Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(F)c(Cl)c1)C(=O)OCC
Yield: 84.9 %

Procedure:
3-Chloro-4-fluoroaniline (30.08 kg) in 8 L ethanol was heated at 40-50° C until a clear solution was obtained. Said solution was added to a 100 gallon glass-lined unit charged with 196 L ethanol. Diethyl ethoxymethylenemalonate (49.1 kg) was then added over an 80 minute period with stirring. The mixture was brought to reflux for one hour and then cooled to near 0° C. with stirring. Crystallization was initiated with seeding when the temperature had reached 27° C. during the cooling process. Stirring was continued for another hour, the solid product was filtered on a ceramic filter, and the filter cake was washed with 3×16 L cold (1°-5° C.) ethanol. The product was dried at 40° C. in vacuo for 19 hours to give 55.4 kg diethyl (3-chloro-4-fluorophenyl)aminomethylenepropanedioate, m.p. 71.5°-72.5° C. (85% yield). The combined filtrate and washes were concentrated to 54 L and a second crop was isolated and dried as before to give 5.6 kg additional product, m.p. 71.5°-72.5° C. for a combined yield of 93.5%.
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][OH:44]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:41][C:42]([CH3:46])([CH3:45])[CH2:43][OH:44])=[O:40])=[CH:15][CH:14]=3)[CH:21]=2)[CH:27]=1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: CC(C)(N)CO
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC(C)(C)CO)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1

Procedure:
Method as described for example 58 using (S)-phenyl(4-(6-(5-fluoro-2-(methylsulfonyl)phenyl)-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)carbamate)(intermediate 32) (100 mg, 0.18 mmol) and 2-amino-2-methylpropan-1-ol (24 mg, 0.27 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound as a yellow solid. (45 mg, 45%)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH2:20][CH2:21][OH:22])[O:13][C:12]1([CH3:24])[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[C@H:14]([CH2:20][CH2:21][O:22][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[O:13][C:12]1([CH3:24])[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H]1[C@H](CCO)OC(C)(C)N1C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC[C@@H]2OC(C)(C)N(C(=O)OCc3ccccc3)[C@H]2CC(C)C)cc1
Yield: 78.7 %

Procedure:
3.89 g of (4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-5-(2-hydroxyethyl)-4-isobutyloxazolidine was dissolved in 15 ml of pyridine, and 2.65 g of p-toluenesulfonyl chloride was added and dissolved therein. The mixture was then reacted at room temperature overnight. The reaction solution thus obtained was concentrated, and precipitated insolubles were filtered off. The filtrate thus obtained was purified by silica gel column chromatography (developer: benzene/ethyl acetate (30/1)) to obtain 4.47 g of (4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-5-(2-p-toluenesulfonyloxyethyl)-4-isobutyloxazolidine as a syrup.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:27])[C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>ClCCl>[C:35]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:27])[C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)(=[O:38])[CH:36]=[CH2:37]
Reactant: C=CC(=O)Cl
Reactant: CN(CCCCCCO)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCN(C)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 23 °C
Reaction time: 72 h
Yield: 67.5 %

