Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:36]1([NH2:39])[CH2:38][CH2:37]1>ClCCl.CN(C=O)C>[CH:36]1([NH:39][CH2:2][C:3]2[N:7]([C:8]3[CH:9]=[C:10]([C:14]4[CH2:20][C:19](=[O:21])[NH:18][C:17]5[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:16]=5[N:15]=4)[CH:11]=[CH:12][CH:13]=3)[N:6]=[N:5][CH:4]=2)[CH2:38][CH2:37]1
Reactant: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: NC1CC1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNC3CC3)c1)=N2
Yield: 68 %

Procedure:
Prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 68) (208 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylamine in DMF according to the method described in Example 47. Obtained as a light yellow solid (155 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[Cl:24])[N:17](S(C3C=CC=CC=3)(=O)=O)[CH:16]=2)[CH:3]=1.CO.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[Cl:24])[NH:17][CH:16]=2)[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(NC3CCCCC3)c2)c2c(Cl)ccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Clc1cc(-c2c[nH]c3nccc(Cl)c23)cc(NC2CCCCC2)n1
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of Example 168c (82 mg, 0.164 mmol) in a mixture of 5 mL THF, 5 mL methanol was added a solution of 27 mg (0.654 mmol) lithium hydroxide in 0.5 mL water. After stirring for 16 hours the reaction mixture was concentrated to dryness and the residue suspended in water and a yellow solid was collected by filtration. Purified by silica gel flash chromatography (eluting with 10% ethyl acetate, 90% dichloromethane) provided the title compound as an off-white powder in 51% yield. MS (ESI+) m/z 361.3 (M+H)+; 1H NMR (300 MHz, DMSO-d6) ppm 1.01-1.39 (m, 5H) 1.53-1.65 (m, 1H) 1.66-1.75 (m, 2H) 1.85-1.95 (m, 2H) 3.54-3.69 (m, 1H) 6.51 (s, 1H) 6.60 (s, 1H) 6.79 (d, 1H, J=7.54 Hz) 7.24 (d, 1H, J=5.16 Hz) 7.81 (s, 1H) 8.23 (d, 1H, J=4.76 Hz) 12.41 (bs, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[CH:16]1[C:24]2[C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl>ClCCl.O>[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5]([C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:24]=3[C:23]=2[CH:25]=1)=[O:15])([OH:10])=[O:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: c1ccc2c(c1)sc1ccccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccccc1C(=O)c1ccc2sc3ccccc3c2c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
To a mixture of aluminum chloride (40.0 g, 300 mmol) in anhydrous dichloromethane (1000 cm3) is added a suspension of phthalic anhydride (14.8 g, 100 mmol) in anhydrous dichloromethane (200 cm3). The suspension is stirred for 30 minutes, cooled to 5° C. and then a solution of dibenzothiophene (20.0 g, 110 mmol) in anhydrous dichloromethane (200 cm3) added drop wise under cooling with ice. After addition, the mixture is allowed to stir at 23° C. for 4 hours. The reaction mixture poured into a solution of water (1000 cm3) and concentrated hydrochloric acid (400 cm3). The product extracted with dichloromethane (2 200 cm3) and the organic extracted with aqueous sodium hydroxide (5%, 500 cm3). The basic layer acidified and the oily precipitate is isolated by decanting away the acidic solution. Water (200 cm3) is added, which solidified the oil and the solid collected by filtration, washed with water (500 cm3) and dried under vacuum to give 2-(o-carboxybenzoyl)dibenzothiophene as a pale yellow solid (35.64 g, 99%). 1H NMR (300 MHz, CDCl3) 8.47-8.52 (m, 1H), 7.99-8.15 (m, 2H), 7.60-7.86 (m, 4H), 7.35-7.57 (m, 4H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[CH:61]=[C:60]1[CH2:68]O>C(OCC)(=O)C.O1CCCC1>[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[CH:61]=[C:60]1[CH2:68][N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:27]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OCc1cc2ccccc2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cc3ccccc3s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.23 g), tributylphosphine (1.52 mL), 1-benzothien-2-ylmethanol (0.56 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 45%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][C:38]2[N:39]=[C:40]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[O:41][C:42]=2[CH3:43])=[CH:31][CH:30]=1)([C:18]([O:20]CC1C=CC=CC=1)=[O:19])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:2]>CO.O1CCCC1.[C].[Pd]>[CH2:1]([O:3][C:4]([CH2:6][C:7]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][C:38]2[N:39]=[C:40]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[O:41][C:42]=2[CH3:43])=[CH:31][CH:30]=1)([C:18]([OH:20])=[O:19])[C:8]([OH:10])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)CC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
Dibenzyl 2-ethoxycarbonylmethyl-2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]malonate (29.5 g, 44.6 mmol) obtained in Example 9 was dissolved in methanol (150 ml) and tetrahydrofuran (150 ml), and 5% palladium carbon (2.0 g) was added. The mixture was vigorously stirred at room temperature under a hydrogen atmosphere (3.3-3.4 atm) for 6 hr. After stirring, the catalyst was removed with celite and the solvent was evaporated to give the title compound (21.0 g, yield 98%) as an orange-yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:17][CH2:18][CH2:19][Cl:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: Oc1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: ClCCCOc1ccccc1OCc1ccccc1
Yield: 97.1 %

