Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=O.[NH2:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])[C:18]([NH2:20])=[O:19].Cl>O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:17]1[C:18](=[O:19])[NH:20][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:16]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: NC(=O)C(N)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 7.9 g of sodium carbonate and 31 ml of water was added dropwise 5.1 g of 1,1-dibromo-3,3,3-trifluoroacetone at such a rate that the temperature of the reaction mixture became not higher than 55° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, followed by adding 39 ml of water and then 3.1 g of 2-amino-2-(2,4-dichlorophenyl)acetamide, and the reaction was allowed to proceed at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. or lower, made acidic by adding 5.4 ml of concentrated hydrochloric acid at the same temperature, and extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=4:1), which afforded 1.54 g (yield, 35%) of the desired compound, 3-(2,4-dichlorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1007; m.p., 192.8° C.). The continued elution with the above solvent system gave 0.53 g of the configurational isomer, 3-(2,4-dichlorophenyl)-5-trifluoromethyl-2-oxo-1,2-dihydropyrazine (m.p., 131.7° C.).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:32])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:18]1[C:29]([OH:31])=[O:30].[O:33]([C:40]1[N:45]=[C:44]([CH:46](O)[CH3:47])[CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:32])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C@H:18]1[C:29]([O:31][CH:46]([C:44]1[CH:43]=[CH:42][CH:41]=[C:40]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:45]=1)[CH3:47])=[O:30]
Reactant: CC(O)c1cccc(Oc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(OC(=O)[C@@H]1[C@H](/C=C\C(=O)OC(C)(C)C)C1(C)C)c1cccc(Oc2ccccc2)n1
Temperature: 20 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A solution of 55.7 g of dicyclohexylcarbodiimide, 2.6 g of 4-dimethylamino-pyridine and 450 ml of methylene chloride were added over 25 minutes at 0° C. to a mixture of 65 g of (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylic acid, 70 g of (RS) 1-(6-phenoxy-2-pyridyl)-ethanol and 650 ml of methylene chloride and the mixture was stirred at 20° C. for 4 hours and was vacuum filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with an 100-4 n-hexane-ethyl acetate mixture yielded 101 g of (RS) 1-(6-phenoxy-2-pyridyl)-ethyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [αD20 =+64° (c=1% in toluene).
Reaction SMILES: Br[C:2]1[C:14](=O)[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[OH:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.CO.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.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>[CH:16]1([N:13]2[C:5]3[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([CH2:22][OH:21])[CH:28]=3)[CH2:14]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CNc1nc(C)c2cc(Br)c(=O)n(C3CCCC3)c2n1
Reactant: OCc1cccc(B(O)O)c1
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: Cc1ccccc1
Solvent: CO
Product: CNc1nc(C)c2c(n1)N(C1CCCC1)CC(c1cccc(CO)c1)=C2
Yield: 84.5 %

Procedure:
6-Bromo-8-cyclopentyl-4-methyl-2-methylamino-8H-pyrido[2,3-d]pyrimidin-7-one (5.00 g, 14.83 mmol), 3-(hydroxymethyl)phenylboronic acid (3.38 g, 22.24 mmol) and Pd(PPh3)4 (0.685 g, 0.593 mmol) were suspended in Toluene (20 mL), MeOH (10 mL) and sat. NaHCO3 (10 mL) and then heated to 100° C. overnight. The reaction was deemed complete by MS and TLC. The organic layer was injected directly onto a column, eluting with CH2Cl2 then 4% MeOH in CH2Cl2. The fractions containing the desired material, as deemed by MS, were combined and evaporated in vacuo to give a greenish beige solid. This was triturated with MeCN and filtered to give crop one, 4.7 g. A second crop was obtained of 0.25 g. A third crop was obtained of 0.10 g. The three crops were deemed to be of sufficient purity based on NMR's and were combined and washed again with MeCN to give a solid (4.39 g, 81.24%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:7][C:8]=1[CH3:9])[OH:6].C(=O)([O-])[O-].[K+].[K+].Br[C:18](Br)([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]2[O:6][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:24][O:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(C)(Br)Br
Reactant: Cc1cc(O)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1COc2cc(C)c(C)cc2O1
Yield: 319.7 %

