Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]#[N:11])=[CH:5][CH:4]=1.O1CCCC1.[OH-].[K+].[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29]>C(O)C>[C:10]([C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=1)([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH2:29][CH2:28][C:27]([O:31][CH2:32][CH3:33])=[O:30])#[N:11]
Reactant: C=CC(=O)OCC
Reactant: N#CC(c1ccc(C(F)(F)F)cc1)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C#N)(c1ccc(C(F)(F)F)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 52.3 g. of α-(α,α,α-trifluoro-p-tolyl)-4-morpholineacetonitrile in 500 ml. of dry tetrahydrofuran is stirred at ambient temperature while 1 ml. portions of 30% potassium hydroxide in ethanol and 25 ml. portions of ethyl acrylate is added every half hour until a total of 5 ml. of the base and 150 ml. of ethyl acrylate is added. After the addition, the mixture is stirred at ambient temperature for 48 hours. Following filtration, the filtrate is concentrated, dissolved in methylene chloride, passed through magnesol and recrystallized from methylene chloride/hexane to afford ethyl γ-cyano-γ(α,α,α-trifluoro-p-tolyl)-4-morpholinebutyrate as cream colored crystals, m.p. 96° -97° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH:22]1[CH2:24][CH2:23]1>[I-].[K+].O>[CH:22]1([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:24][CH2:23]1
Reactant: BrC1CC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OC2CC2)cc1
Temperature: 200 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-hydroxybenzaldehyde (1.20 g), potassium carbonate (2.04 g), potassium iodide (49.0 mg) and N,N-dimethylformamide (9.80 mL), bromocyclopropane (1.02 mL) was added and the mixture was stirred at 200° C. for 3 hours under irradiation with microwaves. After being cooled to room temperature, the reaction mixture was poured into water and extracted with diethyl ether three times. The combined organic layers were washed with saturated brine and thereafter passed through a phase separator to be concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) to give the titled compound as a colorless oil (510 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([N:6](CC2C=CC(OC)=CC=2)[S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[C:25]([OH:26])=[CH:24][C:23]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=4)=[C:22]([F:35])[CH:21]=2)[C:15](=[O:36])[CH:14]=[CH:13]3)(=[O:9])=[O:8])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:53]([CH3:56])[C:54]#[N:55].O>CN(C=O)C>[C:54]([CH:53]([O:26][C:25]1[C:20]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([S:7]([NH:6][C:3]4[CH:4]=[CH:5][O:1][N:2]=4)(=[O:8])=[O:9])=[CH:19][CH:18]=3)[CH:13]=[CH:14][C:15]2=[O:36])=[CH:21][C:22]([F:35])=[C:23]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[CH:24]=1)[CH3:56])#[N:55]
Reactant: CC(Br)C#N
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(-c4cc(F)cc(F)c4)cc3O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C#N)Oc1cc(-c2cc(F)cc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 16 h

Procedure:
To a solution of N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1-(2,3′,5′-trifluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide (0.066 g, 0.104 mmol) in DMF (0.208 ml) at room temperature was added potassium carbonate (0.016 g, 0.115 mmol) followed by 2-bromopropanenitrile (0.014 ml, 0.156 mmol). The reaction mixture was stirred 16 hr. The resulting mixture was transferred to a sep.funnel containing water and the aqueous layer was washed 3× with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The crude material was taken onward to the next step without further purification, assuming quantitative yield. m/z (ESI) 687.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:8]([O:11][CH2:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18]C)=[O:17])[CH:9]=2)[CH2:4][CH2:3]1.CO.[OH-].[Na+].O>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:8]([O:11][CH2:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([OH:18])=[O:17])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCCOc1cc2c(cc1OCc1cccc(C(=O)OC)c1)C(=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCCCCOc1cc2c(cc1OCc1cccc(C(=O)O)c1)C(=O)CC2
Yield: 68 %

