Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:15]=[C:14]([CH3:31])[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH:30][S:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:40])=[O:39])[N:15]=[C:14]([CH3:31])[N:13]=2)(=[O:9])=[O:10])=[N:6][CH:7]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(C)nc1OCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(C)nc1OCCNS(=O)(=O)c1ccccc1

Procedure:
According to the procedure described in Example 4a) 94 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with benzenesulfonylchloride to give 67.2 mg 5-methyl-N-[6-(2-(benzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.68 min, [M+1]+=586.39, [M−1]−=584.42.
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18](=[O:38])[C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[CH:30]=[C:29]5[CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:28]5=[CH:27][C:26]=4[O:25][CH2:24][C:23]=3[CH:37]=2)=[O:15])[CH2:4][CH2:3]1.[Br-:39].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CO.Cl>[CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[CH:30]=[C:29]5[CH2:32][CH2:33][CH:34]([Br:39])[C:35](=[O:36])[C:28]5=[CH:27][C:26]=4[O:25][CH2:24][C:23]=3[CH:37]=2)=[O:38])=[O:15])[CH2:4][CH2:3]1
Reactant: [Br-]
Reactant: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N1C(=O)OC(C)(C)C
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,5S)-1-tert-butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 5-methylpyrrolidine-1,2-dicarboxylate (1.29 g, 2.48 mmol) was dissolved in a solution of DCM (17.5 mL) and MeOH (7 mL), then treated with pyridinium tribromide (873 mg, 2.73 mmol). After stirring at RT for 1 h, the reaction mixture was diluted with DCM and 10% HCl, and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude material was carried on without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=1)[C:50](O)=[O:51]>C1COCC1.C(N(C(C)C)C(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]#[N:15])([NH:16][C:50]([C:49]2[CH:48]=[N:47][CH:46]=[C:45]([CH3:44])[CH:53]=2)=[O:51])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cncc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(C(=O)NC2(C#N)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 40 °C
Yield: 64.8 %

Procedure:
To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (0.485 g, 2.15 mmol, 1.0 equiv; prepared as described in WO 03/104 236 A1 (Bristol-Myers Squibb Company); [CAS RN 331281-25-5]) in anhydrous THF (11 mL) and N-ethyl diisopropylamine (0.44 mL) was added in the presence of (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (1.047 g, 2.37 mmol, 1.1 equiv; BOP reagent) 5-methyl-nicotinic acid (0.295 g, 2.15 mmol, 1.0 equiv) and the reaction mixture stirred at 40° C. during a weekend. The reaction mixture was poured on crashed ice/NH4Cl, extracted with ethyl acetate (2×200 mL) and the combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a mixture of ethyl acetate/triethylamine (97:3) providing 0.48 g (65%) of the title compound as off-white foam. MS (ISP): 345.3 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]([CH3:25])=[CH2:24])[C:3]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]([CH3:25])=[CH2:24])[C:3]=1[O:26][CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)CBr
Reactant: C=C(C)Cc1c(O)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)Cc1c(OCC(=O)OC)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
First, 1.0 g of 1-[4-chloro-6-fluoro-3-hydroxy-2-(2-methyl-2-propenyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione was dissolved in 15 ml of N,N-dimethylformamide, to which 0.43 g of potassium carbonate and 0.4 ml of methyl bromoacetate were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The organic layer was dried and concentrated. The residue was subjected to silica gel chromatography, which afforded 1.0 g of 1-[4-chloro-6-fluoro-3-methoxycarbonylmethyloxy-2-(2-methyl-2-propenyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione.
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[N:9]=[C:8]([N+:10]([O-])=O)[C:7]([O:13][CH2:14][C:15]([O:17]CC)=O)=[CH:6][CH:5]=1>O.CO.[Fe]>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:14][C:15](=[O:17])[NH:10][C:8]=2[N:9]=1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: O=C1COc2ccc(Br)nc2N1
Temperature: 95 °C
Yield: 79.9 %

