Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1>C1COCC1>[CH3:10][C:11]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]3=[N:26][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:22]3[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: Cc1cc(C(F)(F)F)ccc1Oc1ccc(-c2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)ccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 284 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.448 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(2-methyl-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-amine (489 mg) in THF (dry) (40 ml) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the extracted is organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and washed with IPE to give the title compound (390 mg) as a white solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C1N=C(N)C2N=CN([C@@H]3[O:34][C@H](CO)[C@@H](O)[C@@H]3O)C=2N=1.O.OO>C(O)(=O)C.[C].[Pd]>[C@@H:1]1([N:10]2[C:19]3[C:13](=[C:14]([N+:16]([O-:34])=[CH:17][N:18]=3)[NH2:15])[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [Pd]
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Twenty grams of adenosine with a product code of A9251-25G, commercialized by Sigma-Aldrich Japan K.K., Tokyo, Japan, was dispersed in one liter of acetic acid and admixed with 100 mL of 30% hydrogen peroxide solution, followed by stirring the resulting mixture at ambient temperature for five days. An excessive amount of the remaining hydrogen peroxide was decomposed by the addition of five grams of 5% palladium carbon, commercialized by Kawaken Fine Chemicals Co., Ltd., Tokyo, Japan, followed by filtering the mixture to remove the palladium carbon, drying the resulting solution in vacuo, adding ethanol to the dried product to disperse the formed crystals, and filtering the resulting mixture to obtain crude crystals of adenosine N1-oxide. Eight grams of adenosine N1-oxide with a purity of 99.5% was obtained by dissolving the crude crystals in ethanol by heating, filtering the resulting solution, ice-chilling the filtrate to effect recrystallization, and repeating these steps twice.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11]>C(O)(=O)C>[C:4]([CH2:3][CH2:2][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([OH:6])=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C1CCC(=O)O1
Solvent: CC(=O)O
Product: O=C(O)CCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Succinic anhydride (67 mmoles, 6.7 g.) is dissolved in 100 ml. of hot glacial acetic acid and cooled to room temperature. To this, while stirring (67 mmoles, 7.7 g.) L-proline is added. After 20 hours at room temperature, the reaction mixture is concentrated to dryness in vacuo. The residue is extracted three times with hot ethyl acetate and cooled to room temperature. To the pooled extracts containing the 1-(3-carboxypropanoyl)-L-proline, dicyclohexylamine is added and crystals form which are recrystallized from hot isopropanol, yield 11.3 g. The dicyclohexylamine salt has m.p. (170) 175°-177°.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>F.O>[N+:17]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: F
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 53 °C

Procedure:
50 g of anthraquinone are suspended in 50 ml of hydrogen fluoride (85% strength). A mixture of 16 ml of HNO3 (98% strength) and 50 ml of hydrogen fluoride (85% strength) is added dropwise over the course of 1/2 hour, the reaction mixture is then heated for 4 hours to refluxing (53°C) and diluted with 1 liter of water, and the product is filtered off, washed until neutral and dried. 60.5 g of nitroanthraquinone of the following composition are obtained:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([Cl:48])[C:34]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:37]2[CH:38]=[C:33]([Cl:32])[C:34]([OH:49])=[C:35]([Cl:48])[CH:36]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (43 mg, 0.088 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38 mg, 0.132 mmol) to afford the desired product (25 mg, 51%) as an off-white solid: ESI MS m/z 570 [C30H33C12N3O4+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12.[H-].[Na+].[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[S:35](Cl)(=[O:37])=[O:36]>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[S:35]([N:9]1[C:10]2[C:6](=[C:5]3[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]3=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1cc2[nH]ccc2c2c1OCCN(C(=O)OC(C)(C)C)C2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccc(Cl)cc2Cl)c2c1OCCN(C(=O)OC(C)(C)C)C2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
tert-Butyl 6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 36, 25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2,4-dichlorobenzenesulfonyl chloride (28 mg, 0.113 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2,4-dichlorophenyl)sulfonyl]-6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (6 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (4.2 mg). MS m/z 442 [M+H]+.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+]>O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:6]([Br:5])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Br)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Glacial acetic acid (75 mL) was added dropwise with stirring, at 40-50° C. to a mixture of compound of example 150 (15 g, 57.62 mmol) and iron dust (15 g, 0.267 mol) in water (120 mL). The reaction mixture was stirred vigorously at 25° C. for 1 h. It was poured into water (200 mL), basified using saturated aqueous Na2CO3 solution and extracted with EtOAc (3×250 mL). The organic extract was washed, dried (anhydrous Na2SO4) and concentrated to obtain 5-amino-2-bromobenzoic acid which was then converted into title compound as follows.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([NH2:13])=[S:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:15][C:16](=O)[CH3:17]>CN(C=O)C>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:10][C:11]2[S:12][CH:15]=[C:16]([CH3:17])[N:13]=2)=[CH:3][C:2]=1[OH:1]
Reactant: CC(=O)CBr
Reactant: COc1ccc(NC(N)=S)cc1O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(C)cs2)cc1O
Yield: 26 %

