Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[NH2:48][C:49]1[C:50]([C:54](O)=[O:55])=[N:51][O:52][N:53]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:48][C:49]1[C:50]([C:54]([N:43]2[CH2:44][CH2:45][CH:40]([CH2:39][C:38]([NH:37][C:29]3[CH:30]=[CH:31][C:32]4[NH:33][C:34]5[N:35]=[C:19]([NH:20][C:21]6[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=6)[CH2:26][CH2:27][C:28]=3[CH:36]=4)[N:18]=[CH:17][C:16]=5[Cl:15])=[O:46])[CH2:41][CH2:42]2)=[O:55])=[N:51][O:52][N:53]=1
Reactant: Nc1nonc1C(=O)O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Nc1nonc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 4-amino-1,2,5-oxadiazole-3-carboxylic acid as starting materials in 41% yield. LCMS for C27H28ClN10O3 (M+H)+: m/z=575.2.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:12])[C@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1.Cl[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:25]=1[C:24]1[CH2:23][CH2:22][CH2:21][C:20]=1[S:19]2>CN(C=O)C>[CH3:3][N:4]([CH3:12])[CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:25]=2[C:24]2[CH2:23][CH2:22][CH2:21][C:20]=2[S:19]3)[CH2:7][CH2:6]1
Reactant: CN(C)[C@H]1CC[C@H](O)CC1
Reactant: Clc1cccc2sc3c(c12)CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1CCC(Oc2cccc3sc4c(c23)CCC4)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
Sodium hydride (69 mg, 1.73 mmol, 3.00 equiv, 60% dispersion in mineral oil) was treated with trans-4-(dimethylamino)cyclohexan-1-ol (164 mg, 1.15 mmol, 2.00 equiv) in distilled DMF (15 mL) at room temperature for 1 h under nitrogen. Then a solution of 12-chloro-7-thiatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraene (120 mg, 0.57 mmol, 1.00 equiv) in 3 mL of DMF was added via syringe and the resulting solution was stirred for 2 h at 80° C. in an oil bath. After cooling, the reaction was quenched with water and extracted with 5×50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (Waters): Column: Xbridge Prep C18, 5 μm, 19*50 m; water with 0.05% NH4HCO3 and CH3CN (10% CH3CN up to 40% CH3CN in 10 min); flow rate: 20 mL/min; UV detection at 254 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired N,N-dimethyl-4-[7-thiatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yloxy]cyclohexan-1-amine (56.9 mg) as a brown solid. MS (ES): m/z: 317 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 1.49-1.64 (4H, m), 2.04 (2H, d), 2.29 (2H, d), 2.36 (6H, s), 2.43-2.51 (2H, m), 2.99-3.08 (4H, m), 4.37-4.45 (1H, m), 6.67 (1H, d, J=5.6 Hz), 8.27 (1H, d, J=5.6 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+]([O-])=O.[ClH:22].CO.O>C(O)C.C(OCC)(=O)C.[Pd]>[Cl:22][C:3]1[CH:4]=[C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: Cl
Reactant: CCOC(=O)c1sc(-c2ccc(O)c([N+](=O)[O-])c2)nc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(O)c(Cl)c2)nc1C
Temperature: 60 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
5.0 g of Ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate was dissolved in 120 ml of ethanol and 60 ml of ethyl acetate, and 2 ml of concentrated hydrochloride and 500 mg of a 10% palladium/carbon was added thereto, and the mixture was stirred under a hydrogen atmosphere for 24 hours. After the completion of the reaction, methanol and water were added thereto, the mixture was filtered, and the filtrate was concentrated. The resulting crystal was suspended in 25 ml of 2N hydrochloric acid and 25 ml of acetone, and a solution of 1.2 g of sodium nitrite in 8 ml of water was gradually added thereto with ice cooling. Separately, 2.2 g of cuprous chloride was suspended in 15 ml of 2N hydrochloric acid and the diazonium salt solution was gradually added thereto with ice cooling. After the completion of the dropwise addition, the reaction mixture was heated to 60° C., and one hour after the heating, 100 ml of water was added thereto. The precipitated crystal was collected by filtration. This product was purified by silica gel chromatography to give 4.4 g of ethyl 2-(3-chloro-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]2[CH2:15][C:14]3([CH2:20][CH2:19]C[CH2:17][CH2:16]3)[N:13]([C:21]([C:23]3[N:27]=[CH:26][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]=3)=[O:22])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[Cl:41]C1C=C(C(N2CCNC(CC)(CC)C2)=O)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:21]([C:23]3[N:27]=[CH:26][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:41])[CH:29]=4)[N:24]=3)=[O:22])[C:14]([CH2:16][CH3:17])([CH2:20][CH3:19])[CH2:15]2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cccc(Cl)c1)N1CCN(C(=O)c2ncn(-c3ccccc3)n2)C2(CCCCC2)C1
Reactant: CCC1(CC)CN(C(=O)c2cccc(Cl)c2)CCN1
Solvent: O=C(O)C(F)(F)F
Product: CCC1(CC)CN(C(=O)c2cccc(Cl)c2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1

