Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[CH:10]([CH:24]3[O:28][CH2:27][CH2:26][O:25]3)[CH2:9][CH2:8][C@@:7]4([OH:29])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37]([Si:41]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)Cl)([CH3:40])([CH3:39])[CH3:38].O>C1COCC1>[Si:41]([O:20][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][C@H:6]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:23][CH2:22][C@:12]45[C:13]=2[C:14]=1[O:21][C@H:11]4[CH:10]([CH:24]1[O:25][CH2:26][CH2:27][O:28]1)[CH2:9][CH2:8][C@@:7]35[OH:29])([C:37]([CH3:40])([CH3:39])[CH3:38])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxy-6-(1,3-dioxolan-2-yl)morphinan (3.85 g, 10 mmol) was dissolved in 10 ml of THF, then triethylamine (1.01 g, 10 mmol) and tert-butyldiphenyl chlorosilane (2.75 g, 10 mmol) were added with stirring. The whole system was reacted at a temperature ranging from 45° C. to 50° C. for 2 hours. After the reaction was complete, water was added to the system and the resultant mixture was extracted with diethyl ether for 3 times. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated for crystallization to afford a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])N.[OH-:11].[K+].[C:13](Cl)(=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23].Cl>O.C1COCC1>[C:13]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:11])=[O:7])(=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]
Reactant: [OH-]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: C=CCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O
Temperature: 20 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
L-Glutamine (14.62 g, 0.1 mol) and KOH (11.2 g, 0.2 mol) were dissolved in water (200 mL) at 20° C. A solution of 10-undecenoyl chloride (20.3 g, 0.1 mol) in THF (200 mL) was then added over 10 minutes. The reaction was stirred for 16 hours at 20° C. and was then reduced in vacuo to a volume of approximately 250 mL. Concentrated HCl (circa 12M) was added dropwise until the solution was pH 1. The white solid precipitate was collected by filtration. This solid was washed with water (100 mL) and diethyl ether (100 mL). The solid was then dissolved in refluxing toluene (500 mL) and the excess water present was removed by distillation at ambient pressure using a Dean-Stark trap. The solution was then allowed to cool to 20° C. After 16 hours, the white solid precipitate was collected via filtration and recrystallized from EtOAc (500 mL). This solid was dried in vacuo to give N-α-undec-10-enoyl-glutamic acid (9.36 g, 30%) as a white powder.
Reaction SMILES: C[S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[N:10].[Br:11]Br>ClC1C=CC=CC=1>[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[S:2][Br:11])#[N:10]
Reactant: CSc1ccccc1C#N
Reactant: BrBr
Solvent: Clc1ccccc1
Product: N#Cc1ccccc1SBr
Temperature: 100 °C
Reaction time: 5 h
Yield: 85.9 %

Procedure:
74.5 g (0.500 mol) of 2-cyanophenyl methyl sulfide and 250 g of chlorobenzene were placed in a 500 ml four-neck flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser and 96.0 g (0.600 mol) of bromine was added dropwise thereto at about 100° C. over five hours while stirring, followed by stirring for two hours to complete the reaction. The excess bromine was removed with an aqueous sodium carbonate solution and the solvent was distilled off to obtain 92.0 g of crude 2-cyanobenzenesulfenyl bromide. Separately, 172.4 g (2.00 mol) of piperazine and 15 g of chlorobenzene were placed in a 1000 ml four-neck flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser and the molten crude 2-cyanobenzenesulfenyl bromide obtained above was added dropwise thereto at about 130° C. over one hour while stirring, followed by stirring for five hours to complete the reaction. The excess piperazine was removed with water and reaction mixture was acidified with hydrochloric acid, followed by extraction into an aqueous layer. The aqueous layer was basified with an aqueous sodium hydroxide solution to obtain 65.9 g of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. The yield starting from 2-cyanophenyl methyl sulfide was 60.2%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C[O:35][B:36](OC)[O:37]C>O1CCCC1>[C:20]([SiH2:19][O:18][C:17]([CH3:25])([CH3:24])[C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH:9]=[CH:10]2)([CH3:23])([CH3:21])[CH3:22].[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[B:36]([OH:37])[OH:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C(C)(C)O[SiH2]C(C)(C)C)ccc21
Reactant: COB(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-(tert-Butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acid tert-butyl ester (5-3, 38.6 g, 106.7 mmol) in tetrahydrofuran (400 mL) was slowly added at −78° C. a solution of lithium diisopropylamide in tetrahydrofuran (2M, 80.1 mL, 160.1 mmol, 1.5 equiv). The reaction mixture was stirred at the same temperature for 1 h, treated with trimethylborate, warmed up to ambient temperature, and partitioned between ethyl acetate and 0.5N-HCl. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo to give the crude solid. Trituation of the crude product with hexanes followed by filtration and air-drying afforded the desired boronic acid (5-4) as a white powder; 1H NMR (400 MHz, CDCl3) δ7.96 (d, 1H, J=6.8 Hz), 7.54 (s, 1H), 7.47 (s, 1H), 7.32 (d, 1H, J=6.8 Hz), 7.10 (s, 1H), 4.82 (s, 2H), 1.74 (s, 9H), 0.95 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([OH:33])([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH:23]=[CH:24]2)[CH:19]=[CH:18]3)[CH2:15][CH2:14]1)[CH3:12])[C:4]([F:7])([F:6])[F:5].[OH:36]O>>[F:1][C:2]([F:34])([F:35])[C:3]([OH:33])([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[C@@H:23]4[O:36][C@@H:24]42)[CH:19]=[CH:18]3)[CH2:15][CH2:14]1)[CH3:12])[C:4]([F:6])([F:5])[F:7]
Reactant: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: OO
Product: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C