Procedure:
A stirred solution of 4,5-dimethylcatechol (7.0 g.) in dry acetone (45 ml.) was heated under reflux, then potassium carbonate (5 g.) was added followed by the dropwise addition of ethyl dibromopropionate (3.5 g.). The addition procedure was repeated a further three times over 11/4 hours then the reaction was stirred under reflux for a further 33/4 hours. After cooling, the mixture was filtered, the solids washed well with acetone then the combined filtrate concentrated in vacuo. Water (35 ml.) was added, the resulting solid collected, washed with petrol then taken up in ether. The ethereal solution was washed with water, dried (Na2SO4) and evaporated in vacuo to give ethyl 6,7-dimethyl-1,4-benzodioxan-2-carboxylate (10.17 g.), m.p. 70°-71° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[N:6]=1.[ClH:19].[C:20]([N:28]1[CH2:33][CH2:32][CH2:31][C:30]([C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=2)([CH2:34][CH2:35][CH2:36]N2CCC(C(N3CCCC3)=O)CC2)[CH2:29]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(#N)C>[OH2:27].[ClH:56].[ClH:19].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:36][CH2:35][CH2:34][C:30]3([C:50]4[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([Cl:57])[CH:51]=4)[CH2:31][CH2:32][CH2:33][N:28]([C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:29]3)[CH2:11][CH2:12]2)[N:6]=1
Reactant: Nc1nc(C2(c3ccccc3)CCNCC2)cs1
Reactant: O=C(c1ccccc1)N1CCCC(CCCN2CCC(C(=O)N3CCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Nc1nc(C2(c3ccccc3)CCN(CCCC3(c4ccc(Cl)c(Cl)c4)CCCN(C(=O)c4ccccc4)C3)CC2)cs1
Product: O
Yield: 104.5 %

Procedure:
A mixture of 1.04 g of 4-(2-aminothiazol-4-yl)-4-phenylpiperidine (compound of PREPARATION 1.4 in the form of the free base), 1.88 g of the compound obtained in step B of EXAMPLE 1 and 1.1 g of K2CO3 in 20 ml of a DMF/acetonitrile mixture (50/50; v/v) is refluxed for 2 hours. The reaction mixture is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a gradient of a DCM/MeOH mixture (98/2; v/v to 95/5; v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the precipitate formed is filtered off to give 1.2 g of the expected product after crystallization from AcOEt, m.p.=162-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.[CH2:13](OC(OCC)OCC)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[N:12][C:10](=[O:11])[NH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)NNc1ccc(Br)cc1
Product: O=c1ncn(-c2ccc(Br)cc2)[nH]1
Temperature: 25 °C

Procedure:
A solution of compound 52a (10 g, 43 mmol) and triethoxymethane (300 mL) was stirred at 120° C. for 2 h and allowed to cool to rt. The solids were collected by filtration and washed with Et2O (2×50 mL) to obtain compound 52b as a grey solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H6BrN3O: 240.0 (M+H). Found 240.2.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.CC(C)(C)C(=O)CN1C2C=CC=CC=2C(C2C=CC=CN=2)=NN(CC(O)=O)C1=O.[C:69]([O:73][C:74](=[O:84])[N:75](C1C=CC=C(N)C=1)[CH3:76])([CH3:72])([CH3:71])[CH3:70].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:69]([O:73][C:74](=[O:84])[N:75]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:76])([CH3:72])([CH3:71])[CH3:70]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(c2ccccn2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1, step e) except that [1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 5, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.62 (1H, d), 8.10 (1H, d), 8.00 (1H, br s), 7.79 (1H, dt), 7.55 (1H, m), 7.29 (3H, m), 7.13 (1H, d), 7.01 (1H, t), 6.92 (1H, t), 6.48 (1H, dd), 6.30 (1H, dd), 4.68 (2H, br d), 4.45 (2H, br d), 2.80 (1H, br s), 2.78 (3H, s), 1.27 (9H, s). Found: C, 67.18; H, 6.28; N, 16.63%; C28H30N6O3 requires: C, 67.45; H, 6.06; N, 16.86%.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH:6]=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)([OH:3])=[O:2]>CN(C)C=O.CO.[Pd]>[C:1]([C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][CH:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2)([OH:3])=[O:2]
Reactant: O=C(O)c1ccccc1C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Yield: 27.3 %

