Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Si:7]([O:14][CH2:15][C@H:16]1[NH:19][C:18](=[O:20])[C@H:17]1[NH:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].Br[CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)=[O:44]>C(#N)C.CN(C)C=O>[Si:7]([O:14][CH2:15][C@H:16]1[N:19]([CH2:42][C:43]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=2)=[O:44])[C:18](=[O:20])[C@H:17]1[NH:21][C:22]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: COc1ccc(COC(=O)CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)CN2C(=O)[C@@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 114.7 %

Procedure:
Cesium carbonate (1.58 g) was added to a stirred solution of(3S,4S)-4-t-butyldimethylsilyloxymethyl-3-tritylaminoazetidin-2-one (1.45 g) (IV) (H. Mastalerz et al., J. Med. Chem., 1988, 31, 1190-1196) in a mixture of acetonitrile (44 ml) and dimethylformamide (35 ml). 4-Methoxybenzyl bromoacetate (1.44 g) was then added and the mixture stirred at room temperature for 48 h. The mixture was then partitioned between ethyl acetate and water, the organic phase was washed four times with water, and then with brine. The solution was dried over magnesium sulphate and evaporated. The title compound (2.29 g) was isolated by column chromatography of the residue (Silica gel, 3:1 hexane:ethyl acetate as eluent). [α]D21 -9.0°; νmax (CHCl3) 3352, and 1755 cm-1 ; δ(CDCl3) -0.04 (3H, s), 0.00 (3H, s), 0.88 (9H, s), 1.69 (1H, br s), 2.54 (1H, dd, J 3.33 and 11.68 Hz), 3.19 (1H, dd, J 2.05 and 11.68 Hz), 3.38 (1H, m), 3.51 (1H, d, J 17.98 Hz), 3.90 (3H, s), 4.46 (1H, d, J 17.98 Hz), 4.54 (1H, m), 5.06 (1H, d, J 11.79 Hz), 5.15 (1H, d, J 11.81 Hz), 6.94 (2H, d, J 8.68 Hz), 7.2-7.65 (17H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C1([N:23]=[C:24]=[O:25])C=CC=CC=1.Cl.N[OH:28]>C(O)C>[Cl:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:1][C:24](=[O:25])[N+:23]([O-:28])=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Yield: 69.1 %