Procedure:
treating the resulting 26,26,26,27,27,27-hexafluoro-25-hydroxycholest-1,4,6-trien-3-one with hydrogen peroxide to obtain 26,26,26,27,27,27-hexafluoro-25-hydroxy-1α,2α-epoxycholest-4,6-dien-3-one
Reaction SMILES: [C:1]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].NN.[OH-].[K+].C(O)COCCOCCO>O>[CH2:1]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCC(=O)c1cccnc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CCCCCCCCCCCc1cccnc1
Reaction time: 6 h
Yield: 96.2 %

Procedure:
A mixture of 12.2 g (49 mmol) of 3-n-undecanoylpyridine, 7.60 g (0.15 mol) of hydrazine.monohydrate and 5.60 g (0.10 mol) of potassium hydroxide and 50 ml of triethylene glycol was heated at 110° to 125° C. for one hour, and further, at 180° to 185° C. for 6 hours. After cooling, 200 ml of water was added, and the mixture was extracted with diethyl ether, and after washing with water, the extract was dried with anhydrous sodium sulfate. After concentration under a reduced pressure, the residue was purified by distillation under a reduced pressure to obtain 11.0 g of the desired product (yield 95.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[CH2:9]2)=[CH:4][C:3]=1[O:23][CH3:24].CS([C:28]1[N:33]=[CH:32][C:31]2=[CH:34][CH:35]=[C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])[N:30]2[N:29]=1)=O.C(N(CC)C(C)C)(C)C>COCCO.CO>[CH3:24][O:23][C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([N:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:22])[CH3:21])[CH2:18][CH2:19]3)[CH2:9]2)[CH:6]=[CH:7][C:2]=1[NH:1][C:28]1[N:33]=[CH:32][C:31]2=[CH:34][CH:35]=[C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])[N:30]2[N:29]=1
Reactant: COc1cc(N2CCCC(N3CCN(C(C)=O)CC3)C2)ccc1N
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCCC(N3CCN(C(C)=O)CC3)C2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Yield: 38.2 %

Procedure:
A mixture of 1-{4-[1-(4-amino-3-methoxy-phenyl)-piperidin-3-yl]-piperazin-1-yl}-ethanone (80 mg, 0.24 mmol) and 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (46 mg, 0.16 mmol) in 2-methoxyethanol (0.50 mL) and treated with N,N-Diisopropylethylamine (56 μL, 0.32 mmol). The reaction was microwaved on 300 watts, 200 C for 9.5 hours. The sample was diluted with methanol (10 mL), filtered and concentrated. The crude product was purified by RF-HPLC to afford 34 mg of the title compound as an amber powder after lyophyllization. MS=556 (M-TFA+1); NMR (DMSO-d6, ppm): 9.83 (br, 1H), 8.91 (s, 1H), 7.86 (m, 2H), 7.56 (s, 1H), 7.45 (t, J=7 Hz, 1H), 7.20 (d, J=7 Hz, 1H), 7.10 (t, J=7 Hz, 1H), 6.95 (q, J=5 Hz, 14 Hz, 2H), 6.69 (s, 1H), 6.46 (d, J=7 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.50 (m, 4H), 2.91 (t, J=12 Hz, 2H), 2.70 (t, J=10 Hz, 2H), 2.33 (m, 1H), 2.13 (m, 2H), 2.07 (s, 3H), 1.89 (m, 1H), 1.64 (t, J=10 Hz, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:13])[CH2:9][CH2:10][C:11]#[CH:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[N:22][OH:23])=[CH:17][CH:16]=1.O>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:12]=[C:11]([CH2:10][CH2:9][CH2:8][OH:13])[O:23][N:22]=2)=[CH:17][CH:16]=1
Reactant: C#CCCCO
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: OCCCc1cc(-c2ccc(Cl)cc2)no1
Yield: 52.1 %

Procedure:
1.6 ml (11.5 mmol) of triethylamine are added dropwise to a solution, cooled with an ice bath, of 1.18 ml (12.6 mmol) of pent-4-yn-1-ol and of 2.0 g (10.5 mmol) of 4-chloro-N-hydroxybenzenecarboximidoyl chloride (J. Med. Chem., 1998, 41, 4556-4566) in 30 ml of dichloromethane. Reaction is allowed to take place at ambient temperature overnight. 50 ml of dichloromethane and 70 ml of water are added. The organic phase is separated and the aqueous phase is extracted with 2 times 50 ml of dichloromethane. The organic phases are subsequently washed with 2 times 70 ml of water and then with 70 ml of a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel, elution being carried out with a mixture of cyclohexane and of ethyl acetate, to produce 1.3 g (5.47 mmol) of product in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH3:11])[CH:3]=1.[NH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[C:19]([Br:30])[C:18]=2[CH:31]=1>C(O)C>[Br:30][C:19]1[C:18]2[CH:31]=[C:14]([CH2:13][NH:12][C:2]3[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=[C:4]([CH3:11])[CH:3]=3)[CH:15]=[CH:16][C:17]=2[O:21][C:20]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[N:29]
Reactant: Cc1cc(Cl)n2nccc2n1
Reactant: N#Cc1ccccc1-c1oc2ccc(CN)cc2c1Br
Solvent: CCO
Product: Cc1cc(NCc2ccc3oc(-c4ccccc4C#N)c(Br)c3c2)n2nccc2n1
Temperature: 25 °C

Procedure:
A solution of 1.7 g (10.1 mmol) 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine (prepared according to Y. Makisumi, Chem. Pharm. Bull. 1962, 10, 620)and 3.27 g (10.0 mmol) 5-(aminomethyl)-3-bromo-2-(2-cyanophenyl)benzofuran (prepared according to WO 92/09600) in 50 ml dry ethanol was heated with reflux for 5 h. The title compound precipitated upon cooling to room temperature, was filtered with suction, and recrystallized from ethanol to give colorless crystals. yield: 3.5 g (76%), m.p. 210°-215° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13]CC)=O.[CH3:16][NH2:17]>CO>[CH3:16][NH:17][C:11]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:13]
Reactant: CN
Reactant: CCOC(=O)c1cc2ccccc2n1C
Solvent: CO
Product: CNC(=O)c1cc2ccccc2n1C
Temperature: 25 °C

Procedure:
A suspension of ethyl 1-methyl-1H-indole-2-carboxylate (27.10 g, 133.34 mmole) in 40% aqueous CH3NH2 (300 mL) and MeOH (30 mL) was stirred at RT. A solid tended to gradually creep up the walls of the flask, and was washed down periodically with MeOH. The flask was tightly stoppered to keep the material inside the flask. As the reaction proceeded, the solid dissolved, but eventually the product began to precipitate. The reaction was stirred at RT for 5 days, then was concentrated to remove approximately 200 mL of the solvent. The remaining residue was diluted with H2O (300 mL), and the solid was collected by suction filtration and washed with H2O. Drying at 50-60° C. in high vacuum left the title compound (23.45 g, 93%) as a faintly yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J=8.0 Hz, 1 H), 7.27-7.43 (m, 2 H), 7.10-7.20 (m, 1 H), 6.80 (s, 1 H), 6.10-6.30 (m, 1 H), 4.06 (s, 3 H), 3.01 (d, J=4.9 Hz, 3 H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=2)O1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:24]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC1(C)OB(C2=CC(=O)CCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (1.0 equiv.) in degassed dioxane and 2M Na2CO3 was added 4-chloro-3-nitropyridine (1.2 equiv.) and Pd(PPh3)4 (0.05 equiv.). The reaction was heated in an oil bath to 120° C. for 30 min. (reaction can also be carried out in the microwave for 10 min at 120° C.). Cooled to room temperature, then diluted with EtOAc, added H2O—dark solution, lots of emulsions. Filtered to get rid of the solids, then extracted the organic phase, dried with Na2SO4, and concentrated. The crude was purified via silica gel chromatography to yield 3-(3-nitropyridin-4-yl)cyclohex-2-enone (64%, 2 steps). LC/MS=219 (M+H), LC=2.29 min.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH3:8][CH2:9][CH:10]([CH2:12]O)[CH3:11].CC1C=CC=CC=1.O>CCCCCCC>[CH3:1][C:2]([CH3:7])=[CH:3][C:4]([O:6][CH2:11][CH:10]([CH3:12])[CH2:9][CH3:8])=[O:5]
Reactant: CC(C)=CC(=O)O
Reactant: CCC(C)CO
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCC(C)COC(=O)C=C(C)C
Yield: 90.5 %

Procedure:
At room temperature under nitrogen in a 500 ml flask, a mixture of 87.3 g of 3,3-dimethylacrylic acid (0.85 mol) and 134.7 g of DL-2-methyl-1-butanol (1.50 mol, 1.75 eq.) and 4.25 g of para-toluene suflonic acid monohydrate (0.024 mol, 0.026 eq.) was treated with 100 ml heptane and then heated at reflux at 90° C. for 14 hours while 15.4 ml (0.85 mol) of H2O was collected in a Dean-Stark trap. The result was an orange solution. The solution was extracted with MTBE/brine (2×350 ml/200 ml brine). The organic layers were washed with NaHCO3 (200 ml saturated solution), brine (200 ml), dried over MgSO4 and concentrated. 205 g of a orange liquid was recovered, which was purified by distillation over a 30 cm plate-column. 131.1 g of a colorless liquid was recovered (bp 58° C./3.5 torr (4.7 bar) 90.5% yield).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[C:18]([OH:20])=[O:19])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[CH2:36]([N:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:42](Cl)=[O:43])[CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:42](=[O:43])[N:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:14][C@H:13]2[C:18]([OH:20])=[O:19])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)[C@@H]1CNCCN1C(=O)N(c1ccccc1)c1cccc(Cl)c1
Reactant: CCCCCN(CCCCC)C(=O)Cl
Agent: Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.1 %

Procedure:
To a suspension of 1.05 g (2.3 mmole) of (S)-1-[N-(3-chlorophenyl)-N-phenylcarbamoyl]piperazine-2-carboxylic acid hydrobromide (from Step C) in 20 ml of methylene chloride was added 1.23 g (9.5 mmole) of N,N-diisopropylethylamine followed by the dropwise addition of a solution of 523 mg (2.38 mmole) of dipentylcarbamoyl chloride (from Example 3, Step A) in 5 ml of methylene chloride. After stirring 24 hours at 25° C., the solution was extracted with 2N HCl, then H2O and dried over MgSO4. The dried methylene chloride solution was concentrated in vacuo and the residue was dissolved in isopropyl ether and was diluted with Petroleum ether bp. 30°-60° C.) until cloudy. The oil which precipitated was then decanted, redissolved in isopropanol and concentrated in vacuo to yield 464 mg (36%) of (S)-1-[N-(3-chlorophenyl)-N-phenylcarbamoyl]-4-(dipentylcarbamoyl)piperazine-2-carboxylic acid as a glassy solid; TLC showed a single spot, Rf 0.75 (Anal tech SGF plates developed with isoamyl alcohol:acetone:water [5:2:1]).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1.[C-:27]#[N:28].[Na+].[N+:30]([C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)([O-:32])=[O:31]>>[N+:30]([C:33]1[CH:39]=[CH:38][C:36]([NH:37][C:11]2([C:27]#[N:28])[CH2:12][CH2:13][N:8]([C:7]3[CH:6]=[CH:5][C:4]([N:16]4[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]4=[O:26])=[CH:3][C:2]=3[F:1])[CH2:9][CH:10]2[CH3:15])=[CH:35][CH:34]=1)([O-:32])=[O:31]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: [C-]#N
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)C3)c(F)c2)C(=O)O1
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4ccc([N+](=O)[O-])cc4)C(C)C3)c(F)c2)C(=O)O1
Yield: 49 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)-N-{3-[3-fluoro-4-(4-oxo-3-methyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 4-nitroaniline the compound was obtained in 49% yield.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:16])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1[CH3:15])=O)(=[O:3])[CH3:2].CC([O-])=O.[K+].Cl.[O:23]([NH2:25])[CH3:24]>CCO.O>[C:1]([O:4][CH:5]([CH3:16])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=1[CH3:15])=[N:25][O:23][CH3:24])(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OC(C)C(=O)c1ccc(Br)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CON=C(c1ccc(Br)cc1C)C(C)OC(C)=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a mixture of 2-(4-bromo-2-methylphenyl)-1-methyl-2-oxoethyl acetate (5.0 g, 17.5 mmol) and KOAc (2.75 g, 28.0 mmol) in EtOH (90 mL) was added methoxylamine hydrochloride (2.34 g, 28.0 mmol) and the resulting milky suspension was stirred at 70° C. for 4 h. An additional 0.5 equivalents of KOAc and methoxylamine hydrochloride were added and the reaction mixture was stirred at 70° C. for 8 h. The reaction mixture was diluted with water, and the EtOH was removed under reduced pressure. The aqueous residue was extracted with diethyl ether (2×75 mL), and the ether extracts were combined, washed with aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give 2-(4-bromo-2-methylphenyl)-2-(methoxyimino)-1-methylethyl acetate (5.0 g, 91%) as a racemic mixture of the E- and Z-methoxime isomers as a gold oil.
Reaction SMILES: C([O:5]C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]2([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19]([S:27]([C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[N:35]([C:39]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[O:40])[CH2:34][CH2:33]4)(=[O:29])=[O:28])[C:18]2=[O:46])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55]>C(Cl)Cl>[OH2:5].[F:57][C:56]([F:59])([F:58])[C:54]([OH:60])=[O:55].[Cl:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:27]([C:30]1[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[O:40])[CH2:34][CH2:33]3)(=[O:29])=[O:28])[C:18](=[O:46])[C:17]2([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:53])[NH:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CCN(CC)C(=O)N1CCc2cc(S(=O)(=O)N3C(=O)C(NCCC4CCN(C(=O)OC(C)(C)C)CC4)(c4ccccc4Cl)c4cc(Cl)ccc43)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)N1CCc2cc(S(=O)(=O)N3C(=O)C(NCCC4CCNCC4)(c4ccccc4Cl)c4cc(Cl)ccc43)ccc21
Product: O
Reaction time: 0.25 h

Procedure:
A solution of 1.17 g of the compound obtained in EXAMPLE 222 in 7.5 ml of DCM is cooled to +4° C., 15 ml of TFA are added and the reaction mixture is stirred for 3 hours 15 minutes at +4° C. It is concentrated under vacuum, the residue is taken up with DCM and the solvent is evaporated off under vacuum, this operation being repeated twice. The residue is taken up with AcOEt, the organic phase is washed with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 0.6 g of the expected product after trituration in iso ether and then crystallization from a DCM/iso ether mixture. M.p.=133° C.
Reaction SMILES: C[NH:2][C:3]1[N:8]=[C:7]([NH:9]C)[N:6]=[C:5]([NH:11]C)[N:4]=1.[CH2:13]=[O:14]>O>[CH2:13]=[O:14].[N:4]1[C:5]([NH2:11])=[N:6][C:7]([NH2:9])=[N:8][C:3]=1[NH2:2]
Reactant: CNc1nc(NC)nc(NC)n1
Agent: C=O
Solvent: O
Product: Nc1nc(N)nc(N)n1

Procedure:
756.9 g of N,N′,N″-trimethylmelamine, 135 g of water and 584.1 g of a 37% strength aqueous formaldehyde solution are stirred together at room temperature until the methylolmelamines formed are precipitated from the solution. Thereafter, this mixture is combined with the above mixture and a further 350 g of melamine derivative according to Example 1 and heated for 15 min to 60° C. A clear solution is obtained. After freeze-drying, the resin was obtained as a white solid.