Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15]>C1(C)C=CC=CC=1>[CH3:11][O:12][CH:13]([O:16][CH3:17])[C:14](=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1])[NH2:15]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: COC(CN)OC
Solvent: Cc1ccccc1
Product: COC(OC)C(N)=Cc1cccc(Cl)c1Cl

Procedure:
A mixture of 65.7 g. (0.375 mole) of 2,3-dichlorobenzaldehyde and 39.4 g. (0.375 mole) of 2,2-dimethoxyethylamine was refluxed azeotropically in 150 cc. of toluene. When all the water was removed (1-2 hours), the solution was concentrated and distilled to give 2,2-dimethoxy-N-(2,3-dichlorobenzylidene)ethylamine, b.p. 140° C. (0.7 mm.).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[C:27]1[N:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[N:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: Cc1cnc(Br)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Product: Cc1cnc(N2CCC([C@H]3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-bromo-5-methylpyrimidine following a procedure analogous to that described in Example 1. LC (method 5): tR=0.84 min; Mass spectrum (ESI+): m/z=456 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([N+:19]([O-:21])=[O:20])=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH2:8][NH:7]1)=[O:5])[CH3:2]>C1(C)C(C)=CC=CC=1.[C].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c([nH]c3cc([N+](=O)[O-])ccc23)CN1
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2c(cn1)[nH]c1cc([N+](=O)[O-])ccc12
Yield: 65.9 %

Procedure:
400 mg of 7-nitro-1,2,3,4-tetrahydro-β-carbolin-3-carboxylic acid ethyl ester is dissolved in 40 ml of hot xylene and, after the addition of 400 mg of palladium-carbon (10%), is refluxed for 30 hours. The catalyst is filtered off with suction, and washed out well with warm xylene. The filtrate is concentrated in vacuo, and the residue chromatographed on silica gel with chloroform-ethanol (10:2). 260 mg of 7-nitro-β-carbolin-3-carboxylic acid ethyl ester of melting point 321° C. (decomposition) is obtained.
Reaction SMILES: S([O-])(=O)(=O)C.[CH2:6]([N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][OH:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:21][C:22]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:23]=1[O:24][C:25]1[C:34]2[C:29](=[CH:30][C:31](O)=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][N:26]=1>>[CH2:6]([N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][O:20][C:31]2[CH:30]=[C:29]3[C:34]([C:25]([O:24][C:23]4[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:22]=4[Br:21])=[N:26][CH:27]=[N:28]3)=[CH:33][C:32]=2[O:35][CH3:36])[CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1O
Reactant: OCC1CN(Cc2ccccc2)CCO1
Agent: CS(=O)(=O)[O-]
Product: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1OCC1CN(Cc2ccccc2)CCO1

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Note [140] immediately above which is concerned with the preparation of starting materials, the mesylate of N-benzylmorpholin-2-ylmethanol (Synth. Commun. 1980, 10, 59–73) was reacted with 4-(2-bromo-4-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (4.56 g) to give 7-(N-benzylmorpholin-2-ylmethoxy)-4-(2-bromo-4-fluorophenoxy)-6-methoxyquinazoline; Mass Spectrum: M+H+ 554 and 556.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=3)=[CH:26][N:25]=2)=[CH:20][CH:19]=1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].[C:44]([C:48]1[S:52][C:51]([C:53](O)=[O:54])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[C:44]([C:48]1[S:52][C:51]([C:53]([NH:1][C@@H:2]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=4)=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[C:3]([N:5]2[CH2:9][CH2:8][CH2:7][C@H:6]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4])=[O:54])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)cc3)nc2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)cc3)nc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Prepared using General Procedure 7: A stirred solution of (S)-tert-butyl 1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (306 mg, 0.522 mmol) and 5-(tert-butyl)thiophene-2-carboxylic acid (106 mg, 0.574 mmol) in DMF (6 mL) was added TEA (145 μl, 1.043 mmol), cooled to 0° C., then HATU (218 mg, 0.574 mmol) was slowly added over 5 minutes. The reaction was stirred at room temperature for 2 h, then diluted with EA (70 mL), washed with saturated aqueous NaHCO3 (70 mL) and brine (100 mL). The solvent was dried over MgSO4 and removed. The crude product was purified by chromatography 0-30% ACN in DCM to afford 363 mg (92%) of (S)-tert-butyl 1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl) propanoyl)pyrrolidine-2-carboxylate as a sticky solid. LCMS-ESI (m/z) calculated for C44H56N4O5S: 752.4; no m/z observed, tR=11.99 min (Method 10).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][N:12]=2)[N:9]=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:18][CH2:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([N:10]2[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][C:8]([C:19]([F:20])([F:21])[F:22])=[N:9]2)[CH:16]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccnc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccnc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 37 (215 mg, 0.695 mmol) in dichloromethane (6.95 mL) at 0° C. was added triethylamine (0.388 mL, 2.78 mmol) followed by methanesulfonyl chloride (0.163 mL, 2.092 mmol). The resulting solution was allowed to stir at room temperature for 1 h. The solvent was evaporated. The mixture was quenched with a saturated sodium carbonate solution and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. Compound 38 was isolated as an orange solid and used as is for the next step. LRMS (ESI): calc. 387.1; found 388.1 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH2:12](OCC)[CH3:13]>C(OC(=O)C)(=O)C>[CH3:12][C:13]1[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1
Reactant: CCOCC
Reactant: Nc1ccncc1S(N)(=O)=O
Solvent: CC(=O)OC(C)=O
Product: CC1=NS(=O)(=O)c2cnccc2N1

