Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CC(=O)CC.C(O)C.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: CCOC(=O)CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
1,4,5-Triphenylimidazol-2-one was treated with ethyl 9-bromononanoate and potassium carbonate in butanone, followed by sodium hydroxide in ethanol and water, to give after work-up the title compound, m.p. 123°-124° C., Found:C, 76.9;H, 6.9;N, 5.7%;C30H32N2O3 requires: C, 76.9; H, 6.9; N, 6.0%
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:18])[CH2:14][O:13][C:12]([CH2:15][O:16][CH3:17])=[N:11]1>>[C:2]1([CH:1]=[C:15]([C:12]2[O:13][CH2:14][C:10]([CH3:18])([CH3:9])[N:11]=2)[O:16][CH3:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COCC1=NC(C)(C)CO1
Product: COC(=Cc1ccccc1)C1=NC(C)(C)CO1

Procedure:
Benzaldehyde was reacted with 4,4-dimethyl-2-methoxymethyl-2-oxazoline (derived from methoxyacetic acid) to produce 2-(2-phenyl-1-methoxyethenyl)-4,4-dimethyl-2-oxazoline (P-1907), b.p. 122 (0.3 mm)-125 (0.26 mm).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C:10](=[C:27]([CH3:29])[CH3:28])[N:11]1[C:14](=[O:15])[C:13]([Br:17])([Br:16])[CH:12]1S(C1C=C(C)ON=1)(N)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:30])[C:10](=[C:27]([CH3:29])[CH3:28])[N:11]1[C:14](=[O:15])[C:13]([Br:17])([Br:16])[CH:12]1[Br:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(Br)(Br)C1[SH](N)(=O)c1cc(C)on1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(Br)(Br)C1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
3,3-dibromo-alpha-(1-methylethylidene)-2-[(5-methyl-isoxazole-3-yl)-aminosulfinyl]-4-oxo-1-azetidine acetic acid benzyl ester (5.61 g; 0.01 mole) was dissolved in chloroform (120 mL), N-bromosuccinimide (7.12 g; 0.04 mole) was added to the reaction mixture and it was stirred for two hours at room temperature. The reaction mixture was evaporated, methylene chloride and n-hexane were added to the dry residue, the precipitate was sucked off and the filtrate was evaporated to a dry residue. The obtained product was purified by flash chromatography with the solvent system petroleum ether-methylene chloride (1:1). There was obtained 2,3,3-tribromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester (3.05 g, 61.5%), which was subjected to a reaction with silver tetrafluoroborate in methanol analogously to the reaction described under 1a. After isolation 3,3-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester with spectroscopic data identical to those disclosed under 1a was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[C:17]([CH3:34])=[C:18]([CH3:33])[C:19]4[N:20]([C:22](I)=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[N:24]=4)[N:21]=3)[CH2:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:54]2[CH:59]=[CH:58][N:57]=[C:56]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH:55]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.ClCCl>[CH2:1]([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]3[C:17]([CH3:34])=[C:18]([CH3:33])[C:19]4[N:20]([C:22]([C:54]5[CH:59]=[CH:58][N:57]=[C:56]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:65])([CH3:64])[CH3:66])[CH:55]=5)=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[N:24]=4)[N:21]=3)[CH2:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(N2CC3CN(Cc4ccccc4)CC3C2)nn2c(I)c(-c3ccc(F)cc3)nc2c1C
Reactant: CC(C)(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1c(N2CC3CN(Cc4ccccc4)CC3C2)nn2c(-c3ccnc(NC(=O)OC(C)(C)C)c3)c(-c3ccc(F)cc3)nc2c1C
Yield: 72.4 %