Procedure:
Ammonium chloride (44 g, 0.823 mole) was dissolved in H2O (600 mL), and iron powder (−325 mesh, 27.4 g, 0.491 mole) was added. The mixture was mechanically stirred (vigorously), and a solution of ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (50 g, 0.164 mole) in MeOH (800 mL) was added slowly at RT over 3 hours. When the addition was done, the reaction was heated at reflux for 3 hr and then hot-filtered through a pad of Celite®. The filter pad was washed with hot MeOH (500 mL) and the filtrate was concentrated in vacuo. When most of the MeOH was removed, the mixture was filtered to collect the solid, which was washed with water (100 mL). The filtrate was extracted with CHCl3 (300 mL, 2 times) and the organic layer was washed sequentially with water and brine, dried (MgSO4), and concentrated in vacuo. The residue was combined with the solid from the filtration, suspended in glacial AcOH (150 mL), and the mixture was heated at 95° C. for 3 hr. The mixture was then concentrated in vacuo and the residue was triturated with Et2O (200 mL). The solid was collected, washed with ether, and dried to afford the title compound (30 g, 80%): MS (ES) m/e 229.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:6]1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[N:13][C:12]([C:15]3[NH:24][N:23]=[N:22][N:16]=3)=[CH:11][N:10]=2)[CH2:6]1
Reactant: N#Cc1cnc(N2CC(Oc3cc(F)ccc3Br)C2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Br)c(OC2CN(c3cnc(-c4nnn[nH]4)cn3)C2)c1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
A mixture of 5-[3-(2-bromo-5-fluorophenoxy)azetidin-1-yl]pyrazine-2-carbonitrile (0.48 g, 1.36 mmol), sodium azide (0.18 g, 2.7 mmol), and ammonium chloride (0.73 g, 1.36 mmol) in DMF (4 mL) was heated at 130° C. After a period of 4 h, the reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The resulting solid was filtered and washed with water and ether. The solid was taken up in toluene and the solvent evaporated to provide the desired product.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[C:16]([Br:38])[C:15]=1[OH:39].O[C@@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C1C=CC=CC=1>[Br:38][C:16]1[CH:17]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:19]=[C:14]([Br:13])[C:15]=1[O:39][C@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 80 °C
Yield: 90.4 %

Procedure:
Diethylazodicarboxylate (0.437 mL, 2.74 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenol (1.00 g, 1.83 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.494 g, 2.74 mmol), triphenylphosphine (0.72 g, 2.74 mmol) and benzene (12 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80° C. oil bath for 3.5 h. Upon cooling to room temperature, the reaction mixture was diluted with dichloromethane and silica gel (30 mL) was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (96:4 petroleum ether:ethyl acetate) to provide the title compound as a white solid (1.20 g, 90%): mp 138-139.5° C.: NMR (CDCl3); δ8.36 (ddd, J=8, 1, 1 Hz, 1 H), 7.83 (ddd., J=8, 1, 1 Hz, 1 H), 7.68 (ddd, J =8, 7, 1 Hz, 1 H), 7.60 (dd, J=5, 2 Hz, 2 H), 7.60-7.48 (m, 2 H), 7.46-7.28 (m, 6 H), 7.18 (ddd, J=8, 7, 1 Hz, 1 H), 6.74 (ddd, J=8, 1, 1 Hz, 1 H), 5.26 (t, J=8 Hz, 1 H), 3.76 (s, 3 H), 3.59 (dd, J=8, 5 Hz, 2 H); MS (FAB+): [M+], 3 bromine isotope pattern, 722 (30%), 724 (70%) 726 (100%) 728 (35%); Anal. Calc. for C32H21Br3O3S: C, 52.99, H, 2.99, N, 0.00. Found: C, 52.60, H, 2.68, N, 0.07.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[S:18][CH2:19][CH3:20])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O>[Zn].C(O)C>[NH2:15][C:13]1[CH:12]=[CH:11][C:10]([S:18][CH2:19][CH3:20])=[C:9]([S:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:8])=[O:7])[CH:14]=1
Reactant: CCSc1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CCSc1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Temperature: 70 °C
Reaction time: 10 h
Yield: 86.5 %

Procedure:
13.3 g of zinc powder are added in portions to a mixture of 12 g of N-tert-butyl-2-ethylmercapto-5-nitrobenzenesulfonamide, 17.7 g of ammonium chloride, 50 ml of water and 200 ml of ethanol and the mixture is stirred at 70° C. for 10 hours. After the solid has been filtered off and washed out with ethyl acetate, the filtrate is concentrated under reduced pressure. The residue from the filtrate is taken up in ethyl acetate and the mixture is washed with water. After drying over magnesium sulfate, the organic phase is concentrated. 9.4 g of the desired aniline are thus obtained;
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH:23]=[C:22]([C:36]([F:39])([F:38])[F:37])[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:39][C:36]([F:37])([F:38])[C:22]1[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[N:16]=[CH:17]2)[CH:25]=[C:24]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:30][CH:31]=2)[CH:23]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1
Yield: 41.1 %