Procedure:
A mixture of 50 g (0.25 mole) of 2-benzyloxyphenol, 78.7 g (0.5 mole) of 1-bromo-3-chloropropane and 103.7 g of anhydrous potassium carbonate in 1 liter of actone was heated at reflux for 24 hr. The reaction mixture was cooled, filtered and concentrated in vacuo to give 67.2 g of a tan oil as residue. The oil was dissolved in 300 ml of ethyl ether and washed with 100 ml of a 5% sodium hydroxide solution. A solid precipitated, about 200 ml of water was added and the precipitated sold redissolved. Solvent layers were separated and the ethyl ether layer washed twice with a 5% sodium hydroxide solution. The organic layer was next washed with water, brine, and dried over sodium sulfate and concentrated to give 58.4 g (84%) of oil as product.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[NH2:12][CH2:13][C@@H:14]([OH:16])[CH3:15].Cl.NCC(N)=O>>[OH:16][C@@H:14]([CH3:15])[CH2:13][NH:12][C:9]([C@@H:1]1[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:2]1)=[O:11]
Reactant: O=C(O)C1CC12CCCCC2
Reactant: C[C@H](O)CN
Agent: Cl
Agent: NCC(N)=O
Product: C[C@H](O)CNC(=O)[C@H]1CC12CCCCC2

