Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH:4]=1.[CH3:28][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:28])[CH2:16][CH2:15]2)[CH:4]=1
Reactant: COC(=O)c1ccc(SC)cc1O[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(SC)cc1O[C@H]1CC[C@@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 7 h
Yield: 41.8 %

Procedure:
To a mixture of methyl 4-methylthio-2-[cis-4-(t-butoxy-carbonylamino)cyclohexyloxy]benzoate (3.0 g, 7.59 mmol) in THF (15 mL) at −20° C. was added 1 M lithium hexamethyl-disilazide (LiHMDS)/hexane (8.0 ml, 7.97 mmol, 1.05 eq), and the mixture was warmed to 0° C. for 10 min. To the reaction mixture was added methyl iodide (0.5 mL, 7.97 mmol, 1.05 equivalent), the mixture was warmed to room temperature and stirred for 7 h, and the reaction was quenched with satd citric acid. The mixture was diluted with CH2Cl2 and partitioned. The organic layer was dried (Na2SO4) and concentrated. This material was combined with the crude product from a small scaled reaction (500 mg, 1.27 mmol), chromatographed (400 g, SiO2, hexanes to 20% EtOAc/hexanes) and triturated with Et2O to give the title compound as a white solid (1.3 g, 36%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:13]([CH3:21])([CH2:15][CH2:16][C:17](Cl)([CH3:19])[CH3:18])[CH3:14]>ClCCl>[CH3:14][C:13]1([CH3:21])[CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:9]2[CH:10]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]1=2
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 32.5 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Aluminum trichloride (25 g, 0.18 mol) was added portions to a solution of phenol (49.5 g, 0.52 mol) and 2,5-dichloro-2,5-dimethylhexane (101.0 g, 0.55 mol) in dichloromethane (700 mL). The reaction mixture was allowed to stir at 25-40° C. for 2 h, then the dark red mixture was poured onto ice water. Aqueous work up (EtOAc extraction) gave 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-ol 84.8 g (80%) as a white solid, which was recrystallized from hexane to give the product as colorless needles: 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 1H, ArH), 6.78 (d, 1H, ArH), 6.62 (dd, 1H, ArH), 4.55 (s, 1H, OH), 1.65 (s, 4H, 2CH2), 1.25 (s, 12H, 4CH3).
Reaction SMILES: [Cl:1][C:2]1[C:9](Cl)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][O:15][CH2:16][CH2:17][CH2:18][NH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([NH:6][CH3:7])=[CH:8][C:9]=1[NH:19][CH2:18][CH2:17][CH2:16][O:15][CH3:14]
Reactant: COCCCN
Reactant: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Product: CNc1cc(NCCCOC)c(Cl)cc1[N+](=O)[O-]

Procedure:
0.059 mole (13 g) of 4,5-dichloro-2-nitro-N-methylaniline prepared in the previous stage is heated for 4 hours in 40 ml of 3-methoxypropylamine on a steam bath. After dilution with iced water and acidifying with concentrated hydrochloric acid, the expected product is filtered off. Recrystallized from 96° ethanol, it melts at 99° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH2:5][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1cc(Br)cc(Br)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Brc1cc(Br)cc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3,5-Dibromobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24](=[O:28])[O:25]2)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN1CCCC1=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:22]=[CH:23][C:24](=[O:28])[O:25][C:26]=2[CH:27]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: NCC1COc2ccccc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=c1ccc2ccc(OCCCNCC3COc4ccccc4O3)cc2o1
Temperature: 80 °C
Yield: 29.9 %