Procedure:
Following the general procedure for the synthesis of derivatives 6 and 7, a solution of 1-(3-hydroxy-4-methoxyphenyl)thiourea (100 mg, 0.50 mmol) and bromoacetone (83 mg, 0.60 mmol) in dry DMF (2.0 mL) was heated at 60° C. for 6 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 26% yield (30 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([F:25])[CH:3]=1.[ClH:26].Cl.Cl.[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1>>[ClH:26].[ClH:26].[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH:46][C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[C:13]([O:12][CH2:11][C:8]3[C:7]5[C:2]([F:1])=[CH:3][C:4]([F:25])=[CH:5][C:6]=5[O:10][CH:9]=3)[CH:21]=[CH:20][CH:19]=4)=[O:24])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (115) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: C(O[K])(C)(C)C.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]([C:21]([F:24])([F:23])[F:22])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>O1CCOCC1.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=[O:29])[CH:16]([C:21]([F:24])([F:22])[F:23])[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(C(F)(F)F)C1
Reactant: O=Cc1ccccc1F
Agent: CC(C)(C)O[K]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)C(C(F)(F)F)C1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
tBuOK (136 mg; 1.21 mmol; 1.5 eq.) was added to a solution of 4-hydroxy-3-trifluoromethyl-piperidine-1-carboxylic acid tert-butyl ester (239 mg; 0.89 mmol; 1.1 eq.) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at 50° C. for 15 minutes. After cooling down to room temperature, 2-fluoro-benzaldehyde (100 mg; 0.81 mmol; 1 eq.) was added and the reaction was stirred at 50° C. for 30 minutes. The solution was diluted with water and extracted with EA (3×). The combined organics were dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (10% to 30% EA in heptane) afforded the title compound (181 mg, 60%) as colourless oil. HPLC (max plot) 99.9%, Rt 5.02 min. UPLC/MS: (MS+) 274.2 ([M-(Boc)+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[C:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[OH:16])[CH2:11][O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:27]>[Ag]=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[C:14][CH:15]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[O:16][CH3:27])[CH2:11][O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1[C@@H](C#CC(O)c2ccc(Cl)cc2)COC1(C)C
Agent: O=[Ag]
Product: COC(C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 76 %

Procedure:
To (S)-4-[3-(4-chloro-phenyl)-3-hydroxy-prop-1-ynyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.10 g) was added dropwise iodomethane (5.27 ml). To the resulting yellow solution was added silver oxide (5.89 g) and the mixture was heated at 70° C. for 2 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-[3-(4-chloro-phenyl)-3-methoxy-prop-1-ynyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.44 g, 76%) as a colourless oil. MS (ISP): 399.2 ([{37Cl}M+NH4]+), 397.2 ([{35Cl}M+NH4]+).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[S:18][C:17]([CH:19]3[N:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[F:31])[N:22]=[C:21]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[CH2:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:23]1[CH:19]([C:17]2[S:18][C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[CH:15][CH:16]=2)[CH2:20][C:21]([C:32]([F:37])([F:38])[C:33]([F:35])([F:36])[F:34])=[N:22]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(C3=CCNCC3)s2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
5-[5-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-thiophen-2-yl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (480.0 mg, 0.85 mmol) prepared in Example 197 and trifluoroacetic acid (600.0 uL, 7.84 mmol) were added at 0° C. to dichloromethane (5.0 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give 450.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [O-:1]CC.[Na+].[Na].Br[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[N:11]=1.Cl>CC(C)=O.C(O)C>[O:1]=[C:7]1[NH:11][C:10]2[C:12]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=[CH:15][C:9]=2[S:8]1
Reactant: Brc1nc2c(Oc3ccccc3)cccc2s1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(C)=O
Product: O=c1[nH]c2c(Oc3ccccc3)cccc2s1
Reaction time: 0.75 h