Procedure:
A mixture of the compound obtained in Example 3 (2.3 g; 6.01 mmol), methanol (330 ml), sodium hydroxide (0.96 g; 24 mmol) and water (24 ml) is refluxed for 3 hours. The medium is concentrated to dryness. The residue is taken up in water. The basic aqueous phase is washed with ethyl ether and then acidified with 1N HCl. The cream-coloured precipitate formed is dissolved in methylene chloride. The organic phase is washed with water, dried over sodium sulfate and concentrated (1.5 g; 68% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][S:15][C:14]2[CH:18]=[CH:19][C:20]([NH:22][C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[NH:24])=[CH:21][C:13]1=2)C(=O)OC(C)(C)C.Cl.[OH-].[Na+]>CO.O>[CH3:1][NH:2][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][S:15][C:14]2[CH:18]=[CH:19][C:20]([NH:22][C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[NH:24])=[CH:21][C:13]1=2
Reactant: CN(CCN1CCSc2ccc(NC(=N)c3cccs3)cc21)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNCCN1CCSc2ccc(NC(=N)c3cccs3)cc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a stirred solution of tert-butyl methyl(2-(6-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (415 mg, 0.959 mmol) in methanol (4 mL) was added a 3N HCl solution (3.198 mL, 9.59 mmol). The resulting mixture was then stirred at 90° C. for 1 hour. The mixture was then cooled to room temperature, diluted with water, basified with 3N sodium hydroxide to pH 12, and extracted with dichloromethane (3×). The combined organics were dried, filtered, and concentrated then chromatographed in 1:9 (2M NH3 in methanol):ethyl acetate, giving the desired product 28 (165 mg, 51.7%). 1H NMR (DMSO-d6) δ 7.71 (d, J=3.0 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.10-7.06 (m, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.34 (brs, 2H), 6.22 (s, 1H), 6.07 (d, J=8.1 Hz, 1H), 3.62-3.57 (m, 2H), 3.32 (t, J=6.8 Hz, 2H), 3.01-2.97 (m, 2H), 2.64 (t, J=6.8 Hz, 1H), 2.29 (s, 3H). ESI-MS (m/z, %): 333 (MH+, 100), 276 (71); ESI-HRMS calculated for C16H21N4S2 (MH+), calculated: 333.1202, observed: 333.1207; HPLC purity: 97% by area.
Reaction SMILES: [Br:1]NC(=O)CCC(N)=O.[CH3:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][N:12]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][N:12]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1nsc2ncccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nsc2ncccc12

Procedure:
N-Bromosuccinamide (10.7 mmol) was added to a solution of 3-methylisothiazolo[5,4-b]pyridine (10.0 mmol) in carbontetrachloride (20 mL). Benzoyl peroxide (0.82 mmol) was added and the reaction mixture was heated at reflux for 48 h. The reaction mixture was filtered through Celite (ethyl acetate) and the eluent was concentrated to provide crude 3-(bromomethyl)isothiazolo[5,4-b]pyridine as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([OH:25])=[O:24].[C:26](Cl)(=O)C(Cl)=O.CO>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24]
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(F)cc2c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
DMF (5 drops) was added to a suspension of 6-fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (11.2 g, 32.1 mmol) in dichloromethane (120 mL) at 0° C. Oxalyl chloride (4.21 mL, 48.1 mmol) was added slowly. The mixture was stirred at 0° C. for 1 h. Methanol (30 mL) was added to the mixture, the mixture was stirred at 0° C. for 2 h and warmed to room temperature overnight. The solvent was removed under reduced pressure, and the residue was diluted with water and treated with saturated aqueous NaHCO3 until basic. The aqueous mixture was extracted with methylene chloride (three times). The combined organic phases were washed with brine (two times), dried over Na2SO4, filtered, and concentrated. The residue was purified via column chromatography (ISCO, 120 g Silica, 0-30% ethyl acetate/hexanes) to give methyl 6-fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.6 g, 82% yield). MS (m/z) 364.1 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:8])[CH:7]=1)[CH3:2].[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[C:17]([OH:22])([C:16]([F:24])([F:23])[F:15])[C:7]1[C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: COC(=O)C(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCc1[nH]n(-c2ccccc2)c(=O)c1C(O)(C(=O)OC)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 3-ethyl-1-phenyl-5-pyrazolone (94 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a colorless solid (172 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[F:34][C:35]1[CH:57]=[CH:56][C:38]([CH2:39][N:40]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[N:42]=[C:41]2[N:49]2[CH2:55][CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:37][CH:36]=1>>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH2:55][N:49]([C:41]3[N:40]([CH2:39][C:38]4[CH:37]=[CH:36][C:35]([F:34])=[CH:57][CH:56]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:50][CH2:51]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: Fc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)cc1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 47.3 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt)(0.72 g, 1.55 mmol.) and 4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.88 g, 1.52 mmol) to give the title compound: Rf=0.26 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([NH:16][C:17]2[S:18][C:19]([CH:23]=[O:24])=[C:20]([Cl:22])[N:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:28].[K+]>C(O)(C)(C)C.O>[C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([NH:16][C:17]2[S:18][C:19]([C:23]([OH:28])=[O:24])=[C:20]([Cl:22])[N:21]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CC(=O)Nc2nc(Cl)c(C=O)s2)c1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CC(=O)Nc2nc(Cl)c(C(=O)O)s2)c1
Yield: 84.8 %

