in a separate distillation column by distilling off pure chlorobenzene 409 to an 80% by weight phenol content and fed back again into the phenol cycle 405. The chlorobenzene 409 produced in the process is fed back to the beginning of the process.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]2[C:21](=[O:22])[NH:20][C:19]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:18]=3[S:17]2(=[O:30])=[O:29])[CH2:9][CH2:8]1.[CH3:31]N(C=O)C.[H-].[Na+].CI>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]2[C:21](=[O:22])[N:20]([CH3:31])[C:19]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:18]=3[S:17]2(=[O:29])=[O:30])[CH2:11][CH2:12]1
Reactant: COc1ccc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ncccn3)CC1)C(=O)N2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1ccc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ncccn3)CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.028 mol of 2-(3-(4-(2-pyrimidinyl)-1-piperazinyl)propyl)-7-methoxy-1,2,4-benzothiadiazin-3(4H)one 1,1-dioxide is dissolved in 150 mol of absolute DMF, and 0.028 mol of sodium hydride is added to the solution and the mixture is stirred at room temperature for 0.25 hour. Then 0.028 mol of methyl iodide is added and the mixture is stirred at 25° C. for a further 2 hours. The product is precipitated as crystals by dropwise addition of a total of 18 ml of water. It is purified by crystallisation from isopropanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH3:11])[CH3:2].C1(C)C=C(C)C=C(C)C=1S(ON)(=O)=O.CO[CH:29](OC)[N:30](C)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:7]([N:30]=[CH:29][CH:11]=2)[CH:8]=[CH:9][CH:10]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1cccnc1C
Reactant: COC(OC)N(C)C
Agent: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccn2nccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To a clear solution of 2-methyl-nicotinic acid ethyl ester (50.6 g, 306 mmol) in anhydrous methylene chloride (200 mL) was added O-mesitylenesulfonylhydroxylamine (73 g, 337 mmol; prepared according to a literature procedure described in Krause; J. G., Synthesis 1972, 140); in portions at 0° C. The solution obtained was stirred at 0° C. for 15 min, and then at rt for 1 h. Concentration under reduced pressure gave a yellow solid. After the solid was dissolved in anhydrous DMF (300 mL), N,N-dimethylformamide dimethyl acetal (122 mL, 918 mmol) was added at 0° C. The mixture was stirred at 0° C. for 15 min, and then at 90° C. for 3 h. The reaction mixture was concentrated under reduced pressure, mixed with H2O (200 mL), and extracted with Et2O (3×180 mL). The combined organic solutions were washed sequentially with brine (50 mL), 1N aqueous HCl (50 mL), and brine (50 mL), and dried over Na2SO4. Filtration through a SiO2 column, which was then eluted with 30% EtOAc in heptane, gave compound 777A (43.3 g, 74%) as a yellow solid. HPLC: 80% at 3.20 min (retention time) plus 20% corresponding methyl ester at 2.83 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 191 [M+H]+.
Reaction SMILES: C(#N)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][CH:10]=[C:9]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:27])=[CH:21][CH:20]=1.[CH3:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][CH:10]=[C:9]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=3[CH3:38])[CH2:31][CH2:30]2)=[O:27])=[CH:21][CH:20]=1
Reactant: Cc1ccccc1CBr
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCNCC4)cc3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5C)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Acetonitrile (10 ml) was added to the compound (1) (139 mg), 2-methylbenzyl bromide (0.03 ml), and potassium carbonate (81 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (46 mg, yield 45%).
Reaction SMILES: [O:1]([CH3:11])[C@H:2]1[O:10][CH2:9][C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4].C(N(S(F)(F)[F:18])CC)C>>[F:18][C@H:7]1[CH2:9][O:10][C@@H:2]([O:1][CH3:11])[C@@H:3]([OH:4])[C@H:5]1[OH:6].[O:1]([CH3:11])[C@H:2]1[O:10][CH2:9][C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: CCN(CC)S(F)(F)F
Agent: CO[C@H]1OC[C@@H](O)[C@H](O)[C@@H]1O
Product: CO[C@@H]1OC[C@H](F)[C@H](O)[C@@H]1O