Procedure:
1 g of 4-aminopyridine-3-sulfonamide (Preparation 2) is maintained for 4-6 hours at reflux in 10 cm3 of acetic anhydride. After cooling, the reaction mixture is treated with 60 cm3 of diethyl ether. The precipitate obtained is filtered, washed with diethyl ether and dried. It is recrystallized from hot water.
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[C:14]([CH2:19][CH:20]1[C:25](=[O:26])[CH:24]=[CH:23][CH2:22][CH2:21]1)([O:16]CC)=O.C(C(C(C([O-])=O)O)O)(O)=O.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:26]1[C@H:25]2[CH:24]=[CH:23][CH2:22][CH2:21][C@H:20]2[CH2:19][C:14]1=[O:16]
Reactant: CCOC(=O)CC1CCC=CC1=O
Agent: CC(C)[O-]
Agent: O=C([O-])C(O)C(O)C(=O)O
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1C[C@@H]2CCC=C[C@@H]2O1
Temperature: 90 °C
Yield: 85.5 %

Procedure:
To a solution of 13.5 g (66.0 mmoles) of aluminum isopropoxide in 100 ml of toluene was added 2.0 g (11.0 mmoles) of 6-(carbethoxymethyl)-2-cyclohexen-1-one at room temperature, and the solution was heated to 90° C. for 18 hours. The solution was cooled to room temperature, and aqueous saturated sodium hydrogen tartrate and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate, and the combined ethyl acetate extracts were dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude material was purified by Kugelrohr distillation (bp 40°-80° C./0.01 mm Hg) to yield 1.3 g (86%) of cis 3a,4,5,7a-tetrahydro-2(3H)-benzofuranone, as confirmed by NMR and IR data.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[C:1]([O:5][C:6](=[O:32])[N:7]([CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([C:39]([C:38]2[S:37][C:36]3[CH:42]=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:13][CH2:14]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(C)nc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared from amine (281) (200 mg, 0.45 mmol) and acid chloride 6 (170 mg, 6.8 mmol) following Method D.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].Br.[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16]Br)[CH3:13]>CO>[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][S:1][CH2:2][CH2:3][OH:4])[CH3:13]
Reactant: CCN(CC)CCBr
Reactant: OCCS
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCSCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-mercaptoethanol (1.5 mL, 1.7 g, 22 mmol) in methanol (30 mL) was added with stirring sodium carbonate (4 g, 38 mmol), followed by 2-(diethylamino)ethyl bromide hydrobromide (5.0 g, 19 mmol). The reaction mixture was stirred overnight at room temperature and then filtered. The filtrate was concentrated under reduced pressure to give 2-[2-(diethylamino)ethylthio]-ethanol as a clear oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[F:19])[O:9][N:8]=1>O1CCCC1.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:15]=[CH:14][C:13]=2[F:19])[O:9][N:8]=1
Reactant: Fc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccccn2)cc1-c1nc(-c2ccccn2)no1
Yield: 22.8 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-2-fluorophenyl)-1,2,4-oxadiazole (100 mg, 0.312 mmol), pyridine-2-tributyltin (172 mg, 0.468 mmol) and Pd(PPh3)4 (36.1 mg, 0.0312 mmol) in tetrahydrofuran (1 mL) was heated in sealed vial overnight at 100° C. Standard work up afforded 11.3 mg (11%) of 3-(2-pyridyl)-5-[2-fluoro-5-(2-pyridyl)phenyl]-1,2,4-oxadiazole.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)=[CH:4][CH:3]=1.C[CH2:19][O:20]CC.C([Li])CCC.CN(C)C=O>O>[S:12]1[CH:13]=[C:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([CH:19]=[O:20])=[CH:3][CH:4]=2)[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]1=2
Reactant: CCOCC
Reactant: Brc1ccc(C=Cc2csc3ccccc23)s1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(C=Cc2csc3ccccc23)s1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
To a chilled (-70° C.), stirred solution of 3-[2-(5-bromo-2-thienyl)-ethenyl]benzo[b]thiophene (16.98 g) and ether (300 ml) was added n-butyllithium (23 ml of a 2.5M solution in hexanes), under nitrogen, over 5 mins. After stirring for 1.5 hrs, the mixture was added via canula to a solution of N,N-dimethylformamide (19.3 g) and ether (500 ml). The mixture was allowed to warm to room temperature, stirred overnight, and then poured into water (500 ml). The aqueous phase was separated, and the organic phase was washed with 10% aqueous hydrochloric acid, water, and 5% aqueous sodium bicarbonate solution. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give 14.9 g of solid. A lot of similarly prepared material (4.1 g) was combined with the solid, and the combined material was purified by high performance liquid chromatography (silica gel, loaded and eluted with 10% hexane in dichloromethane). The appropriate fractions were combined and evaporated. The residue was recrystallized from toluene/hexane to give 9.25 g (51%) of product, mp 105°-107° C.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:30]([C:33]2[N:34]=[CH:35][N:36]([CH3:38])[CH:37]=2)(=[O:32])=[O:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.O.O1CCOCC1>Cl.C(OCC)C>[CH3:38][N:36]1[CH:37]=[C:33]([S:30]([N:16]([CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:39])=[O:5])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:29]=3)=[CH:22][CH:23]=2)(=[O:31])=[O:32])[N:34]=[CH:35]1
Reactant: Cn1cnc(S(=O)(=O)N(Cc2ccc(-c3ncccn3)cc2)Cc2cccc(OCC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cn1cnc(S(=O)(=O)N(Cc2ccc(-c3ncccn3)cc2)Cc2cccc(OCC(=O)O)c2)c1
Reaction time: 0.33 h