Procedure:
To a solution of 3.60 g (6.34 mmol) of 6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-(4-fluorophenyl)-3-iodo-7,8-dimethylimidazo[1,2-b]pyridazine in 15 mL of a mixture of tetrahydrofuran and water (9:1) are added 6.2 g (19 mmol) of cesium carbonate and 2.4 g (7.6 mmol) of tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-2-yl]carbamate. After sparging with a stream of argon for a few moments, 0.47 mg (0.57 mmol) of a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (PdCl2(dppf).CH2Cl2) is added and the reaction mixture is refluxed under argon for 5 hours. The mixture is then poured into 250 mL of water and the product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off to give a brown solid. The product is purified by chromatography on silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95:5:05) to give 2.91 g of a beige-colored solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH3:17])[CH:24]=2)[S:6]1(=[O:16])=[O:15]
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(N2c3ccccc3CN(CCCCl)S2(=O)=O)c1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (456 mg) was coupled to m-methoxyphenylboronic acid to provide 3-(3-chloropropyl)-1-(3-methoxyphenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (63 mg):
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[Li]CCCC.[Li]C(C)(C)C.[F:21][C:22]([F:42])([F:41])[C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[N:29]=[CH:28]2)=[O:24]>CCOCC.CCCCC.[Cl-].[NH4+]>[F:42][C:22]([F:21])([F:41])[C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[N:29]=[CH:28]2)([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1)[OH:24]
Reactant: Brc1n[nH]c2ccccc12
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCC
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1n[nH]c2ccccc12)C(F)(F)F
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
To a chilled (−78° C.) solution of 97 mg (0.49 mmol) of 3-bromo-1H-indazole in 5 mL of anhydrous ether was added 195 μL (0.49 mmol) of a 2.5 M solution of n-BuLi in hexanes dropwise. After 5 minutes, 590 μL (1.0 mmol) of a 1.7 M solution of tert-BuLi in pentane was added dropwise. The mixture stirred for 15 minutes and then a solution of 151 mg (0.49 mmol) of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone in 3 mL of ether was added dropwise. After 1 hour, the reaction was monitored by thin layer chromatography (30% ethyl acetate-hexanes) and LCMS. The mixture was diluted with 10 mL of saturated aqueous ammonium chloride and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with three 10 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was chromatographed on silica gel using dichloromethane-hexanes (1:1) to load the sample and then eluting with dichloromethane-hexanes (1:1, then 100:0) followed by ethyl acetate-hexanes (2:8). The material from the column was triturated with ether-hexanes to afford 41 mg (19%) of the title compound. MS m/z 427.20 (MH+).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:42])([F:41])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([CH3:40])[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[O:18])[CH:11]=1)(=[O:8])[O:5]CC)[CH3:2].C1N2CCN(CC2)C1>C(#N)C>[CH2:1]([O:3][P:4]([C:9]([F:42])([F:41])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([CH3:40])[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[O:18])[CH:11]=1)(=[O:5])[OH:8])[CH3:2]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)N(C)c3cccc(C(F)(F)P(=O)(OCC)OCC)c3)cc2)cc1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)N(C)c3cccc(C(F)(F)P(=O)(O)OCC)c3)cc2)cc1

Procedure:
A solution of (difluoro-{3-[methyl-(4′-octyloxy-biphenyl-4-carbonyl)-amino]-phenyl}-methyl)-phosphonic acid diethyl ester (compound of example 59 in TABLE 2 below) and aproximately 3 to 5 equivalents of DABCO in acetonitrile solution is heated to 150° C. in a microwave reactor for less then 40 minutes. The mixture obtained is partitioned between EtOAc and 1N aqueous HCl. From the mixture obtained the organic phase is separated, washed with 1N aqueous HCl, and evaporated to dryness. (Difluoro-{3-[methyl-(4′-octyloxy-biphenyl-4-carbonyl)-amino]-phenyl}-methyl)-phosphonic acid monoethyl ester is obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[H-].[Na+].[CH3:17][C:18]1[CH:27]=[C:26]([CH2:28]OC2C=CC(CCl)=CC=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>C1COCC1>[CH3:17][C:18]1[CH:27]=[C:26]([CH2:28][O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: Cc1cc(COc2ccc(CCl)cc2)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(COC2CCNCC2)c2ccccc2n1
Reaction time: 0.42 h
Yield: 15.6 %

Procedure:
To commercially available N-Boc-4-piperidinol (1.00 g, 5.0 mmol) in THF (50 mL) was added NaH (238 mg 60% oil dispersion) and after 25 min, 4-[(2-methyl-4-quinolinyl)methoxy]benzyl chloride (950 mg, 5.00 mmol). After 18 h, the reaction was quenched with water, the THF was removed by rotary evaporator, and the residue was extracted from water with 3×EtOAc. The combined organic extracts were dried over MgSO4, filtered, concentrated, and chromatographed on SiO2 using 40% EtOAc in hexane. Obtained 200 mg (11% yield) of desired product which was treated with TFA (2 mL) in DCM (5 mL) for 1 h. The solvents were removed by rotary evaporator and the product was obtained pure as a free base by extraction from aqueous NaHCO3 with EtOAc after drying over MgSO4, filtering, and concentrating in vacuo. MS found: (M+H)+=257.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:20]([OH:21])=[CH:19][C:17]([NH2:18])=[C:16]([F:22])[CH:15]=1>CC(O)CCC>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:18][C:17]3[CH:19]=[C:20]([OH:21])[C:14]([Cl:13])=[CH:15][C:16]=3[F:22])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCCC(C)O
Product: Oc1cc(Nc2ccnc3cc(Cl)ccc23)c(F)cc1Cl
Yield: 79.8 %

