Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6].Br[CH:28]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=1)[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:32]([O:31][C:29]([CH:28]([C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:43][CH:44]=1)[O:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc(O)c2)c2ccccc21
Reactant: CC(C)Cc1ccc(C(Br)C(=O)OCc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc(OC(C(=O)OCc3ccccc3)c3ccc(CC(C)C)cc3)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 165.9 %

Procedure:
A mixture of ethyl 4-[3-(3-hydroxybenzoyl)indol-1yl]butyrate (984 mg), benzyl 2-bromo-2-[4-isobutylphenyl)acetate (362 mg) and diisopropylethylamine (362 mg) in dichloromethane (10 ml) was stirred at 25° C. for 20 hours, and then refluxed for 70 hours. The mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (20 g) eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 4-[3-[3-[(benzyloxycarbonyl)(4isobutylphenyl)methoxy]benzoyl]indol-1-yl]butyrate (1.05 g) as an oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:25])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][C:40]2[N:43]([CH2:56][CH:57]3C[O:58]3)[N:44]=[C:45]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)[C:39]=2[CH2:38]1)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:15]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:6][CH:57]([OH:58])[CH2:56][N:43]3[C:40]4[CH2:41][CH2:42][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:38][C:39]=4[C:45]([C:46]4[CH:51]=[CH:50][C:49]([C:52]([F:54])([F:55])[F:53])=[CH:48][CH:47]=4)=[N:44]3)[CH2:13][CH2:12]2)=[C:19]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2NS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(Cl)c1N1CCN(CC(O)Cn2nc(-c3ccc(C(F)(F)F)cc3)c3c2CCN(S(C)(=O)=O)C3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
4-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (145 mg, 0.37 mmol) was dissolved in 3 mL of CH2Cl2 and treated with 1.5 mL of trifluoroacetic acid. The reaction mixture was stirred at 25° C. for 1 h before all volatiles were removed. The solid was treated with CH2Cl2 (20 mL) and aqueous KOH (4 N, 10 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The crude oil (90 mg) was dissolved in absolute EtOH (1.0 mL) and treated with 96 mg (0.24 mmol) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was refluxed at 85° C. for 3 h and then the solvent was removed. Column chromatography (silica, 0-5% MeOH/CH2Cl2) provided 138 mg (20% over 4 steps) of N-[3-chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-methanesulfonamide. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.45. MS (electrospray): exact mass calculated for C28H34ClF3N6O5S2, 690.17; m/z found, 691.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.65 and 7.59 (AB pattern, J=8.4 Hz, 4H), 7.36 (d, J=8.1 Hz, 1H), 7.07 (t, J=8.2 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 4.54-4.44 (m, 2H), 4.21-3.94 (m, 3H), 3.77-3.52 (m, 4H), 3.41 (m, 2H), 2.96 (s, 3H), 2.81 (s, 3H), 3.05-2.73 (m, 4H), 2.66-2.20 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5]Br.[Br:10][C:11]1[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][N:14]1[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][C:13]1=[O:17]
Reactant: O=c1cc(Br)cc[nH]1