Procedure:
To a solution of 2-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-N-(4-chloro-5-formyl-thiazol-2-yl)-acetamide (590 mg, 1.436 mmol) in t-butanol (15 mL) stirred at 60° C. was added drop wise potassium permanganate (405 mg, 2.56 mmol) in water (5 mL) over 15 minutes. The resultant reaction mixture was heated at 80′C for 2 h. The reaction mixture was filtered hot through celite and washed with hot 1/1 t-butanol/water. The filtrate was acidified to pH 1 with aqueous 2N HCl and extracted with 9:1 Methylene chloride/methanol (3×75 mL). The organic layers were combined, washed with brine (50 mL), dried over MgSO4, filtered, concentrated under reduced pressure and dried to give 2-{2-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-acetylamino}-4-chloro-thiazole-5-carboxylic acid (0.52 g, 84.8%) as a pale yellow solid. MS m/e 428.0 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[C:11]([O-:15])(=[O:14])[CH:12]=[CH2:13].[C:16]([NH2:20])(=[O:19])[CH:17]=[CH2:18]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:13][CH2:12][C:11]([O-:15])=[O:14])([O-:3])=[O:2].[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:18][CH2:17][C:16]([NH2:20])=[O:19])([O-:3])=[O:2]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: C=CC(N)=O
Reactant: C=CC(=O)[O-]
Product: NC(=O)CCCc1ccccc1[N+](=O)[O-]
Product: O=C([O-])CCCc1ccccc1[N+](=O)[O-]

Procedure:
reaction of ortho-nitrotoluene with an acrylate or acrylamide to give 4-(2-nitrophenyl)butyrate or 4-(2-nitrophenyl)butyramide,
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH3:20])=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:41])=[C:33]([S:35]([NH:38][O:39][CH3:40])(=[O:37])=[O:36])[CH:34]=1.CO>ClCCl>[CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([CH3:20])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([CH3:41])=[C:33]([S:35]([NH:38][O:39][CH3:40])(=[O:36])=[O:37])[CH:34]=4)[N:22]=3)=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccccc1)n2C)c1ccnc(Cl)n1
Reactant: CONS(=O)(=O)c1cc(N)ccc1C
Solvent: CO
Solvent: ClCCl
Product: CONS(=O)(=O)c1cc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCc3ccccc3)n4C)n2)ccc1C

Procedure:
The title compound was prepared following the procedure of Example 2 with N2-benzyl-N5-(2-chloropyrimidin-4-yl)-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (50 mg, 0.13 mmol) and 5-amino-N-methoxy-2-methylbenzenesulfonamide (30 mg, 0.14 mmol) as a white solid (58 mg, 0.10 mmol) after silica gel chromatography with methanol in dichloromethane. 1H NMR (300 MHz, d6-DMSO) δ 10.3 (s, 1H), 9.42 (s, 1H), 8.73 (s, 1H), 7.76-7.80 (m, 2H), 7.40-7.23 (m, 8H), 7.09 (br s, 1H), 6.84 (d, J=7.4 Hz, 1H), 5.61 (d, J=5.3 Hz, 1H), 4.60 (br s, 2H), 4.34 (s, 2H), 3.58 (s, 6H), 3.46 (s, 3H). MS (ESI) m/z=559 [M+H]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:30]([CH3:31])=[CH:29][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]4[CH2:28][CH2:27]O[CH2:25][CH2:24]4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1CCN(C2C=CC=CN=2)CC1.N1C=CC(B(O)O)=CC=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:30]([CH3:31])=[CH:29][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]4[CH2:28][CH2:27][N:40]([CH3:39])[CH2:25][CH2:24]4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc2nc(-c3ccnc(N4CCOCC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CN1CCN(c2ccccn2)CC1
Agent: OB(O)c1ccncc1
Product: Cc1cc2nc(-c3ccnc(N4CCN(C)CC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Prepared in a manner similar to (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-morpholinopyridin-4-yl)benzo[d]thiazol-6-yl)acetic acid except 2-(4-methylpiperazino)pyridine-4-pyridine boronic acid using instead of 2-morpholinopyridine-4-boronic acid. LCMS-ESI+: calc'd for C30H34ClN3O3S: 565.2 (M+H+); Found: 565.3 (M+H+); 1H NMR (400 MHz, CD3OD) δ 8.30 (d, J=4.8 Hz, 1H), 7.89 (s, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.64-7.47 (m, 4H), 7.34 (d, J=5.1 Hz, 1H), 5.26 (s, 1H), 4.77-4.38 (m, 2H), 3.78-3.04 (m, 2H), 2.97 (s, 3H), 2.62 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([F:11])[CH:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>CC(C)=O>[F:11][C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][CH2:9][OH:10]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(CCO)c(F)c1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(CCO)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a stirred solution of 2-(4-amino-2-fluorophenyl)ethanol (1.3 g, 8.38 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (1.32 g, 16.7 mmol, 2.0 eq) and phenyl chloroformate (1.45 g, 9.23 mmol, 1.1 eq) at 0° C. and the mixture was stirred at RT for 2 h. The solvent was evaporated, the residue diluted with EtOAc (50 mL), washed with water (100 mL) followed by brine and the solvent evaporated. The resulting residue was purified by CC using EtOAc/PE (1:4) to get phenyl 3-fluoro-4-(2-hydroxyethyl)phenylcarbamate (1.5 g, 65%, white solid). (TLC system: EtOAc/PE (1:1), Rf: 0.3).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][C@@H:43]([CH2:47][OH:48])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:3]=3[C:2]([F:1])([F:33])[F:32])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH:43]([CH2:47][OH:48])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C(CO)C1

