Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:20]1[CH:26]2[CH:21]1[CH2:22][CH:23]([C:27](OC)=[O:28])[CH2:24][CH2:25]2.N12CCN(CC1)CC2.C1(C)C=CC=CC=1>CO>[O:20]1[CH:26]2[CH:21]1[CH2:22][CH:23]([C:27]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:28])[CH2:24][CH2:25]2
Reactant: COC(=O)C1CCC2OC2C1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOC(=O)C1CCC2OC2C1
Yield: 90.4 %

Procedure:
To a 3-neck 100 mL flask equipped with an argon inlet, stir bar and distillation apparatus was added 1-octadecanol (5.03 g, 19 mmol, obtained from Sigma-Aldrich), methyl 3,4-epoxycyclohexanecarboxylate (ERL-4140, 8.69 g, 56 mmol, obtained from Dow Chemical Company), 1,4-diazabicyclo[2.2.2]octane (DABCO™, 1.02 g, 9.1 mmol, obtained from Sigma-Aldrich) and toluene (15 mL). The reaction mixture was refluxed until methanol ceased collecting in the receiving flask and the completion of the reaction was confirmed by 1H NMR spectroscopy. The still pot from the distillation was diluted with toluene (15 mL) and washed with brine (3×15 mL). The organic layer was separated, dried over MgSO4 and filtered. The solvent was removed in vacuo. The excess methyl 3,4-epoxycyclohexane carboxylate was removed via Kugelrohr distillation under reduced vacuum to give 6.78 g (87%) of a white solid (mp=32-34° C.) of octadecyl 3,4-epoxycyclohexanecarboxylate. 1H NMR (CDCl3, δ): 4.06 (td, J=6.7, 1.9 Hz, 2H), 3.25-3.14 (m, 2H), 2.55-2.45 (m, 1H), 2.31-1.26 (m, 38H), 0.88 (t, J=6.7 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=2)[N:4]2[CH:14]=[CH:15][CH:16]=[C:3]12.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:50][C:51]1[CH:56]=[CH:55][C:54]([NH2:57])=[C:53]([NH2:58])[CH:52]=1>O1CCCC1>[NH2:58][C:53]1[CH:52]=[C:51]([F:50])[CH:56]=[CH:55][C:54]=1[NH:57][C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]1[CH:14]=[CH:15][CH:16]=[C:3]1[C:2]2=[O:1])=[O:13]
Reactant: O=C(O)c1cccc2c1-n1cccc1C2=O
Reactant: Nc1ccc(F)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1NC(=O)c1cccc2c1-n1cccc1C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
In a 250 ml round-bottomed flask under argon, a mixture of 620 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid obtained according to the preceding stage, 1.50 g of o-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and 0.44 ml of diisopropylethylamine in 55 ml of tetrahydrofuran is stirred at ambient temperature for 1 hour. 367 mg of 4-fluoro-o-phenylenediamine are then added and the stirring is maintained for 3 days. The reaction medium is evaporated to dryness under vacuum and the residue is taken up with 15 ml of a mixture of dichloromethane and methanol (90/10 v/v). The organic phase is washed with 10 ml of a saturated solution of sodium bicarbonate, then with 3 times 5 ml of distilled water, and dried over magnesium sulphate. After evaporation to dryness under vacuum, the residue is loaded as a dry spot onto a column of silica gel (40-63 μm) and chromatographed, elution being carried out with a mixture of dichloromethane and methanol (95/5 v/v). 379 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid (2-amino-4-fluorophenyl)amide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:26]2
Reactant: Brc1ccc2c(c1)CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3ccc(Br)cc3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 47.5 %

