Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(C)c(C)cc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 71 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 183 to obtain the titled compound (yield, 71%). 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 2.40 (s, 3H), 3.23-3.30 (m, 4H), 3.74-3.77 (m, 3H), 4.13 (s, 4H), 6.80-6.91 (m, 3H), 7.15-7.20 (m, 1H), 7.36 (br s, 1H), 7.53 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10]Br.CCN(CC)CC>COCCOC>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][NH:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: BrCc1cccc(Br)c1
Reactant: COCCN
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COCCNCc1cccc(Br)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of 2-methoxyethanamine (900 mg, 12 mmol) in DME (15 mL) was added 3-bromobenzylbromide (2.5 g, 10 mmol) and the reaction mixture was stirred at 40° C. (scheme 14). After 30 minutes, Et3N (1.01 g, 10 mmol) was added and the reaction was allowed to stir for another 10 minutes, filtered and the filtrate was concentrated to afford bromide 64 as a colorless oil (2.0 g, 80% yield). MS (m/z): 244.1/246.1 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]>O1CCCC1.CO.[C].[Pd]>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C=Cc2cccc(CC(=O)O)c2)cs1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2cccc(CC(=O)O)c2)cs1
Yield: 91.7 %

Procedure:
3-{2-[2-(Acetylamino)-1,3-thiazol-4-yl]vinyl}phenylacetic acid (4.500 g, 14.88 mmol) was dissolved in a mixed solvent of tetrahydrofuran (225 ml) and methanol (90 ml), and 20% palladium carbon (containing 50% water, 1.800 g) was added. Hydrogenation was performed at room temperature −30° C., 4 atm. After the completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated. Diethyl ether (100 ml) was added to the residue, and the precipitate was collected by filtration. The filtered product was washed 3 times with diethyl ether, and dried under reduced pressure to give 3-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenylacetic acid (4.152 g, 13.64 mmol, yield 91.7%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C@:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])([CH3:11])[CH2:9][OH:10])[CH:7]=1.N1C=CC=CC=1.[S:31](Cl)(Cl)=[O:32]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([C:8]2([CH3:11])[CH2:9][O:10][S@@:31](=[O:32])[N:12]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CN[C@@](C)(CO)c2cc(Br)ccc2F)c(OC)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CN2[S@](=O)OCC2(C)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 99.7 %

Procedure:
To a solution of (R)-2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propan-1-ol (14.1 g, 35.4 mmol, Eq: 1.00) and pyridine (14.0 g, 14.3 ml, 177 mmol, Eq: 5.0) in dichloromethane (258 ml) at 78° C. was dropwise added thionyl chloride (5.05 g, 3.1 ml, 42.5 mmol, Eq: 1.2), stirring was continued at 78° C. for 5 min, the cooling bath was removed and the mixture was slowly warmed up to 23° C. and stirring was continued for 20 min. Extracted with 5% citric acid and sat NaHCO3-sol., dried the organic layer over Na2SO4, filtered off and evaporated totally to give the (R)-4-(5-bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2-oxide (15.7 g, 35.3 mmol, 99.8% yield) as a light yellow oil, which needed no further purification. MS (ISP): m/z=444.1 [M+H]+ and 446.0 [M+2+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)[CH3:12]>>[CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]=1[N+:21]([O-:23])=[O:22])=[O:9]
Reactant: Cc1cc(C(=O)O)c(C)o1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(NC(=O)c2cc(C)oc2C)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2,5-dimethyl-3-furoic acid and 4-ethoxy-2-nitroaniline as an orange solid as described in Example 15. 1H NMR (CDCl3): 10.59 (s, 1H), 8.83 (d, J=9.0, 1H), 7.70 (d, J=3.0, 1H), 7.27-7.25 (m, 1H), 6.24 (s, 1H), 4.08 (q, J=6.9, 2H), 2.62 (s, 3H), 2.30 (s, 3H), 1.45 (t, J=6.9, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:41][CH2:40][P:39]([CH3:43])(=[O:42])[CH2:38][CH2:37]3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:24]=1[NH2:25].Cl>COCCO.C(O)C>[CH3:21][O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:37][CH2:38][P:39]([CH3:43])(=[O:42])[CH2:40][CH2:41]3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:24]=1[NH:25][C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1
Reactant: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cnnc(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: COCCO
Product: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)cnn1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared in Example 73: 0.02 mmol) and 2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline (0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. The reaction mixture is heated in a sealed tube at 140 degree until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: [C:1]1(=[CH:7][CH:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl.CO>O1CCOCC1>[C:1]1(=[CH:7][CH:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([O:14][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[Cl:22])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)C(O)C(C=C1CCCCC1)n1cncn1
Reactant: ClCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)C(OCc1ccccc1Cl)C(C=C1CCCCC1)n1cncn1
Temperature: 65 °C
Yield: 61 %