Procedure:
A stirred mixture of 4'-[(6-hydroxyhexyl)-methylamino]-4-methylsulfonylstilbene (App-Ex. 4, 20.0 g, 52 mmol), triethylamine (6.3 g, 62 mmol) and dry dichloromethane (DCM) was treated dropwise with acryloyl chloride (5.6 g, 62 mmol) in 50 mL of DCM at 23° C. under nitrogen. The resulting solution was stirred at 23° C. for 72 hours, and then filtered. The filtrate was washed successively with saturated NaCl, with saturated NHCO3, and with water. The organic layer was dried (MgSO4), and the solvent was removed at reduced pressure to deposit a yellow oil which gradually crystallized. The product was recrystallized from tetrahydrofuran (THF)/hexanes to yield 15.5 g (68%) of a yellow solid, mp 88°-90° C.
Reaction SMILES: [CH:1]([N:4]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:8])[O:6][CH3:7])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:25]1(=[O:29])[CH2:28][CH2:27][CH2:26]1.Cl>C1COCC1.CCOCC>[CH:9]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:8])[O:6][CH2:7][C:25]1([OH:29])[CH2:28][CH2:27][CH2:26]1)([CH3:11])[CH3:10]
Reactant: COC(=O)N(C(C)C)C(C)C
Reactant: O=C1CCC1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)N(C(=O)OCC1(O)CCC1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.148 g (70 mmol) of methyl N,N-diisopropylcarbamate and 12.424 g (105 mmol) of TMEDA in 200 ml of THF are lithiated at -78° C. with 70 mmol of sec. BuLi. After 1 h, 2.453 g (35 mmol) of cyclobutanone are added in portions (about 500 mg every 30 min). The reaction is complete after 3 h (TLC checking) and the reaction mixture is treated in the cold with 100 ml of ether and 120 ml of 2N hydrochloric acid. After warming to room temperature, the phases are separated and the aqueous phase is extracted three times using 50 ml of ether each time. The combined organic phases are then freed from acid with 50 ml of saturated NaHCO3 solution and dried over magnesium sulphate. After the solvent has been stripped off in vacuo, a crude yield of 12.197 g is obtained, chromatographic purification of which on silica gel using ether/petroleum ether (1:1) gives 3.721 g (46.4% of theory) of the title compound as a colorless liquid.
Reaction SMILES: [C:1](=NO)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(C1C=CC(SC2C=C(C3(OC)CC[O:36]CC3)C=C(F)C=2)=CC=1)C>>[C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(c1ccccc1)c1ccccc1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)Cl)cc3)c2)CCOCC1
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 38 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reactants were heated to 60° C. for 2 hours, benzophenone oxime was reacted with 4-{3-[4-(1-chloroethyl)phenylthio]-5-fluorophenyl}-4-methoxytetrahydropyran to give benzophenone O-}4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyl}oxime as an oil in 38% yield.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC(C(N)C)=CC=1.[F:27][C:28]1[CH:37]=[CH:36][C:31]([O:32][CH2:33][CH2:34][NH2:35])=[CH:30][CH:29]=1>C(Cl)Cl>[F:27][C:28]1[CH:37]=[CH:36][C:31]([O:32][CH2:33][CH2:34][NH:35][C:14]2[CH:15]=[C:10]([NH:9][C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[N:11]=[CH:12][N:13]=2)=[CH:30][CH:29]=1
Reactant: C[C@H](Nc1cc(Cl)ncn1)c1ccccc1
Reactant: NCCOc1ccc(F)cc1
Agent: CC(N)c1ccc(Cl)cc1
Solvent: ClCCl
Product: C[C@H](Nc1cc(NCCOc2ccc(F)cc2)ncn1)c1ccccc1
Temperature: 150 °C
Yield: 54.2 %

