Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:25]3[CH:24]=[CH:23][C:22]4[C:27](=[CH:28][CH:19]=[CH:20][CH:21]=4)[N:26]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: Brc1ccc2cccnc2c1
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3ccccc3n2)C2CCN(CC2)C1

Procedure:
The reaction of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (226 mg, 1.0 mmol; Example 2B) and 7-bromoquinoline (312 mg, 1.5 mmol; Ark Pharm) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.97-2.11 (m, 2H) 2.18-2.30 (m, 2H) 2.43 (s, 3H) 3.10-3.29 (m, 5H) 4.32 (s, 2H) 6.96-7.01 (m, 1H) 7.22 (s, 1H) 7.35 (d, J=8 Hz, 1H) 7.57 (d, J=8 Hz, 1H) 7.62-7.69 (m, 1H) 7.82 (ddd, J=8, 7, 1 Hz, 1H) 7.97-8.05 (m, 2H) 8.52 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 354 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]2)=[CH:4][CH:3]=1.O[C:27]1[CH:28]=[N:29][C:30]([CH3:33])=[N:31][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][O:19][C:27]4[CH:28]=[N:29][C:30]([CH3:33])=[N:31][CH:32]=4)=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(CO)cc2c1=O
Reactant: Cc1ncc(O)cn1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(COc3cnc(C)nc3)cc2c1=O
Yield: 98.2 %

Procedure:
To a solution of compound J (16 mg, 0.047 mmol) and 5-hydroxy-2-methylpyrimidine (6.2 mg, 0.056 mmol) in THF (1 mL) cooled to 0° C. was added triphenylphosphine (27.1 mg, 0.10 mmol) and di-tert-butylazodicarboxylate (17.3 mg, 0.075 mmol). The reaction was concentrated to dryness after 16 hours of stirring. Purification by reverse phase HPLC afforded 20 mg (98%) of the title compound. ES-MS [M+1]+: 434.3.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si:7]([O:24][CH2:25][C:26]1[C:27]([N:38]2[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[C:28]([F:37])[C:29]([F:36])=[C:30]([C:32](=[O:35])[CH2:33]Cl)[CH:31]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:46]1[CH:50]=[N:49][CH:48]=[N:47]1>C(#N)C>[Si:7]([O:24][CH2:25][C:26]1[C:27]([N:38]2[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]2)=[C:28]([F:37])[C:29]([F:36])=[C:30]([C:32](=[O:35])[CH2:33][N:46]2[CH:50]=[N:49][CH:48]=[N:47]2)[CH:31]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1nc[nH]n1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)CCl)c(F)c2F)C[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)Cn3cncn3)c(F)c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (1208 mg, 8.74 mmol) was added to a mixture of 1-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2-chloroethanone (Intermediate 127, 500 mg, 0.87 mmol) and 1H-1,2,4-triazole (66.4 mg, 0.96 mmol) dissolved in 15 ml of Acetonitrile. The mixture was stirred at room temperature for 3 hours. Potassium carbonate was filtered from the mixture, and the filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The organic phases were combined, dried (Na2SO4), and concentrated. The crude residue (482 mg, 91%) contained mainly desired title compound and was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.O>[CH:20]1([CH2:19][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]3[C:10]([I:11])=[N:9]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Fc1cnc2[nH]nc(I)c2c1
Reactant: ICC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cnc2c(c1)c(I)nn2CC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.000 g (38.021 mmol) of 5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine and 13.627 g (41.823 mmol) of cesium carbonate were initially charged in 270 ml of DMF, and 8.785 g (41.823 mmol) of (iodomethyl)cyclopentane were added. The reaction mixture was stirred at RT overnight, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. This gave 6.370 g of the target compound (purity 83%, 49% of theory), which was reacted further as a crude product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:18]([CH3:30])=[N:19][C:20]2[C:25]([C:26]=1C(O)=O)=[CH:24][CH:23]=[CH:22][CH:21]=2.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[C:18]([CH3:30])=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1nc2ccccc2c(C(=O)O)c1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC
Temperature: 160 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (240 mg), 3-hydroxy-2-methyl-quinoline-4-carboxylic acid (232 mg), and 4-dimethylaminopyridine (372 mg) were dissolved in o-dichlorobenzene (10 ml) to prepare a solution which was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (37 mg, yield 11%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:14][C@H:13]2[CH3:26])=[N:4][N:3]=1.[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:19])[CH2:14][C@H:13]3[CH3:26])=[N:4][N:3]=2)=[CH:31][CH:30]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2ccccc12
Reactant: OCc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(CO)cc2)c2ccccc12
Temperature: 100 °C