Procedure:
2,3-Dihydro-1,4-benzodioxin-2-methanamine (1.7 g, 10 mmole), 7-(3-chloropropoxy)coumarin (2.4 g, 10 mmole), diisopropylethylamine (1.3 g, 10 mmole) and sodium iodide (5.0 g, 33 mmole) were combined in 100 ml of N-methylpyrrolidinone and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with 300 ml of dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 100 g of silica gel using chloroform as eluant. The product-containing fractions (Rf=0.15 on silica gel tlc with 1% methanol/chloroform) were combined and concentrated in vacuum and the residue crystallized from isopropanol with the addition of 4N isopropanolic HCl to give 1.1 g of title compound as a tan solid, monohydrochloride, m.p. 213°-215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.N>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)=[CH:28][CH:27]=1
Reactant: Fc1ccc(I)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 93, starting with 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-fluoro-4-iodobenzene in place of 4-bromothioanisole (yield: 245 mg, 54%). mp 195–197° C. 1H NMR (300 MHz, CDCl3) δ 3.08 (s, 3H), 7.19 (m, 4H), 7.25 (m, 2H), 7.41 (d, J=9 Hz, 2H), 7.70 (m, 2H), 7.95 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 455 (M+H)+, 472 (M+NH4)+. Anal. calc. for C23H16ClFN2O3S: C, 60.78; H, 3.52; N, 6.17. Found: C, 60.81; H, 3.53; N, 5.93.
Reaction SMILES: C[O-].[Na+].Cl.Cl.[CH2:6]([NH:13][NH2:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]([CH2:17][C:18]([C:20]1[O:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=1)=O)#[N:16].O>C(O)C>[NH2:16][C:15]1[N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:14]=[C:18]([C:20]2[O:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=2)[CH:17]=1
Reactant: NNCc1ccccc1
Reactant: N#CCC(=O)c1ccc(CO)o1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccc(CO)o2)nn1Cc1ccccc1

Procedure:
44.1 g (817 mmol) of sodium methoxide is added with stirring to a solution of 79.5 g (408 mmol) of benzylhydrazine dihydrochloride in 1.3 l of ethanol. After 15 min 67.4 g (408 mmol) of 2-cyanomethylcarbonyl-5-hydroxymethylfuran are added and the mixture is stirred under reflux for 3 hours. After cooling, 1 l of water is added, the ethanol part is evaporated in vacuo and the precipitated crystals are filtered off with suction. After washing, with water and then with ether, the precipitate is dried over P2O5, 91 g(83% of theory) of product having an m.p. of 163° C. are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=O)[CH2:10][CH2:11][Cl:12].P(Cl)(Cl)(Cl)=O>ClCCl>[Cl:12][CH2:11][CH2:10][C:9]1[N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]2=[CH:7][N:8]=1
Reactant: O=C(CCCl)NCc1cnccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: ClCCc1ncc2cnccn12
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.7 %

Procedure:
To a solution of N-(2-pyrazinylmethyl)-3-chloropropionamide (4.52 g) in dichloromethane (30 ml) was added phosphorus oxychloride (1.29 g) under ice cooling. The mixture was stirred for 3 days at room temperature. The mixture was concentrated, and the residue was poured into ice water (400 ml), followed by neutralization with sodium carbonate. The reaction mixture was subjected to salting out with sodium chloride, and extracted with ethyl acetate-THF (1:1, 150 ml×3). The organic layers were combined and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography [carrier: silica gel, 100 g, developing solvent: ethyl acetate→ethyl acetate-ethanol (9:1)]. The eluate was concentrated and residual solid was washed with diethylether to give the title compound (3.07 g) as colorless solid product.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[CH:41]=[C:42]([CH:44]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:46]=1)[NH2:43].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:43][C:42]1[CH:44]=[C:45]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:46]=[C:40]([F:39])[CH:41]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(N)cc(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(F)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 53 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (250 mg, 0.42 mmol) was treated with 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (250 mg, 1.05 mmol), sodium carbonate (110 mg, 1.05 mmol) and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (100 mg, 0.12 mmol) in a mixture of 1,2-dimethoxyethane (10.6 ml) and water (2.4 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 70% n-hexane-ethyl acetate) to obtain 170 mg (53% yield, 82% purity) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@H:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([NH2:33])=[CH:28][CH:27]=2>>[CH3:22][O:21][CH2:20][CH2:19][O:18][C@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:33][C:29]3[CH:30]=[C:31]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:23])=[CH:32]4)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: COCCO[C@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: COCCO[C@H]1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)C1