Reactant: COC(=O)C(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Cn1ccc(Br)cc1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added to a mixture of 4-bromo-1H-pyridin-2-one (0.55 g) and potassium carbonate (0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was heated to 60° C. and stirred at this temperature overnight. After stirring at 80° C. for another 8 h, the mixture was cooled to room temperature and water was added. The resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to afford the title compound; 3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (0.35 g) was also obtained from this reaction. Yield: 0.29 g (32% of theory); Mass spectrum (ESI+): m/z=288/300 (Br) [M+H]+.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:25]=[CH:24][C:16]3[N:17]([CH2:20][CH:21]4[CH2:23][CH2:22]4)[N:18]=[N:19][C:15]=3[C:14]=2[C:26]([F:29])([F:28])[F:27])=[C:9]([F:30])[N:8]=1)(=O)=O.[CH3:31][N:32]1[C:36](=[O:37])[CH2:35][NH:34][C:33]1=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH:21]1([CH2:20][N:17]2[C:16]3[CH:24]=[CH:25][C:13]([C:10]4[CH:11]=[CH:12][C:7]([CH2:6][N:34]5[CH2:35][C:36](=[O:37])[N:32]([CH3:31])[C:33]5=[O:38])=[N:8][C:9]=4[F:30])=[C:14]([C:26]([F:29])([F:27])[F:28])[C:15]=3[N:19]=[N:18]2)[CH2:23][CH2:22]1
Reactant: CN1C(=O)CNC1=O
Reactant: CS(=O)(=O)OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1C(=O)CN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3C(F)(F)F)c(F)n2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
{5-[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]-6-fluoropyridin-2-yl}methyl methanesulfonate (25 mg, 0.056 mmol) was dissolved in acetonitrile (0.56 mL) and treated with 3-methylimidazolidine-2,4-dione (9.6 mg, 0.084 mmol), cesium carbonate (55 mg, 0.17 mmol) and tetra-n-butylammonium iodide (4.2 mg, 0.011 mmol). The mixture was placed into a preheated oil bath at 85° C. for 30 minutes. The mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with sodium bicarbonate (2×5 mL, aqueous saturated). The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (85:15 to 36:64; water with 0.05% trifluoroacetic acid:acetonitrile with 0.05% trifluoroacetic acid) to afford the titled compound as a white solid. H1-NMR (400 MHz, CDCl3): δ 7.84 (1H, d, J=8.5 Hz), 7.77 (1H, dd, J=9.2, 7.6 Hz), 7.39 (1H, d, J=8.6 Hz), 7.30 (1H, dd, J=7.5, 1.5 Hz), 4.77 (1H, d, J=16.4 Hz), 4.67 (1H, d, J=16.2 Hz), 4.61 (2H, d, J=7.1 Hz), 4.16 (1H, d, J=17.4 Hz), 4.07 (1H, d, J=17.1 Hz), 3.32 (3H, s), 1.49-1.39 (1H, m), 0.78-0.66 (2H, m), 0.61-0.11 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 463.1514 [(M+H)+; calculated for C21H19F4N6O2: 463.1500].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][Cl:19])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>[Pt]=S.[C].CO>[CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][Cl:19]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Agent: S=[Pt]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCl)cc1N
Temperature: 50 °C
Yield: 101.6 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 1.02 g (3.45 mmol) of methyl 5-methoxy-4-(2-chloroethoxy)-2-nitrobenzoate (purity: 98%) obtained in Reference Example III-2 and 20 mL of methanol. The resulting mixture was heated to 50° C. under stirring. To the mixture was added 0.5 g of 3 wt. % platinum sulfide/carbon (containing 65.7% water) at the same temperature. The resulting mixture was heated to the same temperature for one hour, while hydrogen was introduced to the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to precipitate a crystalline product. The crystalline product was dried under reduced pressure, to give 0.91 g (isolated yield: 93.0%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of methyl 5-methoxy-4-(2-chloroethoxy)-anthranilate as a white crystalline product.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[C:6]=1[O:23][CH2:24][CH3:25])=[O:4].[OH-].[Na+].C(O)(=O)C.O>CO>[CH2:24]([O:23][C:6]1[C:7]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[O:16][C:5]=1[C:3]([OH:4])=[O:2])[CH3:25]
Reactant: CCOc1c(C(=O)OC)oc2c3ccccc3n(-c3ccccc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCOc1c(C(=O)O)oc2c3ccccc3n(-c3ccccc3)c12
Temperature: 0 °C
Yield: 15.6 %

Procedure:
A suspension of 12.0 g (0.036 mole) of 3-ethoxy-4-phenyl-4H-furo[3,2-b]indole-2-carboxylic acid methyl ester in 100 ml of methanol was treated with 60 ml of 1.0N aqueous sodium hydroxide. After stirring at reflux for 20 hours, the cooled reaction mixture was added to 1.2 kg ice/water, and the mixture was acidified with acetic acid. The crude product was filtered, stirred in 600 ml water, and refiltered. Recrystallization from ethanol yielded 5.1 g of analytically pure acid containing 0.35 mole of water of hydration, mp 146°-147° C. An additional 1.8 g of product was obtained from the recrystallization filtrate, for a total yield of 6.9 g (59% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][NH:9][C:10](=[O:27])[C@H:11]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[NH:12]C(OC(C)(C)C)=O)[CH3:2].[ClH:30].C(OCC)(=O)C>C(OCC)(=O)C.C(OCC)C>[ClH:30].[CH2:1]([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][NH:9][C:10](=[O:27])[C@H:11]([CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[NH2:12])[CH3:2]
Reactant: CCOC(=O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1CCCCC1
Yield: 86.8 %

Procedure:
To the solution of thus obtained N-t-butoxycarbonyl-β-cyclohexyl-L-alanyl-glycyl-glycine ethy lester (506.2 mg, 1.22 mmol) in ethyl acetate (1 mL) under ice-cold condition, add 4M hydrogen chloride/ethyl acetate (3.0 mL, 12 mmol) with stirring, and then the reaction mixture was stirred for 4.5 hours at room temperature. Diethylether (12 mL) was added and the mixture was stirred under ice-cold condition, then the precipitate was collected by filtration to obtain hygroscopic crude crystals. The crude crystals were suspended in diethylether (10 mL)and collected by filtration to obtain β-cyclohexyl-L-alanyl-glycyl-glycine ethyl ester hydrochloride (370.3 mg) as colorless crystalline powder (yield 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[O:15][CH2:16][C:17]3[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:18]=3[N:19]=1)[CH2:10][CH2:9][CH2:8]2.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[O:15][CH2:16][C:17]3[CH:23]=[C:22]([NH:24][C:28]([CH:25]4[CH2:27][CH2:26]4)=[O:29])[CH:21]=[CH:20][C:18]=3[N:19]=1)[CH2:10][CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CCC2
Reactant: O=C(Cl)C1CC1
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)C4CC4)cc3CO1)CCC2
Yield: 97.1 %

Procedure:
Prepared from rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 22) (162 mg, 0.50 mmol, HPLC 1.090 min) and cyclopropanecarbonyl chloride (53 ul, 0.55 mmol) according to the procedure described for Example 17. Obtained the title compound as an off-white solid (190 mg, 90%, HPLC 1.479 min 93%), MS (ISP) m/e=392.2 [(M+H)+].
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH:28]([CH3:30])[CH3:29])[C:12](=[O:27])[C:13]3[C:18]([C:19]=2/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:6]([O:31][CH3:32])[CH:5]=1>C(O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH:28]([CH3:29])[CH3:30])[C:12](=[O:27])[C:13]3[C:18]([C:19]=2/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:6]([O:31][CH3:32])[CH:5]=1
Reactant: CCOC(=O)/C=C/c1c(-c2ccc(F)cc2OC)n(C(C)C)c(=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(F)ccc1-c1c(/C=C/C(=O)O)c2ccccc2c(=O)n1C(C)C
Yield: 66.2 %

Procedure:
1N Sodium hydroxide solution (13 ml) was added to a solution of the compound (3.00 g) obtained by Step 3 in ethanol (70 ml) at room temperature under stirring. The reaction mixture was stirred at room temperature for 18 hours, and the solvent was distilled off. Water was added to the residue which was washed with ethyl acetate. The aqueous layer was acidified with aqueous potassium hydrogen sulfate solution and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent to give the title compound (1.85 g) as colorless crystals. mp 265°-267° C. (from ethyl acetate-diethyl ether)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH:14]=1)(=O)=O.[OH:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>O1CCOCC1.O.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:31][C:32]1[CH:37]=[CH:36][C:35]([C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH:14]=2)=[CH:34][CH:33]=1
