Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:34]([F:37])([F:36])[F:35])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:27][C:26](=[O:28])[NH:25][C:24](=[O:29])[CH2:23]4)=[O:21])=[C:16]([C:30]([F:33])([F:32])[F:31])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].FC(F)(F)S(O[CH2:50][C:51]([F:54])([F:53])[F:52])(=O)=O>CN(C)C=O.[Cl-].[Na+].O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:34]([F:35])([F:37])[F:36])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:23][C:24](=[O:29])[N:25]([CH2:50][C:51]([F:54])([F:53])[F:52])[C:26](=[O:28])[CH2:27]4)=[O:21])=[C:16]([C:30]([F:33])([F:32])[F:31])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F)N1CC(=O)N(CC(F)(F)F)C(=O)C1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-([4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl]carbonyl)piperazine-2,6-dione (300 mg, 0.53 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), K2CO3 (140 mg, 1.01 mmol, 2.00 equiv), 2,2,2-trifluoroethyl trifluoromethanesulfonate (240 mg, 1.03 mmol, 2.00 equiv). The resulting solution was stirred for 1 h at 20° C. The resulting solution was diluted with 50 mL of brine. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/5). This resulted in 235.9 mg (69%) of 4-([4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl]carbonyl)-1-(2,2,2-trifluoroethyl)piperazine-2,6-dione as a off-white solid. (ES, m/z): [M−H]− 648; 1H NMR (300 MHz, CDCl3) δ: 8.00-8.05 (m, 2H), 7.44-7.53 (m, 4H), 4.94-5.01 (m, 1H), 4.68 (s, 1H), 4.50-4.56 (m, 2H), 4.10-4.16 (m, 3H), 3.76 (d, J=17.4 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=4)[CH:35]=O)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:41][OH:42].C(O)(=O)C>CO.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=4)[CH:35]=[N:41][OH:42])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCC[C@@H](Nc2nccc(-c3c(-c4cccc(C=NO)c4)nc4sccn34)n2)C1
Temperature: 50 °C
Yield: 61.3 %

