Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:9]=[C:8]([C:10]3[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=3)[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:6][N:5]2[CH:24]=1.[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:25][C:24]1[N:5]2[CH:6]=[C:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH:14]=[O:15])=[CH:16][CH:17]=3)=[N:9][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Solvent: ClC(Cl)Cl
Product: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2c1Br
Yield: 79 %

Procedure:
0.2 g (0.64 mmol) 4-(2-Methyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)benzaldehyde, described in intermediate example 15.1, are dissolved in 2.8 mL chloroform and treated with 170 mg (0.96 mmol) N-bromosuccinimide. The mixture is heated for 2.5 hours at reflux. The solvent is removed and the residue purified by chromatography (silicagel, dichloromethane/methanol). 198.4 mg (75.3%) of the desired compound are obtained.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH2:5]1[S:10](=[O:12])(=[O:11])[O:9][CH2:8][CH2:7][CH2:6]1>CO>[CH2:1]([NH:4][CH:5]([S:10]([OH:12])(=[O:11])=[O:9])[CH2:6][CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=S1(=O)CCCCO1
Solvent: CO
Product: C=CCNC(CCC)S(=O)(=O)O
Yield: 36.3 %

Procedure:
A solution of 57 g of allylamine and 136 g of butanesultone in 1 l of methanol was stirred a room temperature for 48 h. After evaporation, washing of the residue with ether and drying under vacuum, 70 g of N-allyl-aminobutane sulphonic acid were obtained.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[CH2:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14]>O>[CH2:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[CH:19][CH:20]=1)[CH2:13][CH3:14]
Reactant: C=C(Cl)c1ccc(CCC)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: C#Cc1ccc(CCC)cc1

Procedure:
Potassium t-butoxide (21.5 g) was added to stirred t-butanol and warmed to gentle reflux. The alkene product from step 2.3 (20 g) was added dropwise and then the mixture was heated under reflux for 3 hrs. Water (100 ml) was added and the product extracted into petroleum spirit (3×100 ml), washed with 10% HCl and water. The crude alkine product was 97% pure by gc. Yield 12 g.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2cc(Cl)sc2n1
Reactant: c1cn[nH]c1
Product: Clc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,6-dichloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-chloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:7][CH2:8][N:9]([S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])(=[O:25])=[O:24])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
4-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.5 g) was dissolved in pyridine (20 ml) at RT and 2-chlorobenzenesulfonylchloride (0.49 g) was added and the mixture was stirred overnight at RT. The pyridine was evaporated off, the residue then dissolved in AcOEt and washed with 0.05M HCl and brine. The layers were separated, the organic layer dried over sodium sulphate and concentrated in vacuo. The residue was chromatographed over silica gel (AcOEt/heptane, gradient from 0 to 25%) to give the desired 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.448 g) as light brown oil. MS (ESI): 390.11 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][C:9](=[O:11])[C:8]([N:12]=[N:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([OH:20])[CH2:6]1)=[O:4].C(N)(=O)C.BrC1CC(=O)NC1=O.BrBr>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([OH:11])[C:8]([N:12]=[N:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([OH:20])[CH:6]=1
Reactant: COC(=O)C1CC(=O)C(N=Nc2ccccc2)=C(O)C1
Agent: BrBr
Agent: CC(N)=O
Agent: O=C1CC(Br)C(=O)N1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(O)c(N=Nc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
54.8 G, of 3-hydroxy-5-keto-4-phenylazo-3-cyclohexene-carboxylic acid methyl ester 12.0 g. of acetamide and 2.0 g. of bromosuccinimide were stirred in 600 ml. of chloroform and treated dropwise with 32.0 g. of bromine dissolved in 400 ml. of chloroform. The reaction temperature was kept below 35° C. Separation of acetamide hydrobromide soon began. The mixture was stirred at room temperature for an additional 30 minutes and the acetamide hydrobromide was removed by filtration. The filtrate was evaporated to dryness and the residue taken up in a small amount of ethanol, removed by filtration under vacuum and washed with ethanol, whereby there was obtained 3,5-dihydroxy-4-phenylazo-benzoic acid methyl ester of melting point 216°-218° C.
Reaction SMILES: BrC(Br)(C)C([O-])=O.[OH-].[K+].[O:10]=[C:11]1[N:19]([CH2:20][CH2:21][CH3:22])[C:18]2[NH:17][C:16]([C:23]3[CH:35]=[CH:34][C:26](/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])=[CH:25][CH:24]=3)=[N:15][C:14]=2[C:13](=[O:36])[N:12]1[CH2:37][CH2:38][CH3:39]>O>[O:10]=[C:11]1[N:19]([CH2:20][CH2:21][CH3:22])[C:18]2[NH:17][C:16]([C:23]3[CH:35]=[CH:34][C:26]([C:27]#[C:28][C:29]([OH:31])=[O:30])=[CH:25][CH:24]=3)=[N:15][C:14]=2[C:13](=[O:36])[N:12]1[CH2:37][CH2:38][CH3:39]
Reactant: CCCn1c(=O)c2nc(-c3ccc(/C=C/C(=O)OCC)cc3)[nH]c2n(CCC)c1=O
Agent: CC(Br)(Br)C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCn1c(=O)c2nc(-c3ccc(C#CC(=O)O)cc3)[nH]c2n(CCC)c1=O