Procedure:
Using an analogous procedure to that described for Example 15, 4,7-dichloroquinoline (198 mg, 1 mmol) was reacted with 4-chloro-2-fluoro-5-hydroxyaniline (194 mg, 1.2 mmol), (as described in EP 61741 A2), in 2-pentanol (5 ml) to give 7-chloro-4-(4-chloro-2-fluoro-5-hydroxyanilino)quinoline (258 mg, 72%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:36][CH2:35][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:26]3[CH2:36][CH2:35][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CCOC(=O)C1CCN(C(=O)Cc2csc(-c3cnn(C(C)(C)C)c3-c3ccc(F)cc3)n2)CC1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and ethyl isonipecotate and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:17]=[C:16]([O:18]C)[C:15]2[C:10](=[C:11]([O:22][CH3:23])[CH:12]=[CH:13][C:14]=2[O:20][CH3:21])[C:9]=1[O:24]C)[CH2:3][CH2:4][CH2:5][CH2:6]C.[N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[OH:1][CH:2]([C:8]1[C:9](=[O:24])[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:20][CH3:21])[CH:13]=[CH:12][C:11]=2[O:22][CH3:23])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(O)c1cc(OC)c2c(OC)ccc(OC)c2c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCCCC(O)C1=CC(=O)c2c(OC)ccc(OC)c2C1=O
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
3.6 g (10.3 mmole) of 2-(1-hydroxyhexyl)-1,4,5,8-tetramethoxynaphthalene was dissolved in 50 ml of acetonitrile and then a solution of 14.2 g (25.0 mmole) of cerium (IV) ammonium nitrate dissolved in 50 ml of distilled water was added dropwise thereto over 30 minutes through a dropping funnel in a cooling bath (0°-5° C.). The reaction mixture was stirred at normal temperature for 2 hours. After adding 100 ml of distilled water thereto, the reaction mixture was extracted twice with dichloromethane solvent, dried over anhydrous magnesium sulfate and then filtered through filter paper. The resulting filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (silica gel 4.0×15 cm) using the solvent condition which increases the amount of ethylacetate so that the n-hexane/ethylacetate ratio can vary from 5:1 to 1:3, to obtain 1.2 g of the title compound as a yellow precipitate.
Reaction SMILES: Br.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C.C(OCC)(=O)C>[CH2:10]([O:12][C:13](=[O:18])[C:14]([O:9][C:6]1[CH:7]=[N:8][C:3]([NH2:2])=[CH:4][CH:5]=1)([CH3:16])[CH3:15])[CH3:11]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccc(O)cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(N)nc1
Reaction time: 16 h
Yield: 69.1 %

Procedure:
To a flask containing 6-aminopyridin-3-ol hydrobromide (2 g, 10.5 mmol) and ethyl-2-bromo-2-methylpropanate (2.04 g, 10.5 mmol) in anhydrous acetonitrile (25 ml) was added cesium carbonate (10.7 g, 33 mmol) and the material was stirred for 16 hours under argon atmosphere. Water (60 ml) and ethyl acetate (60 ml) were added and the material was shaken in a reparatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×50 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. to provide a golden brown solid (1.626 g)(M+H)+=225 m/e.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.[OH:26][CH2:27][CH:28]([CH2:30]O)[OH:29]>ClCCl.O1CCCC1>[OH:29][CH:28]([CH2:27][OH:26])[CH2:30][O:23][C:22](=[O:24])[C:21](=[O:25])[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Reactant: OCC(O)CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(OCC(O)CO)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The acid chloride, prepared from 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzene-acetic acid (0.5 g) as described in Example 6, was dissolved in dichloromethane (10 mL) and added dropwise to a stirred, cold (<-50° C.) mixture of glycerine (0.9 mL) in tetrahydrofuran (10 mL). The cooling bath was removed and the mixture stirred for 1 hour at room temperature. The mixture was diluted with dichloromethane and washed once with saturated aqueous sodium bicarbonate, once with water, and the organic solution was dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate) to provide, after crystallization from ethyl acetate-hexane, 0.25 g of rac.-4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid 2,3-dihydroxypropyl ester as a colorless solid, mp 124°-125° C.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7]Cl)(=[O:5])=[O:4])[CH3:2].[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([S:3]([CH2:6][CH2:7][NH:13][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCCl
Reactant: CCCCN
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCNCCS(=O)(=O)CC
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A solution of 15.7 g of chloroethyl ethyl sulfone in 50 ml of toluene is added dropwise within 10 min to a solution of 73 g of n-butylamine and 10.1 g of triethylamine in 100 ml of toluene at an internal temperature of 50° C. The mixture is stirred at 50° C. for 5 h and allowed to cool to room temperature, the precipitate is filtered off with suction, and the filtrate is concentrated in a rotary evaporator. The remaining yellow oil (18.7 g) is reacted without further purification.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].[CH2:13]([OH:16])[C:14]#[CH:15]>O1CCCC1>[CH2:13]([O:16][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]#[CH:15]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCC(=O)CC(=O)OCC
Yield: 95.3 %