Procedure:
By using the same synthesis strategy as for (3-chloro-phenyl)-[1-(1-phenyl-1H-[1,2,4]-triazole-3-carbonyl)-1,4-diaza-spiro[5.5]undec-4-yl]-methanone the following compounds were prepared from (3-chloro-phenyl)-(3,3-diethyl-piperazin-1-yl)-methanone trifluoroacetate as amine and the respective carboxylic acid:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]2[N:8]([CH:22]=[CH:23][N:24]=2)[C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[C:11]([CH:20]=O)[CH:10]=2.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.[BH4-].[Na+]>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][CH2:20][C:11]1[CH:10]=[C:9]2[C:14]([N:15]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])[C:7]3[N:8]2[CH:22]=[CH:23][N:24]=3)=[CH:13][C:12]=1[C:16]([F:17])([F:18])[F:19]
Reactant: O=Cc1cc2c(cc1C(F)(F)F)nc(NCCCO)c1nccn12
Reactant: Nc1ccccn1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: OCCCNc1nc2cc(C(F)(F)F)c(CNc3ccccn3)cc2n2ccnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.7 %

Procedure:
To a solution of 4-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)imidazo[1,2-a]quinoxaline-8-carbaldehyde (25 mg; 0.07 mmol; 1 eq), 2-aminopyridine (20 mg; 0.21 mmol; 3 eq) and titanium tetraisopropoxide (60 mg; 0.21 mg; 3 eq) in anhydrous tetrahydrofuran (0.2 ml) with a few 4A molecular sieves stirred under Ar at rt for 5 h is added sodium borohydride (3 mg; 0.07 mmol; 1 eq). The resulting reaction mixture is then stirred under Ar at rt for 16 h. Partition (aqueous ammonium chloride/ethyl acetate), filtration over Celite, extraction of the aqueous phase (ethyl acetate), reunion of the organic phases, drying (magnesium sulphate) and purification by prep CCM on silicagel (dichloromethane/methanol 95:5) affords the title product (7.4 mg; 0.018 mmol; 25%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:11][CH:10]2[C:6]([C:12]3[S:13][C:14]([F:17])=[CH:15][CH:16]=3)([NH:7][O:8][CH2:9]2)[CH2:5]1)[CH:2]=[CH2:3].[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:1]([N:4]1[CH2:11][CH:10]2[C:6]([C:12]3[S:13][C:14]([F:17])=[CH:15][CH:16]=3)([N:7]([C:27]([NH:26][C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[S:28])[O:8][CH2:9]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CC2CONC2(c2ccc(F)s2)C1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: C=CCN1CC2CON(C(=S)NC(=O)c3ccccc3)C2(c2ccc(F)s2)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.9 %