Procedure:
A solution of 13.1 g (0.15 mol) of 1-cyclohexylidene-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pentan-3-ol (Example 2) in 50 ml of dioxane was added dropwise to a suspension of 2.0 g of 80% strength sodium hydride in 50 ml of dioxane and the mixture was then warmed to 65° C. for 45 minutes. After cooling, 10.0 g (0.06 mol) of 2-chlorobenzyl chloride were added dropwise and the mixture was heated under reflux overnight. 5 ml of methanol were then added and the reaction was concentrated. The residue was taken up in methylene chloride and the methylene chloride mixture was washed several times with water. The organic phase was dried over sodium sulphate, concentrated and finally degassed under a high vacuum. 14.2 g (72% of theory) of 1-cyclohexylidene-3-(2-chlorobenzyloxy)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pentane were obtained as a yellowish oil with a refractive index of nD20 =1.5349.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:21]([OH:23])=O)[CH2:16][CH:15]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]([C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1)[NH2:25].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:21]([NH:25][NH:24][C:26]2[N:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][N:27]=2)=[O:23])[CH2:14][CH:15]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:16]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC1CC(CN(C=O)OCc2ccccc2)(C(=O)O)C1
Reactant: NNc1nccc(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCCC1CC(CN(C=O)OCc2ccccc2)(C(=O)NNc2nccc(C(F)(F)F)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
To a mixture of (1-[(benzyloxy-formyl-amino)-methyl)]-3-butyl-cyclobutanecarboxylic acid (0.10 g, 0.31 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.067 g, 0.37 mmol), NMM (0.095 g, 0.93 mmol) and HOAt (0.05 g, 0.37 mmol) in DMF (3 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.072 g, 0.37 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.07 g, 47%). MH+480.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:6]([NH2:18])[CH:5]=1.N1C=CC=CC=1.[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36])([O-:28])=[O:27]>ClCCl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[C:6]([NH:18][S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N+:26]([O-:28])=[O:27])(=[O:36])=[O:37])[CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After dissolving 3-amino-4-tert-butoxycarbonylaminobenzoic acid methyl ester (817.3 mg, 3.07 mmol) in dichloromethane (10 ml), pyridine (0.373 ml, 4.60 mmol) and 2-nitrobenzenesulfonyl chloride (815 mg, 3.68 mmol) were added in an ice bath, and the mixture was stirred at room temperature for 4 hours. Pyridine (0.050 ml) and 2-nitrobenzenesulfonyl chloride (135 mg) were added, and stirring was continued for 2 hours. The reaction mixture was concentrated under reduced pressure, water (30 ml) was added, and then extraction was performed with ethyl acetate (20 ml×3 times). The obtained organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the crystallized residue was suspended in n-hexane-ethyl acetate (4:1), filtered, and dried to obtain 4-tert-butoxycarbonylamino-3-(2-nitro-benzenesulfonylamino)-benzoic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[N:10]=2)[CH:7]=1.[NH:23]1[CH2:26][CH2:25][C:24]1=[O:27]>>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:23]3[CH2:26][CH2:25][C:24]3=[O:27])=[CH:7][N:6]2[CH:8]=1
Reactant: O=C1CCN1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(I)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(N3CCC3=O)ccc2n1
Yield: 6 %