Procedure:
A solution of ethyl 4-chloroacetoacetate (294 g) in tetrahydrofuran (200 ml) was added over 3hours to a stirred, ice-cooled suspension of sodium hydride (150 g of a 80% dispersion in mineral oil) in tetrahydrofuran (500 ml) at such a rate than the reaction temperature remained ≤20°. A solution of prop-2-ynol (100 g) in tetrahydrofuran (200 ml) was then added over 2 hours to the above mixture with stirring and ice-cooling at such a rate that the reaction temperature never exceeded +25°. The mixture was then stirred at room temperature for 16 hours, poured into 2 M HC1 (900 ml) and the layers separated. The organic layer was evaporated and the resulting red oil was separated in a separating funnel from the mineral oil. The red oil was taken up in dichloromethane and the resulting solution was washed several times with water, dried over Na2SO4 and evaporated to give the title compound (313 g) as a dark oil which was used directly in Preparation 8.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=[CH:13][C:12]([C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([OH:18])[CH2:16]Cl)=[CH:11][CH:10]=1.CN(C)C=O>CO>[C:9]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:14]=[CH:13][C:12]([C:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([OH:18])[CH2:16][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:11][CH:10]=1
Reactant: OC(CCl)(c1ccc(F)cc1)c1ccc(-c2ccccc2)cc1
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: OC(Cn1ccnc1)(c1ccc(F)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Yield: 27.9 %

Procedure:
20.2 g (0.297 mol) of imidazole are added to a solution of 9.5 g (0.175 mol) of sodium methylate in 49 ml of methyl alcohol. A slution of 44.3 g (0.135 mol) of 1-(4-biphenylyl)-2-chloro-1-(4-fluorophenyl)-ethanol in 103 mol of dimethylformamide is then added dropwise, and the reaction mixture is heated to 60° C. for 90 minutes. It is concentrated by distilling off the solvent in vacuo, and the residue is stirred with water. The crystals which remain are washed with acetonitrile and recrystallised from ethyl alcohol. 13.5 g (28% of theory) of 1-(4-biphenylyl)-1-(4-fluorophenyl)-2-(imidazol-1-yl)-ethanol of melting point 220° C. are obtained.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:21]([CH2:23]Cl)=[N:22][C:18]=2[CH:17]=1>>[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])[C:21]([CH2:23][N:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7]3)=[N:22][C:18]=2[CH:17]=1
Reactant: CCS(=O)(=O)c1c[nH]c2ccccc12
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Product: CCS(=O)(=O)c1cn(Cc2nc3cc(Cl)ccc3n2CCCS(C)(=O)=O)c2ccccc12

Procedure:
Example 1-5 was prepared in analogy to Example 1-2 by using 3-ethanesulfonyl-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24]([Cl:25])=[C:23](SC)[N:22]=[C:21](SC)[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl>C(O)C.[Ni]>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]2[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][N:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(NCC2CCN(C(=O)OCc3ccccc3)CC2)c(Cl)c(SC)n1
Agent: [Ni]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncncc2Cl)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-[(5-Chloro-2,6-bis-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (1.0 g, 2.2 mmol) was suspended in ethanol (15 mL) and ethyl acetate added to give a homogeneoussolhution, and excess Raney nickel was added. The resulting reaction mixture was stirred overnight. More Raney Nickel was added and the reaction mixture was heated to 80° C. for 3 h. The mixture was filtered and the solids were washed with hot ethanol/ethyl acetate several times. The organics were concentrated and the resulting residue was purified by silica gel chromatography (isopropanol/methylene chloride). The product was dissolved in ether and treated with ethereal HCl (2.2 mmol) to form the HCl salt which was collected by filtration. The resulting 4-[(5-chloro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester hydrochloride salt was collected by filtration as a colorless solid.