Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.CN([CH:35]=[O:36])C>C1COCC1.C(OCC)(=O)C>[CH3:9][C:10]1[CH:15]=[C:14]([C:16]2[S:20][C:19]([CH:35]=[O:36])=[N:18][CH:17]=2)[CH:13]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=2)[CH:11]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C=O)s2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a flask was added tetrahydrofuran (60 mL) and the solution was cooled to −78° C. Lithium diisopropylamide (19.8 mL, 35.7 mmol) was added and the mixture was allowed to cool to −78° C. INTERMEDIATE 4 (4.0 g, 11.90 mmol) was dissolved in THF (60 mL) and added in portion. The solution was stirred for 30 minutes. DMF (1.30 g, 17.84 mmol) was dissolved in THF (60 mL) and added over a period of five minutes. The solution was then allowed to warm to room temperature. The reaction mixture was then diluted with ethyl acetate, washed with saturated ammonium chloride, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel column chromatography to yield 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carbaldehyde (3.5 g, 81%). MS ESI: [M+H]+ m/z 364.8. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.91 (s, 1H), 8.86 (d, J=5.3, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 731 (d, J=5.2, 1H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][C:2](=CC)[C:3](Cl)=[O:4].[CH3:8][C:9]1[CH:14]2[C:15]([CH3:17])([CH3:16])[CH:12]([CH2:13]2)[CH2:11][CH:10]=1.[CH2:18](Cl)[CH2:19]Cl>[Cl-].[Zn+2].[Cl-]>[C:15]([C:12]12[CH2:13][CH:14]([C:9]([CH3:8])=[CH:10][CH2:11]1)[C:3](=[O:4])[CH:2]([CH3:1])[CH:18]2[CH3:19])([CH3:16])=[CH2:17]
Reactant: ClCCCl
Reactant: CC1=CCC2CC1C2(C)C
Reactant: CC=C(C)C(=O)Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: C=C(C)C12CC=C(C)C(C1)C(=O)C(C)C2C
Yield: 7.1 %

Procedure:
Method a) A mixture of 11.81 g 2-methyl-but-2-enoyl chloride (0.10 mol) and 1.36 g zinc chloride (0.01 mol, 0.1 eq.) in 100 ml ethylene chloride was treated with a soln. of 136 g α-pinene ((1S)-(−)/(1R)-(+) 90:10, 1 mol, 10 eq.) in 150 ml ethylene chloride and the resulting mixture was stirred 45 min. at 25° C., 2.5 h at 50° C., and 1 h at 80°. After cooling, the reaction mixture was washed with aq. sat. NaCl soln. and aq. sat. NaHCO3 soln. The aq. phases were extracted with Et2O, dried (Na2SO4), and concentrated. The crude product (48 g) filtered (SiO2, hexane/Et2O 200:6→200:13) and the residue (5.1 g) treated with 1 g LiOH.H2O in 75 ml MeOH at 25° C. for 48 h. The resulting mixture was poured into aq. sat. NaCl soln. and extracted with hexane. The combined org. phases were dried (Na2SO4), concentrated and purified by FC (SiO2, hexane/Et2O 100:3) gave 1.6 g (7.1%) of compound 11.
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28].OO[S:43]([O-:45])=[O:44].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+].[C:54](#N)C>O>[CH3:54][S:43]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:21][S:22]([CH2:25][CH3:26])(=[O:23])=[O:24])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28])(=[O:45])=[O:44]
Reactant: O=S([O-])OO
Reactant: CC#N
Reactant: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3SC)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3S(C)(=O)=O)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Temperature: 40 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
N-[7-(2-Methylthiophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]ethanesulfonamide (0.02 g, 0.03 mmol) obtained in Example 45, step 3 was dissolved in acetonitrile (1 mL) and water (0.5 mL), OXONE (0.05 mg, 0.08 mmol) was added, and the mixture was stirred at 40° C. for 1 hr. Aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=95/5) to give the title compound (0.02 g, 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH2:15][CH3:16])[CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+]([C:20]1C=C([C@@H](CC)CC(O)=O)C=CC=1)([O-])=O.S(=O)(=O)(O)O>CO>[CH3:20][O:13][C:12](=[O:14])[CH2:11][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:15][CH3:16]
Reactant: CCC(CC(=O)O)c1cccc([N+](=O)[O-])c1
Reactant: CC[C@@H](CC(=O)O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC(CC(=O)OC)c1cccc([N+](=O)[O-])c1

Procedure:
To a solution of (±)-3-(3-nitrophenyl)pentanoic acid (XXIV, 30.21 g, 135 mmol, in methanol (250 mL) is added concentrated sulfuric acid (0.6 mL). The resulting mixture is heated to reflux for 3 hours. Upon cooling, the mixture is partitioned between ethyl acetate and sodium bicarbonate (5% aqueous). The aqueous layer is separated and back-extracted with two additional portions of ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give the title compound, TLC (silica gel GF) for acetic acid/ethyl acetate/hexane (2/20/80) Rf=0.54, for ethyl acetate/hexane (20/80) Rf=0.54; NMR (CDCl3, TMS) 0.80, 1.56-1.83, 2.55-2.75, 3.05-3.2, 3.57, 7.4-7.55 and 8.03-8.12 δ.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[C:7]([O:9][CH3:10])=[O:8].[CH3:17][N:18]1[C@@H:23]2[C@@H:24]3[O:26][C@@H:25]3[C@H:19]1[CH2:20]C(O)[CH2:22]2.[Na].Cl>C1(C)C=CC=CC=1>[CH3:17][N:18]1[C@@H:23]2[C@@H:24]3[O:26][C@@H:25]3[C@H:19]1[CH2:20][CH:10]([O:9][C:7]([C:6]([OH:11])([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:22]2
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Reactant: CN1[C@@H]2CC(O)C[C@H]1[C@@H]1O[C@@H]12
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN1[C@@H]2CC(OC(=O)C(O)(c3cccs3)c3cccs3)C[C@H]1[C@@H]1O[C@@H]12
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
38.15 g (0.15 mole) of methyl di-(2-thienyl)glycolate and 23.28 g (0.15 mole) of scopine are mixed, 0.34 g (0.015 gram atom) of sodium is added and the mixture is melted in a heating bath at 90° C. under a water jet vacuum. The reaction lasts 2.5 hours. 100 ml of absolute toluene are then added and the mixture is stirred at a heating bath temperature of 90° C. until a solution is produced. The reaction solution is cooled to room temperature and stirred into a mixture of ice and hydrochloric acid cooled using ice. The hydrochloride of the basic ester crystallising out is filtered off under suction and washed using a small amount of water and a large amount of diethyl ether. The filtrate phases are separated off and the aqueous phase is extracted using diethyl ether. The hydrochloride filtered off under suction is suspended in the (acid) aqueous phase and converted to the base while monitoring the temperature and adding the corresponding amount of sodium carbonate; the base is extracted using methylene chloride. The combined methylene chloride phases are dried over sodium sulphate. After distilling off the methylene chloride, crystals remain which are purified over active charcoal and recrystallised from acetonitrile. Pale yellow crystals (from acetonitrile), m.p. 148°-49° C.;
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=3[C:19]#[N:20])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[CH:33]1([C:37](O)=[O:38])[CH2:36][CH2:35][CH2:34]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[C:19]([C:18]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:17]=1[O:16][CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:37]([CH:33]3[CH2:36][CH2:35][CH2:34]3)=[O:38])[CH2:3][CH2:4]2)[CH2:15][CH2:14]1)#[N:20]
Reactant: O=C(O)C1CCC1
Reactant: N#Cc1cc(F)ccc1OC1CCN(CC[C@H]2CC[C@H](N)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1OC1CCN(CCC2CCC(NC(=O)C3CCC3)CC2)CC1

Procedure:
The title compound was prepared analogously to example 1 (1.5) from Trans 2-{1-[2-(4-Amino-cyclohexyl)-ethyl]-piperidin-4-yloxy}-5-fluoro-benzonitrile; trifluoro-acetic acid salt and cyclobutanecarboxylic acid using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate and N-ethyldiisopropylamine in dimethylformamide (DMF). The residue was taken up on methanol and purified with preparative HPLC on reversed phase eluting with acetonitrile/water. MS (m/e): 428.0. (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:23][NH:22][C:10](=[O:11])[C:9]=2[C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC1(O)OC(=O)C(c2ccsc2)=C1c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c(=O)c(-c2ccsc2)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 40 %

Procedure:
A mixture of 3.77 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(3-thienyl)-2(5H)-furanone, 0.73 g of hydrazine monohydrate and 30 ml of 1-butanol was heated under reflux for 0.5 hours. The reaction mixture was cooled to 0° C. The deposited solid was collected by filtration. The solid was washed with a mixed solvent of hexane and t-butyl methyl ether, and dried under reduced pressure, to obtain 1.49 g of 5-(4-chlorophenyl)-6-methyl-4-(3-thienyl)-2H-pyridazin-3-one.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15](OC)=[O:16])=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Li+].[BH4-].CCCCCC.C(OCC)(=O)C>C1COCC1>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccn(S(=O)(=O)c2ccc(C)cc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)n2ccc(CO)c2)cc1
Yield: 90.3 %

Procedure:
To a solution of 10 (15.6 g, 0.063 mol) in 250 mL anhydrous THF was added LiBH4 (1.8 g, 0.08 mol) at 60° C. water bath for 24 h. The reaction was quenched by the addition of 1 M H2SO4 solution. The resulting solution was extracted with dichloromethane. The extracts were washed with saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulphate, filtered and evaporated under vacuum to give light yellow solid which subjected to flash chromatography (silica gel, hexane:ethyl acetate=2:1) to afford 11 as a white solid (14.3 g, 90%). 1H NMR (CDCl3, δ/ppm), 7.74 (m, 2H), 7.29 (d, 2H), 7.12-7.09 (m, 2H), 6.29 (m, 1H), 4.46 (s, 2H), 2.39 (s, 3H), 1.86 (b, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][O:4][C:5](=[O:7])[CH:6]=1.N1C=CC=CC=1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15].O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:21](=[O:22])[C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:25][CH:24]=2)[O:4][C:5](=[O:7])[CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(=O)o[nH]1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(=O)on1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
4 gm of 3-methyl-3-isoxazolin-5-one was added to 20 ml of toluene along with 3.5 gm of pyridine. 8.2 gm of 4-nitrobenzoyl chloride in 80 ml of toluene was added dropwise. The solution was stirred at room temperature for 4 hours. Afterwards, the system was poured into 200 ml water. The resulting solution was filtered and the organic phase then separated and dried over sodium sulfate. The toluene was removed by stripping to give 6.9 gm of a mixture of 3-methyl-2-(4'-nitrobenzoyl)-3-isoxazolin-5-one and 3-methyl-5-hydroxyisoxazolyl4'-nitrobenzoate. The crude product was recrystallized in ethanol to give 4.6 gm of the mixture. The product 3-methyl-2-(4-nitrobenzoyl)-3-isoxazolin-5-one was separated by column chromatography using 200 gm of E.M. silica gel 60 in an 80×90 mm column and a 2% solution of acetone in methylene chloride as the elutant. Listed as compound number 1, Table I.
Reaction SMILES: C(O[CH2:7][C:8]1[CH:13]=[CH:12]C=[CH:10][CH:9]=1)(=O)C(C)=C.[C:14](OCCOCCCC)(=O)C(C)=C.[C:27]([OH:31])(=O)[CH:28]=[CH2:29].SCCC(OC)=O.N(C(C1CC1)(C)C#N)=NC(C1CC1)(C)C#N.N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH3:10][CH2:9][CH:8]([CH2:13][CH2:12][C:27]([OH:31])([CH2:28][CH3:29])[CH3:14])[CH3:7]
Reactant: C=C(C)C(=O)OCc1ccccc1
Reactant: C=C(C)C(=O)OCCOCCCC
Reactant: C=CC(=O)O
Agent: CC(C#N)(N=NC(C)(C#N)C1CC1)C1CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: COC(=O)CCS
Product: CCC(C)CCC(C)(O)CC
Reaction time: 1 h

Procedure:
To the solution was dropwise added a mixed solution of 48 g of benzyl methacrylate, 40 g of 2-butoxyethyl methacrylate, 12 g of acrylic acid, 2.6 g of methyl 3-mercaptopropionate and 1.2 g of 2,2'-azobis(2-cyclopropylpropionitrile) (abbreviated as ACPP) over a period of one hour, followed by stirring for one hour. To the reaction mixture was added 0.8 g of ACPP, followed by reacting for 2 hours. Further, 0.5 g of 2,2'-azobis(isobutyronitrile) (abbreviated as AIBN) was added thereto, the reaction temperature was adjusted to 80° C., and the reaction was continued for 3 hours. After cooling, the reaction mixture was passed through a nylon cloth of 200 mesh to obtain a white dispersion which was a latex of good monodispersity with a polymerization rate of 97% and an average grain diameter of 0.19 μm. The grain diameter was measured by CAPA-500 manufactured by Horiba Ltd. (hereinafter the same).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11](O)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.C(Cl)Cl>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:12][N:13]1[C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc(F)cc1Br
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
Add potassium hydroxide (1.15 g, 17.5 mmol, fresh powder) to a solution of tert-butyl 2-(2-bromo-4-fluorophenyl)-2-hydroxyethylcarbamate (1.19 g, 3.56 mmol) and p-toluenesulfonyl chloride (0.75 g, 3.88 mmol) in dry THF (50 mL). Stir the mixture overnight at RT. Dilute with DCM, and wash with water and aqueous saturated sodium chloride. Dry over sodium sulfate and concentrate. Purify by column chromatography (hexane to 5% ethyl acetate in hexane) to give the title compound as a colorless oil (0.46 g, 41%). 1H NMR (400 MHz, CD3Cl) δ 1.47 (s, 9H), 2.08 (d, J=3.2 Hz, 1H), 2.67 (d, J=5.6 Hz, 1H), 3.59 (dd, J=3.6 Hz, 6.0 Hz, 1H), 7.00 (m, 1H), 7.28 (m, 1H), 7.35 (m, 1H).
Reaction SMILES: [O-2].[Zn+2:2].[C:3]([OH:22])(=[O:21])[CH2:4][CH2:5]CCCCCCCCCCCCCCC.[C:23]([OH:27])(=[O:26])[CH:24]=[CH2:25]>C1(C)C=CC=CC=1>[C:3]([O-:22])(=[O:21])[CH:4]=[CH2:5].[Zn+2:2].[C:23]([O-:27])(=[O:26])[CH:24]=[CH2:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: C=CC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: C=CC(=O)[O-]
Temperature: 55 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a 4000 liter jacketed stainless steel reactor, at room temperature, were fed successively toluene (1472 kg), zinc oxide (310 kg, 99% purity, 3.77 kmol) and stearic acid (56.0 kg, 0.197 kmol). Then, the temperature was raised to 55±5° C. To the reactor was added dropwise acrylic acid (506 kg, 7.02 kmol) over 2.5 hours, and continued the stirring while keeping at this temperature for additional 2 hours in order to complete the reaction. To this reaction mixture was added Sinopol 1536 (2.0 kg, HLB 12.8, comprising mainly polyoxyethylene alkyl ether). After stirring for additional 30 minutes, the resulting cream-like mixture was fed into a paddle dryer for distilling off toluene and water under reduced pressure, and pulverizing the powder. A modified zinc acrylate as a white fine powder was thus obtained (780 kg, 96.7% yield). Moisture content is<0.5 wt %, acryl content is 56.1 wt % and an analyzed ash content is 38 wt %. IR spectrum (KBr): λ 2917, 2848, 1644, 1575, 1522, 1447, 1433, 1373, 1365, 1274, 1067, 974 cm−1. After discharging the material, no cluster stuck on the blade in the dryer was observed, and no cake was detected in the powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.ClC(O[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=1)=O.N1C=CC=C[CH:40]=1.COCCOCCO>C(Cl)Cl.ClCCCl>[CH:22]1([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)[C:16]([C:17]#[N:18])=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:30]=[CH:40][N:36]=3)=[CH:7][CH:6]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccncc1
Solvent: COCCOCCO
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOc1ccc2c(C#N)c(-c3ccc(NCCc4ccccn4)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (40 mg, 0.12 mmol), prepared as in example 1CM, step B, is combined with 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), DCE (0.4 mL), and pyridine (25 μL, 0.31 mmol). This suspension is stirred at room temperature for 1 h. 2-(2-methoxyethoxy)ethanol (150 μL, 1.25 mmol) is added. This mixture is heated at 75° C. overnight. The reaction mixture is then diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol by-product. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2/EtOAc, 4/1), followed by trituration with hexanes/acetone (2/1) yields 1-cyclobutyl-6-ethoxy-2-[4-(2-pyridin-2-yl-ethylamino)-phenyl]-1H-indole-3-carbonitrile (23 mg, 42%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([OH:28])[CH:3]=1.[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:29][O:30][C:31](=[O:34])[CH2:32][O:28][C:4]1[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][C:8]([N:10]1[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12][C@H:11]1[CH3:25])=[O:9]
Reactant: COC(=O)CBr
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)COc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 169.8 %

Procedure:
To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.30 g, 0.75 mmol) and bromo-acetic acid methyl ester (0.14 mL, 1.5 mmol) in dioxane (3 mL) was added cesium carbonate (0.50 g, 1.5 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound (0.61 g).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2C=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N)CCC.C1(=O)CCCCC1>C(OC(=O)C)C>[CH2:21]([N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Solvent: CCCCN
Solvent: CCOC(C)=O
Solvent: O=C1CCCCC1
Product: CCCCN(C(=O)Nc1ncc(SCC(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from n-butylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O>CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1 L) was added K2CO3 (40 g, 296 mmol) and tert-butyl piperazine-1-carboxylate (28 g, 148 mmol). The mixture was stirred at 65° C. overnight. After cooling down, it was poured into water (2 L). The precipitated solid was collected and dried under vacuum. It was then further purified by flash column eluting with 20:1 petroleum ether/ethyl acetate and then with methylene chloride to give 115a as a yellow solid (17 g, 37%). MS: [M+H]+ 309.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>CC(C)=O>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: CC(C)CCBr
Reactant: Sc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)CCSc1ccc(Br)cc1

Procedure:
A mixture of 15 g (79 mmol) of 4-bromo-thiophenol (Compound 42), 3.16 g (79 mmol) of powdered sodium hydroxide and 150 ml of acetone was heated at reflux for 15 minutes. The refluxing mixture was then treated dropwise with a solution of 12 g (79 mmol) of 1-bromo-3-methylbutane (Compound 51) in 25 ml of acetone and then refluxed for a further 18 hours. The mixture was allowed to cool and the solvent removed in-vacuo. The residue was taken up in 25 ml of water and the mixture basified with 2 N NaOH solution. The mixture was extracted with ether and the combined ether extracts washed successively with 1 N NaOH, water and saturated NaCl and then dried (MgSO4). The solvent was removed in-vacuo and the residue distilled (113-117 degrees C., 0.2 mm) to give the title compound as a colourless oil. PMR (CDCl3): & 0.93 (6H, d, J~6.6 Hz), 1.47-1.58 (2H, m), 1.65-1.80 (1H, m), 2.90 (2H, t, J~7.8 Hz), 7.18 (2H, d, J~8.6 Hz), 7.39 (2H, d, J~8 6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].N12CCN(CC1)CC2>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[C:12](=[CH2:13])[C:11]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: C=C(C(=O)OC)C(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-chloro-3-fluorobenzaldehyde (50.0 g) and methyl acrylate (42.6 mL) in acetonitrile (158 mL) was added 1,4-diazabicyclo[2.2.2]octane (10.6 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (69.1 g).