Procedure:
4-[(1S)-(1-phenylethyl)amino]-6-chloropyrimidine, (Intermediate III, Compound of Example 6), (234 mg, 1.0 mmole) and [2-(4-fluorophenoxy)ethyl]amine (357 mg, 2.3 mmole) were combined in a 2 mL pressure vial which was then securely capped. The vial was heated at 150° C. for 20 hours. After cooling, the solid mass was dissolved in CH2Cl2 (25 mL) and extracted with saturated sodium carbonate (25 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from CH2Cl2 (5 mL) to afford the titled compound as a white solid (191 mg, 54%). 1H NMR (CDCl3) δ 1.54 (d, J=6.6 Hz, 3H), 3.54 (q, J=5.5 Hz, 2H), 3.94 (t, J=5.5 Hz, 2H), 4.59 (p, J=6.6 Hz, 1H), 5.05 (broad m, 1H), 5.08 (s, 1H), 5.34 (broad d,1H), 6.77 (m, 2H), 6.95 (t, J=9.1 Hz, 2H), 7.23 (m,1H), 7.32 (d, J=4.4 Hz, 4H), 8.09 (s, 1H), LC/MS (MH+) m/e 353.79 obs.
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3][C:2]1=[O:9].[CH3:10][C:11]([CH3:13])=[CH2:12].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>ClCCl>[C:11]([O:7][C:6]([C@@H:5]1[CH2:4][CH2:3][C:2](=[O:9])[NH:1]1)=[O:8])([CH3:13])([CH3:12])[CH3:10]
Reactant: C=C(C)C
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A pressure flask is charged with (S)-(−)-2-pyrrolidone-5-carboxylic acid (25 g, 193.6 mmol) and dichloromethane (100 mL) and the stirred suspension is cooled in a dry ice acetone bath. Liquid 2-methylpropene (150 mL) is added followed by concentrated sulfuric acid (0.5 mL). The pressure flask is sealed and the reaction mixture is stirred at room temperature for 48 h. The pressure flask is cooled in a dry acetone bath and the reaction mixture is diluted with dichloromethane (500 mL) and treated with a saturated solution of sodium bicarbonate until the effervescence is ceased. The organic layer is separated, washed with saturated solution of sodium bicarbonate (300 mL), brine (300 mL), dried over anhydrous Na2SO4 and solvent removed in vacuo to give the title compound as a white crystalline solid. The crude material is used without purification.
Reaction SMILES: Cl[CH:2](Cl)[C:3]([OH:5])=[O:4].[H-].[Na+].[CH:9]1([C:15]2[CH:16]=[CH:17][C:18]([OH:30])=[C:19]([C:21]([CH3:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])[CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCOCC1>[CH:9]1([C:15]2[CH:16]=[CH:17][C:18]3[O:30][CH:2]([C:3]([OH:5])=[O:4])[O:22][C:21]([CH3:29])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[CH:20]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(O)C(Cl)Cl
Reactant: CC(O)(c1ccccc1)c1cc(C2CCCCC2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(c2ccccc2)OC(C(=O)O)Oc2ccc(C3CCCCC3)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A solution of 14.18 g of dichloroacetic acid in 150 ml of dioxane was added with stirring at room temperature to a mixture of 11.8 g of sodium hydride as a 50% oil suspension, 120 ml of dioxane and 1.05 g of dibenzo-18-courone-6 and then a solution of 20.74 g of the product of Step B in 250 ml of dioxane was added dropwise thereto. The mixture was stirred at 80° C. for 2 hours and was cooled and poured into ice. The aqueous phase was washed with 300 ml of ether, was acidified with 30 ml of concentrated hydrochloric acid and was extracted 3 times with 250 ml of ether. The ether phase was washed twice with 100 ml of water and was extracted twice with 250 ml of aqueous 5% sodium bicarbonate solution. The aqueous phase was washed with 100 ml of ether, acidified with 60 ml of concentrated hydrochloric acid and was extracted 3 times with 250 ml of ether. The decanted organic phase was washed with water until the wash water was neutral, dried over magnesium sulfate and was evaporated to dryness under reduced pressure to obtain 18.7 g of raw 6-cyclohexyl-4-methyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of 2 diastereoisomeric racemates).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([Si:24]([C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:43][C:40]1[CH:39]=[CH:38][C:37]([Si:24]([C:31]2[CH:32]=[CH:33][C:34]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)=[CH:35][CH:36]=2)([C:21]2[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:42][CH:41]=1
Reactant: Brc1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc(Br)cc2)cc1
Reactant: OB(O)c1cccc2c1sc1ccccc12
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc(-c3cccc4c3sc3ccccc34)cc2)cc1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A mixture solution of dibenzo[b,d]thiophen-4-ylboronic acid (2.5 g, 10.96 mmol), bis(4-bromophenyl)diphenylsilane (11.92 g, 24.11 mmol), Pd(PPh3)4 (0.253 g, 0.219 mmol), and K2CO3 (9.09 g, 65.8 mmol) in toluene (90 mL) and water (30 mL) was stirred at 90° C. under nitrogen overnight. After cooling to room temperature, the organic phase was isolated, and the aqueous phase was extracted with toluene. The combined organic solution was dried over Na2SO4. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane:DCM(9/1, v/v) as eluent to yield (4-bromophenyl)(4-(dibenzo[b,d]thiophen-4-yl)phenyl)diphenylsilane (5.2 g, 79%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][CH2:15]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:28]=2[N:29]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][N:25]([CH2:15][CH:14]=[CH:13][C:12]3[CH:17]=[CH:18][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][CH:11]=3)[CH2:26][CH2:27][C:28]=2[N:29]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC=Cc1ccc(OCc2ccccc2)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc(OCc3ccccc3)cc1)CC2
Yield: 13 %