Procedure:
To a stirred and cooled suspension of N-tert-butyl-3-{1-[6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (example 293) (0.110 g, 0.19 mmol) in dichloromethane (0.69 mL) was added TFA (4.3 mL) and the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield after silica gel column chromatography with heptane/EtOAc and trituration with diethyl ether the title compound as a white solid (0.040 g, 40%). MS (ISP) 513.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.[Li]CCCC.[Cl:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:18]=1.CCOCC>C1COCC1>[Cl:16][C:17]1[N:18]=[C:19]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:20]=[C:21]([O:10][CH:8]2[CH2:9][CH:3]3[N:2]([CH3:1])[CH:6]([CH2:5][CH2:4]3)[CH2:7]2)[N:22]=1
Reactant: CN1C2CCC1CC(O)C2
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1C2CCC1CC(Oc1nc(Cl)nc(N3CCOCC3)n1)C2
Temperature: 78 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
In a three neck flask equipped with stirring bar under N2 atmosphere tropine (1 g, 4.24 mmol) was suspended in (anhydrous) THF (15 mL). The mixture was cooled to 78° C. and BuLi (2M in THF) (5.53 ml, 1.2 eq) was added dropwise and the mixture was allowed to warm to 25° C. over 30 minutes. To the reaction mixture 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (996 mg, 4.24, mmole) was added and allowed to stir overnight. For work up, ether (100 mL) was added. The organic layer was washed with water (20 mL) and brine (20 mL) and dried over MgSO4. filtered and the solvents were removed to obtain a colorless oil. Further purification by flash-chromatography using CH2Cl2/MeOH/NH3 (15:1:0.1) gave the product as white solid (600 mg, 42% yield); MS (ESI) m/z 340
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[CH3:7][N:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:1][CH:2]([CH3:6])[C:3]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[N:8]([CH3:7])[CH2:17]2)=[O:4]
Reactant: CC(Br)C(=O)Br
Reactant: CN1Cc2ccccc2NC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2c(c1)CN(C)C(=O)N2

Procedure:
2-Bromopropionyl bromide (71.02 g) is added dropwise to a stirred mixture of 3,4-dihydro-3-methyl-2(1H)quinazolinone (26.75 g) and anhydrous aluminum chloride (54.98 g) in carbon disulfide (350 ml). The reaction mixture is stirred under reflux for 5 hrs., the carbon disulfide decanted, and the residue treated with HCl (6N). The resulting solid is filtered, and washed with water and dried in vacuo to obtain 6-(2-bromopropionyl)-3,4,dihydro-3-methyl-2(1H)-quinazolinone which is used in the next step.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C:5]([F:23])=[C:6]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[CH2:7][O:8][CH2:9][CH2:10][O:11]C1CCCCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O>[F:23][C:5]1[C:6]([CH2:7][O:8][CH2:9][CH2:10][OH:11])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:4]=1[CH:3]=[O:2]
Reactant: COc1cc(COCCOC2CCCCO2)c(F)c(C(OC)OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=O)c(F)c(COCCO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
2-[2-(3-Dimethoxymethyl-2-fluoro-5-methoxybenzyloxy]ethoxy]tetrahydropyran (1.035 g) was dissolved in 10 ml of THF and 3 ml of water, and 1 g of p-toluenesulfonic acid was added thereto. The resulting mixture was stirred at room temperature overnight, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give the title compound (305 mg).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH2:18][OH:19])([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:20])[CH:3]=1.[C:21]([C:25]1[CH:30]=[C:29]([CH2:31][OH:32])[C:28]([CH3:33])=[CH:27][C:26]=1[S:34]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:24])([CH3:23])[CH3:22].CCN(CC)CC>C(#N)C>[C:21]([C:25]1[CH:30]=[C:29]([CH2:31][OH:32])[C:28]([CH3:33])=[CH:27][C:26]=1[S:34][C:3]1[C:4](=[O:20])[O:5][C:6]([CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH2:18][OH:19])([CH:8]([CH3:9])[CH3:10])[CH2:7][C:2]=1[OH:1])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)C1(CCc2ccsc2CO)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(SC2=C(O)CC(CCc3ccsc3CO)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16b using 4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-24; 1 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.05 mmol), NEt3 (2.2 mmol) in acetonitrile (5 mL). The product was chromatographed over silica gel using 97.5:2.5 CH2Cl2:MeOH, mp 87-90° C. MS (APCI): 503 (M−H).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:6]=1.C([Li])CCC.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:26]([O:25][C:23]([C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=1)=[O:24])[CH3:27]
Reactant: FC(F)(F)c1cccc(-c2csc(Cl)n2)c1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(Cl)nc1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 10.1 g (38.3 mmole) of 2-chloro-4-(3-trifluoromethyl-phenyl)-thiazole in 120 mL of tetrahydrofuran at −78 degrees was added over 20 minutes, 20 mL of 2.5 M n-butyl lithium in hexanes. The mixture was stirred for 2 hours and then 19 mL (93.4 mmole) of ethyl chloroformate was added quickly. The mixture was stirred for 15 minutes, then the cooling bath was removed. After 25 minutes, the reaction was quenched by the addition of 150 mL of 1M hydrochloric acid. The mixture was stirred for 5 minutes, and then diluted with 1 L of ethyl acetate. The ethyl acetate layer was washed twice with 150 mL of water, once with 100 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-hexanes (gradient 10:90-50:50) to give 5.62 g of 2-chloro-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a golden oil.
Reaction SMILES: C([N:9]1[C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13][N:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1>N>[C:24]1([N:12]2[CH2:13][CH2:14][N:15]3[C:16](=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=43)[NH:9][CH2:10][CH2:11]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(c1ccccc1)N1CCN(c2ccccc2)CCn2c1nc1ccccc12
Agent: N
Product: c1ccc(N2CCNc3nc4ccccc4n3CC2)cc1