Procedure:
A mixture of 12.6 g (0.05 mole) of 2-amino-5-chlorobenzophenone and 6.55 g (0.055 mole) of phenyl isocyanate was heated on a steam-bath for 30 min., and then 250 ml ethanol and 10.43 g (0.15 mole) of hydroxylamine hydrochloride were added and mixture was refluxed for 2 days and then cooled. The solid precipitate that formed was collected on a filter, washed with ethanol, and dried in air to give 9.42 g (69%) of 6-chloro-4-phenyl-2(1H)-quinazolinone 3-oxide as yellow crystals, mp 267°-269°.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:26](N(C)C1C=NC=CC=1C1C=CC=CC=1C)=[O:27])(=[O:22])=[O:21].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:18][CH:2]([F:1])[CH2:3][N:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[C:26](=[O:27])[C:25]1[CH:43]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:45]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:24]=1
Reactant: Fc1ccccc1-c1ccncc1NCC(F)F
Reactant: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(C(=O)N(CC(F)F)c2cnccc2-c2ccccc2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(2,2-difluoroethyl)-4-(2-fluorophenyl)pyridin-3-amine (112 mg, 444 μmol) in CH2Cl2 (3 mL) was added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (119 mg, 444 μmol, example 114, intermediate) and 2-bromo-1-ethylpyridinium tetrafluoroborate (146 mg, 533 μmol) and N,N-diisopropylethylamine (115 mg, 155 μL, 888 μmol). The reaction mixture was stirred at room temperature for 24 hours and then concentrated under vacuum. The residue was dissolved in 30 mL 1M aqueous HCl and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL 1M aqueous HCl and 30 mL 10% aqueous NaHCO3 solution and 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. Yellow solid (84 mg, 38%). MS (ESI): m/z=503.085 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12.CI.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:22][O:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(c3ccccc13)Nc1ccccc1S2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
To a solution of 5-hydroxy-12H-benzo[a]phenothiazine (2.65 g) and methyl iodide (2.5 ml) in DMF (dimethylformamide) (10 ml) there was added powdered potassium carbonate (2.0 g). The mixture was stirred at room temperature and after 15 minutes, another addition of potassium carbonate (2.0 g) and methyl iodide (2.0 ml) was done. The mixture was stirred for a further 20 minutes, then it was diluted with ethyl acetate (100 ml and washed with water (60 ml) twice, dried and evaporated down. The residue was triturated with ether to afford solid crude product which was filtered (1.7 g). This crude product was chromatographed on a column of silica gel, eluting with dichloromethane to afford pure title compound (1.33 g), m.p. 168°-170° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: C1=COCCC1
Reactant: Oc1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: Ic1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 Grams of p-iodophenol, 8 ml of dihydropyrane and a catalytic amount of p-toluenesulfonic acid was dissolved in 30 ml of anhydrous ether, all of these were mixed together and stirred at a room temperature for 2 hours. The reaction mixture was washed with water, dried then the solvent was removed by evaporation to yield 12.4 g of 4-(2-tetrahydropyranyloxy)-1-iodobenzene in the form of yellow oily substance. Boiling point: 84°-87° C. (at 25 mm Hg).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]=[N+:21]=[N-:22])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:4][CH2:3]1.C([O:30][C:31](=[O:34])[C:32]#[CH:33])(C)(C)C.C(OCC)(=O)C>O1CCOCC1>[O:25]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:33]=[C:32]([C:31]([OH:34])=[O:30])[N:22]=[N:21]4)[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:6][CH2:7]1
Reactant: C#CC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)c1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Yield: 40.2 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one (6.9 g, 18.83 mmol) (Reference Example 2) was dissolved in dry 1,4-dioxane (15 ml), 2-propynoic acid t-butylester (4.75 g, 37.67 mmol) was added and the resulting mixture was refluxed for 12 hours under vigorous stirring. Ethyl acetate (30 ml) was added and the resulting precipitate was filtered, washed with ethyl acetate and dried as a white solid (5 g). This solid was suspended in dichloromethane (16 ml), followed by drop wise addition of trifluoroacetic acid (8 ml) and the resulting mixture was stirred over night. The solvent was removed under vacuum and the residue was purified by precipitation from dichloromethane to give the title product as an off-white solid (3.3 g).
Reaction SMILES: S(=O)(=O)(O)O.[CH:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OC)(=O)[CH:15]=[CH2:16].S([O-])([O-])(=O)=[O:21].C([N+](CC)(CC)CC)C.C([N+](CC)(CC)CC)C.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH2:10]([CH:9]1[O:21][C:6](=[O:13])[CH2:7][CH2:8]1)[CH2:11][CH2:12][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC=O
Reactant: C=CC(=O)OC
Reactant: O=S(=O)([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[N+](CC)(CC)CC
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCC1CCC(=O)O1
Yield: 224.7 %