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 3-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [O:1]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](N(CC)CC)C.[Cl:26]C(OCC)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)(Cl)Cl.C1COCC1.CCOCC>[ClH:26].[CH3:19][N:10]1[CH2:9][CH:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11]1
Reactant: c1ccc(OC2CNCCc3ccccc32)cc1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CN1CCc2ccccc2C(Oc2ccccc2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of 1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine (3.9 g, 16 mmole) of Example 28b and triethylamine (1.8 g, 18 mmole) in chloroform (50 ml) was slowly added ethyl chloroformate (1.9 g, 18 mmole) in chloroform (10 ml). The reaction mixture was stirred two hours at ambient temperature, then was evaporated to an oil which was stirred with water and extracted with ether. The organic extracts were washed with dilute HCl, water, then dried (saturated NaCl, anhydrous MgSO4). The solution was filtered and concentrated to an oil (4.7 g, 93%). A solution of the oil in THF (40 ml) was slowly added to a cooled suspension of LiAlH4 (1.7 g, 45 mmole) in THF (100 ml). After stirring three hours at ambient temperature, the mixture was cooled, diluted with ether, then quenched by slow addition of saturated NH4Cl. The mixture was filtered, washed with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered and concentrated to an oil which was converted by the addition of ethereal HCl to the hydrochloride salt (3 g 69%, d 211°-214° C.). This material was recrystallized from a 20:1 solution of ethyl acetate/methanol to yield 3-methyl-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine hydrochloride, d 224°-225° C.
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:3]([CH2:18][CH2:19][C:20]#[CH:21])[C:4](N1[C@@H](C2C=CC=CC=2)COC1=O)=[O:5].[O:28]1CCCC1.OO.[OH-].[Li+]>O>[OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:3]([CH2:18][CH2:19][C:20]#[CH:21])[C:4]([OH:5])=[O:28]
Reactant: C#CCC[C@@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@H](O)c1ccccc1
Reactant: C1CCOC1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C#CCC[C@@H](C(=O)O)[C@H](O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a stirred solution of 65.0 g (179 mmol) of (4S)-3-{(2R)-2-[(S)-hydroxy(phenyl)methyl]hex-5-ynoyl}-4-phenyl-1,3-oxazolidin-2-one from Step B above in 1050 mL of a 20 to 1 mixture of anhydrous tetrahydrofuran to water at 0° C. under an atmosphere of nitrogen was added 77.0 mL (894 mmol) of a 35% aqueous hydrogen peroxide solution at a rate slow enough to keep the internal temperature below 3° C. Next, 395 mL (395 mmol) of a 1.0 M aqueous lithium hydroxide solution was added at a rate slow enough to keep the internal temperature of the reaction below 5° C. and the resulting mixture was stirred for 3 h at 0° C. The reaction was quenched with 755 mL (984 mmol) of a 1.3 M aqueous sodium sulfite solution at a rate slow enough to keep the internal temperature of the mixture below 5° C. All volatiles were removed in vacuo and the remaining aqueous phase was extracted with ethyl acetate (3×200 mL). The aqueous phase was then cooled to 0° C. and acidified with a 6 M aqueous hydrogen chloride solution until a pH of 3 was achieved. The aqueous phase was then extracted with ethyl acetate (3×300 mL) and the combined organics were washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a 5-10% ethyl acetate and 3% acetic acid in hexanes gradient to afford the title compound as a colorless gum (32.0 g, 82.0%). 1H NMR (500 MHz, CDCl3): δ 7.39-7.28 (m, 5H), 4.85 (d, J=8.2, 1H), 3.03-2.97 (m, 1H), 2.29-2.15 (m, 2H), 1.97 (t, J=2.5 Hz, 1H), 1.93-1.82 (m, 1H), 1.62-1.55 (m, 1H). LC-MS: m/z (ES) 201.0 (MH-H2O)+.