Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][NH:5][S:6]([CH3:9])(=[O:8])=[O:7].[H-].[Na+].Br[CH2:14][C:15]1[S:23][C:22]2[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:20][C:19]([Cl:30])=[N:18][C:17]=2[CH:16]=1>O1CCCC1>[Cl:30][C:19]1[N:20]=[C:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:22]2[S:23][C:15]([CH2:14][N:5]([CH2:4][CH2:3][N:2]([CH3:10])[CH3:1])[S:6]([CH3:9])(=[O:8])=[O:7])=[CH:16][C:17]=2[N:18]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CN(C)CCNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2-dimethylamino-ethyl)-methanesulfonamide (50 mg) in tetrahydrofuran under nitrogen was added sodium hydride, 60% dispersion in mineral oil, (13 mg). The reaction mixture was stirred at room temperature for 30 minutes, the 6-Bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine in tetrahydrofuran (5 ml) was added dropwise. The reaction mixture was stirred for 5 days. The solvents were removed in vacuo to give a crude product which was purified by flash chromatography to yield N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(2-dimethylamino-ethyl)-methanesulfonamide (35 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[C:25](F)[CH:24]=2)=[N:4][C:5]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)C(=O)OC(C)(C)C)=[CH:6][CH:7]=1.[CH3:31][O:32][CH2:33][C@H:34]([NH:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1)[CH3:35].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[C:25]([NH:43][C@H:40]3[CH2:39][CH2:38][C@H:37]([NH:36][C@H:34]([CH3:35])[CH2:33][O:32][CH3:31])[CH2:42][CH2:41]3)[CH:24]=2)=[N:4][C:5]([NH:8][CH2:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: COC[C@@H](C)N[C@H]1CC[C@H](N)CC1
Reactant: CC(C)(C)OC(=O)N(CC1CCCOC1)c1ccc(Cl)c(-c2cc(F)ncc2Cl)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H](C)N[C@H]1CC[C@H](Nc2cc(-c3nc(NC[C@@H]4CCCOC4)ccc3Cl)c(Cl)cn2)CC1
Temperature: 110 °C

Procedure:
To a scintillation vial was added racemic tert-butyl 3,5′-dichloro-2′-fluoro-2,4′-bipyridin-6-yl((tetrahydro-2H-pyran-3-yl)methyl)carbamate (114 mg, 0.250 mmol), trans-N1-((R)-1-methoxypropan-2-yl)cyclohexane-1,4-diamine (70 mg, 0.376 mmol) and DIPEA (0.088 ml, 0.501 mmol) followed by NMP (0.1 ml). The mixture was heated at 110° C. for 60 hr then concentrated in vacuo. The resulting residue was purified by reverse phase prep HPLC and lyapholized. The resulting white solid was free based by dissolving in EtOAc and then washing with 1M NaOH (×3), water (×2), saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was then purified by chiral separation chromatography to yield 3,5′-dichloro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-(((S)-tetrahydro-2H-pyran-3-yl)methyl)-2,4′-bipyridine-2′,6-diamine (mg), LCMS (m/z): 522.1/523.9 (MH+), tR=0.675 min. and 3,5′-dichloro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-(((R)-tetrahydro-2H-pyran-3-yl)methyl)-2,4′-bipyridine-2′,6-diamine (mg) LCMS 522.1/523.9 (m/z): (MH+), retention time=0.675 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8](CCCCCCCCCCCCCCC)[C:4]=1[C:5](Cl)=[O:6].[NH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1.C(N(CC)CC)C>ClCCl>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([NH:27][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:29][C:30]=1[C:36]([F:37])([F:38])[F:39])#[N:33]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Methoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1.OS(O)(=O)=O.C(Cl)Cl.CO.[CH3:19][CH2:20]O>>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:19][CH3:20])=[O:7])=[N:2]1
Reactant: O=C(O)c1cc[nH]n1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cc[nH]n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A 100 mL Schlenk tube was dried under vacuum, filled with nitrogen and charged with 0.5 g (4.461 mmol, 1.0 eq) 1H-pyrazol-3-carboxylic acid which was dissolved in 20 mL EtOH. After adding 1.31 g (0.72 mL, 13.382 mmol, 3.0 eq) conc. H2SO4 the colorless reaction mixture was heated to reflux (100° C.) and stirred at this temperature for 4 h. TLC analysis (DCM/MeOH 95:5) indicated full conversion of the starting material. After cooling to rt the mixture was transferred to a flask to remove the solvent at a rotary evaporator. The colorless residue was diluted in 20 mL water and neutralized with 17 mL saturated aqueous NaHCO3 solution. Thereby a white solid precipitated. The aqueous layer was extracted with EtOAc (4×50 mL), dried over MgSO4 and the solvent was evaporated under reduced pressure to yield the pure title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: N#Cc1cnccc1Cl
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc(CNc2ccncc2C#N)cc1
Yield: 93.2 %

Procedure:
A solution of 4-chloronicotinonitrile (1.00 g, 7.22 mmol), 4-methoxybenzylamine (1.03 ml, 7.94 mmol) and potassium carbonate (1.20 g, 8.66 mmol) in propan-2-ol (20 mL) was heated under reflux for 18 hours. The solvent was concentrated in vacuo and the residue partitioned between EtOAc (150 mL) and water (50 mL). The organic phase was dried (Na2SO4), filtered and evaporated to give a brown oil. The oil was pre-adsorbed onto H-MN and purified by flash column chromatography (Si-PPC, cyclohexane:EtOAc, gradient 80:20 to 0:100) to provide the title compound as a white solid (1.61 g, 93%). 1H NMR (CDCl3, 300 MHz) 8.46 (d, J=0.7 Hz, 1H), 8.30 (dd, J=6.1 Hz, 0.7 Hz, 1H), 7.24 (dd, J=8.6 Hz, 2.1 Hz, 2H), 6.92 (dd, J=8.6 Hz, 2.1 Hz, 2H), 6.55 (d, J=6.1 Hz, 1H), 5.35 (br t, 1H), 4.40 (d, J=5.6 Hz, 2H), 3.82 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.O.O[N:12]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:12])=[O:9])=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(Br)s1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A solution of 5-bromo-thiophene-2-carboxylic acid (4.51 g, 21.78 mmol), 3-hydroxybenzotriazole hydrate (3.24 g, 23.96 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (4.6 g, 23.96 mmol) in DMF (70 mL) is stirred at room temperature for 2 hours. The reaction mixture is then cooled to 0° C. and aq. 35% NH3 (2.2 mL) is added. The mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the residue dissolved in EtOAc, washed with 1N NaHCO3, and brine. The organic layers are combined, dried over MgSO4, filtered and concentrated to afford the title compound (3.78 g, 84%). HPLC (254 nm): Rt 2.46 min (96.5%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)([OH:3])=O.[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC>>[N:15]1([C:1](=[O:3])[CH2:4][C:5]2[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Reactant: C1CCCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)Cc1cccc(CC(=O)N2CCCCCC2)c1
Yield: 49.9 %

Procedure:
Prepared from (3-carboxymethyl-phenyl)-acetic acid (990 mg), azepane (500 g), 1-hydroxybenzotriazole (690 mg), Hunigs base (0.89 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980 mg), using the method of Example 44 (step a), to give 700 mg of the sub-titled compound as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.Cl.[CH3:11][N:12]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]1[C:18]([O:20][CH3:21])=[O:19].C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[C:3]([NH:17][C:15]2[CH:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:12]([CH3:11])[CH:16]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(N)cn1C
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Nc2nc(Cl)ncc2Br)cn1C

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine, 5-bromo-2,4-dichloropyrimidine and N-methyl-2-carbomethoxy-4-aminopyrrole hydrochloride with added diisopropylethylamine were reacted to produce the desired product 5-bromo-2-chloro-N—(N-methyl-2-carbomethoxypyrrol-4-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.21 (s, 1H), 7.43 (d, 1H, J=1.8 Hz), 7.13 (br s, 1H), 6.84 (d, 1H, J=1.8 Hz), 3.95 (s, 3H), 3.82 (s, 3H); LCMS: ret. time: 26.96 min.; purity: 91%; MS (m/e): 346 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[I:11]I>C(O)(=O)C>[I:11][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=1[OH:10]
Reactant: II
Reactant: CC(C)c1cccc(O)c1
Solvent: CC(=O)O
Product: CC(C)c1ccc(I)c(O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 160.8 %

Procedure:
A mixture of 3-isopropylphenol (670 mg, 4.92 mmol), KIO3 (210 mg, 0.98 mmol), and I2 (500 mg, 1.97 mmol) in acetic acid was stirred for 3 days at room temperature. The solvent was removed at reduced pressure. The residue was diluted with Et2O and washed with aq. NaHCO3, aq. Na2S2O3, and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography to give the title compound (830 mg, 64%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.C[S-:24].[Na+].Cl>CN(C)C=O.O>[CH2:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[CH2:16][CH2:17][CH2:18][N:12]1[C:4]1[CH:3]=[C:2]([SH:24])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: C[S-]
Reactant: Clc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (2 g, 6.47 mmol) and sodium thiomethoxide (2.4 g, 34 mmol) in dry N,N-dimethylformamide (20 mL) was heated with stirring overnight under reflux. The reaction mixture was cooled to 50° C. and the volatile components were evaporated under reduced pressure to give a residue which was dissolved in 30 mL of chilled water and carefully acidified with 20% hydrochloride aid to pH 4-5 under argon. The resultant solution was extracted with chilled dichloromethane (30 mL×3). The dichloromethane fractions were combined and washed with chilled brine (30 mL×2) and then concentrated under reduced pressure at room temperature to give the crude product. It was used in next step without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7](O)[CH2:8][OH:9]>>[C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: OCCO
Product: N#CCC(=O)OCCO
Yield: 74 %

Procedure:
Cyanoacetic acid was esterified with ethylene glycol according to U.S. Pat. No. 3,644,466 (col. 7-8, Ex. 3) to give the product in 74% yield.
Reaction SMILES: [CH3:1][C@H:2]([C@H:6]([CH3:10])[CH2:7][CH2:8][CH3:9])[C:3](O)=[O:4].[Cl-].[Cl:12]C=[N+](C)C>ClCCl>[CH3:1][C@H:2]([C@H:6]([CH3:10])[CH2:7][CH2:8][CH3:9])[C:3]([Cl:12])=[O:4]
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)O
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Solvent: ClCCl
Product: CCC[C@@H](C)[C@@H](C)C(=O)Cl
Reaction time: 1.5 h

Procedure:
To a solution containing 2.0 g (13.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 20 mL of dichloromethane was added 2.1 g (16.6 mmol) of chloromethylene dimethyl-ammonium chloride. After stirring the resulting solution under nitrogen for 1.5 hours, the solvent was evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. Butyl lithium (32.7 ml, 52.4 mmol) was added to a solution of diisopropylamine (4.9 g, 48.5 mmol) in dry THF (20 mL) under nitrogen at 0° C. and stirred for 20 minutes. The solution was cooled to −78° C. and 4.3 g (48.5 mmol) of ethyl acetate was added. The solution was stirred at that temperature for 45 minutes. (2R,3R)-2,3-Dimethyl-hexanoyl chloride in dry THF (20 mL) was slowly added to the ethyl acetate enolate at −78° C. and the resulting reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and was cooled to 0° C. The reaction was quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 2.7 g (89.2% yield) of the titled compound as an oil.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][C:6](=[CH:9][O:10]C)[CH2:5][CH2:4]2)[O:2]1.O>C(O)(=O)C>[CH:9]([CH:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]1)=[O:10]
Reactant: COC=C1CCC2(CC1)OCCO2
Solvent: O
Solvent: CC(=O)O
Product: O=CC1CCC(=O)CC1
Yield: 92.7 %

Procedure:
A mixture of 10.55 g of 1,1-ethylenedioxy-4-(methoxymethylene)cyclohexane, 130 ml of water and 200 ml of glacial acetic acid was heated to reflux for 1 hour. The solvent was subsequently distilled off on a rotary evaporator and the distillate was extracted twice with methylene chloride. The distillation residue (a yellow oil) was diluted with 200 ml of water, neutralized with sodium carbonate solution and extracted three times with methylene chloride. The organic phases were washed with saturated sodium carbonate solution and the aqueous phases were back-extracted with methylene chloride. The organic phases were dried over magnesium sulphate and evaporated. Distillation of the residual, yellow oil gave, at 70° C./0.15 Torr, 6.7 g (93%) of 4-formylcyclohexanone.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Cl:6].[CH3:7][C:8]1([OH:18])[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH2:10]3)[CH2:14]2.C(N(CC)CC)C>C1COCC1>[CH3:7][C:8]1([O:18][CH2:2][O:3][CH2:4][CH2:5][Cl:6])[CH:9]2[CH2:17][CH:13]3[CH2:12][CH:11]([CH2:16][CH:15]1[CH2:14]3)[CH2:10]2
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Reactant: ClCCOCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(OCOCCCl)C2CC3CC(C2)CC1C3
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A two neck Kjeldahl flask of 50 ml into which a stirrer was put was charged with 1.55 g (12 mmol) of chloroethyl chloromethyl ether obtained in Example 1 (1), 1.66 g (10 mmol) of 2-methyl-2-adamantanol, 1.52 g (15 mmol) of triethylamine and dried THF, and it was equipped with a coiled condenser to reflux and stir the solution for 8 hours. Triethylamine hydrochloride was filtered, and gas chromatographic analysis was carried out to find that 2-methyl-2-adamantanol was converted by 46.2% and that 2.04 g (7.9 mmol, isolation yield: 78.8%) of a colorless liquid which was the intended product was obtained at a selectivity of 97.3%.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]2[CH:11]=[C:12]([CH:15]=[O:16])[O:13][CH:14]=2)=[N:3][CH:2]=1.P([O-])(O)(O)=[O:18].[Na+].Cl([O-])=O.[Na+]>CS(C)=O.O>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]2[CH:11]=[C:12]([C:15]([OH:18])=[O:16])[O:13][CH:14]=2)=[N:3][CH:2]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1cc(-c2ncnc3[nH]ccc23)co1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc(-c2ncnc3[nH]ccc23)co1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
600 mg [2.82 mMols] of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carbaldehyde was dissolved in 5.0 mL of DMSO/2.0 mL of water and stirred with 210 mg [1.75 mMols] of sodium dihydrogen phosphate, reducing the temperature as cold as possible so as not to effect crystallization. 532 mg sodium chlorite [5.88 mMols] in 4.0 mL of water was slowly added dropwise to this stirring solution. Solution was allowed to warm to ambient temperature and diluted with water to effect precipitation. The fine flocculent material was centrifuged down and washed with water and re-centrifuged. The oily pellet was transferred to a RB with acetonitrile and the solvents were removed under reduced pressure. The residue was stirred with a mixture of MTBE/acetonitrile (4:1) overnight and the powder isolated in the morning via suction filtration, washed with the same mixture and air dried. The material, (yield 64.6%) a beige powder, was utilized without further purification. LC/MS m+1 230/m−1 228.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[C:4]([F:26])[CH:3]=1.[OH-].[Na+].[NH2:29]O.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[C:4]([F:26])[CH:3]=1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(Cl)cc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 97.6 %

