Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:19]([C:16]2[S:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[O:22][C@H:23]4[CH2:27][CH2:26][O:25][CH2:24]4)[C:10]=3[C:17]=2[CH3:18])=[O:20])[CH2:31][CH2:30]1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c12
Reactant: CN1CCC(N)CC1
Product: Cc1c(C(=O)NC2CCN(C)CC2)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c12

Procedure:
Prepared analogously to example 1.4 from 4-{4-fluoro-2-[(S)-(tetrahydro-furan-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 1-methyl-piperidin-4-ylamine.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7](=[S:13])[S:8][CH2:9][C:10](Cl)=[CH2:11])=[C:4]([CH3:16])[CH:3]=1.[Br:17]C1C=CC(NC(=S)[S-])=C(C)C=1.C([NH+](CC)CC)C>>[Br:17][C:15]1[CH:2]=[CH:3][C:4]([CH3:16])=[C:5]([N:6]=[C:7]2[S:13][C:10]([CH3:11])=[CH:9][S:8]2)[CH:14]=1
Reactant: Cc1cc(Br)ccc1NC(=S)[S-]
Reactant: C=C(Cl)CSC(=S)Nc1ccc(Br)cc1C
Agent: CC[NH+](CC)CC
Product: Cc1csc(=Nc2cc(Br)ccc2C)s1

Procedure:
By the procedure of Example 1, 2-chloroallyl 4-bromo-2-methyldithiocarbanilate is prepared substituting triethylammonium 4-bromo-2-methyldithiocarbanilate for the 4-chloro derivative of the same and cyclized as in Example 1 to yield 2-(4-bromo-o-tolyl)imino-4-methyl-1,3-dithiole in good yield and purity.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([C@H:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH2:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)=O)=[CH:7][CH:6]=2)[CH2:2]1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([C@H:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH2:12]/[C:13](/[C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)=[N:30]\[OH:31])=[CH:7][CH:6]=2)[CH2:2]1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CNC3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CNC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from (R)-3-(4-(azetidin-3-yl)phenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=386.0 ([M+H]+).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][C:10]([C:12]1[CH:17]=[C:16](OC)[CH:15]=[CH:14][N:13]=1)=[O:11].C[C:22](O)=[O:23]>Cl.O>[CH3:22][O:23][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:2]3[C:3]([C:8](=[O:20])[CH:9]=2)=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:13][CH:14]=1
Reactant: COc1ccnc(C(=O)CC(=O)c2ccccc2O)c1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: COc1ccc(-c2cc(=O)c3ccccc3o2)nc1
Temperature: 100 °C
Yield: 98 %

Procedure:
1-(2-Hydroxy-phenyl)-3-(4-methoxy-pyridin-2-yl )-propane-1,3-dione (870 mg, 3.21 mmol) was dissolved in a mixture of 48% HCl (1 mL) and AcOH (10 mL) and heated at 100° C. for 1 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried and concentrated to give 2-(5-methoxy-pyridin-2-yl)-chromen-4-one (794 mg, 98%).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].[CH3:7][PH:8](=[O:10])[CH3:9]>C(OCC)(=O)C>[CH3:7][P:8]([CH3:9])([CH:3]([OH:4])[C:2]([OH:6])=[O:5])=[O:10]
Reactant: C[PH](C)=O
Reactant: O=CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CP(C)(=O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
14.8 g (0.2 mol) of glyoxylic acid hydrate in 80 ml of ethyl acetate are added dropwise to a solution of 15.6 g (0.2 mol) of dimethylphosphine oxide in 80 ml of ethyl acetate. During this addition, the temperature rises slightly. The mixture is stirred at 25° C. for 24 hours and the product is filtered off with suction and washed with a little ethyl acetate to give, after drying, 20.2 g (66.5%) of the desired product of melting point 206°-208°.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[Cl:23])=[C:13]([Cl:24])[C:8]2[N:9]=[CH:10][N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].C1COCC1.O.[OH-].[Na+].Cl>O>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[N:11]([CH3:12])[CH:10]=[N:9][C:8]=3[C:13]=2[Cl:24])=[C:17]([Cl:23])[CH:18]=1
Reactant: COC(=O)c1cc2c(ncn2C)c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc21
Reaction time: 4 h