Procedure:
To a mixture 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzaldehyde (0.81 g, 0.14 mmol) and hydroxylamine hydrochloride (0.0107 g, 0.154 mmoL) in methanol (2.0 mL) was added 0.2 mL of acetic acid. The mixture was heated at 50° C. for 2 hours. After cooled to room temperature, the mixture was diluted with dichloromethane (10 mL), washed with saturated aqueous sodium bicarbonate (5 mL×3), water (5 mL), dried over sodium sulfate and concentrated. Product was purified by flash chromatography on silica gel (methanol:dichloromethane:ethylacetate=0.5:7:2) to afford 0.051 g (61%) of the title compound as an off-white solid. M.p.=238-240° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 11.14 (s, 1H), 8.70 (bs, 1H), 8.17 (s, 1H), 8.11 (d, J=5.6 Hz, 1H), 7.8 (s, 1H), 7.77-7.74 (m, 2H), 7.68-7.64 (m, 3H), 7.60-7.57 (m, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.40 (d, J=5.2 Hz, 1H), 3.93 (br. s, 1H), 3.74-3.71 (m, 1H), 3.48-3.45 (m, 1H), 2.5-2.4 (m, 1H), 2.33 (t, J=10.4 Hz, 1H), 1.89-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.40-1.32 (m, 1H). LCMS: 594 [M+H].
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43]>C1(C)C=CC=CC=1.C(O)C>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43].[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[C:42]([NH:44][C:45]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][N:18]=2)=[CH:28][CH:29]=1)=[S:46])=[O:43]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C(N=C=S)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4c(Cl)cccc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
2,6-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,6-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,6-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (56 mg, yield 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-])=O.[CH3:13][C:14](OC(C)=O)=[O:15]>CO.N1C=CC=CC=1.[Pd]>[CH2:8]1[C:9]2[C:5](=[C:4]([NH:1][C:14](=[O:15])[CH3:13])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])c1cccc2c1CCC2
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc2c1CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of commercially available 4-nitroindane (10 g, 61.3 mmol) and 10% Pd/C (1 g) in MeOH (200 mL) was stirred vigorously under an atmosphere of hydrogen overnight at rt. The reaction was filtered through a pad of Celite® and concentrated, and residual solvent was removed by combining the reaction with toluene followed by evaporation. The crude reaction was taken up in pyridine (100 mL), and Ac2O (20 mL) was added and the reaction stirred for 16 h at rt. The reaction was evaporated and the crude product was purified by flash chromatography (5% MeOH in EtOAc/hexane (1:1) to give the title compound (9.12 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([OH:41])=O)[CH:34]=1)C1C=CC=CC=1.[NH2:42][CH2:43][CH2:44][CH:45]1[CH2:49][CH2:48][CH2:47][N:46]1[CH3:50]>>[CH3:50][N:46]1[CH2:47][CH2:48][CH2:49][CH:45]1[CH2:44][CH2:43][NH:42][C:39]([C:35]1[CH:34]=[C:33]([C:10]2[CH:11]=[C:12]([C:23]3[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=3)[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])[CH:38]=[CH:37][CH:36]=1)=[O:41]
Reactant: CN1CCCC1CCN
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)NCCC3CCCN3C)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid and 2-(2-aminoethyl)-1-methylpyrrolidine as described in general procedure D. LCMS: 481 [M+H].
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br.Br[CH2:45][C:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1)=[O:47]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:45][C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)=[O:47])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3ccccn3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(pyridin-2-yl)ethanone hydrobromide and isolated as dark-brown solid. MS (m/e): 402.3 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:26]([O:28]C(C)(C)C)=[O:27])=[N:11][C:12]([CH2:16][C:17]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O.O>[CH2:1]([O:8][C:9]1[C:10]([C:26]([OH:28])=[O:27])=[N:11][C:12]([CH2:16][C:17]([CH3:18])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:25])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC(C)(C)c2ccccc2)nc(O)c1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Cc1nc(O)c(OCc2ccccc2)c(C(=O)O)n1)c1ccccc1
Temperature: 85 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
tert-Butyl 5-(benzyloxy)-6-hydroxy-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxylate (55) (260 mg, 598 μmol, Eq: 1.00) was stirred in tetrahydrofuran/water. Lithium hydroxide monohydrate (126 mg, 2.99 mmol, Eq: 5) was added. The reaction mixture was heated at 85° C. for 7 hours, cooled, and stirred at room temperature for 16 hours. 1N HCl was added until precipitate forms (about 10 ml). The mixture was diluted with water, extracted three times with ethyl acetate, washed with brine and dried over magnesium sulfate. The solvent was removed on a rotary evaporator to give 5-(benzyloxy)-6-hydroxy-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxylic acid (56) as a white solid (155 mg, 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:16][C:14]([F:17])([F:15])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:3][C:2]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: C1CCNC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCCC3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 64 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 64%; MS: m/z=403 (M+H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16]Br)=[O:5].[C-:25]#[N:26].[Na+].[Cl-].[NH4+]>CS(C)=O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][C:25]#[N:26])=[O:5]
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CBr)c2n1C(=O)OC(C)(C)C
Reactant: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2cc(Cl)cc(CC#N)c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 1.00 g (2.4 mmol) of 7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in DMSO (10 ml) at RT, 012 g of sodium cyanide was added. The reaction mixture was stirred at RT for one hour, poured on a saturated aqueous ammonium chloride solution and the product was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (SiO2, EtOAc/Hex 9/1) afforded 0.31 g (36%) of 5-chloro-7-cyanomethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester as a light yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.C([C:8]1[C:9](=[O:22])[NH:10][C:11]2[CH2:12][CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16]=2[CH:17]=1)#N.[OH-].[Na+]>O>[CH:17]1[C:16]2[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12][C:11]=2[NH:10][C:9](=[O:22])[CH:8]=1
Reactant: N#Cc1cc2c([nH]c1=O)CCc1ccccc1-2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1ccc2c([nH]1)CCc1ccccc1-2
Temperature: 0 °C