Procedure:
A known compound, methyl α-D-lyxopyranoside [Compound 50] of the formula ##STR90## is reacted with diethylaminosulfur trifluoride [(C2H5)2 NSF3 ] to fluorinate selectively only the 4-hydroxyl group of Compound 50, whereby there is produced methyl 4-deoxy-4-fluoro-α-L-ribopyranoside [Compound 51] of the formula ##STR91## as a 4-deoxy-4-fluoro derivative of Compound 50, with accompanying reversion of the steric configuration of the starting compound.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6](CS([O-])(=O)=O)[CH2:5][O:4]2)[CH2:2]1.[NH2:13]CCCO.[CH2:18]1C[O:21][CH2:20][CH2:19]1>>[CH2:2]1[C:3]2([CH2:7][CH:6]([NH:13][CH:20]([OH:21])[CH2:19][CH3:18])[CH2:5][O:4]2)[CH2:1]1
Reactant: C1CCOC1
Reactant: NCCCO
Reactant: O=S(=O)([O-])CC1COC2(CC2)C1
Product: CCC(O)NC1COC2(CC2)C1
Yield: 93 %

Procedure:
To a solution of (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (336 mg, 1.75 mmol) in dry THF (3 mL) was added 3-aminopropan-1-ol (656.3 mg, 8.75 mmol, TCI). The reaction was refluxed overnight. The mixture was concentrated in vacuo to give a brown residue, which was chromatographed with a silica gel column (8:1 (v/v) EtOAc/MeOH) to give the title compound as pale yellow oil (280 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C:12](OC)=[O:13].[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH2:12][OH:13]
Reactant: COC(=O)c1c(F)ccc2nn(C)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc2c(CO)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of methyl 5-fluoro-2-methyl-2H-indazole-4-carboxylate (4.10 g, 19.7 mmol) in tetrahydrofuran (197 mL) was slowly added a solution (1 M, 59.1 mL, 59.1 mmol) of diisobutylaluminum hydride in hexane at −78° C., and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (3.30 g, yield 93%).
Reaction SMILES: OC1C=C([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3COCC[Si](C)(C)C)[CH3:21])C=CC=1.Br[CH2:41][C:42]([NH2:44])=[O:43].Cl.[OH:46][C:47]1[CH:48]=[C:49](N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)[CH:50]=[CH:51][CH:52]=1>CC#N.CO>[CH3:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17](=[O:18])[N:8]([CH:41]([O:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:42]([NH2:44])=[O:43])[C:9]([CH:20]([NH:22][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)[CH3:21])=[N:10]2
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Reactant: NC(=O)CBr
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(O)c3)c(=O)c12
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(C(Oc3ccccc3)C(N)=O)c(=O)c12

Procedure:
Compound 126 (300 mgs, 0.54 mmol) was treated with 2 bromo acetamide using the procedure outlined above for compound 127. The reaction was under reflux for 24 hrs in CH3CN. This intermediate was treated with 4N HCl in MeOH for 1 hour, following the procedure described for compound 121 (step D), to provide compound 145. m/z=471 (M+H). The structure of compound 145 is shown below.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@@H:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:11][CH:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCC[C@@H](C)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCCCCCC(C)OC(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 43 %

Procedure:
27.6 g of p-hydroxybenzoic acid and 39.0 g of (R)-2-octanol were refluxed for 10 hours in 300 ml of benzene in the presence of 0.5 ml of conc. sulfuric acid. Then, the reaction solution was cooled to the room temperature, and then concentrated and purified by column chromatography, to obtain 21.5 g of p-hydroxybenzoic acid 1-methylheptyl ester. (yield: 43%)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([N:17]([CH3:19])[CH3:18])=[O:20]
Reactant: CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Reaction time: 2 h
Yield: 75.9 %