Procedure:
To a sodium ethoxide solution prepared with sodium metal (460 mg) and anhydrous ethanol (50 ml) was added 2-bromo-4-phenoxybenzothiazole (3.0 g). The mixture was refluxed with stirring 45 minutes. The solvent was removed under reduced pressure to give a residue, to which was added 10% hydrochloric acid (30 ml) and acetone (50 ml). The resultant mixture was refluxed with stirring for 2 hours. The solvent was removed under reduced pressure to give a residue, which was recrystallized from a mixture of ethanol and n-hexane to give crystalline 2-oxo-4-phenoxybenzothiazoline (2.0 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][NH:4][C:3]1=[O:11].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.ClCCl>[CH3:1][N:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][N:4]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:3]1=[O:11]
Reactant: Brc1ncccn1
Reactant: COC(=O)C1CNC(=O)N1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C1CN(c2ncccn2)C(=O)N1C
Temperature: -40 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
A suspension of methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (316 mg, 2 mmol) (prepared as described in step (ii) of Example 8) in THF (10 ml) was stirred at −40° C. Lithium hexamethyldisilazide (2 ml, 1M solution in THF) was added dropwise and the mixture was stirred at −40° C. for 15 minutes and then at −70° C. for 1 hour. A solution of 2-bromopyrimidine (318 mg, 2 mmol) in THF (1 ml) was added dropwise and the reaction was stirred at −70° C. for 1 hour and then warmed to 0° C. over 1 hour and then stirred at room temperature overnight. The reaction mixture was diluted with citric acid solution and dichloromethane. The organic layer was separated, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give crude methyl 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylate (144 mg) which was used in the next step, LC/MS [M+H]+=237. (ii) A stirred solution of methyl 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylate (144 mg, 0.6 mmol) in THF (1.5 ml) at 0° C. was treated with lithium hydroxide (72 mg, 3 mmol) in water (1 ml) and the reaction mixture was stirred at 0-5° C. for 1 hours. The reaction was acidified to pH 2 with 2N hydrochloric acid and the solvent was evaporated. The residue dried to give 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylic acid which was used crude in the next step, LC/MS [M+H]+=223.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([OH:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([O:13][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc2cccnc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc2cccnc2c1OCc1ccccc1
Yield: 77 %