Procedure:
To a stirred solution of 5-allyl-6a-(5-fluoro-2-thienyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (4.22 g, 16.59 mmol) in tetrahydrofuran (83 mL) is added benzoyl isothiocyanate (2.7 mL, 19.9 mmol). The resulting solution is stirred under nitrogen at room temperature for 19 hours. The solution is concentrated and the residue is purified by silica gel flash chromatography eluting with hexanes/ethyl acetate (two-step gradient from 80:20 to 70:30 to 60:40) to give the title compound (6.92 g, 100%). ES/MS (m/e): 418 (M+H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9][CH2:10][CH2:11][F:12])[S:8][C:4]=2[CH:3]=1.[CH3:15][N:16]([C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=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>[F:12][CH2:11][CH2:10][S:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([C:27]3[CH:26]=[CH:25][C:24]([N:16]([CH3:15])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:29][CH:28]=3)[CH:14]=[CH:13][C:5]=2[N:6]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FCCSc1nc2ccc(Br)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2ccc3nc(SCCF)sc3c2)cc1
Temperature: 95 °C

Procedure:
A mixture of 6-Bromo-2-(2-fluoroethylthio)benzo[d]thiazole (60 mg, 0.2 mmol), tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (68 mg, 0.2 mmol), and tetrakis(triphenylphosphine)palladium (11 mg, 0.01 mmol) in 2 mL dioxane and 0.5 mL of a 1 M Na2CO3 aqueous solution was heated at 95° C. in a microwave reactor for 10 min. After cooling to rt, it was diluted with EtOAc (30 mL) and washed with brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified with silica chromatography (5% to 30% EtOAc in hexane) to afford tert-butyl 4-(2-(2-fluoroethylthio)benzo[d]thiazol-6-yl)phenyl(methyl)carbamate as a clear wax (15 mg, 18%). MS (ESI) m/z 419 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:18][CH2:17]1.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CN(C)C(=O)C.O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:27]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:19]3[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]3)=[CH:30][CH:29]=1)=[N:1]2
Reactant: CN1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S([O-])O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4CCN(C)CC4)cc3)nc2c1
Temperature: 150 °C

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (150 mg, 0.76 mmol) and 4-(4-methyl piperazin-1-ylmethyl)benzaldehyde (166 mg, 0.76 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (149 mg, 0.84 mmol) and p-TSA (319 mg, 1.68 mmol) were added and the reaction mixture was heated at 150° C. for 3 h. The mixture was cooled to room temperature and water was added and neutralized by addition of NaHCO3. The solvent was removed under reduced pressure to give the crude product. The crude was purified by column chromatography (silica gel 230-400 mesh; 4% NH3 in methanol/CH2Cl2 as eluent) to give the product 5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one as a free base, which was converted to the hydrochloride salt (115 mg, 35%). Selected data: MS (ES) m/z: 395.2; MP 275-277° C. (hydrochloride).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.OC1C2N=NNC=2C=CC=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C.[C:49]([C:51]1[N:56]=[CH:55][C:54]([C:57]2[C:69]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]([C:70]4[CH:78]=[CH:77][C:73]([C:74]([OH:76])=O)=[C:72]([NH:79][CH:80]5[CH2:85][C:84]([CH3:87])([CH3:86])[N:83]([CH3:88])[C:82]([CH3:90])([CH3:89])[CH2:81]5)[CH:71]=4)[C:61]=3[CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)#[N:50]>CN(C)C=O.O>[C:49]([C:51]1[N:56]=[CH:55][C:54]([C:57]2[C:69]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]([C:70]4[CH:78]=[CH:77][C:73]([C:74]([NH2:8])=[O:76])=[C:72]([NH:79][CH:80]5[CH2:81][C:82]([CH3:89])([CH3:90])[N:83]([CH3:88])[C:84]([CH3:87])([CH3:86])[CH2:85]5)[CH:71]=4)[C:61]=3[CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)#[N:50]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CN1C(C)(C)CC(Nc2cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc2C(=O)O)CC1(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Oc1cccc2[nH]nnc12
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C(C)(C)CC(Nc2cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc2C(N)=O)CC1(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.5 %