Procedure:
290 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 200 mg of 5-bromoisoindoline, 290 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 220 mg of the target compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:43][C:44](=[O:52])[C@H:45]([CH2:47][C:48]([O:50]C)=[O:49])[NH2:46]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:46][C@H:45]([C:44]([OH:43])=[O:52])[CH2:47][C:48]([OH:50])=[O:49])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@@H](CC(=O)O)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and L-Aspartic acid dimethyl ester hydrochloride (40 mg, 0.2 mmole) were processed as in Examples 213A and 224B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.46-13.35 (br.s, 2 H), 8.95 (s, 1 H), 8.13 (d, 1 H), 7.26 (m, 6 H), 7.18 (m, 3 H), 7.03 (m, 1 H), 6.96 (m, 2 H), 6.88 (m, 4 H), 4.54 (m, 1 H), 4.05 (s, 2 H), 4.01 (s, 2 H), 2.91 (s, 3 H), 2.69 (m, 1 H), 2.55 (m, 3 H), 2.39 (s, 3 H), 2.12 (t, 2 H), 1.76 (m, 2 H); MS (APCI+) m/z 674 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:14]1[S:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1.O>C(#N)C>[N+:19]([C:16]1[S:15][C:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cnc(N2CCNCC2)s1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 74.3 %

Procedure:
To a solution of piperazine (18.2 g) and potassium carbonate (12.6 g) in acetonitrile (150 ml) was added 2-bromo-5-nitrothiazole (14.7 g) at 40° C. and the mixture was stirred at 60° C. for 40 min. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown solid (11.2 g). The obtained brown solid was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give the title compound (4.8 g) as yellow crystals.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[NH:13][CH:14]=[C:6]([C:7]=23)[CH2:5][N:4]=1)[NH2:2].[C:15](=O)(O)[O-].[Na+]>C(O)=O>[CH:11]1[C:12]2[C:3]3=[N:1][N:2]=[CH:15][N:4]3[CH2:5][C:6]3=[CH:14][NH:13][C:8]([C:7]=23)=[CH:9][CH:10]=1
Reactant: O=C([O-])O
Reactant: NNC1=NCc2c[nH]c3cccc1c23
Agent: [Na+]
Solvent: O=CO
Product: c1cc2c3c(c[nH]c3c1)Cn1cnnc1-2
Temperature: 100 °C

Procedure:
5-Hydrazino-1,3-dihydropyrrolo[4,3,2-de]isoquinoline hydrofluoroborate (300 mg), described in Example 8, in formic acid (98%, 4 ml) is heated at 100°C for 2 hours. The mixture is then poured into a saturated sodium bicarbonate solution. The precipitate is collected to give the title compound, mp 248° - 249°C, nmr (DMSO-d6) δ 5.65 (2H), 7.3 (4H), 8.5 (1H), 11.3 (1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H][H].[CH3:27]I>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([N:19]([CH3:27])[C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C(=O)Nc1ccc(OCCc2ccccc2)c(Cl)c1
Reactant: CI
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)N(C)c1ccc(OCCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of sodium hydride (0.48 g; 0.01 mol-as 50% dispersion in oil) and THF (25 ml) is prepared and maintained under a nitrogen atmosphere. Then 3-[3-chloro-4-(phenethyloxy)phenyl]-1,1-dimethylurea (3.19 g; 0.01 mol) is added to the above mixture. Hydrogen is evolved and a thick paste forms. After about 15 minutes methyl iodide (1.4 g; 0.01 mol) is added and the reaction mixture stirred for two hours at room temperature. After two hours reaction time the paste redissolves. Next, most of the THF is removed under vacuum, the residue dissolved in methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated to afford the title product as an oil.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:46])(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].[Na+]>CC(C)=O.O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:46][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 57.1 %