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester 10ee (21 mg, 0.048 mmol) is dissolved into 2:1 THF/water (1.2 mL) and NaOH (0.190 mL, 1.0 M aqueous solution, 0.190 mmol) is added. After stirring for 4 hours the reaction is diluted with water and acidified to pH 2 by addition of 1.0 M HCl. The mixture is then extracted with 3:1 EtOAc/THF (3×), dried (Na2SO4) and concentrated to give quantitative yield of desired product as a white solid. MS APCI (+) m/z 414, 416 (M+, Br pattern) detected.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([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.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[C:28]2=[O:36])=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:33](=[O:34])[CH2:32][N:29]2[CH2:30][CH2:31][C:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)[C:28]2=[O:36])[CH2:16][CH2:15]1)([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
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzhydrylpiperazine (0.54 g, 2.14 mmol) in dichloromethane (20 mL) under nitrogen was added the product from Example 58D (0.71 g, 2.14 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.82 g, 4.29 mmol) and N,N-dimethylpyridin-4-amine (0.013 g, 0.11 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.37-7.41 (m, 4H), 7.25-7.33 (m, 8H), 7.16-7.23 (m, 2H), 6.94-7.01 (m, 4H), 4.19 (s, 1H), 4.14 (s, 2H), 3.58 (t, J=4.7 Hz, 2H), 3.49 (t, J=6.5 Hz, 2H), 3.38-3.42 (m, 2H), 2.75 (t, J=6.5 Hz, 2H), 2.36 (t, J=4.8 Hz, 2H), 2.29 (t, J=4.6 Hz, 2H).
Reaction SMILES: [OH-].[K+].[CH2:3]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:24][CH:23]=3)=[C:20]([CH3:38])[N:19]=[C:18]([CH3:39])[C:17]=2[C@H:40]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C:41]([O:43]C(C)C)=[O:42])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)C>[CH2:3]([CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:24][CH:23]=3)=[C:20]([CH3:38])[N:19]=[C:18]([CH3:39])[C:17]=2[C@H:40]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C:41]([OH:43])=[O:42])[CH2:14][CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(Cc3ccccc3)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(Cc3ccccc3)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 25.3 %

Procedure:
The potassium hydroxide (86 mg, 1.54 mmol) was added to a station (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (102 mg, 0.154 mmol) in ethanol (3 mL) and stirred for 12 h at 90° C. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep HPLC to give (S)-2-(4-(4-benzylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid 24.3 mg (25%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.37 (m, 2H), 7.24-7.22 (m, 2H), 7.18-7.12 (m, 4H), 7.10 (t, J=7.7 Hz, 2H), 6.99-6.92 (m, 3H), 5.77 (s, 1H), 4.21 (t, J=6.6 Hz, 2H), 3.47-3.37 (m, 4H), 3.06 (t, J=6.2 Hz, 2H), 2.46-2.44 (m, 2H), 2.42 (s, 3H), 2.01 (s, 3H), 1.66 (t, J=10.6 Hz, 1H), 1.44-1.41 (m, 1H), 1.34-1.22 (m, 3H), 1.09 (m, 9H). UPLC (M+H)=625.4.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.C[N:10]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C@H:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:11]1.C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1.Cl[C:45]([O:47][CH2:48][CH3:49])=[O:46]>CCOCC.O>[CH2:48]([O:47][C:45]([N:10]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[C@H:12]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:11]1)=[O:46])[CH3:49]
Reactant: CN1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](c2ccccc2)C1
Reactant: CCOC(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)N1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](c2ccccc2)C1