Reactant: O=C(OCc1ccccc1)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1ccc(O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CC=C(c2ccc(O)cc2)CC1
Temperature: 80 °C
Yield: 66.4 %

Procedure:
Sodium carbonate (96 g, 909.79 mmol) was added to benzyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (123.1 g, 303.26 mmol) and 4-hydroxyphenylboronic acid (46.0 g, 333.59 mmol) in a mixture of dioxan (1000 mL) and water (250 mL). The resulting mixture was bubbled with nitrogen for 10 minutes then 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (5.49 g, 7.58 mmol) was added and the reaction mixture was heated at 80° C. for 1 hour, then cooled to room temperature. The reaction mixture was diluted with DCM (2 L) and washed with water (2 L). The aqueous washing was re-extracted with DCM (1 L), then the combined organics were washed with saturated brine (500 mL), dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 30% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness then triturated with isohexane, filtered and is dried to afford benzyl 4-(4-hydroxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (62.3 g, 66.4%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12](N)[CH:13]=[CH2:14].CCOCC>ClCCl>[CH2:14]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH:13]=[CH2:12]
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C=CCN
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCNS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 4-bromobenzenesulfonamide (6.80 g 26.6 mmol) in dichloromethane (50 mL) was added allylamine (5.0 mL, 66.5 mmol) at 0° C. The clear, colorless solution was stirred at room temperature for 1 h. The reaction mixture was poured into ether (100 mL) and washed with 10% aq HCl (50 ML), water (2×50 mL), and saturated aq NaHCO3 (50 mL). The organic phase was dried (MgS04) and concentrated. The residue crystallized upon treatment with hexane to provide 7.03 g (96% yield) of the desired product as fine, white crystals. Mp: 63-65° C. (lit. 64-65° C. See Keasling, H. H.; Schumann, E. L.; Veldkamp, W. J. Med. Chem. 1965, 8, 548). 1H NMR (400 MHz, CDCl3): δ 7.77-7.72 (m, 2H), 7.69-7.64 (m, 2H), 5.71 (ddt, J=17.1, 10.2, 6.0 Hz, 1H), 5.18 (dq, J=17.1, 1.5 Hz, 1H), 5.12 (dq, J=10.2, 1.5 Hz, 1H), 4.67 (t, J=6.0 Hz, 1H), 3.61 (tt, J=6.0, 1.5 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 139.0, 132.6, 132.4, 128.6, 127.6, 118.0, 45.7.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].[CH2:21](O)[CH3:22]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([O:19][CH2:21][CH3:22])=[O:18]
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1ccccc1O2
Product: CCOC(=O)C(C)c1ccc2c(c1)CCc1ccccc1O2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
An amount of 190 mg of 2-(10,11-dihydro dibenzo[b,f]-oxepin-2-yl)-propionic acid was dissolved in 5 ml of ethanol containing 10% hydrogen chloride and the resulting mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off to obtain the residue, which was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain pale brown oil, which was chromatographed over silica gel, eluted with benzene, and there was obtained 185 mg of ethyl 2-(10,11-dihydro dibenzo-[b,f]oxepin-2-yl)-propionate as pale yellow oil.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>N1C=CC=CC=1>[CH2:25]([O:24][CH2:23][CH:21]([CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:22][S:49]([C:46]1[CH:47]=[CH:48][C:43]([CH3:53])=[CH:44][CH:45]=1)(=[O:51])=[O:50])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(O)COCCCCCCCC/C=C\CCCCCCCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCCOCC(COCCCCCCCC/C=C\CCCCCCCC)OS(=O)(=O)c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