Procedure:
To a mixture of 60 ml of concentrated sulfuric acid and 15 ml of water, add 22.2 gm of 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one. Heat the system at reflux for 24 hours. Cool the system and pour the solution into 1 liter of ice/water. Neutralize the solution with 10N NaOH solution. Extract the solution with 300 ml of chloroform and dry the organic solution over anhydrous magnesium sulfate. Filter the solution and remove the solvent by stripping to give the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6](=[O:25])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15](I)=[C:14]([Cl:24])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[F-].[Cs+].O>COCCOC.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].CCOC(C)=O>[CH:1]1([CH2:4][O:5][C:6](=[O:25])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:31]3[CH:32]=[CH:33][C:28]([C:27]([F:38])([F:37])[F:26])=[CH:29][CH:30]=3)=[C:14]([Cl:24])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(I)c(OCC2CC2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)c(OCC2CC2)c1
Temperature: 100 °C
Yield: 67 %

Procedure:
To a solution of 2-(3-chloro-5-cyclopropylmethoxy-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.09 g, 0.19 mmol) in DME (anhydrous, 10 mL) under argon atmosphere were added 4-trifluoromethylphenylboronic acid (0.04 g, 0.2 mmol), CsF (0.07 g, 0.46 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.06 g, 0.08 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). A mixture of water and EtOAc (15 mL/15 mL) was added and the layers were separated. The organic phase was dried over MgSO4, then evaporated to give a crude yellow oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (20:1-9:1) to give 2-(2-chloro-6-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.063 g, 70%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.66 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.08 (s, 1H), 6.88 (s, 1H), 4.01-3.86 (m, 2H), 3.77 (d, J=6.6 Hz, 2H), 3.65 (t, J=7.9 Hz, 1H), 2.04-1.95 (m, 1H), 1.71-1.62 (m, 1H), 1.59-1.48 (m, 1H), 1.20-1.02 (m, 2H), 0.96-0.94 (m, 6H), 0.56-0.46 (m, 4H), 0.27-0.25 (m, 2H), 0.16-0.15 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.5, 157.0, 141.2, 138.9, 133.6, 130.8 (two signals), 127.8, 124.5 (q), 124.3 (q, 1JCF=271.0 Hz), 121.6, 111.0, 73.3, 69.7, 49.6, 42.7, 26.1, 22.6, 22.4, 10.0, 9.8, 3.3, 3.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9]([CH2:12]O)=[CH:8][C:7]=2[CH:14]=1.[Br:15]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9]([CH2:12][Br:15])=[CH:8][C:7]=2[CH:14]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)C=C(CO)CO2
Solvent: CC#N
Product: COc1ccc2c(c1)C=C(CBr)CO2
Reaction time: 0.25 h

Procedure:
6-Methoxy-3-(hydroxymethyl)-2H-1-benzopyran (4.35 g, 22.6 mmol) is dissolved in 70 ml of dry acetonitrile and treated with dibromotriphenylphosphorane (9.56 g, 22.6 mmol). After 15 min, the mixture is evaporated in vacuo. The residue is triturated with 100 ml of an ether/hexane mixture (1:1). The solid is removed by filtration (medium frit) and washed with several 50 ml portions of the ether/hexane mixture. The organic extracts are combined and evaporated to give 6-methoxy-3-(bromomethyl)-2H-1-benzopyran which is used without any further purification.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:15]1([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([OH:27])[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C.O>[CH3:14][C:4]([S:10]([CH3:13])(=[O:12])=[O:11])([CH2:3][CH2:2][N:24]1[CH:25]=[CH:26][C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:22][C:23]1=[O:27])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Oc1cc(-c2ccccc2)ccn1
Reactant: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(CCn1ccc(-c2ccccc2)cc1=O)S(C)(=O)=O
Temperature: 60 °C
Yield: 61.4 %