Procedure:
Trans-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (500 mg, 1.30 mmol) (from example 45, step 1) was dissolved in MeOH (6 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.381 mL, 1.30 mmol) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.079 mL, 1.30 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (6.67 mL, 40.05 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.45 g, 98%) as a slightly yellow dry film. MS m/z 355 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]3[C:18]4[C:23]([CH:24]=[CH:25][C:10]2=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:5][CH:4]=1.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:15](=[O:16])[CH2:14][C:13](=[O:17])[NH:12][C:11]3[C:18]4[C:23]([CH:24]=[CH:25][C:10]2=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:5][CH:4]=1)=[O:30]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NCc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: O=C1CC(=O)N(c2ccc(CNC(=O)c3ccccc3Cl)cc2)c2ccc3ccccc3c2N1

Procedure:
By using 5-[4-(aminomethyl)phenyl]-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 43, (3), and 2-chlorobenzoyl chloride, the title compound was obtained in the same manner as that of Example 43, (5).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[CH2:15][NH:16]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.Br>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)[CH2:15][NH2:16])=[CH:9][CH:8]=2)=[CH:37][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)NCC(Nc2ccc(Oc3ccc(Cl)cc3)cc2)c2cccc(C(F)(F)F)c2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Product: NCC(Nc1ccc(Oc2ccc(Cl)cc2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
A solution of N-(2-(4-(4-chlorophenoxy)phenylamino)-2-(3-(trifluoromethyl)phenyl)ethyl)-4-methylbenzenesulfonamide (358 mg, 0.638 mmol) and phenol (180 mg, 1.92 mmol) in 30 wt % HBr in acetic acid (3.5 mL) is heated at 80° C. for 2 h. After cooling down to room temperature, most of the solvent is removed under vacuo. The residue is then quenched with cold saturated NaHCO3 aqueous solution (40 mL) and extracted with EtOAc (3×20 mL). The combined organic layer is concentrated and purified by reverse phase HPLC to provide N1-(4-(4-chlorophenoxy)phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamine (128 mg, 49% yield) as a light yellow oil-like product.
Reaction SMILES: [NH2:1][C:2]([CH3:11])([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CO>[CH2:23]([O:22][C:20]([NH:1][C:2]([CH3:11])([CH2:6][C:7]([F:8])([F:9])[F:10])[C:3]([OH:5])=[O:4])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(N)(CC(F)(F)F)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(CC(F)(F)F)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 2-amino-4,4,4-trifluoro-2-methylbutanoic acid (255 mg, 1.4 mmol) and triethylamine (800 ul, 4.2 mmol) in MeOH (3 ml) was cooled to 0° C. and benzyl chloroformate (509 mg, 2.98 mmol) was added dropwise. The solution was warmed to RT overnight and concentrated in vacuo. The residue was suspended in EtOAc and extracted with sat. NaHCO3, the aqueous layers acidified with conc. HCl, and the resulting milkly suspension extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the title compound. LRMS (ESI/APCI, negative): 304 [M−H+].
Reaction SMILES: Cl[Si](C)(C)C.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[S:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14].Cl>ClCCl>[CH3:21][O:20][C:18]([C:17]1[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=1[S:13]([NH:6][C:11]1[CH:24]=[CH:25][C:16]2[C:9](=[CH:8][CH:7]=[CH:22][CH:17]=2)[C:10]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14])=[O:19]
Reactant: c1ccncc1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 133A (0.50 g, 2.48 mmol) in dichloromethane (8.0 mL) was treated with chlorotrimethylsilane (3.0 mL of 1M solution in CH2Cl2, 2.98 mmol) and pyridine (8.0 mL), stirred at room temperature for 1 hour, treated with methyl 2-(chlorosulfonyl)benzoate (0.873 g, 3.72 mmol), stirred overnight at room temperature treated with 1N HCl (20 mL), and extracted with dichloromethane (2×). The combined organic phases were dried (MgSO4), filtered, and concentrated. The resulting residue was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 400 (M+H)+; (ESI(−)) m/e 398 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.85 (d, 7.90, 1H), 7.80 (d, 1H), 7.72 (m, 2H), 7.65 (ddd, 1H), 7.56 (m, 2H), 7.50 (d, 1H), 3.80 (s, 3H), 3.78 (s, 3H).