Procedure:
The title compound was prepared from (3S)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-[3-(2-methoxy-ethoxy)-pyrrolidin-1-yl]-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 451.2 (MH+); HPLC Rf: 4.357 min.; HPLC purity: 97%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH:12]1[O:16][CH2:15][CH2:14][O:13]1.O1CCCC1.C([Li])CCC.[CH:27]1[C:32]([CH:33]=[O:34])=[CH:31][C:30]2[O:35][CH2:36][O:37][C:29]=2[CH:28]=1>C(=O)=O.CC(C)=O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:3]1[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH:33]([C:32]1[CH:27]=[CH:28][C:29]2[O:37][CH2:36][O:35][C:30]=2[CH:31]=1)[OH:34]
Reactant: COc1cc(Br)c(C2OCCO2)cc1OC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C2OCCO2)c(C(O)c2ccc3c(c2)OCO3)cc1OC
Temperature: -78 °C
Yield: 30 %

Procedure:
To a flame dried four necked round bottom flask (100 mL) were added 2-(2-bromo-4,5-dimethoxyphenyl)-1,3-dioxolane (formula VII; 1.0 g, 0.9934 mole) and anhydrous tetrahydrofuran (25 ml) under nitrogen atmosphere. The flask was cooled to −78° C. in dry ice-acetone bath; n-Butyllithium (5.3 ml, 0.005 mole) was added drop wise with stirring at −78° C. and stirred for 15 minutes. A separate flame dried flask was charged with Piperonal (0.517 g, 1.0034 mole) and dry tetrahydrofuran (6 ml). The Piperonal solution was cannulated to the reaction mixture during 30 minutes and after the addition, reaction mixture was slowly warmed to room temperature and further stirred for 2.5 hours. After the consumption of all bromine compound, as confirmed by TLC (50:50, EtOAc:Hexane), reaction mixture was quenched by the addition of saturated ammonium chloride solution and extracted with ethyl acetate (3×20 ml). All the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield 80% of crude product. The crude product was purified by column chromatography using column of 2 meter length, diameter 2.5 cm and filled with silica gel 60-120 (column chromatographic grade). Finally column eluted with EtOAC:Hexane (50:50), to get pure product (2-(1,3-Dioxolane-2-yl)-4,5-dimethoxy phenyl) (benzo(d)(1,3)dioxol-5-yl)-methanol with 30% yield. The total time required was about 7 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22]OS(C)(=O)=O)=[CH:4][C:3]=1[F:28].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH2:22][C@H:9]1[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:28])[CH:4]=2)[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 192.3 %

Procedure:
To a solution of tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (4.00 g) in DMF (46 mL) was added sodium azide (891 mg), and the mixture was stirred at 70° C. overnight. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel filtration to give the title compound (6.76 g).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C@@H:25]1[O:29][C:28](=[O:30])[NH:27][CH2:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:26][C@H:25]([CH3:24])[O:29][C:28]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: C[C@H]1CNC(=O)O1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)OC4=O)nc3)CC2)c(C)c1
Yield: 89.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (748 mg) described in Preparation Example 73 and (S)-5-methyloxazolidin-2-one (243 mg) described in Preparation Example 42, the title compound (706 mg) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:32][CH:33]([F:35])[F:34])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[CH:24][CH:25]=1)=[C:8]2[O:32][CH:33]([F:35])[F:34]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(C(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A solution of {8-chloro-4-difluoromethoxy-3-[4-(2,2-dimethylpropionyl)benzyl]-2-ethylquinolin-5-yloxy}acetic acid methyl ester (0.071 g) in tetrahydrofuran (5.0 mL) was treated with 1.0M aqueous lithium hydroxide solution (0.28 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated to low bulk under reduced pressure, acidified by the addition of 0.1M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound as a yellow solid (0.040 g).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>>[NH2:19][CH:20]1[CH2:24][CH2:23][N:22]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:21]1
Reactant: NC1CCNC1
Reactant: Clc1ccc(OCCOc2nccnc2Cl)cc1
Product: NC1CCN(c2nccnc2OCCOc2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and 3-aminopyrrolidine (247 mg, 2.87 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 123 mg (69%) of the title product. Anal. (C16H19CIN4O2) H, N; C: calcd. 57.40; found, 56.9.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Reactant: ClCc1cccnc1SCC1CC1
Product: O=C(O)CCc1ccc(OCc2cccnc2SCC2CC2)c(Cl)c1
Yield: 62.8 %