Procedure:
Ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (25.02 g, 87.1 mmol) was added to a mixture of 4-phenylpyridin-2-ol (12.40 g, 72.43 mmol) and cesium carbonate (49.70 g, 152.5 mmol) in THF (150 mL). The reaction was stirred and heated at 60° C. overnight. The reaction was diluted with ethyl acetate (200 mL) and water (200 mL); the organics were separated and the aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organics were dried (MgSO4), filtered, and concentrated to afford a crude solid. The crude was purified via flash chromatography using an Analogix SF65-400 g column and eluted with ethyl acetate in heptane (30-80%) to afford the title compound as a white solid (16.79 g, 61.4%). LC-MS m/z 378.6 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.12 Hz, 3H) 1.58 (s, 2H) 2.41-2.62 (m, 2H) 3.09 (s, 3H) 3.90-4.01 (m, 1H) 4.20-4.32 (m, 3H) 6.40-6.45 (m, 1H) 6.73 (d, J=1.56 Hz, 1H) 7.31 (d, J=7.03 Hz, 1H) 7.37-7.46 (m, 2H) 7.50-7.55 (m, 2H).
Reaction SMILES: I[C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>>[CH3:7][C:4]1[S:3][C:2]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=1
Reactant: Cc1cnc(I)s1
Reactant: C1CNCCN1
Product: Cc1cnc(N2CCNCC2)s1
Yield: 32 %

Procedure:
Prepared in analogy to example 2 (b) from 2-iodo-5-methyl-thiazole and piperazine. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a yellow oil (yield 32%). MS (m/e): 184.3 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: COc1cccc(Sc2sc(CN(C)C(=O)OC(C)(C)C)cc2Br)c1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(Sc2sc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Temperature: 105 °C
Reaction time: 4 h
Yield: 74.5 %

Procedure:
tert-Butyl ({4-bromo-5-[(3-methoxyphenyl)thio]-2-thienyl}methyl)methylcarbamate (596 mg), (2-fluorophenyl)boronic acid (225 mg), sodium carbonate (341 mg) and tetrakis(triphenylphosphine)palladium (0) (155 mg) were suspended in a mixture of 1,2-dimethoxyethane (10 mL) and water (4 mL), and the suspension was stirred at 105° C. for 4 hr under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→9:1) to give the title compound as a colorless oil (yield 459 mg, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][N:7]3[CH:14]=[C:13]([CH3:15])[CH:12]=[C:8]3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:20])=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][N:7]3[CH:14]=[C:13]([CH3:15])[CH:12]=[C:8]3[C:9]([Cl:20])=[N:10][C:4]=2[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2n(c1)Cc1ccc(Cl)cc1NC2=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: Cc1cc2n(c1)Cc1ccc(Cl)cc1N=C2Cl
Temperature: 25 °C

Procedure:
To a suspension of 1.1 g of 8-chloro-2-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-11-one in 20 mL of chlorobenzene is added 680 mg of phosphorous oxychloride. The mixture is heated at 100°-110° for 1 hour, then allowed to cool to room temperature. Methylene chloride (150 mL) is added to the stirred reaction mixture which is then poured into a mixture of ice and aqueous sodium carbonate. After being shaken vigorously, the methylene chloride layer is separated, the aqueous layer is further extracted with 200 ml of diethyl ether; the combined extracts are dried (anhydrous magnesium sulfate), decolorized with charcoal, and evaporated to dryness to yield 8,11-dichloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine as a viscous oil which is used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[O:14]=[C:6]1[N:5]([CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][C:26]3([N:22]([C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=4)[CH2:23][NH:24][C:25]3=[O:32])[CH2:31][CH2:30]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7]1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C1NCN(c2ccc(F)cc2)C12CCN(CCCn1c(=O)[nH]c3ccccc31)CC2

Procedure:
A mixture of 4.6 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5 parts of 1-(p-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one, 10 parts of sodium carbonate, 0.2 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling, the precipitated product is filtered off and triturated twice: first in a boiling mixture of 4-methyl-2-pentanone and 2-propanol and then in boiling methanol. It is filtered off again and crystallized from a mixture of N,N-dimethylformamide and water, yielding 4.5 parts of 8-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one; mp. 215.4° C.