Procedure:
A suspension of the above dibromopropionate (3.00 g, 5.26 mmol) in an anhydrous ethanolic solution (150 ml) of potassium hydroxide (1.5 g, 26 mmol) was refluxed for 21 hours, then diluted over 3 hours with water (250 ml) as the ethanol was allowed to evaporate. The cooled solution was treated with 1 N HCL until a precipitate formed (pH 10) which was extracted with methylene chloride (100 ml). The aqueous phase was made strongly acidic with 1 N HCL. The thick precipitate was filtered and dried to yield a solid. A portion of this solid (0.65 g) was recrystallized from 50% ethanol (50 ml) to give the title compound as a yellow solid as the hemihydrate; mp slow dec. starting at 260° C. Analysis for (C20H20N4O4.5 H2O): C, 61.69; H, 5.44; N, 14.39. Found: C, 61.85; H, 5.38; N, 14.45.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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.O>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Clc1ccnc(Cl)n1
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: O
Solvent: COCCOC
Product: FC(F)(F)c1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 71.6 %

Procedure:
A mixture of 2,4-dichloro-pyrimidine (4.0 g, 27 mmol), 4-trifluoromethyl phenyl boronic acid (5.1 g, 27 mmol), tetrakis(triphenylphosphine)palladium(0) (1.5 g, 1.3 mmol), potassium phosphate (11 g, 54 mmol), 1,2-dimethoxyethane (50 mL) and water (10 mL) was heated to 80° C. under a blanket of nitrogen in a sealed tube. After 5 h, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified directly by FCC to afford a white solid (5.0 g, 72%). MS (ESI): mass calcd. for C11H6ClF3N2, 258.0; m/z found, 259.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.74 (d, J=5.2, 1H), 8.23 (d, J=8.1, 2H), 7.80 (d, J=8.2, 2H), 7.71 (d, J=5.2, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26]CC3C=CC(OC)=CC=3OC)[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nc(C)cc(NCC3CCN(C(=O)OCc4ccccc4)CC3)n2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 4-{[2-(2,4-dimethoxy-benzylamino)-6-methyl-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylic acid benzyl ester from Step 1 above (0.4 g, 0.79 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL). The resulting reaction solution was stirred at rt for 1 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1-10 (10% NH4OH in MeOH)/99-90 CH2Cl2) to give 4-[(2-amino-6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):356.36
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2([C:20]([OH:22])=O)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1>C1COCC1.CN(C)C=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2([C:20]([Cl:4])=[O:22])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)C1(C(=O)Nc2ccc(F)cc2)CC1