Procedure:
To 150 ml of acetone-water (2:1) are added 1.3 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 1.0 g of sodium stearate and the mixture is refluxed for 4 hours and allowed to stand at room temperature (15°-25° C.) overnight. The solvent is then distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the residue is dissolved in 100 ml of ethanol. To the solution is added 0.3 g of activated carbon and the insoluble material is filtered off. The solvent is distilled off to give a colorless viscous oil, which is allowed to stand at room temperature (15°-25° C.) to give 1.1 g of the above-identified compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a solution of 5-aminoindane (2.0 g, 15.0 mmol) in 5 mL of anhydrous pyridine at 0° C. was added acetic anhydride (2.1 mL, 22.5 mmol) and the solution was stirred at rt for 3 h. The solution was then added to 50 mL of water and the resulting solid filtered and washed with water, then dried under vacuum to yield the title compound (2.23 g, 78%). 1H NMR (CDCl3): 7.44 (s, 1H), 7.2 (bs, 1H), 7.12 (s, 2H), 2.88 (q, 4H), 2.18 (s, 3H), 2.09 (p, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]2[CH2:13][S:12][C:11](=[O:14])[N:10]=2)[C:3]1=[O:15].[F:16][C:17]([F:38])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:38][C:17]([F:16])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24](/[CH:27]=[C:13]2/[C:9]([NH:8][CH:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]3=[O:15])=[N:10][C:11](=[O:14])[S:12]/2)[CH2:23][CH2:22]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN1CCCC(NC2=NC(=O)SC2)C1=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN1CCCC(NC2=NC(=O)S/C2=C\C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)C1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a solution of 1-methyl-3-[(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)amino]piperidin-2-one (220 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (339 mg) in 2-propanol (5 mL) was added piperidinium acetate (141 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (158 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]#[N:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:1][CH2:2][C:3]1([CH2:6][C:7]#[N:8])[CH2:5][CH2:4]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCC1(CO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(CC#N)CC1
Temperature: -10 °C

Procedure:
To a solution of [1-(hydroxymethyl)cyclopropyl]acetonitrile (prepared according to the procedure described in WO2005/105749 Example 2/Step 4, incorporated by reference) (1 eq.) in DCM at −40° C. was added triethylamine (3 eq.) and then methanesulfonyl chloride (1.5 eq.). The reaction was warmed to −10° C. over 1 h, and it was diluted with DCM and quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O.[CH3:19]O>>[ClH:17].[CH3:19][O:11][C:10](=[O:12])[C@H:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=1)[NH2:9]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CO
Product: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of O-methyl-L-tyrosine (1.44 g, 7.4 mmol) in methanol (30 ml) was stirred at 0° C. and thionyl chloride (1 ml, 13.4 mmol) added dropwise. After stirring for 15 min. at ambient temperature the reaction was heated at reflux for 2 h. After cooling the solvent was evaporated to give crude O-methyl-L-tyrosine methyl ester hydrochloride salt as a yellow solid This was partitioned between saturated aqueous sodium hydrogen carbonate (80 ml) and ethyl acetate (150 ml), and the aqueous layer back extracted with ethyl acetate (2×80 ml). The combined organics were dried over anhydrous sodium sulphate, filtered and concentrated to give O-methyl-L-tyrosine methyl ester as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].[C:19](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[O:12][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C(=O)OC)c(O)c1