Procedure:
330 mg of (1H-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (BOP), 100 mg of hydroxybenzotriazole (HOBT), 54 mg of ammonium chloride and 0.41 ml of diisopropylethylamine are successively added to a solution of 280 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]benzoic acid in 30 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 12 hours and then diluted with distilled water and extracted with ethyl acetate. The organic phase is subsequently washed with distilled water and a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane, acetonitrile and methanol (85/7.5/7.5 by volume), so as to give 60 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]benzamide in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[CH:15])[CH2:9][CH2:8]1.[C:16](=[O:18])=[O:17].O>CCCCCC.O1CCCC1.CO>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[C:15][C:16]([OH:18])=[O:17])[CH2:9][CH2:8]1
Reactant: O=C=O
Reactant: C#CCN1CCN(C)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CO
Product: CN1CCN(CC#CC(=O)O)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium in hexane (17.2 mL, 2.5M in n-hexane) was slowly added to 1-methyl-4-prop-2-ynyl-piperazine (6.0 g, 43.5 mmol) in 40 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 hr at −78° C., then dry carbon dioxide was passed through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The dry acid was dissolved in methanol, and the insoluble salt was removed via filtration. The filtrate was collected and dried in vacuo to give 7 g of 4-(4-methyl-piperazin-1-yl)-but-2-ynoic acid: mass spectrum (m/e):M−H 181.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH2:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H-].[Na+]>CN(C=O)C>[CH2:23]([N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[C:3]([OH:2])=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(C)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(F)cc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(N(Cc2ccccc2)S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a solution of 0.50 g (1.171 mmol) of the product of Example 65 in 10 mL of DMF was added 0.485 mL (4.684 mmol) of benzyl alcohol and 0.187 g (4.684 mmol) of 60% sodium hydride. The eaction mixture was stirred for 18 h at room temperature and the quenched with 5% HCl solution. The resulting mixture was extracted with ether and the combined organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved 10 mL of MeOH-THF (1:1) and 4.7 mL of 1N sodium hydroxide solution was added. The resulting mixture was heated to reflux for 18 h and then cooled to room temperature, acidified with 5% HCl and extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. Triturion of the residue with edter provided 0.432 g (74%) of the desired product as a white solid. Electrospray Mass Spec: 502.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:46])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH:34][S:35]([CH2:38][CH2:39][CH2:40][OH:41])(=[O:37])=[O:36])=[O:33])=[C:28]([O:42][CH:43]([CH3:45])[CH3:44])[CH:27]=3)=[CH:22][CH:21]=2)C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:46])[CH2:9][NH:10][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH:34][S:35]([CH2:38][CH2:39][CH2:40][OH:41])(=[O:37])=[O:36])=[O:33])=[C:28]([O:42][CH:43]([CH3:44])[CH3:45])[CH:27]=3)=[CH:22][CH:21]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(=O)(=O)CCCO
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1cc(-c2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)ccc1C(=O)NS(=O)(=O)CCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 151 %

Procedure:
To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4′-[[[(3-hydroxypropyl)sulfonyl]amino]-carbonyl]-3′-isopropoxy-4-biphenylyl]ethyl]carbamate (231 mg) in 1,4-dioxane (2.3 ml) was added 4N hydrogen chloride in 1,4-dioxane (2.3 ml) and the mixture was stirred at room temperature for 5 hours. The precipitates were collected by filtration, washed with 1,4-dioxane, and dried under reduced pressure to give 4′-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-N-[(3-hydroxypropyl)sulfonyl]-3-isopropoxy-4-biphenylcarboxamide hydrochloride (158 mg) as a white solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:42]=[CH:41][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:30]=[C:31]([O:33][C@H:34]4[CH2:38][CH2:37][N:36]([CH3:39])[C:35]4=[O:40])[CH:32]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20](C(OC(C)(C)C)=O)[N:19]=3)=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1>C(#N)C>[N:1]1([C:5]([C:7]2[CH:42]=[CH:41][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:30]=[C:31]([O:33][C@H:34]4[CH2:38][CH2:37][N:36]([CH3:39])[C:35]4=[O:40])[CH:32]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][NH:20][N:19]=3)=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(C(=O)Nc3ccn(C(=O)OC(C)(C)C)n3)c2)C1=O
Solvent: CC#N
Product: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(C(=O)Nc3cc[nH]n3)c2)C1=O
Temperature: 150 °C
Yield: 81.9 %