Procedure:
((S)-1-Dimethylcarbamoyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (2.0 g, 6.85 mmol) was dissolved in methylene chloride (20 mL) at 0° C. Trifluoroacetic acid (20 mL) was added. The mixture was stirred for 2 h and evaporated. The residue was dissolved in methylene chloride and very carefully basified using saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted using methylene chloride. The combined organic extracts were washed with water and brine, and then dried over sodium sulfate to give (S)-2-amino-N,N-dimethyl-3-phenyl-propionamide (1.0 g, 76%) as yellow oil.
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.Cl.[C:12]([NH:16][NH2:17])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(O)C>[C:12]([N:16]1[C:9]([NH2:10])=[C:6]([C:7]#[N:8])[C:4]([CH3:5])=[N:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(C)=C(C#N)C#N
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c(N)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a mixture of (1-ethoxyethylidene)malononitrile (68 g, 0.5 mol) and tert-butylhydrazine hydrochloride (62.3 g, 0.5 mol) in ethanol (500 mL) was added triethylamine (70 mL, 0.5 mol). The reaction mixture was stirred at room temperature for 2 hours, then was cooled in ice and the product was collected by filtration and washed with ether to afford 85.9 g of 1-tert-butyl-3-methyl-5-amino-1H-pyrazole-4-carbonitrile 2/3 Et3N.HCl. An additional 46.2 g of the desired product was also obtained by concentration of the mother liquor and recrystallization of the residue from ethanol.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
A solution of 4-cyanopiperidine (5.00 g) in 10% aqueous sodium carbonate solution (100 mL) was cooled to 0° C. and treated dropwise with benzyl chloroformate (9.30 g). The resulting mixture was warmed to room temperature and stirred for 16 hours. The biphasic mixture was extracted with ethyl acetate. The organic extracts were washed with water and brine, combined, dried, filtered and evaporated. The resulting oil was purified by chromatography, with ethyl acetate:hexane (gradient 1:4, 1:2) as eluent, to give the protected piperidine as a clear oil (9.64 g); MS: m/z=245(M+1); NMR (CDCl3): 7.35 (m, 5), 5.13 (s, 2), 3.71 (m, 2), 3.44 (m, 2), 2.81 (m, 1), 1.88-1.60 (m, 4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH2:5][CH:6]=O.[CH3:17][O:18]C(=O)CC1C=CC(Cl)=C(Cl)C=1.COC(OC)CCBr.Cl>>[CH3:1][O:2][C:3](=[O:16])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH2:5][CH2:6][CH:17]=[O:18]
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C(CC=O)c1ccc(Cl)c(Cl)c1
Agent: COC(CCBr)OC
Agent: Cl
Product: COC(=O)C(CCC=O)c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-oxo-butyric acid methyl ester (example 2, step 1) the title compounds was prepared from 3,4-dichloro-phenyl-acetic acid methyl ester (commercially available), and 3-bromopropionaldehyde dimethylacetal and subsequent treatment with HCl aq. MS (m/e): 274.1/276.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([SH:16])=[N:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27].C(OCC)(=O)C>CN(C=O)C.O>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][S:16][C:13]1[CH:14]=[CH:15][C:10]([C:9](=[O:17])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:11][N:12]=1)[CH2:30][CH3:31]
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(S)nc1
Reactant: CCCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)CSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of of N-(4-fluorophenyl)-6-mercaptonicotinamide (0.024 g, 0.097 mmol, see Example 1) in 2 mL of DMF was added cesium carbonate (0.094 g, 0.29 mmol) and propyl bromoacetate (0.025 μL). The mixture was stirred for 30 minutes and poured into ethyl acetate and water. The organic layer was removed, dried over sodium sulfate, filtered, and the solvents removed in vacuo. Purification by trituration using ethyl acetate/hexanes gave 34 mg (76%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s 1H), 8.88 (m, 1H), 8.12 (m, 1H), 7.73 (m, 2H), 7.49 (m, 1H), 7.18 (m, 2H), 4.09 (s, 2H), 4.02 (m, 2H), 1.54 (m, 2H), 0.82 (m, 3H); MS (EI) m/z 347.06 (M−H)−.
Reaction SMILES: [C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15](SC)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][NH2:23]>C(O)C>[C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([N:22]([CH3:21])[NH2:23])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2
Reactant: CNN
Solvent: CCO
Product: CN(N)c1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
2.9 g of 6-benzoyl-5,6,7,8-tetrahydro-3-methylmercaptopyrido[4,3-c]pyridazine and 1.5 g of methylhydrazine are heated in 20 cc of 95% ethanol in an autoclave at a bath temperature of 150° for 18 hours, and the mixture is subsequently worked up as described in Example 47. The biscentisinate of the title compound has a M.P. of 166°-168° (decomp.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[CH:10]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:9]2[C:8]1=[O:17].C(N(CC)CC)C.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.CC(C)=O>[C:25]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[CH:10]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:9]2[C:8]1=[O:17])(=[O:28])[CH:26]=[CH2:27]
Reactant: C=CC(=O)Cl
Reactant: O=C1C2CCCCC2C(=O)N1CCOCCO
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CC(=O)OCCOCCN1C(=O)C2CCCCC2C1=O
Reaction time: 12 h
Yield: 59.5 %