Procedure:
To a solution of methyl 2,4-dihydroxybenzoate (25.1 g) in acetone (250 ml) are added methyl bromoacetate (14.9 ml) and potassium carbonate (21.7 g), and the mixture is refluxed for 3 hours. The mixture is filtered, and the filtrate is concentrated, and the residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=3:1) to give ethyl 2-(3-hydroxy-4-methoxycarbonylphenoxy)acetate (31.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](C1NC=CN=1)(C1NC=CN=1)=[O:34]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH2:16][O:17][C:33]2=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(CO)Cc2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)OCC2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
4-[1-(4-Chloro-benzyl)-2-hydroxy-ethylamino]-piperidine-1-carboxylic acid tert-butyl ester, the intermediate alcohol was dissolved in 15 mL of methylene chloride. Triethylamine (0.423 g, 0.00418 mol, 583 uL 1.2 equiv) was added followed by portionwise addition of carbonyl diimidazole (0.68 g, 0.00418 mol, 1.2 equiv). The mixture was stirred at room temperature and then quenched with water (15 mL). The organic layers were separated and the remaining aqueous layer was extracted with methylene chloride (3×15 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The crude oil was purified by silica gel chromatography (methylene chloride to 10% methanol in methylene chloride gradient) to afford 4-[4-(4-chloro-benzyl)-2-oxo-oxazolidin-3-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.1 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:23]2[CH:22]=[C:21]([CH3:20])[CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: Cc1ccnc(CN)c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccnc(CNc2nc(N)nc(-c3ccco3)c2C#N)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(4-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]=CN(C)C)[CH:25]=3)=[O:23])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.C(O)(C(F)(F)F)=O.O>[NH2:30][C:26]1[CH:25]=[C:24]([C:22]([C:16]2[C:15]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:35]([F:37])([F:38])[F:36])[CH:4]=3)(=[O:10])=[O:9])=[CH:20][C:19]([CH3:21])=[CH:18][N:17]=2)=[O:23])[CH:29]=[CH:28][N:27]=1
Reactant: COCN(c1cc(C)cnc1C(=O)c1ccnc(N=CN(C)C)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(C(=O)c2ccnc(N)c2)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A mixture of 4-chloro-N-{2-[2-(dimethylamino-methyleneamino)-pyridine-4-carbonyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzene sulfonamide (23 mg, mmol) in 5% H2SO4 in TFA (4 mL) and water (1 mL) was stirred at 50° C. for 2 days. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and treated with saturated aqueous NaHCO3 solution slowly till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was column purified (SiO2, 10% MeOH—CH2Cl2) to afford N-[2-(2-amino-pyridine-4-carbonyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoro methyl-benzenesulfonamide (12 mg) in 63% yield. 1H NMR (400 MHz, CDCl3) δ 10.75 (s, 1 H), 8.24 (s, 1 H), 8.18 (m, 1 H), 8.07 (dd, 1 H), 7.95 (d, 1 H), 7.75 (d, 1 H), 7.63 (d, 1 H), 7.15 (s, 1 H), 6.95 (d, 1 H), 2.25 (s, 3H); ESMS m/z (relative intensity): 471.0 (M+H)+ (100).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.O1CCCC1.[H-].[Na+].C([O:15][C:16](=[O:19])[CH2:17]Br)C>C(O)C>[N:1]1([CH2:17][C:16]([OH:19])=[O:15])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)CBr
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cn1cccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 g of pyrazole in 250 ml of abs. tetrahydrofuran is added dropwise in a nitrogen atmosphere within 1/2 hour at 20°-30°, with stirring and cooling, to 38.7 g of sodium hydride in 100 ml of abs. tetrahydrofuran. The reaction mixture is stirred for a further 3 hours at 40°; it is then cooled towards 5° and, with good cooling, 160.7 g of bromoacetic acid ethyl ester in 100 ml of abs. tetrahydrofuran is added dropwise at 0°-10° during 1 hour. Stirring is maintained overnight at room temperature; there is then added dropwise 150 ml of ethanol; stirring is continued for 1 hour, and the suspension is subsequently concentrated by evaporation. To the residue is added a solution of 74 g of NaOH tablets in 600 ml of 60% methanol (aqueous), and refluxing is carried out for 40 minutes. The solution is then cooled, and washed twice with 200 ml of ether. The aqueous phase is made acid to a congo-red indicator (about pH 2) with conc. hydrochloric acid at 5° with cooling, and the solution is continuously extracted during 24 hours with methylene chloride. The extract is concentrated by evaporation, and recrystallised from ether/tetrahydrofuran. The crystals melt at 167°-169°.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:16][NH:15][CH2:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:23](Cl)(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CCCCCC>[C:23]([N:15]1[CH2:14][C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:7][C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:16]1)(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: C1CCC2(CC1)CNCC1(CCCCC1)N2
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)N1CC2(CCCCC2)NC2(CCCCC2)C1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
In a 500 ml. 3-necked flask equipped with stirrer, condenser with drying tube, thermometer, dropping funnel and nitrogen inlet was placed a solution of 15.6 g. (0.07 moles) of 7,15-diazadispiro[5,1,5,3]hexadecane in 150 ml. of dry pyridine. Under a dry nitrogen atmosphere, the solution was cooled to 5° C with an external ice bath and a solution of 21.2 g. (0.07 moles) of stearoyl chloride in 50 ml. of hexane was added dropwise with stirring over a 20 minute period. The reaction mixture was then allowed to warm to room temperature and stir for about 16 hours. The reaction mixture was filtered and the filtrate was taken up in ether, washed well with water, then with 2N NaOH solution. The filtrate was again filtered by suction, and the ether solution dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from acetonitrile, yielding colorless crystals, m.p. 56°-59° C.