Procedure:
7-Methyloxy-8-hydroxyquinoline (1.10 g; 6.29 mmol) and K2CO3 (1.30 g; 9.43 mmol) in 30 ml of dry acetonitrile are stirred for 10 minutes under argon. Benzyl chloride (0.87 ml, 7.54 mmol) is then added and the reaction medium is heated under reflux overnight. After returning to ambient temperature, the precipitate is filtered, washed with CH2Cl2 and the filtrate is concentrated under reduced pressure. The oil obtained is dissolved again in CH2Cl2 (50 ml) and washed in succession with an aqueous solution of NaOH 2 N (4×50 ml) and water (1×50 ml). The organic phase is dried over anhydrous Na2SO4 and the solvent is evaporated under reduced pressure to yield 7-methyloxy-8-[(phenylmethyl)oxy]quinoline in the form of a brown oil (1.28 g; 4.84 mmol, yield=77%). NMR-1H (250 MHz, CDCl3) δ, ppm: 8.94 (dd, 3J (H, H)=4.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.06 (dd, 3J (H, H)=8.5 Hz, 4J (H, H)=1.5 Hz, 1H); 7.59-7.51 (m, 3 H); 7.36-7.24 (m, 5H); 5.40 (s, 2H); 3.92 (s, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 151.3 (CH); 149.5 (Cq); 142.9 (Cq); 141.2 (Cq); 137.4 (Cq); 135.3 (CH); 127.9 (CH); 127.4 (CH); 127.1 (CH); 123.6 (Cq); 122.9 (CH); 118.5 (CH) 114.8 (CH); 75.2 (CH2); 56.1 (CH3). MS (CID, NH3): m/z=266 (MH+). Analysis (%) for C17H15NO2.0.05 CHCl3: calculated C, 75.49. H, 5.59. N, 5.16. found C, 75.74. H, 5.40. N, 5.33.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH:12]=O)[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[N:11]=[C:10]([CH:12]=[CH:22][CH:23]=[O:24])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=Cc1cccc(-n2cccn2)n1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1cccc(-n2cccn2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 6-(1H-pyrazol-1-yl)-2-pyridinecarboxaldehyde (prepared as described in J. Med. Chem. 1998, 41, 5070) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(Cl)Cl.C(N(CC)CC)C>>[CH2:11]([O:10][C:8]([C@H:5]1[CH2:4][CH2:3][C@@H:2]([O:1][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:7][CH2:6]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)[C@H]1CC[C@@H](O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@@H](OS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl cis-4-hydroxycyclohexanecarboxylate (4.30 g, 25.0 mmol), p-toluenesulfonyl chloride (7.14 g, 37.4 mmol) and DCM (100 mL, 2000 mmol) was added triethylamine (6.96 mL, 49.9 mmol) at rt. The mixture was stirred at 25° C. overnight. The solution was transferred to a separatory funnel, washed with 2 M HCl to remove base, then washed with sat. NaHCO3. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 10-20% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ=1.16 (t, J=7.2 Hz, 3H), 1.52-1.67 (m, 8H), 2.31-2.40 (m, 1H), 2.42 (s, 3H), 4.05 (q, J=7.1 Hz, 2H), 4.66 (br. s., 1H), 7.47 (m, J=7.8 Hz, 2H), 7.80 (m, J=8.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.C(O)(=O)C>[C].[Pd].C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CCCC(=O)O)cc1
Reaction time: 9 h

Procedure:
After 4-(4-methoxyphenyl)-4-oxobutanoic acid (40 g) was added to (not completely dissolved in) a mixed solvent of acetic acid (100 ml) and THF (100 ml), 10% palladium-carbon (50%-wet) (4 g) was added thereto and the resulting mixture was stirred for 9 hours under a hydrogen atmosphere (0.4 MPa). The catalyst was removed by filtration through Celite and toluene was added to the residue. The solvent was distilled off under reduced pressure to obtain 4-(4-methoxyphenyl)butanoic acid quantitatively.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:4]=1[CH2:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[O:30][CH3:31].[CH2:32]([OH:35])[CH2:33][OH:34]>>[CH3:31][O:30][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([O:28][CH3:29])[C:22]=1[CH2:21][C:4]1[C:5]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:6][CH:7]=[N:8][C:3]=1[O:34][CH2:33][CH2:32][OH:35]
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncnc(Cl)c2Cc2c(OC)cccc2OC)cc1
Reactant: OCCO
Agent: [Na]
Product: C=Cc1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2Cc2c(OC)cccc2OC)cc1
Temperature: 150 °C

Procedure:
60 mg of sodium were added to 2 ml of ethylene glycol at 70° C. Thereafter, 223 mg of N-[6-chloro-5-(2,6-dimethoxybenzyl)-4-pyrimidinyl]-p-vinyl-benzenesulfonamide were added and the reaction mixture was heated at 150° C. for 4.5 hours. The ethylene glycol was distilled under reduced pressure, the residue was taken up in EtOAc/H2O and extracted once with ethyl acetate. Thereafter, the aqueous phase was acidified with 1N HCl and extracted four times with ethyl acetate. The organic phase was dried, filtered and concentrated under reduced pressure. The residue was chromatographed over 50 g of SiO2 with methylene chloride/ethyl acetate 1:1. There were obtained 50 mg of N-[5-(2,6-dimethoxybenzyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-vinylbenzenesulfonamide, melting point 138°-139° C.