Procedure:
Oxalyl chloride (12.6 kg) was added to a solution of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and N,N-dimethylformamide (DMF; 0.23 kg) at a rate such that the batch temperature did not exceed 25° C. This solution was used in the next step without further processing.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[CH:5]=[N:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cncc(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
To a stirred solution of (5-bromopyridin-3-yl)methanol (LVI) (1.60 g, 8.5 mmol, 1 eq), phthalimide (1.24 g, 8.5 mmol, 1 eq) and PPh3 (3.33 g, 12.75 mmol, 1.5 eq) in anhydrous THF (15 mL) was added DEAD (2.21 g, 12.75 mmol, 1.5 eq) dropwise at 0° C. under N2. Then the reaction mixture was stirred at room temperature for 6 h. The mixture was washed with saturated NaHCO3 solution (15 mL), water (15 mL) and brine (15 mL) subsequently. The organic layers were dried over MgSO4, concentrated under reduced pressure, the resultant residue was purified by flash chromatography on silica gel (PE:EtOAc=4:1) to give 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (LVII) (2.5 g, 7.88 mmol, 82.3% yield) as a white solid. ESIMS found for C14H9BrN2O2 m/z 317 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[C:28]1(=[O:49])[N:32]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[C:31](=[O:44])[C:30]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:29]12.[OH-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:43][C:40]4[CH:39]=[CH:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][N:32]5[C:28](=[O:49])[C:29]6=[CH:48][CH:47]=[CH:46][CH:45]=[C:30]6[C:31]5=[O:44])=[CH:42][CH:41]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Reaction time: 5 h
Yield: 6 %

Procedure:
To a stirred solution of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl) piperazine (24 g) and 14.5 g of 4-(3-phthalimidopropyloxy)phenol in dimethylsulfoxide (500 ml) at 50° under nitrogen was added sodium hydroxide (1.9 g) in water (15 ml), and the solution was stirred for 5 hours 55°-60°. After standing at room temperature overnight, the reaction was poured into water (1 L) and the oil was extracted using ethyl acetate. The extract dried over sodium sulfate was evaporated in vacuo and the residual material was dissolved in acetonitrile. The supernatant was decanted from some insoluble material and then hydrogen chloride was bubbled into the solution to precipitate the product as the dihydrochloride salt. Methanol was added to the mixture to redissolve the salt and the solution was concentrated until a solid started to precipitate. The solid was collected by filtration to give 2 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-[2 -[4-(3-phthalimidopropyloxy)phenoxy]ethyl]piperazine as its di-hydrochloride salt, mp 233°-246°. The filtrate was evaporated and the resulting oil was crystallized from methanol yielding an additional 8.3 g of the same material, mp 225°-240°
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)(O)[O-].[Na+].[I:15]I>CCO.O>[I:15][C:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: II
Reactant: c1ccn2cncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Ic1ncn2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of imidazo[1,5-a]pyridine (0.50 g, 4.23 mmol) in EtOH (8 mL) and water (4 mL) was added sodium bicarbonate (1.07 g, 12.7 mmol) followed by iodine (1.61 g, 6.35 mmol). The dark maroon-brown heterogeneous reaction mixture was stirred at room temperature overnight then quenched with aqueous 10% Na2S2O3, diluted with water and extracted with EtOAc (3×). The combined organics were washed with water, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/hexanes to afford 649 mg (63%) of 1-iodo-imidazo[1,5-a]pyridine as a light brown solid (light sensitive). 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.13 (s, 1H), 7.92 (d, J=6.8 Hz, 1H), 7.33 (d, J=9.4 Hz, 1H), 6.80 (dd, J=9.4, 6.8 Hz, 1H), 6.56-6.69 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]([OH:25])=O)[CH:5]=[CH:6][CH:7]=1.[NH3:26]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]([NH2:26])=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncc(C(=O)O)c(Nc3cccc(Br)c3)c2cc1OC
Reactant: N
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(Br)c3)c2cc1OC
Temperature: 0 °C

Procedure:
A mixture of 4.03 g of 4-[(3-bromophenyl)amino]-6,7-dimethoxy-3-quinolinecarboxylic acid, 3.24 g of carbonyldiimiazole, and 100 ml of dimethylformamide was heated at 55 for 30 m, cooled to 0° C., and saturated with ammonia gas. After warming to 25 the resulting solution was stirred for 45 m, heated at 50, and evaporated to remove dimethylformamide. The residue was stirred with water, and the resulting solid was filtered, washed with water, and dried. Recrystallization from acetone gave a grey solid, mp 239-242° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[C:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)#[N:39]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([C:33]([F:35])([F:34])[F:36])[CH:24]=2)[CH:12]=[C:13]([C:43]2[CH:44]=[CH:45][C:40]([C:38]#[N:39])=[CH:41][CH:42]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C#N)cc2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 57 %