Procedure:
Tert-butyl 3-[[3-[4-(azetidine-1-carbonyl)phenoxy]-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoyl]amino]pyrazole-1-carboxylate (Intermediate 14) (388 mg, 0.67 mmol) was dissolved in acetonitrile (5 mL) and heated in a microwave for 12 minutes at 150° C., the solution was concentrated under reduced pressure to afford the product (261 mg, 82%). 1H NMR δ (300 MHz, CDCl3) 2.06-2.21 (m, 1H), 2.34 (quintet, 2H), 2.49-2.63 (m, 1H), 2.92 (s, 3H), 3.31-3.52 (m, 2H), 4.15-4.38 (m, 4H), 4.87 (t, 1H), 6.77 (s, 1H), 6.80 (s, 1H), 6.98 (d, 2H), 7.17 (s, 1H), 7.38 (s, 1H), 7.48 (s, 1H), 7.61 (d, 2H), 10.29 (s, 1H); m/z 476 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C@H:10]2[CH2:15][C@@H:14]([C:16](=[O:23])[CH2:17][C:18](OCC)=[O:19])[CH2:13][CH2:12][N:11]2[C:24]([O:26][CH3:27])=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[C:1]([C:5]1[S:9][C:8]([C@H:10]2[CH2:15][C@@H:14]([C:16]3[O:23][NH:30][C:18](=[O:19])[CH:17]=3)[CH2:13][CH2:12][N:11]2[C:24]([O:26][CH3:27])=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(C)(C)C)s2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(C)(C)C)s1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 49.2 %

Procedure:
Cis-methyl 2-(5-tert-butylthiophen-2-yl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (963 mg, 2.43 mmol) was dissolved in methanol (15 mL) and cooled to −40° C. NaOH (0.641 mL, 2.43 mmol) dissolved in water (1 mL) was added and stirred for 20 min. Hydroxylamine (50% by weight in water, 0.149 mL, 2.43 mmol) was added and the reaction stirred at −40° C. for 3 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M HCl (12.58 mL, 75.48 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (150 mL) and water (150 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (150 mL). The combined organic phase were dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 35-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(5-tert-butylthiophen-2-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (436 mg, 49.1%) was isolated as a white solid. MS m/z 363 (M−H)−
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]([CH:18]=[C:19]([F:21])[CH:20]=1)[O:10][Si](C(C)(C)C)(C)C.[CH3:22][N:23]([CH2:25][CH:26]1[CH2:32][CH2:31][CH:30]2[CH:28]([CH2:29]2)[C:27]1=[O:33])[CH3:24].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)Cl>[CH3:24][N:23]([CH2:25][CH:26]1[CH2:32][CH2:31][CH:30]2[CH:28]([CH2:29]2)[C:27]1([C:7]1[CH:8]=[C:9]([OH:10])[CH:18]=[C:19]([F:21])[CH:20]=1)[OH:33])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(Br)c1
Reactant: CN(C)CC1CCC2CC2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]C(C)(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CC1CCC2CC2C1(O)c1cc(O)cc(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
Add a solution of t-BuLi (19.4 mL, 25.2 mmol) via syringe to a solution of (3-bromo-5-fluoro-phenoxy)-tert-butyl-dimethyl-silane (6.99 g, 22.9 mmol) in THF (100 mL) at −78° C. under N2. After being stirred at −78° C. for 1 hour, add dropwise a solution of 3-dimethylaminomethyl-bicyclo[4.1.0]heptan-2-one (2.55 g, 15.3 mmol) to the reaction mixture and stir the reaction mixture at −78° C. for additional 2 hours. Quench the reaction with saturated NH4Cl solution (30 mL). Extract the resultant aqueous mixture with EtOAc (100 mL×3). The combined organic layers are washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Treat the residue with TBAF (6.00 g, 22.9 mmol) in CH2Cl2 (80 mL) at ambient temperature for 4 hours. Concentrate the mixture, and purify the residue by preparative HPLC to give 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol as white solid (592 mg, yield: 13.9%). MS (m/z): 280 (M+1).