Procedure:
A mixture of 1-benzoyl-1,2,3,4,5,6-hexahydro-4-phenyl[1,3,6]triazocino[1,2-a]benzimidazole (10.00 g) from Example 2 and methanolic ammonia (1150 ml), presaturated at 0°, was stirred magnetically and heated in a sealed bomb at 100° for 4 days. The resulting cooled solution was filtered and the filtrate was evaporated to a syrup which crystallized. The residue was dissolved in dichloromethane-methanol and the solution was evaporated to a syrup. Crystallization from methanol gave crude titled product; wt. 5.24 g (72%), mp=158°-159°. The mother liquor was evaporated to a crystalline residue which was subjected to an oil pump vacuum. A solution of the residue in a minimum volume of warm dichloromethane was applied to a column (56×3.2 cm) of dry column grade neutral alumina prepacked in toluene. Elution was with toluene (400 ml), toluene-dichloromethane (4:1, 500 ml) followed by dichloromethane. The product was eluted with dichloromethane. The fractionation was monitored by t.l.c. on Alox-25 uv254 plates with dichloromethane-methanol (19:1) as developer. Fractions which contained only product were evaporated to a syrup which crystallized. Recrystallization with decolorization from methanol gave product; wt. 0.93 g (13%), mp=158°-160°. This material, combined with material obtained above, was recrystallized with decolorization from methanol to give pure titled product; wt. 5.46 g, mp=159°-160°.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2I)=[O:15])[CH2:10][CH2:9]1.[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2[C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1
Reactant: OB(O)c1ccncc1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2ccncc2)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 7, [4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-methanone (example 46) was reacted with pyridin-4-yl-boronic acid to give the title compound as light yellow oil. MS: 530.2 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][CH:4]=1)[CH3:2].[CH2:16]([Li])CCC.CI>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:14])([CH3:15])[N:13]=2)=[C:7]([CH3:16])[CH:8]=1)[CH3:2]
Reactant: [Li]CCCC
Reactant: CCc1ccc(C2=NC(C)(C)CO2)cc1
Solvent: C1CCOC1
Solvent: CI
Product: CCc1ccc(C2=NC(C)(C)CO2)c(C)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of the product from step (i) (43 g) in tetrahydrofuran (600 ml) at -10° C. was added n-butyllithium (2.5M solution in hexanes, 94 ml). The mixture was stirred for 2.5 hours at 0° C. then cooled to -30° C. and treated with methyl iodide (62 ml). The mixture was warmed to room temperature and partitioned between ethyl acetate and water. The organic phase was dried and evaporated and the residue purified by chromatography eluting with 5% ethyl acetate in isohexane. Yield 28.4 g.