Procedure:
A mixture of 3.63 g of the free base of Example 3, 1.6 g of anhydrous potassium carbonate and 25 ml of anhydrous benzene is treated with 1.22 ml of ethyl chloroformate, and the mixture is allowed to reflux 18 hours under nitrogen. Then another 0.44 ml of ethyl chloroformate is added and the mixture is refluxed 18 hours, then poured into a mixture of 100 ml of water and 100 ml of ether. The aqueous phase is extracted with ether. The combined ether extracts are washed with water and saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated in vacuo to a gum. This material is chromatographed on silica gel, using chloroform as solvent. A fraction of pure material and two fractions of slightly less pure material are obtained. The product of trans-1-ethoxycarbonyl-4-(4-nitrophenoxy)-3-phenylpiperidine is obtained as a glass.
Reaction SMILES: [C:1]([S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)(=O)[CH3:2].C[O-].[Na+].CO.C(Br)[C:19]1[CH:24]=[CH:23]C=[CH:21][CH:20]=1.[Cl-].[NH4+]>CO>[CH2:1]([S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)[C:2]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)Sc1ncn2ccsc12
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc(CSc2ncn3ccsc23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 396 mg of 7-acetylthioimidazo[5,1-b]thiazole in 2 ml of methanol was cooled in ice. A 1.018 M sodium methoxide/methanol solution (2.16 ml) was added to the cooled solution, and the mixture was stirred for 30 min. Benzyl bromide (0.262 ml) was added thereto, and the mixture was stirred at that temperature for 2 hr. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with brine twice, and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=30:1) to prepare 419 mg of 7-benzylthioimidazo[5,1-b]thiazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1)CCC>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>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)OC)cc(-c2cnccn2)c1
Yield: 73.9 %

Procedure:
To dimethyl 5-bromoisophthalate (617 mg, 2.26 mmol) in toluene (10 ml), 2-tributylstannyl pyrazine (1 g, 2.71 mmol) was added followed by Pd(PPh3)4 (102 mg, 0.09 mmol). Then reaction mixture was refluxed for 22 h. Then the reaction mixture was filtered through celite and volatiles were removed under vacuum. Crude residue was column chromatographed (50% ethylacetate/50% Hexanes) to obtain 455 mg of dimethyl 5-(pyrazin-2-yl)isophthalate as a pale yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:34])[NH:16][C:17](=[O:33])[N:18]([CH2:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=3[F:32])[C:19]=2[CH3:20])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.ClCCl.[Pd]>[F:32][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([F:31])([F:30])[F:29])[C:22]=1[CH2:21][N:18]1[C:19]([CH3:20])=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15](=[O:34])[NH:16][C:17]1=[O:33]
Reactant: Cc1c(N2CCN(Cc3ccccc3)CC2)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(N2CCNCC2)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Yield: 77.7 %