Procedure:
(R)-(4-(4-chlorophthalazin-1-yl)-3-methylpiperazin-1-yl)(phenyl)methanone (JK-5) (150 mg, 0.409 mmol), 4-(hydroxymethyl)phenylboronic acid (93.2 mg, 0.613 mmol), and tetrakis(triphenylphosphine)palladium (0) (23.6 mg, 0.023 mmol) were dissolved in toluene (4 mL) and aqueous sodium carbonate (2.0 M, 0.400 mL) under an atmosphere of argon. The reaction was heated at 100° C. for 15 hours, then cooled and taken up in ethyl acetate (80 mL). After washing with aqueous K2CO3 (10%), water, and then saturated sodium chloride, the organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-100% ethyl acetate gave a pale yellow solid, JK-28. MS (M+H)+=439.2.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[F:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:7]=4[C:8]=3[CH:9]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(OC)c(F)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.1 g, 2.3 mmol), 2-(3-Fluoro-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.59 g, 3.4 mmol), Na2CO3 (2 M, 5.4 mL), and Pd(PPh3)2Cl2 (260 mg, 0.23 mmol) in toluene/ethanol (1:1, 15 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 2-(3-Fluoro-4-methoxy-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 60% yield.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl([O-])(=O)(=O)=O.[Li+].[O:11]1[CH2:13][CH:12]1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[N:18][CH:19]=1>C(#N)C>[N:1]([CH:12]([C:14]1[CH:19]=[N:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:16][CH:15]=1)[CH2:13][OH:11])=[N+:2]=[N-:3]
Reactant: FC(F)(F)COc1ccc(C2CO2)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: [N-]=[N+]=NC(CO)c1ccc(OCC(F)(F)F)nc1
Reaction time: 5 h
Yield: 36.8 %

Procedure:
Sodium azide (1.05 g, 16.2 mmol) and lithium perchlorate (6.45 g, 60.7 mmol) are added to a solution of 5-(oxiran-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (0.89 g, 4.04 mmol, Step-5, single enantiomer) in acetonitrile (100 mL) is refluxed with stirring for 5 hours. White precipitate is filtrated and filtrate is concentrated in vacuo. The residue is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (1:1) to give 0.39 g (37% yield) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:32])[CH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][C:27](O)=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[C@H:22]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:32])[CH2:23][CH2:24]3)[C:5]([C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: OCCCNc1nc(Cl)ccc1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ccc3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a solution of 3-{[6-chloro-3-(trifluoromethyl)-2-pyridinyl]amino}-1-propanol (Example 302) (0.63 g, 2.45 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.45 g, 2.05 mmol) in THF (6.80 mL) was added triphenylphosphine (0.70 g, 2.66 mmol) and 1,1′-azodicarbonyl)-dipiperidine (0.68 g, 2.66 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (0.58 g, 62%) was isolated after column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 7.65 (d, 1H), 7.02 (d, 1H), 6.76 (d, 1H), 6.69 (dd, 1H), 6.60 (d, 1H), 6.48 (b, 1H), 4.15 (q, 2H), 4.04 (t, 2H), 3.65 (q, 2H), 3.46 (qt. 1H), 2.92-2.68 (m, 3H), 2.42-2.30 (m, 2H), 1.78-1.68 (m, 1H), 1.27 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][CH2:28][N:29]([CH2:39][CH2:40][OH:41])[S:30]([C:33]1[S:34][C:35](Br)=[CH:36][CH:37]=1)(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][N:29]([CH2:39][CH2:40][OH:41])[S:30]([C:33]1[S:34][C:35]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)=[CH:36][CH:37]=1)(=[O:32])=[O:31]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: O=S(=O)(c1ccc(Br)s1)N(CCO)CCO
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1)N(CCO)CCO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.53) (165 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (61 mg, 20%). MS (EI) 604.1 [(M)+]; mp 129° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH:7]=1.[O:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:5]3[CH:4]=[CH:3][C:2]([N:32]4[CH2:33][CH2:34][O:30][C:31]4=[O:35])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][O:10][C:9]3=[O:13])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCOC3=O)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCOC3=O)CC2)c(C)c1
Yield: 17.3 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}oxazolidin-2-one (207 mg) described in Preparation Example 120 and oxazolidin-2-one (43.5 mg), the title compound (40.1 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][N:4]=1)#[N:2].N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.C(OCC)C>[Si:20]([O:10][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[CH:8]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1cc(CO)ccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(C#N)c1
Reaction time: 1 h