In 5 ml of pyridine was dissolved 150 mg (0.25 mmol) of 1,3-O-dioleylglycerol followed by addition of 77 mg (0.40 mmol) of p-toluenesulfonyl chloride and the mixture was heated at 60° C. and stirred for 2 days. After completion of the reaction, the solvent was distilled off and the residue was diluted with water and extracted with ether. The extract was dried and concentrated to provide 150 mg (80%) of 1,3-O-dioleyl-2-O-(p-toluenesulfonyl)glycerol as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH3:26])[C:21]([CH:24]=O)=[N:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:24][C:21]1[C:20]([CH3:26])=[CH:19][C:18]([Cl:17])=[CH:23][N:22]=1)[CH:8]1[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCCN)C1CC1
Reactant: Cc1cc(Cl)cnc1C=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: Cc1cc(Cl)cnc1CNCCCCN(C(=O)OC(C)(C)C)C1CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
A mixture of (4-amino-butyl)-cyclopropyl-carbamic acid tert-butyl ester (0.228 g, 1.00 mmol), 5-chloro-3-methyl-pyridine-2-carbaldehyde (0.141 g, 1.00 mmol) and K2CO3 (0.138 g, 1.00) in MeOH (5 mL) was stirred for 16 h. The mixture was filtered through a celite cake and the filtrate was cooled at 0° C. NaBH4 (0.038 g, 1.0 mmol) was added to the filtrate, and the mixture was stirred for 30 min. Saturated aqueous NaHCO3 (20 mL) was added and MeOH was removed. The aqueous residue was extracted with CH2Cl2 (3×30 mL). The organic extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (200:10:1 CH2Cl2/MeOH/NH4OH), affording {4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-cyclopropyl-carbamic acid tert-butyl ester as a pale yellow oil (0.155 g, 44%). 1H NMR (CDCl3) δ 0.54-0.59 (m, 2H), 0.69-0.75 (m, 2H), 1.45 (s, 9H), 1.54-1.61 (m, 4H), 2.30 (s, 3H), 2.45-2.50 (m, 1H), 2.69-2.74 (m, 2H), 3.18-3.23 (m, 2H), 3.85 (s, 2H), 7.43 (s, 1H), 8.34 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH:22][NH2:23])=[O:21])[CH:4]=1.O.[F:26][C:27]([F:34])([C:30]([F:33])([F:32])[F:31])[CH:28]=O.C1C=CC=CC=1.Cl>C(OCC)(=O)C.O>[F:26][C:27]([F:34])([C:30]([F:33])([F:32])[F:31])[CH:28]=[N:23][NH:22][C:20](=[O:21])[C:5]1[CH:4]=[C:3]([N:2]([CH3:24])[CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[N:6]=1
Reactant: O=CC(F)(F)C(F)(F)F
Reactant: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=CC(F)(F)C(F)(F)F)c1
Reaction time: 8 h

Procedure:
4-dimethylamino-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.30 g, 0.00088 mol) was mixed with 2,2,3,3,3-pentafluoropropionaldehyde monohydrate (0.29 g, 0.00088×2.0 mol) and benzene, and further with a small amount of concentrated hydrochloric acid. The obtained mixture was refluxed and dehydrated for about 8 hours using a water separator. The obtained reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and the organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated. The obtained concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21]>O1CCOCC1.O>[CH3:24][O:23][C:19](=[O:22])[CH2:20][S:21][C:4]1[C:5]([CH:9]=[O:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: COC(=O)CS
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)CSc1nc(N)nc(Cl)c1C=O
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a mixture of 2-amino-4,6-dichloro-5-pyrimidinecarbaldehyde (Apin, 2.00 g, 10.4 mmol) in dioxane (20 mL) was added triethylamine (1.60 mL, 11.5 mmol) and methyl thioglycolate (1.90 mL, 21.2 mmol). After about 3 hours, the reaction mixture was diluted with water (30 mL) and then filtered, washed with additional water to give (2-amino-6-chloro-5-formyl-pyrimidin-4-ylsulfanyl)-acetic acid methyl ester (1.801 g, 66%) as a yellow solid; RP-HPLC (Table 1, Method a) Rt 1.85 min, m/z (ESI+) 262.0 (M+H)+.