Procedure:
HCl. A solution of (3-(((1-methyl-1H-imidazole-4-sulfonyl)-(4-pyrimidin-2-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid tert-butyl ester prepared of Example 10, Step B (0.094 g, 0.17 mmol) in 1N HCl in diethyl ether was stirred for 20 minutes as a precipitate formed. To the mixture was added 1 mL water and 1 mL dioxane and the reaction was stirred for 3 hours. The solvent was removed in vacuo, azeotroping with ethanol to yield the title compound as a solid (54 mg). 1H NMR (400 MHz, CD3OD) δ 9.09 (m, 2H), 8.95 (bs, 1H), 8.24 (d, 2H), 8.04 (s, 1H), 7.71 (s, 1H), 7.44 (d, 2H), 7.13 (m, 1H), 6.82 (d, 1H), 6.76 (d, 1H), 6.69 (s, 1H), 4.61 (s, 2H), 4.54 (s, 2H), 4.46 (s, 2H), 3.92 (s, 3H); MS 494 (M+1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][SH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:15][CH:16]=[C:17]([F:19])[F:18]>>[C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][S:11][C:17]([F:19])([F:18])[CH2:16][Cl:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: FC(F)=CCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CS)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CSC(F)(F)CCl)C(=O)O

Procedure:
N-Boc-L-cysteine is reacted with 2-chloro-1,1-difluoro-ethene in the same manner as described in J. Chem, Res. Miniprint 12, 1990; p 2868 to form N-Boc-S-(2-chloro-1,1-di fluoroethyl)-L-cysteine. N-Boc-S-(2-chloro-1,1-difluoroethyl)-L-cysteine is reacted with potassium phthalimide in DMF at 100° C. to form the phthalimide. The phthalimide is treated with hydrazine in ethanol to form the amine. The amine is treated with ethyl acetimidate hydrochloride to form the amidine. This material is purified via C-18 chromatography to afford the Boc compound. The Boc group is removed with HCl/dioxane (4 N) in acetic acid to afford the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].I[CH3:24]>O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH2:19][CH2:18][CH:17]([O:20][CH3:24])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2=CC(O)CC2)cc1OC1CCCC1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C2=CC(OC)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
3-(3-Cyclopentyloxy-4-methoxyphenyl)-cyclopent-2-en-1-ol (150 mg, 0.55 mmol) (E10) was added to a suspension of powdered potassium hydroxide (89%, 138 mg, 2.2 mmol) under an argon atmosphere and then iodomethane (35μl, 0.56 mmol ) was added. The resulting mixture was stirred at room temperature for 3 hr, poured into water and extracted with ether. The ether extracts were washed three times with water, dried (sodium sulfate) and concentrated under reduced pressure. Purification by flash chromatography, eluting with 2:1 hexanes/ether, provided the title compound as an oil (120 mg, 76%).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.[Cl:22][C:23]1[N:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=1.C(N(CC)CC)C>C(#N)C>[Cl:22][C:23]1[N:24]=[N:25][C:26]([N:19]2[CH2:18][CH2:17][N:16]([C:13]3[CH:12]=[CH:11][C:10]([N:5]4[CH2:6][CH2:7][C@@H:8]5[CH2:9][N:2]([CH3:1])[CH2:3][C@H:4]45)=[CH:15][CH:14]=3)[CH2:21][CH2:20]2)=[CH:27][CH:28]=1
Reactant: CN1C[C@H]2CCN(c3ccc(N4CCNCC4)cc3)[C@H]2C1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1C[C@H]2CCN(c3ccc(N4CCN(c5ccc(Cl)nn5)CC4)cc3)[C@H]2C1
Temperature: 60 °C