Procedure:
As described for Example 60, 6-iodo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine (100 mg, 0.25 mmol) was converted, using 2-azetidinone instead of benzamide, to the title compound (4.8 mg, 6%) which was obtained as a light yellow oil. MS: m/e=345.0 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:31])C.[Li+].[OH-]>>[CH2:33]([O:32][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:31])[C:4]([OH:35])=[O:3])[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], [rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic acid as colorless solid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][O:6][N:7]=[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][OH:26])=[CH:16][C:11]=2[O:10][CH2:9]1>O1CCCC1>[CH3:5][O:6][N:7]=[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:25]([OH:26])[C:3]([NH:2][CH3:1])=[O:4])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CN=C=O
Reactant: CON=C1COc2cc(OCc3ccccc3NO)ccc21
Solvent: C1CCOC1
Product: CNC(=O)N(O)c1ccccc1COc1ccc2c(c1)OCC2=NOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
0.38 g of methyl isocyanate was added to a solution of 2.0 g of N-[2-(3-methoxyimino-2,3-dihydro-benzofuran-6-yloxymethyl)phenyl]-N-hydroxyamine in 50 ml of tetrahydrofuran, and they were stirred at room temperature for 8 hours. The reaction liquid was concentrated under reduced pressure to obtain 2.3 g of N-[2-(3-methoxyimino-2,3-dihydro-benzofuran-6-yloxymethyl)phenyl]-N-hydroxy-N′-methylurea. This product was dissolved in 20 ml of N,N-dimethylformamide. 0.95 g of methyl iodide and 0.98 g of anhydrous potassium carbonate were added to the solution, and they were stirred at room temperature for 4 hours. The reaction solution was diluted with 200 ml of diethyl ether, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate) to obtain 1.4 g of the title compound (having a m.p. of 109-112° C. and 1H-NMR data shown in the following table].
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:11][CH:10]([NH:12]C(=O)OC(C)(C)C)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:12][CH:10]1[CH2:11][N:8]([C:6]([C:5]2[CH:20]=[CH:21][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)c2ccc(Br)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CN(C(=O)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of compound 16c (810 mg, 2.28 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (7 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated. To the residue was added CH2Cl2 and 1N aqueous NaOH solution until the pH of the aqueous layer was approximately 8. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 16d (570 mg). MS m/z (M+H+) 254, 256.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([Br:10])[Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC=CC=1.[Br:20]Br.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Br:20])([Br:9])[Br:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(C(Br)Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1ccc(C(Br)(Br)Br)cc1
Yield: 86 %

Procedure:
A solution of 100 parts of p-nitrobenzal bromide in 1,000 parts of chlorobenzene is stirred with a solution of 80 parts of bromine plus 160 parts of 50% sodium hydroxide in 1,000 parts of water at 50° C for 10 hours. The bottom layer is separated and evaporated to dryness to give 110 parts (86% yield) of p-nitrobenzotribromide, m.p. 66°-70° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([CH2:12][C:13]([OH:15])=[O:14])[CH2:11][CH2:10]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH:20]=[O:21].O>C1COCC1>[CH:9]1([CH:12]([CH:20]([C:19]2[CH:22]=[CH:23][C:24]([F:25])=[C:17]([F:16])[CH:18]=2)[OH:21])[C:13]([OH:15])=[O:14])[CH2:11][CH2:10]1
Reactant: O=C(O)CC1CC1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(C1CC1)C(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of lithium diisopropylamide (2.0M in hexanes, 46.4 mL, 92.8 mmol) in 20 mL of THF at −40° C. under a nitrogen atmosphere was added cyclopropylacetic acid (4.65g in 20 mL of THF, 46.4 mmol), dropwise. The mixture was stirred in the cold for 15 minutes and warmed to ambient temperature. After 1 hour, the reaction slurry was cooled in an ice bath and 3,4-difluorobenzaldehyde (5.2 mL, 47.1 mmol) in 10 mL of THF was added dropwise. The mixture was warmed to ambient temperature and allowed to stir for 2 hours. The mixture was poured into 200 mL of cold water and the layers separated. The organic layer was washed with water (3X), and the combined aqueous layers were washed with ethyl ether (2X), and then acidified with 3N hydrochloric acid. The water layer was extracted with ethyl ether (3X) and the combined ether layers were dried over sodium sulfate, filtered, and evaporated to dryness to yield the title compound as an oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl[C:25]1[N:30]=[CH:29][C:28]([I:31])=[CH:27][N:26]=1>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:25]5[N:30]=[CH:29][C:28]([I:31])=[CH:27][N:26]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: Clc1ncc(I)cn1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: Ic1cnc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)nc1