Procedure:
To a solution of 5-(4-benzyl-piperazin-1-yl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione (1.48 g, 3.11 mmol) in 10 mL of methanol/dichloromethane (1/1) was added 10% palladium/carbon (280 mg), after which the solution was stirred at room temperature for 5 hrs in a hydrogen atmosphere. Following the removal of palladium/carbon therefrom by filtration through cellite, the solution was concentrated. The residue was purified using amine silica gel chromatography (eluent: dichloromethane/methanol, 30/1→10/1) and dried in a vacuum to afford 934 mg of the compound as a white solid. (yield 79%). 1H NMR (300 MHz, CDCl3) δ 2.32 (3H, s), 2.52 (2H, m), 2.83 (2H, m), 2.96 (2H, m), 3.43 (2H, m), 5.37 (2H, s), 7.22 (1H, d), 7.40 (1H, dd), 7.54 (1H, d)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[N:7]1([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([C:28]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][CH2:3][C:4]([N:33]1[CH2:34][CH2:35][N:30]([C:28]([C:22]2([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][CH2:12][N:7]4[CH2:8][CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:18]=3)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:29])[CH2:31][CH2:32]1)=[O:5]
Reactant: O=C(N1CCNCC1)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)N1CCN(C(=O)C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Methoxyacetyl chloride (55 μl, 0.6 mmol) was added dropwise at 0° C. to a solution of 1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}carbonyl)piperazine of example 181 (200 mg, 0.5 mmol) and N,N-diisopropylethylamine (100 μl, 0.6 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (20 ml) and washed with 2N sodium hydroxide (20 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (20 ml). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 90:10:1 by volume) to provide the title compound (160 mg, 67%). HRMS ESI+ m/z 474.2952 [MH]+.
Reaction SMILES: C([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][F:11])C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[ClH:28].C(O)C>CO.[Pd]>[ClH:28].[F:11][CH2:10][C@@H:9]([NH2:8])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[C@@H](CF)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Solvent: CCO
Product: CC(C)(C)[C@H](N)CF
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)—N-benzyl-1-fluoro-3,3-dimethylbutan-2-amine (4.12 g, 19.68 mmol) in methanol (50 mL) was added 10% palladium on carbon (2.095 g, 1.968 mmol). The reaction mixture was shaken under H2 atmosphere (60 Psi) for 24 h, a 1.25 M solution of HCl in ethanol (31.5 mL, 39.4 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solid was filtered through Celite, washed with methanol. The filtrate was concentrated to give the title compound (3.1 g). 1H NMR (400 MHz, DMSO-d6) δ 0.96 (s, 9H), 3.11-3.20 (m, 1H), 4.55-4.82 (m, 2H), 8.26 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][CH:2]2[CH3:1])=[CH:17][C:18]=1[C:24]([F:25])([F:26])[F:27])#[N:21]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
A 4.46 g portion of t-butyl 3-methylpiperazine-1-carboxylate synthesized in Reference Example 2, 6.74 g of 4-fluoro-2-trifluoromethylbenzonitrile and 7.76 ml of diisopropylethylamine were stirred in 50 ml of DMF at 100° C. for 2 days. The reaction solution was diluted with water and extracted with ethyl acetate, the organic layer was washed and dried and then the solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (3:1, v/v) to obtain 5.6 g of the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([CH3:23])[CH:3]=1.[CH2:24]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([NH:1][CH3:24])=[CH:3][C:4]=2[CH3:23])[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: Cc1cc(N)ncc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1cc(C)c(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To 1,1-dimethylethyl (2S)-4-[(6-amino-4-methyl-3-pyridinyl)methyl]-2-methyl-1-piperazinecarboxylate (D100) (0.067 g, 0.21 mmol) in dry MeOH (4 mL) under an argon atmosphere was added paraformaldehyde (0.019 g, 0.63 mmol) and sodium methoxide (0.057 g, 1.00 mmol). The mixture was stirred at 50° C. overnight then sodium borohydride (0.024 g, 0.63 mmol) was added and the reaction stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between DCM and saturated aqueous NaHCO3 and stirred for 0.5 h. The aqueous phase was extracted with DCM (3×5 mL) and the combined organics were dried and concentrated to give a crude colourless oil. Column chromatography eluting with 0-10% MeOH/DCM gave the crude title compound as a colourless oil (0.037 g) which was used in the next step without further purification. MS (ES): MH+ 335.3.
Reaction SMILES: [Cl:1][CH:2]([CH2:7][C:8]([Cl:14])([Cl:13])[C:9]([Cl:12])([F:11])[F:10])[CH2:3][C:4](O)=[O:5].S(Cl)([Cl:17])=O>CN(C)C=O>[Cl:1][CH:2]([CH2:7][C:8]([Cl:14])([Cl:13])[C:9]([Cl:12])([F:11])[F:10])[CH2:3][C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC(Cl)CC(Cl)(Cl)C(F)(F)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CC(Cl)CC(Cl)(Cl)C(F)(F)Cl