Procedure:
The product of Example 49B (30 mg, 0.105 mmole), 3,6-dichloropyridazine (18.8 mg, 0.126 mmole), and triethylamine (45 ml, 0.036 mmole) were dissolved in 1 ml of acetonitrile and heated at 60° C. under N2 for 24 hours. The mixture was cooled to room temperature, quenched with water and extracted with dichloromethane (5×). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure and purified by chromatography (eluting with a mixture of 0.5% ammonium hydroxide and 5% methanol in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.24 (s, 1H) 7.21 (s, 1H) 6.91-6.96 (m, 2H) 6.53-6.58 (m, 2H) 4.13-4.21 (m, 1H) 3.72-3.83 (m, 4H) 3.50-3.61 (m, 1H) 3.36-3.45 (m, 1H) 3.11-3.19 (m, 4H) 2.99-3.08 (m, 1H) 2.60-2.80 (m, 4H) 2.46 (s, 3H) 2.13-2.23 (m, 1H) 1.89-2.04 (m, 1H); MS, (M+H)+=399.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:11]3[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:37])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1>CS(C)=O>[CH3:25][O:26][C:27](=[O:37])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:15]2[C:10]3[C:9]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)[O:17][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:31]=1
Reactant: COC(=O)COc1cccc(N)c1
Reactant: Fc1ccc(-c2c(-c3ccc(Br)cc3)oc3ncnc(Cl)c23)cc1
Solvent: CS(C)=O
Product: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccc(Br)cc4)c(-c4ccc(F)cc4)c23)c1
Yield: 44.5 %

Procedure:
Heat 400 mg (0.991 mmol) of 6-(4-bromophenyl)-4-chloro-5-(4-fluorophenyl)furo[2,3-d]pyrimidine (for preparation see WO 03/018589) and 215.5 mg (1.19 mmol) of 3-aminophenoxyacetic acid methyl ester to 150° C. in an oil bath for 1.5 h. After cooling, take up the residue in DMSO and filter through silica gel (eluent: dichloromethane/ethyl acetate 10:1). 242 mg of a mixture are isolated, which is purified by preparative HPLC. 120 mg (15% of theory) of the target compound are obtained as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[Cl:34][CH2:35][CH2:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][CH:39]=1>>[Cl:34][CH2:35][CH2:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([CH2:42][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]3[OH:13])[CH:5]=2)=[CH:40][CH:39]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(OCCCl)cc1
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCCl)cc3)c3c(F)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 2-(3) and 4-(2-chloroethyloxy)benzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 483/485 (M+NH4). 1H-NMR (DMSO-d6) δ 3.20-3.50 (m, 4H), 3.63-3.70 (m, 2H), 3.91 (t, J=5.1 Hz, 2H), 4.02 (s, 2H), 4.20 (t, J=5.0 Hz, 2H), 4.53 (t, J=5.5 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 5.16 (d, J=5.0 Hz, 1H), 5.20 (d, J=5.8 Hz, 1H), 5.37 (d, J=9.2 Hz, 1H), 6.74 (dd, J=11.2, 7.9 Hz, 1H), 6.86 (d, J=8.7 Hz, 2H), 7.07 (m, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.21 (s, 1H), 7.36 (d, J=8.3 Hz, 1H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][O:33][C:34](=[O:37])[CH2:35]Br>>[CH3:32][O:33][C:34](=[O:37])[CH2:35][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:9]2[N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:30][CH:29]=1
Reactant: Oc1ccc(CCc2ccccc2-c2nc3ccccc3n2CC2CCCCC2)cc1
Reactant: COC(=O)CBr
Product: COC(=O)COc1ccc(CCc2ccccc2-c2nc3ccccc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 4-{2-[2-(1-cyclohexylmethyl-1H-benzoimidazol-2-yl)-phenyl]-ethyl}-phenol and bromo-acetic acid methyl ester (CAS Reg. No. 96-32-2). Off-white semi-solid (77%). MS (Turbo Spray): m/z=497.4 (M+H).