Procedure:
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (35 mg, 0.16 mmol) obtained in Step C of Preparation Example 18 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (42 mg, 0.18 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (38 mg, 74%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[NH2:24][C:25]1[C:26]([OH:32])=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([NH:24][C:25]1[C:26](=[O:32])[NH:27][CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:5])[CH3:2]
Reactant: Nc1cc(Cl)cnc1O
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cc(Cl)c[nH]c1=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate B and 3-amino-5-chloropyridin-2-ol. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography (CH2Cl2/MeOH, 99:1→97:3). tR: 1.15-1.18 min (LC-MS 2); ESI-MS: 527.1/529.1/531.1 [M+H]+ (LC-MS 2); Rf: 0.41 (CH2Cl2/MeOH 9:1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][OH:8])=[N:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:6][C:5]([CH2:7][OH:8])=[N:4][N:3]=2)=[CH:12][CH:11]=1
Reactant: OCc1nnc(Br)s1
Reactant: OB(O)c1ccc(F)cc1
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: Cc1ccccc1
Solvent: CCO
Product: OCc1nnc(-c2ccc(F)cc2)s1
Temperature: 100 °C
Yield: 65.7 %

Procedure:
To a solution of (5-bromo-1,3,4-thiadiazol-2-yl)methanol (1.2 g, 6.153 mmol) in toluene (40 mL) and ethanol (40 mL) was added 4-fluorophenyl boronic acid (1.026 g, 7.384 mmol) and 2 M solution of aqueous Na2CO3. The reaction mixture was degassed with argon, Pd(PPh3)4 (0.354 g, 0.355 mmol) was added, the reaction mixture again degassed with argon for 10 min, and the mixture heated to 100° C. for 2 h. The reaction mixture was evaporated under vacuum to remove the ethanol, diluted with water (50 mL), extracted with ethyl acetate (200 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage IsoleraOne® column (using 30% ethyl acetate and hexane) to give (5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methanol as pale yellow solid (0.85 g, 65% yield); LC-MS m/z calculated for [M+H]+ 211.03, found 211.1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]#[N:10])[C@H:4]([CH2:11][OH:12])[CH2:3]1.C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[NH:10][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C@H:4]([CH2:11][OH:12])[CH2:3]1
Reactant: N#CCCN1C[C@H](O)C[C@H]1CO
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@H](O)C[C@H]3CO)cc12

Procedure:
In the same manner as in Example 10b (a) and using (3R,5S)-5-hydroxymethylpyrrolidin-3-ol described in Collect. Czech. Chem. Commun., vol. 61, pp. S234-S237 (1996), 3-[(2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile is obtained. In the same manner as in Example 1b (e) and using 3-[(2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{2-[(2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[OH:24])[O:14][N:13]=1)C.Cl>O.O1CCOCC1>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([OH:24])=[C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:25])=[O:6])[CH:16]=2)[CH:22]=1
Reactant: CCOC(=O)CCCCc1cc(-c2cc(Cl)ccc2O)on1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCc1cc(-c2cc(Cl)ccc2O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Add a solution of LiOH.H2O (2.14 g, 51.0 mmol) in water (30 mL) to a rapidly stirred solution of 5-[5-(5-chloro-2-hydroxy-phenyl)-isoxazol-3-yl]-pentanoic acid ethyl ester (3.30 g, 10.2 mmol) in dioxane (60 mL), stir at room temperature overnight. After 1 hour, acidify to pH 1 with 5N HCl solution and place in refrigerator. Filter out solids and rinse with water to afford the title compound (2.73 g, 91%). MS (IS) 296 (M+1)+.