Procedure:
A suspension of 8 g of 10-(2-carboxybenzylidene)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one in 350 ml of dimethylformamide and 50 ml of methanol is hydrogenated in the presence of 1 g of 10% palladium-on-charcoal for 20 hours at 10 bar and at a temperature in the region of 20° C. The reaction mixture is filtered on clarcel and the filtrate is evaporated under reduced pressure. The beige-coloured residue obtained is triturated with 200 ml of boiling methanol, filtered and dried at 100° C. under vacuum (1 mmHg; 0.13 kPa); 2.2 g of 10-(2-carboxy-benzyl)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one are obtained in the form of an off-white solid melting above 260° C. (Analysis, % calculated C: 70.58, H: 4.23, N: 11.76, O: 13.43, % found C: 70.6, H: 4.3, N: 12.1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([C:36]([F:39])([F:38])[F:37])=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[CH:25]=[N:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:27]=3)=[CH:22][C:21]=2[C:36]([F:37])([F:39])[F:38])=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c(CCl)cn2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)cc2C(F)(F)F)cc1C

Procedure:
In analogy to the procedures described in example 101A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyridine (example 108D]) to give 2-methyl-2-{2-methyl-4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101] to yield the title compound as off-white crystalls of mp. 148–149° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6](=[S:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[NH:17][C:18]([NH:20][C:21]([O:23][CH3:24])=[O:22])=[S:19])=[O:4]>CO.O>[CH3:24][O:23][C:21]([NH:20][C:18](=[S:19])[NH:17][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[NH:7][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[S:25])[NH2:14])=[O:22]
Reactant: COC(=O)NC(=S)Nc1ccc([N+](=O)[O-])cc1NC(=S)NC(=O)OC
Solvent: CO
Solvent: O
Product: COC(=O)NC(=S)Nc1ccc(N)cc1NC(=S)NC(=O)OC
Temperature: 25 °C
Yield: 52.6 %

Procedure:
1,2-Bis-(3-methoxycarbonyl-2-thioureido)-4-nitrobenzene (9.7 g; 0.025 mole) and ferrous chloride tetrahydrate (1.13 g) were finely powdered together and suspended in a mixture of methanol (110 ml) and water (10 ml). The vigorously stirred suspension was then heated to reflux and reduced iron powder (6.53 g) was added in portions during five minutes. When the addition was complete, the reaction mixture was refluxed for a further forty five minutes and filtered. The dark brown filter cake was extracted with boiling methanol (2 × 120 ml), and the hot methanol solutions were combined with the hot aqueous methanol filtrate and evaporated to 200 ml. The solution was cooled to room temperature and the solid which separated was filtered off to give 3,4-bis-(3-methoxycarbonyl-2-thioureido)aniline (4.70 g), m.p. 186-187° C. (with decomposition), in the form of off-white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH2:45])[CH2:36][CH2:37][CH3:38].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45][C:27]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33])[CH2:36][CH2:37][CH3:38]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCc1ccccc1NC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 69 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (119 mg) was suspended in toluene (12 ml), after the addition of triethylamine (2.4 ml), triphosgene (133 mg) was added, and the admixture was refluxed with heat for 2 minutes. 2-n-Butylphenylamine (0.13 ml) was added to the reaction mixture, and the admixture was refluxed with heat for 10 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with chloroform, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (4/1) to obtain 130 mg of the title compound (yield: 69%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1([Mg]Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1.O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Reactant: Cl[Mg]C1CCCCC1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](O)C2CCCCC2)C1
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)C2CCCCC2)C1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (2.8 g, 13.8 mmol) was dissolved in THF (50 mL) under nitrogen and cooled at −78° C. Cyclohexylmagnesium chloride (2.0M in ether; 10.0 mL, 20.0 mmol, 1.4 eq) was added via syringe over approximately 10 minutes. The resulting mixture was stirred at −78° C. for 20 minutes, then placed in an ice bath for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl (15 mL). THF was removed under reduced pressure, and the remaining material was extracted with EtOAc (3×30 mL). The organics were washed with water (25 mL) and saturated aqueous NaCl (25 mL), dried over Na2SO4, and concentrated to yield the crude product. This material was dissolved in McCN (10 mL), water (8 mL), and MeOH (11 mL). The material was purified by preparative HPLC in 3 portions (2″ C18 column; 20-50% MeCN over 1 hour; the desired compound was recovered at ˜46%). The fractions were collected from the first eluting and second eluting, separately, and the MeCN was removed. Each fraction was extracted with DCM (3×125 mL), dried over Na2SO4, and concentrated to yield (S)-3-((S)-cyclohexylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.1 g; 1st eluting peak) and (S)-3-((R)-cyclohexylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.7 g; 2nd eluting peak).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl-]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:13])=[O:12])=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Reactant: C1CCNCC1
Agent: [Cl-]
Product: O=C(O)c1c(Cl)ccc(S(=O)(=O)N2CCCCC2)c1Cl