Procedure:
Using a procedure similar to that described in Example 86 except starting with 4-amino-1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidine (prepared as described in Example 8b) and 2-chloro-5-iodopyrimidine, the title compound was obtained as a white solid (100%), mp 240° C. (dec); MS(CI): 509 (M+H); NMR (300 MHz, DMSO-d6): 9.95(br s, 1H), 8.50-8.45(m, 2H), 7.68(b, 1H), 7.37-7.32(m, 4H), 7.03-6.95(m, 4H), 4.45(s, 1H), 4.35-4.31(m, 2H), 4.18-3.80(br m, 1H), 3.58-3.38(m, 4H), 2.73(s, 2H), 2.08-1.87(m, 4H).
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][N:30]=1.Cl>N1C=CC=CC=1>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[S:33][C:32]([NH:34][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[N:31][N:30]=1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nnc(CCCCCBr)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCBr)s2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
To a solution of 4-dodecylbenzenesulfonyl chloride (1.53 g, 4.42 mmol) in pyridine (15 mL) was added 5-(5-bromopentyl)-1,3,4-thiadiazol-2-amine. (1.00 g, 4.02 mmol). The reaction mixture was stirred at room temperature for 5 h, then 2 mol/L HCl (25 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL). The organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel 60 (70-230 mesh) eluted with CH2Cl2:MeOH 49:1 to give 1.39 g of product as a solid contaminated with N-(5-(5-chloropentyl)-1,3,4-thiadiazol-2-yl)-4-dodecyl benzenesulfonamide in about 60% yield. 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3, J=6.9 Hz), 1.25-1.30 (m, 18), 1.55-1.58 (m, 4), 1.73-1.88 (m, 4), 2.64 (t, 2, J=7.8 Hz), 2.83 (t, 2, J=7.8 Hz), 3.42 (t, 1, J=6.6), 3.55 (t, 1, J=6.3 Hz), 7.27 (d, 2, J=8.1 Hz), 7.84 (d, 2, J=8.1 Hz); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.6, 26.0, 27.3, 27.4, 27.5, 29.3, 29.4, 29.5, 29.6, 29.7, 30.5, 31.1, 31.8, 31.9, 32.0, 33.2, 35.8, 44.5, 126.5, 128.9, 138.3, 148.3, 158.5, 168.2; HRMS (ESI+, m/z) calculated for C25H41BrN3O2S2 558.1824, observed 558.1819 (M+H)+; HRMS (ESI+, m/z) calculated for C25H41ClN3O2S2 514.2329, observed 514.2330 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH2:4][CH2:3]1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]=1[S:26](=[O:29])(=[O:28])[NH2:27]>C(N(CC)CC)C>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][N:2]2[CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:14][CH3:15])[CH2:6][CH2:7]2)=[O:22])=[CH:19][C:18]=1[S:26](=[O:28])(=[O:29])[NH2:27]
Reactant: COc1ccccc1N1CCN(N)CC1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(NC(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 1 g of 1-amino-4-(2-methoxyphenyl)piperazine and 1 ml of triethylamine was added 1.25 g of 4-chloro-3-sulfamoylbenzoyl chloride under stirring at room temperature. The reaction mixture was stirred at room temperature for 9 hours. The resulting precipitate was filtered, washed with water and recrystallized from ethanol to afford a title compound in a yield of 1.20 g (60%) as colorless needle crystals, mp 231°-233° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:22])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[C:23]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1C(O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:22])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1

Procedure:
By the same procedure as in Example 26-D), while using (2S)-1-(tert-butoxycarbonyl)-2-(1-hydroxy-2-phenoxyethyl)pyrrolidine (1.93 g) and N-(tert-butoxycarbonyl)-L-proline (1.36 g), there was obtained 2. i0 g of the title compound.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].C(Cl)(Cl)Cl.C[Si]([N:17]=[N+]=[N-])(C)C>C(O)C>[CH3:3][C:2]1[NH:17][C:1](=[O:8])[O:7][C:5](=[O:6])[CH:4]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC1=CC(=O)OC1=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1cc(=O)oc(=O)[nH]1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
At room temperature, to a mixture of 44.8 g of citraconic anhydride and 60 ml of chloroform was added 50.0 g of trimethylsilylazide. The mixture was stirred at 50 to 60° C. for 5 hours. After the reaction mixture was cooled with an ice, 25.0 g of ethanol was added, followed by further stirring for 30 minutes. The resulting solid was collected by filtration, and washed with a mixed solvent of chloroform and ethanol to obtain crude 4-methyl-2H-1,3-oxazine-2,6-(3H)-dione represented by the formula: