Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][OH:7])[CH:8]=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1cccc(O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CCO)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 3-hydroxyphenethyl alcohol (6.0 g, 43.4 mmol) in 275 mL of CH2Cl2 was added 6.55 g (43.4 mmol) of TBDMS-Cl (tert-butyldimethylsilyl chloride), cooled to 0° C., then added 7.0 mL (86.8 mmol) of pyridine. The reaction mixture was stirred at ambient temperature overnight. Upon concentration, the crude mixture was purified by silica gel flash chromatography (eluted with hexane then 5% EtOAc/hexane) to provide 8.9 g of a clear oil: 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.04 (m, 1H), 6.60 (m, 3H), 3.73 (t, J=6.9 Hz, 2H), 2,65 (t, J=6.9 Hz, 2H), 0.83 (s, 9H), −0.03 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35]>>[C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:24][CH:25]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOCCBr
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Product: COCCOCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1

Procedure:
7.43 g (20 mmol) of N-benzyloxycarbonyl-tyrosine-tert-butyl ester is reacted with 1-bromo-2-(2-methoxyethoxy)-ethane to alkylated phenol analogously to Example a).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:4][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1)[C:2]#[CH:3]
Reactant: C1=COCCC1
Reactant: C#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C#CCOC1CCCCO1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
To a stirred solution of propargyl alcohol (5g, 90 mmol) and dihydropyran (37.5 g, 0.44 mol, 5 equiv) in CH2Cl2 (300 ML), was added p-toluenesufonic acid (30 mg). The mixture was stirred at 20° C. for 1.5 hours. The solvent was removed by rotary evaporation. The residue was taken up in ether (150 mL) and washed with aqueous saturated NaHCO3 (120 mL), saturated NaCl (120 mL), water (200 mL). The organic layer was dried (MgSO4) and concentrated to yield a yellow oil. Purification by distillation under reduced pressure gave Tetrahydro-2-(2-propynyloxy)-2H-pyran (47) (12 g, 97%) as a colorless oil: bp: (40° C., 0.05 mm Hg). ##STR20##
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]([OH:16])=O)([O-:3])=[O:2].[C:17]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:14]([C:9]2[C:10]3[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:7][CH:8]=2)=[O:16])=[CH:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: O=C(O)c1cccc2c([N+](=O)[O-])cccc12
Product: CC(C)(C)c1ccc(CNC(=O)c2cccc3c([N+](=O)[O-])cccc23)cc1
Yield: 42.6 %

Procedure:
Using 5-nitronaphthalene-1-carboxylic acid (197 mg, 0.907 mmol) and 4-tert-butylbenzylamine (107 mg, 0.998 mmol), the same operation as the Example 104(2) gave the title compound as a light yellow solid (140 mg, 42.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[N+:12]([O-])=O>C(O)(=O)C.O.[Zn]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[NH2:12]
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cccc(C)c1N
Yield: 81.7 %

Procedure:
In this example 0.02 mole of 2-methyl-6-methoxycarbonyl-nitrobenzene in 25 ml of acetic acid was added dropwise to a slurry containing 6.5 g of zinc dust suspended in 25 ml of water at 30°-35° C. The resulting exothermic reaction is controlled by maintaining the mixture at about room temperature (about 20°-25° C.) through external cooling. The reaction product mixture was filtered to remove the zinc dust and the filtrate, then washed sequentially with methylene chloride and water, and then extracted with methylene chloride. The extract was washed with an aqueous ammonium hydroxide, then with water and filtered through diatomaceous earth. The filtrate was then dried and evaporated affording 2.7 g of the title product as an oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[CH2:8]([N:10]([CH2:18][CH3:19])[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH3:9].C(=O)([O-])O.[Na+]>ClCCl>[CH2:5]([O:4][C:2]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([N:10]([CH2:18][CH3:19])[CH2:8][CH3:9])=[CH:16][CH:15]=1)=[O:3])[CH3:6]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(N(CC)CC)cc1
Reaction time: 96 h
Yield: 72.4 %

Procedure:
Ethyl chloroformate (5.0 mL, 52 mmol) was added to a stirred mixture of N,N-diethyl-p-phenylenediamine hydrochloride (10 g, 50 mmol) and sodium hydrogen carbonate (23.0 g) in dichloromethane (120 mL) at room temperature under nitrogen. After four days at room temperature, the precipitate which had formed was removed by filtration through a pad of celite. The solid residue was washed with dichloromethane and the combined dichloromethane extracts were concentrated to produce a black oil, which was redissolved in dichloromethane (110 mL) and stirred with silica (100 cc) for 30 minutes. The silica was then removed by filtration through celite. The residue was washed with additional dichloromethane (3×30 mL) and the combined dichloromethane extracts were concentrated to give N-ethoxycarbonyl-4-diethylaminoaniline (8.55 g, 73% yield) as a pale gray solid which melted at 31°-33° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][C:3]([CH2:9][C:10]([NH2:12])=[O:11])=[C:2]([NH:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=1
Reactant: NC(=O)Cc1cnc(Cl)cc1Cl
Reactant: NC1CCCCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Cc1cnc(Cl)cc1NC1CCCCC1
Yield: 93 %

Procedure:
200 mg of 4,6-dichloropyridine-3-carboxyamide synthesized according to the method described in US2006/0217417 was dissolved in 2 mL of ethanol, to which 156 mg of cyclohexylamine and 203 mg of N,N-diisopropylethylamine were added, and heated at reflux for 8 hours. After cooling, the solvent was evaporated, and 10 mL of water was added to the residue, neutralized by adding 2 mol/L hydrochloric acid in water under ice cooling, extracted with chloroform, and the extract was dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was recrystallized from chloroform-hexane to obtain 243 mg (92%) of the title compound as colorless needle crystals.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][CH2:34][C@@H:35]([OH:37])[CH3:36])(=[O:32])=[O:31]>>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([NH:33][CH2:34][C@@H:35]([OH:37])[CH3:36])(=[O:32])=[O:31])=[CH:10][CH:11]=2)=[CH:16][N:17]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Reactant: C[C@H](O)CNS(=O)(=O)c1ccccc1Br
Product: C[C@H](O)CNS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and (S)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide. MS (ESI): mass calcd. for C18H19N5O3S, 385.12; m/z found, 386.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.92 (s, 2H), 8.61-8.57 (m, 1H), 8.09 (d, J=8.0, 1H), 7.91 (dd, J=8.2, 2.3, 1H), 7.82 (d, J=8.2, 1H), 7.70 (m, 1H), 7.62 (m, 1H), 7.41 (d, J=6.8, 1H), 3.70-3.61 (m, 1H), 2.79-2.66 (m, 2H), 1.04 (d, J=6.3, 3H).
Reaction SMILES: ClC1C=CC=C([C:8](OO)=[O:9])C=1.[CH3:12][O:13][CH:14]1[C:19](=[O:20])[NH:18][C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[S:15]1>CO>[CH3:12][O:13][C:14]1([O:9][CH3:8])[C:19](=[O:20])[NH:18][C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[S:15]1
Reactant: COC1SC(c2ccncc2)=C(C)NC1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: COC1(OC)SC(c2ccncc2)=C(C)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
m-Chloroperbenzoic acid (2.8 g) was added to a stirred solution of 2 -methoxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (2.7 g) in methanol (100 ml) under ice/water-cooling. The reaction mixture was further stirred at ambient temperature for 2 hours. Methanol was removed under reduced pressure and the residue was dissolved in ethyl acetate, was washed with saturated sodium bicarbonate aqueous solution and successively with water, and was dried over magnesium sulfate. Ethyl acetate was removed under reduced pressure and the residue was crystallized from ether to give the titled compound (2 g, yield 66.7%) as pale yellow powder.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13]2>C(N(CC)CC)C.C1(C)C=CC=CC=1>[O:21]=[C:11]1[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][C:8]([CH2:7][O:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])=[C:17]2[N:12]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][S:18][C:16]=12
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1CCc1ccsc1-2
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)OCc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Reaction time: 2 h

Procedure:
A few drops of triethylamine and three 0.24 ml portions of ethyl isocyanate were added to a suspension of 1.02 g of 4,5-dihydro-10-(hydroxymethyl)-8-phenyl-7H-thieno[2,3-a]quinolizin-7-one in 11.5 ml of toluene, whereby the mixture was stirred at 85° for about 2 hours between each of the additions. After the reaction was finished, the mixture is evaporated in vacuo. By recrystallization of the residue from ethanol, there was obtained pure (4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizin-10-yl)methyl-ethylcarbamate of m.p. 136°-137°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH:24]3[CH2:26][CH2:25]3)=[C:21]([Cl:23])[CH:22]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH:24]3[CH2:25][CH2:26]3)=[C:21]([Cl:23])[CH:22]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 5-chloro-4-[(5-chloro-6-cyclopropylpyridin-3-yl)oxy]-2-fluorobenzoate (Preparation 264, 54.0 g, 135.59 mmol) in dichloromethane (270 mL) was added trifluoroacetic acid (30.76 mL, 406.77 mmol). The resulting solution was heated at 45° C. for 24 hours and concentrated under reduced pressure at 45° C. tert Butyl methyl ether (100 mL) was added to the residue and the resulting slurry stirred at room temperature for 2.5 hours, filtered, washed with tert butyl methyl ether (20 mL) and dried to give the title compound as an off-white solid (45.0 g, 97%).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]2[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]#[N:27])[CH:20]=3)[NH:15]2)[CH:11]=[CH:12][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:26]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]([C:10]1[CH:9]=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:13]=[CH:12][CH:11]=1)[CH2:23][C:22]2([CH3:25])[CH3:24])#[N:27]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C#N)ccc3N2)c1
Reaction time: 8 h
Yield: 60.1 %

Procedure:
Ethanesulfonyl chloride (104 mg, 0.81 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (77 mg, 0.97 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. It was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford ethanesulfonic acid [3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (120 mg, yield: 60.0%). MS (ESI+APCI) M+1=370.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:34]2[CH2:33][CH2:32][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Br:24])[CH:26]=3)[CH2:36][CH2:35]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: Brc1cccc(N2CCNCC2)c1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 80.6 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(3-bromophenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:5][N:6]=1.[CH2:21]([C:23]1[C:28](/[CH:29]=[CH:30]/[O:31][CH3:32])=[CH:27][CH:26]=[CH:25][C:24]=1B1OC(C)(C)C(C)(C)O1)[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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>[CH2:21]([C:23]1[C:28](/[CH:29]=[CH:30]/[O:31][CH3:32])=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:5][N:6]=1)[CH3:22]
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1C(F)(F)F
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 120 °C
Yield: 64 %

Procedure:
To a suspension of 2-bromo-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D4) (55 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (64.8 mg) and tripotassium phosphate (79 mg) in N,N-dimethylformamide (DMF) (4 mL) and water (1 mL) under nitrogen was added Pd(Ph3P)4 (17.31 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. After cooling the reaction, water was added. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, the residue was purified by column chromatography to afford 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D18) (43 mg) as a yellow oil. MS (ES): C23H23F3N2O2S requires 448. found 449.1 (M+H+).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH2:22][C:23](=[O:25])[CH3:24])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:14][CH2:13]1>O1CCCC1>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH2:22][C:23]([OH:25])([CH3:1])[CH3:24])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:14][CH2:13]1
Reactant: CC(=O)Cc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)Cc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 57 %

Procedure:
Methylmagnesium bromide (3.0 M in ether; 0.49 mL, 1.45 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2-oxopropyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (61 mg, 0.145 mmol) in tetrahydrofuran (5 mL). After 2 h, the reaction was quenched with saturated aqueous ammonium chloride. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→96% dichloromethane/methanol) gave the title compound (36 mg). MS 436.2 (M+1).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]([CH:13]([CH2:23][CH2:24][CH2:25][CH:26]([O:32]CC1C=CC=CC=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:12])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][C:11]([CH:13]([CH2:23][CH2:24][CH2:25][CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:12]
Reactant: [H][H]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)O)C(=O)CCOCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(=O)CCO
Yield: 97 %

Procedure:
A magnetically stirred solution of 8-(3-benzyloxypropionyl)-12-benzyloxyheptadecanoic acid (2.37 g., 4.4 millimole) in ethanol (50 ml.) is subjected to hydrogenation at atmospheric pressure at 23° C. in the presence of a 10% palladium on charcoal catalyst (0.3 g.) for one hour. The hydrogen uptake is 2.4 ml. (100% theory). The catalyst is removed by filtration and the solvent is removed by evaporation in vacuo to give 8-(3-hydroxypropionyl)-12-hydroxyheptadecanoic acid . 1/3 chloroformate as a viscous, colorless liquid (1.55 g., 97% yield); pmr (CDCl3) δ0.88 (3H,t), 2.03 (H,m), 2.32 (2H,t), 2.68 (2H,t, J=5.5 cps.), 3.65 (H, b.s.), 3.86 (2H,t, J=5.5 cps.), 5.50 (3H, exchangeable s) and 7.32 (1/3H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[C:15]([F:18])[C:14]([F:19])=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[C:15]([F:18])[C:14]([F:19])=[CH:13]3)[C:34]([NH:33][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:35])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: Fc1cc2nn(-c3cccc(Cl)c3)c(Nc3cccc(Cl)c3)c2cc1F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(NC1CCCCC1)N(c1cccc(Cl)c1)c1c2cc(F)c(F)cc2nn1-c1cccc(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-phenyl)-[2-(3-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 d under reflux conditions to give the title compound as white solid. MS: m/e=515.4 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1([CH3:12])[CH2:11][CH2:10][CH2:9][NH:8]1.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:6][C:7]2([CH3:12])[CH2:11][CH2:10][CH2:9][N:8]2[C:18]1=[O:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC1(CNCc2ccccc2Cl)CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC12CCCN1C(=O)N(Cc1ccccc1Cl)C2
Reaction time: 4 h
Yield: 22 %

Procedure:
To a cold (0° C.) solution of (2-chloro-benzyl)-((rac)-2-methyl-pyrrolidin-2-ylmethyl)-amine (0.5 g, 1 eq) in DCM (15 mL) was added a solution of triphosgene (0.5 eqv) in DCM (5 mL) over a period of 5 minutes followed by the addition of triethylamine (3 eq). The reaction mixture was allowed to stir for 4 h. After the completion of the reaction on TLC, the reaction mixture was quenched with 1M HCl (10 mL) and extracted with DCM (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated using rotary evaporator to give sticky crude, which was then purified with column chromatography (1-2% Methanol:DCM, Mesh Size-100-200 silica, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to afford the desired product (rac)-2-(2-chloro-benzyl)-7a-methyl-hexahydro-pyrrolo[1,2-c]imidazol-3-one as white solid (22-70%). MS (ES+): 265.5 (MH+))
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)/[CH:5]=[N:17]/[S@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1cc(F)cc(Br)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@](=O)/N=C/c1cc(F)cc(Br)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 3-bromo-5-fluorobenzaldehyde (5 g, 24.63 mmol) and (S)-2-methylpropane-2-sulfinamide (3.28 g, 27.1 mmol) in DCE (82 mL) was added copper(II) sulfate (anhydrous) (7.86 g, 49.3 mmol). The suspension was stirred under nitrogen at 60° C. overnight. The reaction mixture was cooled down, filtered through a plug of celite, and rinsed with DCM. The filtrate was concentrated to yield the crude product. The crude product was purified by flash chromatograph eluting with 0-30% EtOAc in heptane to yield the product (S,E)-N-(3-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide (7.5 g, 24.49 mmol, 99% yield) as a light yellow color oil. LCMS (m/z): 306.1/308.1 (MH+), 1.04 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][OH:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=1.N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][O:13][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=1
Reactant: CC(C)(O)c1cc(Br)ccc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)c1cc(Br)ccc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
2-[5-Bromo-2-(hydroxymethyl)phenyl]propan-2-ol (1.1 g, 4.4 mmol) and imidazole (0.78 g, 12 mmol) were dissolved in N,N-dimethylformamide (5 mL), and tert-butyldimethylchlorosilane (0.86 g, 5.7 mmol) was added, followed by stirring at room temperature overnight. Water was added to the reaction solution, followed by extraction with hexane, and subsequently the extract was washed sequentially with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: hexane/ethyl acetate) to afford the title compound (1.1 g, 3.1 mmol) as a colorless oil (yield 70%).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[NH3:10]>>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH2:10])[C:2]=1[NH2:1]
Reactant: N
Reactant: Nc1c(Cl)ncnc1Cl
Product: Nc1ncnc(Cl)c1N
Temperature: 118 °C

Procedure:
A suspension of 5-Amino-4,6-dichloropyrimidine (3 g, 0.02 mol) in ammonia (25 mL, 7N/MeOH, 0.175 mole) was heated at 118° C. overnight (under pressure). The reaction was cooled to 23° C., filtered and washed with ethanol to obtain 1.92 g (70%).