Procedure:
The title compound was prepared in 57% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Intermediate A) and 4-cyanophenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:24])=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(O)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1

Procedure:
The product from Example 181b (1.6 g, 5.6 mmol) was treated with oxalyl chloride (0.86 g, 6.7 mmol) and catalytic DMF at room temperature for 6 h. The excess oxalyl chloride was removed under vacuum. The residue was chased with benzene to \give the title compound (1.66 g, 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37]([O:39]C(C)(C)C)=[O:38])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[C:10]([C:37]([OH:39])=[O:38])=[N:11][C:12]([CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH2:21][CH2:22]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C(=O)O)c1OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 5-(benzyloxy)-2-{(1-[4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine-4-carboxylate (0.81 g, 1.4 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL), and an aqueous sodium hydroxide solution (5 M, 10 mL, 50 mmol) was added, followed by stirring at 50° C. for 15 minutes. The reaction solution was cooled to room temperature, and hydrochloric acid (5 M, 10 mL, 50 mmol) was added, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure to afford 5-(benzyloxy)-2-{(1-[4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidine-4-carboxylic acid as a yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6](C(CN)O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[CH:18](O)([CH3:20])[CH3:19]>C1(C)C=CC=CC=1.[Pd]>[CH3:19][C:18]1([CH3:20])[C:7]2([CH3:6])[CH:8]3[CH2:9][CH:10]1[CH2:11][CH:12]23
Reactant: NCC(O)Cc1ccccc1
Reactant: CC(C)O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C2CC3C(C2)C31C
Temperature: 20 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
53 ml of concentrated sulfuric acid is added to a solution of 95 ml of benzylethanolamine in 690 ml of toluene. The suspension that is produced is heated to boiling for 2 hours. The water that is produced in this case (14 ml) is separated with the aid of a water separator. After cooling to 20° C., the reaction mixture is mixed with 1300 ml of water and absorptively precipitated for 10 minutes, and the organic phase is separated. Then, the aqueous phase is quickly added to a solution of 92.2 g of NaOH in 95 ml of water that is introduced in a second reaction vessel. The reaction mixture is heated to boiling. 880 g of water-N-benzylaziridine emulsion in a third reaction vessel is distilled off through a distillation bridge. The emulsion is mixed with 880 ml of ethanol and heated to 60° C. To this end, a solution of 38.0 g of p-TsOH in 19 ml of water is added within 8 hours via a metering pump. After the addition is completed, it is refluxed for two hours. Then, the reaction mixture is mixed with a solution of 12.0 g of NaOH in 20 ml of water. The precipitated product is filtered and recrystallized from 600 mlof 2:1 ethanol-THF mixture. The tetrabenzylcyclene (53 g) thus obtained is dissolved in 500 ml of isopropanol and hydrogenated with 10 g of Pd/C (10%) at 80° C. and 20 bar of H2 pressure. After the catalyst is filtered off, the reaction solution is concentrated by evaporation, andthe product is recrystallized from toluene. 15.9 g (55% of theory) of cyclene is obtained as colorless crystals. Melting point 110°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH:24]=[O:25])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH2:26](O)[CH2:27][OH:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:27]1[O:28][CH:24]([CH2:23][S:22][C:11]2[S:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)[O:25][CH2:26]1
Reactant: OCCO
Reactant: COc1ccc(-c2nc(SCC=O)sc2-c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(SCC3OCCO3)sc2-c2ccc(OC)cc2)cc1

Procedure:
0.2 g of 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]acetaldehyde are dissolved in 50 ml of toluene. While stirring vigorously, 1 ml of ethylene glycol and then 0.2 g of p-toluenesulphonic acid are added. The mixture is heated for 40 hours in a water separator, cooled to 20°, filtered with suction, crystallised from hexane/benzene and dried under reduced pressure to constant weight. 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]acetaldehyde-ethyleneacetal is obtained in the form of a viscous oil.