Procedure:
The circulation type electrolytic apparatus as described in Example 24 and 10 wt% sulfuric acid as an anolyte were used. As a catholyte was used a mixture of 73.9 g (0.648 mol) of heptanal, 18.6 g (0.216 mol) of methyl acrylate, 418 g of water, 53 g (0.149 mol) of tetraethylammonium sulfate and 36 g (0.062 mol) of tetra-n-butylammonium sulfate. The electrolysis was carried out at a catholyte temperature of 27° to 29° C. and a current density of 10.0 A/dm2 while stirring the catholyte in the electrolytic apparatus by circulating the catholyte at a flow rate of 200 cm/sec between the cathode chamber and the catholyte tank. A mixture of 45.9 g (0.403 mol) of heptanal and 48.8 g (0.567 mol) of methyl acrylate was fed into the catholyte tank little by little over five hours during the electrolysis. When the relative current quantity reached 66%, the electrolysis was stopped. During the electrolysis, the voltage fluctuated between 5.8 V and 5.9 V. After the electrolysis, the catholyte was allowed to stand so as to be separated into an organic phase and a water phase. The organic phase was washed with 50 g of water and, then, distilled. 10 g of methyl acrylate was recovered from the organic and water phases. 66 g of heptanal was recovered from the organic phase. By distilling the organic phase, 22 g of dimethyl adipate as a by-product and 57 g of 4-n-hexyl-4-butanolide were obtained. The results are summarized as follows:
Reaction SMILES: C([Cl:11])([O:3][CH2:4][C:5]1C=CC=CC=1)=O.[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>ClCCl>[ClH:11].[C:4]([O:15][CH2:14][C:13]([NH2:12])([CH3:17])[CH3:16])(=[O:3])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)N
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dichloromethane solution containing 17.1 g (0.1 mol) carbobenzoxychloride at 0° was added dropwise with stirring 18.4 g (0.2 mol) 2-amino-2-methyl-1-propanol. The reaction mixture was stirred at room temperature overnight and the 2-amino-2-methyl-1-propanol hydrochloride which formed was removed by filtration. Removal of the dichloromethane under reduced pressure afforded a colorless, viscous liquid. Distillation gave 14.9 g (0.07 mol), 70%, 2-carbobenzoxyamino-2-methyl-1-propanol, bp 144°-148° (0.3 mm); ir (neat) 3400, 3020, 2980, 1710, 1510, 1455, 1270, 1070, 730 and 680 cm-1 ; pmr (CDCl3) δ 7.2 (s, 5H), 5.4 (bs, 1H), 4.9 (s, 2H), 4.2 (bs, 1H), 3.4 (s, 2H) and 1.2 (s, 6H) ppm.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1.C1C=CC=CC=1>O>[C:20]1([CH3:30])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[C:20]1([CH3:30])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[CH2:11]([O:9][C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH2:7])[NH2:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: NCCCC[C@H](N)C(=O)OCc1ccccc1
Yield: 84 %

Procedure:
30 g of L-lysine (20.5·10-2 mole) and 70 ml of distilled benzyl alcohol (67.6·10-2 mole) are introduced into an extractor of the Dean-Stark type; 88.5 g of paratoluene sulfonic acid monohydrate (46.5·10-2 mole) and 300 ml of benzene are added. The mixture is heated at reflux until all of the water formed in the reaction has been removed. The solution is transferred to a beaker to which 100 ml of methanol are added. The salt is precipitated by the addition of 500 ml of ethyl ether at room temperature. The precipitate is taken up by warming in 300 ml of methanol and reprecipitated by ethyl ether. 100 g of the N,N'-ditosylate of L-lysine benzyl ester are recovered; yield=84%, M.P.=163° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[C:3]=1[CH2:10][NH:11][CH3:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[C:25]=1[C:36]#[N:37])[C:17](O)=[O:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[C:25]=1[C:36]#[N:37])[C:17]([N:11]([CH2:10][C:3]1[C:4]([OH:9])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[CH3:12])=[O:18]
Reactant: N#Cc1c(Oc2ccc(C(=O)O)cc2Cl)cccc1-c1ccncn1
Reactant: CNCc1c(C)cc(C)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c(CN(C)C(=O)c2ccc(Oc3cccc(-c4ccncn4)c3C#N)c(Cl)c2)c(O)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.6 %