Procedure:
To a solution of 2-cyano-4-hydroxymethylpyridine (step 1, 3.63 g, 27.06 mmol) in DMF (50 ml) were added imidazole (4.42 g, 64.95 mmol) and TBDMSCl (4.89 g, 32.47 mmol) at room temperature. After stirring for 1 h, the mixture was diluted with diethyl ether (300 ml), washed with water (100 ml×4), and dried (MgSO4). Removal of solvent gave the title compound. 1H-NMR (CDCl3) δ: 8.65 (1 H, d, J=5.1 Hz), 7.68 (1 H, s), 7.46 (1 H, d, J=4.9 Hz), 4.78 (2 H, s), 0.96 (9 H, s), 0.13 (6 H, s).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:11]=[CH:12][C:4]=2[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C(COC)OC>[CH3:1][CH:2]1[C:7](=[S:28])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1Oc2ccc(Cn3ccnc3)cc2NC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: CC1Oc2ccc(Cn3ccnc3)cc2NC1=S
Temperature: 25 °C
Reaction time: 46 h
Yield: 57.4 %

Procedure:
390 mg (1.603 mmol) of (±)-2-methyl-3-oxo-6-[(1-imidazolyl)-methyl]-3,4-dihydro-2H-1,4-benzoxazine is dissolved in 42 ml of dimethoxyethane, mixed with 1.297 g (3.206 mmol) of Lawesson's reagent and stirred for 46 hours at room temperature. After the solvent is spun in, the residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol). The fractions that are obtained by chromatography are removed from the polar contaminants by shaking with saturated sodium bicarbonate solution. 238.5 mg (57%) of the desired product is isolated, ting point 206-210° C.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)([CH3:38])[CH3:37]>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([C:43]3[CH:42]=[CH:41][CH:40]=[C:39]([CH:36]([CH3:38])[CH3:37])[CH:44]=3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CC(C)c1cccc(B(O)O)c1
Product: CC(C)c1cccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)c1

Procedure:
5-{-4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (100 mg, 0.17 mmol) was treated as described in general procedure G using 3-isopropylphenyl boronic acid to provide 5-{4-[4-(2,4-dichloro-phenyl)-2-(3′-isopropyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:5][C:6]=1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:14][CH2:13]2.[Li+].[OH-].O.Cl>CCO.C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:5][C:6]=1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([CH2:19][C:20]([OH:22])=[O:21])[CH2:14][CH2:13]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3oc(-c4ccccc4)nc3C)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(-c2ccccc2)oc1CCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
Ethyl {(1S)-5-[2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)ethoxy]-2,3-dihydro-1H-inden-1-yl}acetate (0.135 g, 0.33 mmol) was dissolved in EtOH (6 mL), and LiOH (0.024 g, 1.0 mmol) was added. Water was added (3 mL) and THF was added until the cloudy solution became clear. The resulting mixture was stirred overnight at rt. HCl (2N) was added to adjust the pH to 2, then extracted three times with ethyl acetate. The organic layers were combined, dried, and concentrated to give the {(1S)-5-[2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)ethoxy]-2,3-dihydro-1H-inden-1-yl}acetic acid (0.039 g, 30.6% yield) as colorless oil. ES-MS m/z 378.2 ((MH)+); HPLC RT (min) 3.22; 1H NMR (Acetone-d6) δ 8.1 (s br 1H) 8.0-7.95 (m, 2H), 7.52-7.43 (m, 3H), 7.15(d, 1H),6.81 (s, 1H), 6.73 (d, 1H), 4.27 (t, 2H) 3.47-3.40 (m, 1H), 3.18 (t, 2H), 2.90-2.68 (m, 3H), 2.41-2.29 (m, 2H), 2.18 (s, 3H), 1.77-1.68 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])[CH3:30]>>[CH:18]([N:13]1[C:12]([C:35]2[CH:36]=[CH:37][C:32]([C:29](=[O:31])[CH3:30])=[CH:33][CH:34]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(=O)c1ccc(-c2c3c(nn2C(C)C)CCNCC3)cc1
Yield: 94.7 %