Procedure:
2,6-Dichloro-5-chlorosulfonylbenzoic acid (960 mg.; 3.3 m moles) is added portion-wise to 1.95 g. (0.0165 mole) of piperidine in 15 ml. of drymethylene chloride, and the mixture heated to reflux for 1.5 hrs. The solvent and excess amine are removed under reduced pressure and the residue dissolved in 15 ml. of 2N sodium hydroxide. The aqueous base solution is extracted (2 x 50 ml.) with ether and acidified with 6N hydrochloric acid. The precipitated gum is filtered, dried and allowed to crystallize in hexane, 1.1 g., m.p. 145°-150° C. A small sample is recrystallized from acetonitrile, m.p. 142°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([C:14]#[CH:15])[N:11]=[C:10]2[CH3:16])[CH:5]=[CH:6][C:7]=1[Cl:8].I[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([C:14]#[C:15][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)[N:11]=[C:10]2[CH3:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(I)ccn1
Reactant: C#Cc1cn(-c2ccc(Cl)c(Cl)c2)c(C)n1
Product: Cc1cc(C#Cc2cn(-c3ccc(Cl)c(Cl)c3)c(C)n2)ccn1
Product: Cl

Procedure:
4-[1-(3,4-Dichloro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridine hydrochloride (2) [MS: m/e=341.9 (M+H+)] was prepared in analogy to the method as described in Example 1 Method B starting from 1-(3,4-dichloro-phenyl)-4-ethynyl-2-methyl-1H-imidazole (IV-2) and 4-iodo-2-methyl-pyridine. For further purification the compound was precipitated as its HCl salt from an etheral solution. Method C:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20](Cl)=[O:21]>C1C=CC=CC=1>[ClH:16].[CH3:1][N:2]([CH2:3][C:4]1([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:17]([Cl:16])[CH:18]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CNCC1(N2CCCCC2)CCCCC1
Solvent: c1ccccc1
Product: CN(CC1(N2CCCCC2)CCCCC1)C(=O)c1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
Solutions of 1-[1-[(methylamino)methyl]cyclohexyl] piperidine (1.1 g., 0.005 mole) in dry benzene (25 ml) and 3,4-dichlorobenzoyl-chloride (1.0 g., 0.005 mole) in dry benzene (50 ml) were mixed and heated under reflux (steam bath) for 1 hr. The precipitate was filtered washed with benzene and dried. (1. 6 g.) m.p. 222° (dec.)
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][Cl:23]>CCO>[ClH:23].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: Fc1ccccc1CCl
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: Fc1ccccc1CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Yield: 45 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-fluorobenzyl chloride (0.187 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 141 mg of the product 210. 1H NMR (DMSO-d6) δ 11.28 (s, 2 H), 7.80-7.65 (m, 1 H), 7.60-7.40 (m, 1 H), 7.40-7.20 (m, 2 H), 7.20-7.00 (m, 6 H), 7.00-6.80 (m, 4 H), 5.80 (s, 2 H), 4.85 (s, 2 H); MS: m/z 363 (M++1).