Procedure:
A mixture of 4,6-Dimethyl-3-((methylamino)methyl)pyridin-2-ol (28 mg, 0.17 mmol), 3-chloro-4-(2-cyano-3-(pyrimidin-4-yl)phenoxy)benzoic acid (50 mg, 0.14 mmol), triethylamine (42 mg, 0.42 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (65 mg, 0.17 mmol) in dichloromethane (20 mL) was stirred at room temperature for 15 hours. Water (20 mL) was added to the mixture. The organic phase was separated and concentrated in vacuo to give a residue. The residue was further purified by preparative-HPLC to provide 3-chloro-4-(2-cyano-3-(pyrimidin-4-yl)phenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-N-methylbenzamide (Compound I-17) as a white solid (34 mg, 49%). LRMS (M+H+) m/z: calcd 499.1. found 499. HPLC purity (214 nm): 94%.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6](Cl)=[N:5][S:4][N:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C.C(OCC)C>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][S:4][N:3]=1
Reactant: Sc1ccccc1
Reactant: O=c1c(Cl)nsnc1Cl
Agent: CN(C)C
Solvent: CCOCC
Product: O=c1c(Cl)nsnc1Sc1ccccc1
Reaction time: 3 h

Procedure:
In one portion 2.5 g of trimethylamine was added to a solution of 4.6 g of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one in 75 ml of ethyl ether in a 250 ml flask. A solution of 2.8 g of thiophenol in 25 ml of ethyl ether was then added dropwise to the flask during a 15 minute period. The reaction was allowed to stir for 3 hrs. after which it was filtered. The filter cake was washed with ether, and the filter cake was discarded. Successively, the ether solution was washed twice with 50 ml of water and once with 50 ml of saturated sodium chloride solution. The ether solution was then dried over anhydrous sodium sulfate. The ether was evaporated, leaving a solid residue which was recrystallized from 75 ml of cyclohexane. The yellow-orange 3-chloro-5-phenylthio-4H-1,2,6-thiadiazin-4-one weighed 3.6 g, mp 99.5°-101.5° C. (Lit. mp 102.5°-103.5° C, J. Geevers and W. P. Trompen, supra.). The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:12])[N:3]=1.S(=O)(=O)(O)O.[Cl:18]Cl.[OH-].[K+]>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Cl:18])=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1ccc(C(F)(F)F)c(Cl)n1
Reactant: ClCl
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1nc(Cl)c(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 200 ml four necked flask equipped with a thermometer, a stirrer and a reflux condenser were placed 7 g of 2-amino-5-trifluoromethyl-6-chloropyridine, 10 ml of carbon tetrachloride and 70 ml of 20% sulfuric acid to give a homogeneous solution. Chlorine gas was introduced thereinto while cooling the flask at 0° C., and the reaction was carried out for 4 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction product was poured into ice water and neutralized with a potassium hydroxide solution. 50 ml of methylene chloride was added thereto, followed by washing with water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated off. The solid thus obtained was washed with n-hexane to obtain 6.7 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[S:9][C:8]2[C:7]([CH:10]=O)=[C:6]([C:12](OCC)=[O:13])[N:5]([CH3:17])[C:4]=2[CH:3]=1.O.[NH2:19][NH2:20].BrC1SC2C(C=O)=C(C(OCC)=O)NC=2C=1>C(OCCO)C>[CH3:17][N:5]1[C:6]2[C:12]([NH:19][N:20]=[CH:10][C:7]=2[C:8]2[S:9][C:2]([Br:1])=[CH:3][C:4]1=2)=[O:13]
Reactant: NN
Reactant: CCOC(=O)c1c(C=O)c2sc(Br)cc2n1C
Agent: CCOC(=O)c1[nH]c2cc(Br)sc2c1C=O
Solvent: CCOCCO
Solvent: O
Product: Cn1c2cc(Br)sc2c2cn[nH]c(=O)c21
Reaction time: 8 h
Yield: 93.7 %

