Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.Cl.[CH2:8]([C:11]1[N:15]2[CH2:16][CH2:17][CH2:18][N:19]=[C:14]2[S:13][C:12]=1[C:20]([Cl:22])=[O:21])[CH2:9][CH3:10].[CH2:23]([O:25][C:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)=[O:27])[CH3:24].CN(C1C=CC=CN=1)C>CN(C)C=O>[ClH:22].[CH2:23]([O:25][C:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:20]([C:12]2[S:13][C:14]3=[N:19][CH2:18][CH2:17][CH2:16][N:15]3[C:11]=2[CH2:8][CH2:9][CH3:10])=[O:21])=[CH:36][CH:35]=1)=[O:27])[CH3:24]
Reactant: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Reactant: CCOC(=O)CCCCCSc1ccc(N)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCC1=C(C(=O)Nc2ccc(SCCCCCC(=O)OCC)cc2)SC2=NCCCN21
Temperature: 70 °C
Reaction time: 16 h
Yield: 36.5 %

Procedure:
In the mixture of 50 ml of pyridine and 5 ml of dimethylformamide was suspended 0.95 g of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride (described in Example 13). To the suspension was added 1.0 g of 4-(5-ethoxycarbonylpentylthio) aniline prepared in a similar manner as described in Reference Example 7 and added 43.4 mg of dimethylaminopyridine, followed by stirring at 70° C. for 16 hours. The reaction mixture was concentrated and to the concentrate was added saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with chloroform. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous potassium carbonate. The solvent was removed under reduced pressure. The residue was dissolved in ethanol. To the mixture was added saturated hydrogenchloride diethylether solution and stirred at room temperature, following by removing the solvent under reduced pressure. The residue was purified by silica gel column chromatography (silica gel:100 g) using a mixed solvent of chloroform and methanol (10:1 by volume) as an eluent. To the resulting substance was added saturated hydrogenchloride diethylether solution. The solvent was removed under reduced pressure. The residue was recrystallized from methanol-diethylether to obtain 632 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([Si](CC)(CC)CC)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C2C(=NC=CC=2)N(S(C2C=CC(C)=CC=2)(=O)=O)C=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC[Si](CC)(CC)c1cc2cc(Cl)cnc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)n2cc(Br)c3cccnc32)cc1
Agent: [F-]
Solvent: CCOC(C)=O
Product: Clc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
Compound 41 (4.37 g, 0.0164 mol) was dissolved in THE Molecular sieve (10 g of 3 A) was added followed by TBAF (32.75 mL, 0.0328). The reaction mixture was stirred for 5 h at rt. Diluted with ethyl acetate and washed several times with water, brine and the organic layer was dried and concentrated in vacuo to an oil that was subjected to flash chromatography (30% EtOAc-70% hexanes) to give 02.3 g (90%) of the desired material 42. 1H NMR DMSO d6 11.8 (bs, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.5 (s, 1H), 6.5 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([S:13](Cl)(=[O:15])=[O:14])[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].[CH2:30]([CH2:32][NH2:33])[OH:31]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([S:13]([NH:33][CH2:32][CH2:30][OH:31])(=[O:15])=[O:14])[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: NCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCO)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reaction time: 1 h

Procedure:
Compound 496 (0.07 g, 0.15 mmol) was dissolved in pyridine (0.4 mL) and ethanolamine (0.011 mL, 0.18 mmol) was added. The solution was kept at room temperature for 1 h after which it was concentrated in vacuo. The residue was dissolved in EtOAc and H2O and the phases were separated. The water phase was extracted with EtOAc (×2) and the combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 3:7→1:0 as the eluent. This afforded the title compound as a solid. 13C NMR (CD3OD) δ 196.5, 161.2 (dd), 158.0 (dd), 151.9, 143.3, 142.0, 139.5, 136.5, 135.2, 133.2, 129.9, 128.2, 127.8, 127.8 (dd), 125.7 (dd), 116.5, 113.1, 112.7 (dd), 105.8 (dd), 61.8, 46.3, 20.3
Reaction SMILES: [C-]#N.[Na+].C1(C)C=CC=CC=1.C[NH:12][CH2:13][CH2:14]NC.Br[C:18]1[CH:19]=[C:20]([O:26][CH3:27])[C:21]([O:24][CH3:25])=[CH:22]C=1>N.[Cu]I>[CH3:25][O:24][C:21]1[CH:22]=[C:14]([CH:18]=[CH:19][C:20]=1[O:26][CH3:27])[C:13]#[N:12]
Reactant: COc1ccc(Br)cc1OC
Reactant: CNCCNC
Agent: [Cu]I
Agent: N
Agent: [C-]#N
Solvent: Cc1ccccc1
Product: COc1ccc(C#N)cc1OC
Temperature: 110 °C
Reaction time: 24 h
Yield: 88.6 %

Procedure:
A Schlenk tube was charged with NaCN (204 mg, 4.16 mmol), CuI (66 mg, 0.35 mmol, 10 mol %), and KI (114 mg, 0.687 mmol, 20 mol %), briefly evacuated and backfilled with argon three times. Anhydrous toluene (2.4 mL), N,N′-dimethylethylenediamine (370 μL, 3.48 mmol), and 4-bromoveratrole (500 μL, 3.46 mmol) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 24 h. The resulting suspension was allowed to reach room temperature, diluted with 30% aq ammonia (2 mL), and extracted with ethyl acetate (4×4 mL). The combined organic phases were dried over MgSO4, concentrated, and the residue was purified by distillation at reduced pressure (bp 160° C. @ 1 Torr) to provide the desired product as pale yellow solid (500 mg, 91% yield). Mp 60-62° C. (lit. 63.0-63.5° C., See Murahashi, S.-I.; Naota, T.; Nakajima, N. J. Org. Chem. 1986, 51, 898). 1H NMR (400 MHz, CDCl3, J values are reported in Hz, lit. See Murahashi, S.-I.; Naota, T.; Nakajima, N. J. Org. Chem. 1986, 51, 898): δ 7.29 (dd, J=8.3, J=2.0, 1H), 7.08 (d, J=2.0, 1H), 6.91 (d, J=8.3, 1H), 3.94 (s, 3H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 153.2, 149.6, 126.9, 119.7, 114.3, 111.6, 104.3, 56.54, 56.51; IR (neat, cm−1): 2225, 1598, 1583, 1519, 1245, 1158, 1139, 1018, 876, 811, 617. Anal. Calcd. for C9H9NO2: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.02; H, 5.72; N, 8.69.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:12]1([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Li+]>C1(C)C=CC=CC=1.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>[C:12]1([C:2]2[N:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccnc1-c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-chloronicotinate (3.10 g, 18.1 mmol), phenyltributyltin (6.30 g, 17 mmol), lithium chloride (5.04 g, 120 mmol), and tetrakis(triphenylphosphine)palladium (1.12 g, 1 mmol) in toluene (65 ml) was degassed and then stirred under a nitrogen atmosphere overnight at 90° C. and at reflux for 5 hours. The cooled reaction mixture was filtered, the filtrate evaporated, and the residue partitioned between acetonitrile (50 ml) and hexane (5×20 ml). The combined hexane layers were extracted with hydrochloric acid (lM, 4×10 ml), the extracts washed with ethyl acetate (15 ml), and basified (4M NaOH). The resulting suspension was extracted with dichloromethane (4×10 ml), the combined extracts dried over MgSO4 and evaporated to leave a colourless oil. Meanwhile, the acetonitrile layer from above was evaporated and the residual oil dissolved in diethyl ether (50 ml) and ethyl acetate (25 ml) and the solution extracted with hydrochloric acid (1M, 4×10 ml). Basification of the acid extracts (4M NaOH) and extraction of the resulting suspension with dichloromethane (4×10 ml) followed by drying of the combined extracts with MgSO4 and evaporation gave an oil which was combined with that obtained as described above (2.62 g).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1.CN(C=O)C>O>[Br:1][C:2]1[N:6]=[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:21])[O:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:12][CH2:13]2)[S:4][N:3]=1
Reactant: Clc1nc(Br)ns1
Reactant: CC(C)COC(=O)NC1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COC(=O)NC1CCN(c2nc(Br)ns2)CC1
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-5-chloro-1,2,4-thiadiazole (0.21 g, 1.1 mmol), isobutyl piperidin-4-ylcarbamate (0.23 g, 1.2 mmol), and DMF (2 mL) was sealed in a microwave vessel and heated by microwave irradiation at 100° C. for two minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield isobutyl 1-(3-bromo-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate. LC/MS: m/z 365.0 (M+H)+ at 3.20 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=[CH:15][N:6]1[C:5]2=[O:19].[NH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(=O)(O)[O-].[Na+].ClCCl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[C:12]([C:16]([NH:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:18])=[CH:13][CH:14]=[CH:15][N:6]1[C:5]2=[O:19]
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1cccn2c(=O)c3cc(I)ccc3nc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCN1CCCC1)c1cccn2c(=O)c3cc(I)ccc3nc12
Reaction time: 66 h

Procedure:
To a room temperature solution of 2-iodo-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxylic acid (2.0 g; 4.97 mmol), 1-(2-aminoethyl)pyrrolidine (1.26 ml; 9.94 mmol), N,N-diisopropylethylamine (4.33 ml; 24,8 mmol), and dichloromethane (50 ml) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.3 g; 7.45 mmol) in one portion. After a stirring period of 66 hours, the reaction mixture was diluted with half-saturated sodium bicarbonate (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic phases were washed with brine (70 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by repeated flash chromatography. The first purification on silica gel (250 g; elution with 10% methanol/chloroform) was followed by a second purification (250 g silica gel; elution with 45% methanol/ethyl acetate followed by a gradient elution with 10-20% methanol/chloroform) to provide product as a bright lemon yellow solid: 1.82 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.S1(CCCC1)(=O)=O.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 35.4 %

Procedure:
To a mixture of 308 mg (purity: 99.0%; 1.85 mmol) of 4-hydroxy-3,6-dichloropyridazine and 824 mg (5.47 mmol) of 2-cyclopropyl-6-methylphenol were added sulfolane (2.76 g) and 332 mg (5.63 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 181 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 36%) and 7.1 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 1.4%) were obtained.
Reaction SMILES: [NH3:1].[C:2]([C:5]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10](OC)=[CH:9][C:6]=1[C:7]#[N:8])(=[O:4])[CH3:3]>CS(C)=O>[C:2]([C:5]1[C:6]([C:7]#[N:8])=[CH:9][C:10]([NH2:1])=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)(=[O:4])[CH3:3]
Reactant: N
Reactant: COc1cc(C#N)c(C(C)=O)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(=O)c1cc([N+](=O)[O-])c(N)cc1C#N
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
Ammonia was bubbled through a solution of 2-acetyl-5-methoxy-4-nitrobenzonitrile (0.80 g. 3.6 mmol) in 10 ml of dry dimethylsulfoxide with stirring at 80° C. for 45 min. Then the solution was poured into 100 ml of ice-water The product was isolated by filtration and washed with water to afford 0.71 g (95%) of the title compound. M.p. 255°-260° C.; 1H-NMR (DMSO-d6): 2.57 (s, 3H, COCH3), 7.50 (s, 1H, ArH), 8.20 (broad s, 2H, NH2), 8.65 (s, 1H, ArH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)CCCC2
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2c(c1)CCCC2
Yield: 97.1 %

Procedure:
A suspension of 15.8 g of 3-nitro-5,6,7,8-tetrahydroquinoline [synthesized according to the method as described in Bull. Chem. Soc. Jpn. Vol. 63 (1990), 2820] and 1.6 g of 5% palladium carbon in 300 ml of methanol is hydrogenerated at ordinary temperature under atmospheric pressure. The catalyst is filtered off, and the filtrate is concentrated in vacuo to remove the solvent. The resultant crude product is recrystallized from methylene chloride-isopropyl ether to give 12.76 g of the titled compound 1. Yield: 97%
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]2([CH3:36])[CH2:35][O:34][CH2:33]2)[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]3([CH3:36])[CH2:33][O:34][CH2:35]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC1(CC2NC(C(=O)OC(C)(C)C)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)COC1
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 112b (1.0 g, 1.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methyl-oxetan-3-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 91%).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].O1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:3]1([C:2]2[NH:9][CH:15]=[C:16]([C:17]3[C:18]4[C:18](=[CH:2][CH:3]=[CH:4][CH:5]=4)[CH:17]=[CH:16][CH:15]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccccc1
Reactant: C1CCOC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: c1ccc(-c2nc(-c3cccc4ccccc34)c[nH]2)cc1
Temperature: 25 °C

Procedure:
A suspension consisting of 31.3 g (0.20 mol) of benzamidine hydrochloride, 10.8 g (0.20 mol) of sodium methylate, and 150 mL of tetrahydrofuran was heated under reflux for one hour. After cooling to 25° C., a solution consisting of 49.8 g (0.2 mol) of ω-bromo-1-acetonaphthone and 100 mL of tetrahydrofuran was added dropwise such that the internal temperature did not exceed 30° C. After completion of addition, 10.8 g (0.20 mol) of sodium methylate was added, and the mixture was heated under reflux for one hour. Next, the reaction mixture was cooled to room temperature, insoluble matters were filtered off, and the filtrate was evaporated to dryness in vacuo. The residual solid was successively washed with water and acetonitrile and then dried to obtain a crude crystal as a desired material. This crude crystal was recrystallized from acetonitrile to obtain 18.0 g (yield: 33.3%) of a grayish blue crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]([CH2:18][CH3:19])[CH2:16][OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(O)(C)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]([CH2:18][CH3:19])[CH2:16][OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC[C@H](CO)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CC(C)O
Product: CC[C@H](CO)Nc1c(N)cnc2ccccc12
Yield: 98.9 %

Procedure:
(2R)-2-[(3-Nitroquinolin-4-yl)amino]butan-1-ol (238 g), isopropanol (5 L) and catalyst (23.8 g of 5% platinum on carbon) were combined in a stainless steel vessel and hydrogenated at 50 psi (3.5 Kg/cm2) for 16 hours. The reaction mixture was filtered through a layer of Celite® filter agent to remove the catalyst. The filtrate was concentrated under reduced pressure to provide 208.3 g of (2R)-2-[(3-aminoquinolin-4-yl)amino]butan-1-ol as an amber oil. The reaction was run a second time on the same scale.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([C@H:21]1[CH2:25][C@@H:24]([CH2:26][CH3:27])[N:23]([C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=2)[CH2:22]1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][N:16]([CH3:19])[C:15]2=[O:20])=[CH:10][N:9]=1.[NH:45]1[CH2:50][CH2:49][CH:48]([OH:51])[CH2:47][CH2:46]1>CC(O)C>[F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:40])([F:42])[F:41])[CH:38]=1)[CH2:6][N:7]([C@H:21]1[CH2:25][C@@H:24]([CH2:26][CH3:27])[N:23]([C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([N:45]3[CH2:50][CH2:49][CH:48]([OH:51])[CH2:47][CH2:46]3)[N:29]=2)[CH2:22]1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][N:16]([CH3:19])[C:15]2=[O:20])=[CH:10][N:9]=1
Reactant: OC1CCNCC1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C)C3=O)cn2)CN1c1nc(Cl)ncc1Cl
Solvent: CC(C)O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C)C3=O)cn2)CN1c1nc(N2CCC(O)CC2)ncc1Cl
Temperature: 80 °C
Reaction time: 12 h
Yield: 71.4 %

Procedure:
To a mixture of 1-(2-{(3,5-bis-trifluoromethyl-benzyl)-[(3S,5R)-1-(2,5-dichloro-pyrimidin-4-yl)-5-ethyl-pyrrolidin-3-yl]-amino}-pyrimidin-5-yl)-3-methyl-imidazolidin-2-one (30 mg, 0.05 mmol) in i-PrOH (1 mL) is added piperidin-4-ol (23 mg, 0.23 mmol). The reaction mixture is stirred at 80° C. for 12 hours. After removal of solvent, the mixture is washed with brine and extracted with EtOAc. The combined organic layer is dried over MgSO4 then concentrated under reduced pressure to give 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{(3S,5R)-1-[5-chloro-2-(4-hydroxy-piperidin-1-yl)-pyrimidin-4-yl]-5-ethyl-pyrrolidin-3-yl}-amino)-pyrimidin-5-yl]-3-methyl-imidazolidin-2-one (26 mg, 79%) after purification by silica gel column chromatography (eluent: EtOAc:MeOH=20:1).
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:6][N:5](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[C@@H:4]2[C@@H:24]([OH:27])[CH2:25][O:26][C@H:3]12.Cl[C@@H]1CN(C(OCC2C=CC=CC=2)=O)[C@@H]2[C@@H](O)CO[C@H]12.[H][H]>[Pd].C(O)C>[Cl:1][C@@H:2]1[CH2:6][NH:5][C@@H:4]2[C@@H:24]([OH:27])[CH2:25][O:26][C@H:3]12
Reactant: [H][H]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1C[C@@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Agent: [Pd]
Agent: O=C(OCc1ccccc1)N1C[C@@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Solvent: CCO
Product: O[C@H]1CO[C@H]2[C@@H]1NC[C@H]2Cl
Reaction time: 4.5 h

Procedure:
Preparation of (3R, 3aR, 6R, 6aS)-(9H-Fluoren-9-yl)methyl 6-chloro-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (78). Ethanol (3.5 mL) was added dropwise to a mixture of 10% palladium on charcoal (25 mg) and (3R, 3aR, 6R, 6aS)-benzyl 6-chloro-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (198 mg, 0.67 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 4.5 hours before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol (20 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with toluene (3×5 mL) to obtain (3R, 3aR, 6R, 6aS)-6-chlorohexahydro-2H-furo[3,2-b]pyrrol-3-ol (77) which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH2:49])=[CH:47][CH:48]=1)=[O:42])[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH:34]2[CH2:40][CH2:39][CH:38]1[CH2:37][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH:49][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:25])[CH3:1])[N:14]([CH:15]5[CH2:20][CH2:19][N:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:47][CH:48]=1)=[O:42])[CH2:35]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCN(C(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCN(C(C)(C)C)CC1
Yield: 49.1 %

Procedure:
Following general N—C coupling procedure 1, 1, 7-(1-tert-Butyl-piperidin-4-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (90 mg, 0.247 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (90 mg, 0.272 mmol, 1.1 eq) which gave 3-{6-[7-(1-tert-Butyl-piperidin-4-yl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (80 mg) in 47% yield. MS m/z 660.3 (M+H)+.
Reaction SMILES: Br[CH:2]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[N:10][CH:11]=1)[C:3]#[N:4]>[C].[Pd].O1CCOCC1>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:2][C:3]#[N:4])=[CH:11][N:10]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(Br)C#N)cn1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC#N)cn1
Yield: 80.4 %

Procedure:
A mixture of 2-bromo-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]propionitrile (2.0 g), palladium-carbon (5%, 0.2 g) and dioxane (30 ml) was subjected to catalytic reduction under 1 atmospheric pressure at room temperature. The catalyst was filtered off, then the filtrate was concentrated under reduced pressure. The concentrate was subjected to a silica gel column chromatography. From the fractions eluted with ethyl acetate--hexane (2:3, v/v), was obtained 3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]propionitrile (1.3 g, 78%), which was recrystallized from ethyl acetate--hexane to give colorless crystals, m.p.105°-106° C.