Procedure:
The title compound (168 mg) was prepared according to Example 189 using 255 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 341 mg of 4-acetylphenylboronic acid. MS (ESI): exact mass calculated for C18H23N3O, 297.18; found, m/z 298.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.17-8.15 (m, 1H), 7.69-7.67 (m, 1H), 7.51-7.49 (m, 1H), 7.37-7.35 (m, 1H), 4.65 (br s, 1H), 4.46-4.38 (m, 1H), 4.00-3.50 (m, 2H), 3.48-3.42 (m, 1H), 3.25-3.17 (m, 1H), 3.13-2.81 (m, 2H), 2.67 (s, 1.5H), 1.55 (s, 1.5H), 1.44-1.40 (m, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[CH3:9][C:10]1([CH2:14][OH:15])[CH2:13][O:12][CH2:11]1.[OH-].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].O>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][CH2:14][C:10]1([CH3:9])[CH2:13][O:12][CH2:11]1
Reactant: CC1(CO)COC1
Reactant: BrCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC1(COCCCCCCBr)COC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A two phase system composed of 1,6-dibromohexane (74.06 g, 0.30 mmol) in hexanes (100 mL) and 3-methyl-3-oxetanemethanol (10.0 g, 0.10 mmol), NaOH (65.02 g, 1.63 mol), and Bu4NBr (0.5 g, 1.55 mmol) in H2O (100 mL) was stirred at 0° C. in an ice bath for 30 min. The reaction mixture was warmed up to room temperature and stirred at room temperature for 1 day. It was then heated at 100° C. for additional 2 h. The reaction mixture was allowed to cool down to room temperature and H2O was added. The mixture was extracted with hexanes three times. The combined organic phase was dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The crude product was distilled under vacuum to give colorless liquid (b.p. 90-92° C., 0.1 mmHg) (13.75 g, 53%). 1H NMR (300 MHz, CDCl3, δ): 4.48 (d, J=5.5 Hz, 2H), 4.33 (d, J=5.9 Hz, 1H), 3.45 (s, 2H), 3.44 (t, J=6.4 Hz, 2H), 3.39 (t, J=6.8 Hz, 2H), 1.85 (m, 2H), 1.58 (m, 2H), 1.30-1.50 (m, 4H), 1.28 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3, δ): 80.17, 76.12, 71.34, 39.94, 33.71, 32.70, 29.34, 27.93, 25.34, 21.35. HRMS-FAB (m/z): [M+H]+ calcd for C11H22BrO2, 265.0803; found, 265.0802.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7](/[CH:10]=[CH:11]\[S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.O.Cl>ClCCl>[OH:2][CH2:3][C:5]1[N:6]=[C:7](/[CH:10]=[CH:11]\[S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:8][CH:9]=1
Reactant: COC(=O)c1csc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: OCc1csc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A solution of 3.48 g of 4-methoxycarbonyl-2-((Z)-2-tritylthioethen-1-yl)thiazole in 70 ml of dichloromethane was cooled in ice, and 18.7 ml of a 1.0 M diisobutylaluminum hydride/toluene solution was added dropwise to the cooled solution under an argon atmosphere. The mixture was stirred at the same temperature for one hr. Water was then added to the reaction solution, and the mixture was adjusted to pH 2.5 by the addition of 1 N aqueous hydrochloric acid. The insolubles were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 2.88 g of the title compound.