Procedure:
Prepared from 4-benzyloxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform for one hour at 50° C. Yield: 13% of theory, Melting point: 135°-140° C. (ether).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:9][C:8]2=1)#[N:4].Cl[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C)C=O.C(OCC)(=O)C>[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=1)[C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:9][C:8]2=1)#[N:4]
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(C#N)cc3c2C1
Reactant: Fc1cccnc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2ncccc2F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
Suspend sodium hydride (60% suspension in mineral oil, 114 mg, 1.64 mmol) in dimethylformamide (7 mL) and cool to 0° C. Add a solution of N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 3) (385 mg, 1.37 mmol) in dimethylformamide (3.5 mL). After several minutes, warm the reaction to room temperature, and stir for 30 min, after which time add 2-chloromethyl-3-fluoro-pyridine (Preparation 60). Stir the reaction overnight and then dilute with ethyl acetate (100 mL). Wash the reaction mixture sequentially with brine (3×75 mL), water (75 mL), and brine (75 mL). Separate the organic layer, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Purify using flash chromatography [silica gel, gradient from 0:100 to 20:80 (90:10:1 dichloromethane:methanol:concentrated ammonium hydroxide):dichloromethane] to provide 184 mg (38%) of the title compound as an off-white solid. m.p.=213-216° C.; MS: m/z 391 [C23H23FN4O+1]+; 1H NMR (300 MHz, DMSO-d6): δ 8.29-8.31 (m, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.71-7.78 (m, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.38-7.44 (m, 2H), 5.56 (s, 2H), 3.99-4.04 (m, 1H), 2.73-3.00 (m, 3H), 2.49-2.55 (m, 1H), 2.37 (septet, J=6.8 Hz, 1H), 1.96-2.00 (m, 1H), 1.76-1.83 (m, 1H), 1.01 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[C:5]([OH:8])=[N:6][CH:7]=1.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[C:5]([O:8][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:6][CH:7]=1
Reactant: COc1cc2nccc(Oc3cc(Cl)cnc3O)c2cc1OC
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc(Cl)cnc3OC3CCCC3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
4-(5-Chloro-2-hydroxy-pyridin-3-yloxy)-6,7-dimethoxyquinoline (39 mg) was suspended in N,N-dimethylformamide (7 ml). Cyclopentyl bromide (0.3 ml) and potassium carbonate (300 mg) were added to the suspension, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and 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 (29 mg, yield 62%).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[ClH:27]>>[OH:1][C:3]1([CH2:2][Cl:27])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CCl)CC3)c(F)c2)C(=O)O1
Temperature: 55 °C

Procedure:
A mixture of (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (18.0 mmol) and aqueous hydrochloric acid was heated at a temperature 50-60° C. for 12 hours to provide crude (S)—N-{3-[4-(4-hydroxy-4-chloromethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide which was purified by silica gel column chromatography and used further.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][S:30][CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([N:27]4[CH2:32][CH2:31][S:30][CH2:29][CH2:28]4)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Reactant: C1CSCCN1
Product: c1ccc(COc2ccc(Nc3ncnc4cnc(N5CCSCC5)cc34)cc2)cc1

Procedure:
Prepared according to Procedure C from 4-(4-benzyloxyanilino)-6-chloropyrido[3,4-d]pyrimidine and thiomorpholine; δH (CDCl3) 9.00 (1H,s), 8.59 (1H,s), 7.59 (2H, d), 7.28-7.50 (5H,m), 7.03 (2H,d), 6.56 (1H,s), 5.09 (2H,s), 3.92-4.18 (4H,m), 2.62-2.92 (4H,m); m/z (M+1)+430.
Reaction SMILES: [C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C>CS(C)=O>[C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH:13]=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a stirred solution of N-Cbz-L-prolinol (5 g, 21.26 mmol, from steps 24b or 24c above)in 20 mL of anhydrous DMSO were added 8.89 mL (63.79 mmol) of triethylamine and 10.75 g (63.79 mmol) of SO3 -pyridine complex in 35 mL of DMSO. The reaction mixture was stirred at room temperature for 10 min, then poured into 200 mL of ice water. The mixture was extracted with ether, the extract was dried over Na2SO4 and concentrated to afford the title product, 3.058 g (70% yield).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[Cl:14][C:15]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:16]=1[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)=[O:18].O>CN(C=O)C>[Cl:14][C:15]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:16]=1[C:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:11]2[C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=3[CH:9]=[CH:10]2)=[CH:25][CH:26]=1)=[O:18]
Reactant: Cn1ncc2[nH]ccc2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (757 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 1.5 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:3) to provide the title compound as white powder (511 mg, yield 62%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:8]2[O:9][C:10]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: Cc1cccc2nc(S)oc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cccc2nc(N3CCN(C)CC3)oc12
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (454 mg) was dissolved in anhydrous toluene (6 ml), the resulting solution was mixed with 2-mercapto-7-methylbenzoxazole (300 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 2 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (2.0 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 2-(4-methyl-1-piperazinyl)-7-methylbenzoxazole (392 mg).