Procedure:
The N-methylated product 63 (420 mg, 1.33 mmol) was dissolved in warm 2-ethoxyethanol (26 mL). To a refluxed solution of hydrazine monohydrate (1 mL, 31.9 mmol) and 2-ethoxyethanol (5 mL) under nitrogen was added prepared N-methylated product 62 solution dropwise over a 2 hr period and the solution continued to reflux for additional 1 hr. After cooling to room temperature, about half of the 2-ethoxyethanol was removed under reduced pressure and the remaining solution was refrigerated at −20° C. overnight. The precipitate was filtered and washed with 2-ethoxyethanol to give desired pyridazinone 64 (354 mg, 94%) as a white solid.
Reaction SMILES: [ClH:1].O[CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].O.[CH2:15]([NH2:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(O)(C)C>[ClH:1].[CH2:15]([NH:33][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6.45 g of D-glucosamine hydrochloride are dissolved in 30 ml of isopropanol and 10 ml of water at 60° C., and 12.1 g of stearylamine are added. The resulting clear solution is stirred for a further 10 min and then cooled to room temperature. The product which has crystallized out is filtered off with suction and washed first with ethanol/water (5:2, v/v), then with ethanol and finally with ether. The residue is dried under high vacuum.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]([NH2:20])=[O:19])[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:21])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:30])[C:5]=2[CH:14]=1)(=[O:19])[NH2:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(N)=O)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(N)=O)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
564 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carboxamide were dissolved in 20 ml of dichloromethane at room temperature and 540 mg of m-chloroperbenzoic acid were added. After stirring at room temperature overnight the mixture was washed with sodium bisulphite solution, sodium bicarbonate solution and water. The organic phase was dried over sodium sulphate and evaporated to give a solid which was recrystallized from isopropanol to yield 164 mg of 2-(6-carbamoyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 248-250° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](Cl)=[O:44].N.C(Cl)[Cl:51].CO>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:48]([Cl:51])=[CH:40][CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: N
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 35 with 72 μl (0.515 mmol) of triethylamine and 60 μl (0.468 mmol) of 3-chlorobenzoyl chloride to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.71, FD-MS: M+ =566.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)([CH3:21])([CH3:20])[CH3:19].O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:21][C:18]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:19])[CH3:20]
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1ccccc1C(=O)c1ccccc1

Procedure:
6.78 g (30mmol) of o-benzoylbenzoic acid, 5.13 g (30 mmol) of L-proline t-butyl ester, 4.05 g (30 mmol) of 1-hydroxybenzotriazole hydrate and 6.18 g (30 mmol) of DCC in 100 ml methylene chloride were reacted in the manner described in Example 25 for the coupling of o-benzoylbenzoic acid with L-proline t-butyl ester. A standard work-up as described in Example 25 afforded a viscous gum which was purified by flash chromatography on silica gel with 40:1/methylene chloride:methanol as eluant to give an amorphous solid. The isolated yield of the title compound was 8.6 g (76%). TLC (90:10/CH2Cl2 :MeOH): Rf =0.80. 1H NMR (CDCl3) δ: 7.30-7.80(m,9H,); 4.06-4.38(m,1H); 3.36-3.65(m,2H); 1.78-2.32(m,4H); 1.32(s),1.43(s,9H). I.R. (KBr): 1595, 1627, 1661, 1733 cm-1. Low Resolution Mass Spectrum: 380 (p+1). Standard Combustion Analysis Calculated: C,72.80; H,6.64; N,3.69. Found: C,72.37; H,6.59; N,3.76.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14]>>[Cl:1][C:2]1[N:3]=[C:4]([N:11]([CH3:10])[C@H:12]([CH3:15])[CH2:13][OH:14])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CN[C@@H](C)CO
Reactant: Clc1cc(Cl)nc(Cl)n1
Product: C[C@H](CO)N(C)c1cc(Cl)nc(Cl)n1

Procedure:
The title compound was prepared by a procedure similar to that described for D27 starting from 2,4,6-trichloropyrimidine and (S)-2-(methylamino)propan-1-ol.