Procedure:
A one liter, three necked flask was equipped with overhead stirrer, nitrogen atmosphere and an addition funnel. The flask was charged with 100 g of N-(2-hydroxyethoxyethyl)hexahydrophthalimide (0.41 mol.), 42 g of triethylamine (0.41 mol.), 1 g of phenothiazine and 400 ml of acetone. Next, 38 g of acryloyl chloride (0.41 mol.) was added slowly to the flask via the addition funnel over 45 minutes. The reaction was stirred for an additional 12 hours. The triethylamine hydrochloride salt was removed by filtration and the remaining mother liquor was evaporated with a rotoevaporator. The resulting red-orange liquid was dissolved in chloroform and extracted with HCl(10%), NaCl(aq.), NH4OH(10%), NaCl(aq.) and dried over MgSO4. The chloroform was removed with a rotoevaporator to yield 72 g (59%) of an orange-red liquid. The product was confirmed by IR and 13C NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[Cl:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][F:58])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.N>CC(O)C.CO>[Cl:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:51][CH2:52][N:53]([CH2:56][CH2:57][F:58])[CH2:54][CH2:55]3)[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([NH:40][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=3)[C:20]([NH:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])=[O:21])[CH:5]=[CH:4][N:3]=2)[CH:41]=1
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(Cl)cc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: N
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(Cl)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 11.6 %

Procedure:
In a 10 mL vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 5-chloro-4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)aniline (0.192 g, 0.520 mmol) were taken up in iPrOH (3 mL) and pyridinium p-toluenesulfonate (0.203 g, 1.04 mmol) was added. The vial was sealed and heated to 80° C. overnight. When reaction was complete by MS, it was cooled rt, neutralized with 7N ammonia in MeOH, adsorbed onto silica gel and flash chromatographed. Fractions containing the desired product were concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.040 g, 12%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.44 (br. s., 1H), 8.58 (s, 1H), 8.33 (s, 1H), 8.28 (d, J=5.3 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.78-7.95 (m, 2H), 7.75 (d, J=9.0 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.45-7.55 (m, 1H), 7.33-7.45 (m, 1H), 7.11-7.28 (m, 2H), 7.03 (t, J=7.0 Hz, 1H), 6.83 (s, 1H), 6.55 (d, J=5.3 Hz, 1H), 4.57 (t, J=4.9 Hz, 1H), 4.45 (t, J=4.9 Hz, 1H), 3.84 (s, 3H), 3.08-3.51 (m, 2H), 2.09-2.92 (m, 13H), 1.72-2.00 (m, 2H), 1.41-1.72 (m, 2H). MS (M+H, ES+) 796.