Procedure:
276 g of 2,4,4,5-tetrachloro-5,5-difluoropentane-1-carboxylic acid, 300 ml of thionyl chloride and 1 ml of N,N-dimethylformamide are mixed together, and the mixture is heated within 1 hour to 60° C. and finally refluxed for 1 hour. After the excess thionyl chloride has been distilled off, the residue is fractionally distilled to thus obtain 250.2 g (85% of theory) of 2,4,4,5-tetrachloro-5,5-di-fluoropentane-1-carboxylic acid chloride in the form of a clear liquid, which boils at 95°-97° C./2000 Pa.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:15]=[C:14](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[O:26])[CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[S:34]1[CH:38]=[CH:37][C:36]([Mg]Br)=[CH:35]1>C1COCC1>[C:1]([O:5][C:6]1[CH:15]=[C:14](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:36]3[CH:37]=[CH:38][S:34][CH:35]=3)[OH:26])[CH:12]=2)[N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Br[Mg]c1ccsc1
Reactant: CC(C)(C)Oc1cc(/C=C/c2cccc(F)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(/C=C/c2cccc(F)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3ccsc3)ccc2n1
Reaction time: 3 h

Procedure:
To a solution of (E)-(2-(tert-butoxy)-4-(3-fluorostyryl)quinolin-6-yl)(4-chlorophenyl)methanone (90 mg, 0.196 mmol) in THF (2 mL) was slowly added thiophen-3-ylmagnesium bromide (1.04 mL, 0.313 mmol, 0.3M in toluene) and the resulting solution was kept at 0° C. for 3 hr. The reaction was quenched with saturated NH4Cl at 0° C. and the aqueous layer was extracted with EtOAc. The combined organics were purified by silica column chromatography (20-30% EtOAc/hexanes) to yield (E)-(2-(tert-butoxy)-4-(3-fluorostyryl)quinolin-6-yl)(4-chlorophenyl)(thiophen-3-yl)methanol.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([N:22]([CH:29]([CH3:31])[CH3:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:21])[C:15]2[CH:32]=[CH:33][CH:34]=[CH:35][C:14]=2[C:13]([CH3:36])=[N:12]1>C(Cl)Cl>[CH:29]([N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](=[O:21])[CH2:19][N:16]1[C:15]2[CH:32]=[CH:33][CH:34]=[CH:35][C:14]=2[C:13]([CH3:36])=[N:12][CH:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[C:17]1=[O:18])([CH3:31])[CH3:30]
Reactant: O=C=Nc1ccccc1
Reactant: CC1=NC(N)C(=O)N(CC(=O)N(c2ccccc2)C(C)C)c2ccccc21
Solvent: ClCCl
Product: CC1=NC(NC(=O)Nc2ccccc2)C(=O)N(CC(=O)N(c2ccccc2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
According to Process A, phenyl isocyanate (0.065 mL, 0.602 mmol) is added to a solution of 2-(3-Amino-5-methyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (219 mg, 0.602 mmol), prepared as in Intermediate 24, under nitrogen in DCM (3 mL). The reaction mixture is stirred at ambient temperature overnight and then concentrated in vacuo. The residue is dissolved in ethyl acetate, washed twice with 1N HCl, dried over anhydrous magnesium sulfate, and then concentrated again to a residue. The crude product is purified by reversed-phase HPLC on a C-18 column with 60% acetonitrile in aqueous trifluoroacetic acid (0.1% v/v) over 30 min. at 100 mL/min. Fractions containing the product are combined, frozen and lyophilized to provide the title compound as a white lyophile (92 mg, 0.190 mmol). 1H NMR (300 MHz, CDCl3) δ=1.02-1.25 (m, 6H); 2.59 (s, 3H); 4.08 (d, J=16.9 Hz, 1H); 4.17 (d, J=16.9 Hz, 1H); 4.93-5.00 (m, 1H); 5.56 (d, J=6.3 Hz, 1H); 7.02-7.61 (m, 14H); MS(FAB): [M+H]+ =484.