Procedure:
The title compound was prepared as described in Example 3 substituting the product from Example 6 for the product from Example 1B and substituting (S)-1-amino-2-propanol, purchased from Aldrich, for 2-aminoacetamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 3.80 (m, 1H), 3.16 (m, 2H), 1.20-1.70 (m, 11H), 1.13 (d, 3H), 1.02 (dd, 1H), 0.69 (dd, 1H); MS (CI) m/z 212 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]CC2C=CC=CC=2)[C:10]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:31]O>CC(O)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14](=[O:31])[CH:13]=[CH:12][C:11](=[O:15])[C:10]=1[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Reactant: OO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1C=CC(=O)C(OCc2ccccc2)=C1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,2,3-tribenzyloxybenzene 8 (2.0 g, 5.0 mmol) in HOAc (30 mL), K3Fe(CN)6 (0.82 g, 2.5 mmol) and 30% H2O2 (1.3 g, 11.5 mmol) were added and the resulting solution stirred at room temperature for 18 h. The solution was diluted with 50 mL CH2Cl2 and the organic layer subsequently washed with H2O, saturated aqueous NaHCO3 and brine. Drying and concentration resulted in a red oil. Purification by radial chromatography (2 mm thickness, EtOAc/hexane, 1:19, v/v) afforded 9 as a red oil. 1H NMR (CDCl3): δ7.36-7.32 (m, 10 H), 6.58 (s, 2 H), 5.20 (s, 4 H). 13C NMR (CDCl3): δ184.1, 145.2, 136.1, 134.6 128.5, 128.4, 128.1, 75.1. Anal. Calcd for C20H18O4: C, 74.99; H, 5.03. Found: C, 75.04; H, 5.06. HRMS (FAB) calcd for C20H16O4 (M+H+): 320.1049. Found: 320.1059.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]([CH3:30])=[CH:26]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:24]=[C:25]([CH3:30])[CH3:26])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=CB(O)O
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)=Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 12 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (150 mg, 0.338 mmol) and 2,2-dimethylethenylboronic acid (67 mg, 0.670 mmol), resin-bound PPh3Pd (519 mg, 0.069 mmol) and Na2CO3 (0.338 mL, 2M) in DME (3 mL) is heated in a microwave apparatus at 12° C. for 20 min. The mixture is filtered through Celite, washed with MeCN and concentrated. The residue is purified by reverse phase chromatography using a gradient of 10-60% EtOH/H2O as eluent to afford the title compound: (M−1)−=371.
Reaction SMILES: [NH2:1][C:2]([C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:24]=[C:23]([CH3:25])[C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([CH3:22])[CH:18]=3)=[C:11]([CH3:26])[CH:10]=2)[N:5]=1)=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.O>[C:2]([C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:10]=[C:11]([CH3:26])[C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([CH3:22])[CH:18]=3)=[C:23]([CH3:25])[CH:24]=2)[N:5]=1)#[N:1]
Reactant: Cc1cc(CCCOc2c(C)cc(-c3noc(C(N)=O)n3)cc2C)on1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CCCOc2c(C)cc(-c3noc(C#N)n3)cc2C)on1
Temperature: 0 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
To a chilled (0° C.) suspension of the product of Example 38 (1.60 g, 4.50 mmol) and dry pyridine (11.2 mL) in dry tetrahydrofuran (27 mL) was added trifluoroacetic anhydride (1.90 mL, 13.5 mmol). The mixture was stirred at 0° C. for 4 hours and at room temperature for 18 hours, diluted with water (100 mL), and extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with 1N HCl (3×), brine, dried (MgSO4), and concentrated in vacuo. The red solid obtained (1.67 g) was chromatographed (Silica Gel 60, 20% ethyl acetate in hexanes) to give 1.38 g (90.8%) of pure title compound as a white solid, mp 93°-4° C. (ethyl acetate and hexanes).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:13]=[C:12](Cl)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][C:12]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:13]=2)=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: CC(C)(C)Nc1nc(Cl)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Temperature: 80 °C
Yield: 84.6 %

Procedure:
To a solution of 2-tert-butylamino-6-chloro-nicotinonitrile (4, 630 mg, 3 mmol) in DMF (100 mL) were added 2-bromo-5-hydroxy-benzaldehyde (603 mg, 3 mmol) and K2CO3 (828 mg, 6 mmol). The reaction was heated at 80° C. for 24 h. After cooling to r.t., DMF was removed in vacuo. Purification was accomplished by Biotage silica gel chromatography with a 2.5%-10% EtOAc/hexanes gradient to afford 950 mg (85% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([NH2:22])=[CH:20][C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31]>CCOC(C)=O.C1CCCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:21]([NH:22][C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31])=[CH:20][C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:18]2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(C2CCN(C(=O)OCc3ccccc3)CC2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(C2CCN(C(=O)OCc3ccccc3)CC2)n1
Yield: 41.1 %

Procedure:
To a solution of Intermediate 16b (550 mg, 1.54 mmol) in aqueous NaOH solution (1M, 3.85 mL, 3.85 mmol) and EtOAc (5 mL) at RT, was added 2,2,2-trichloroethyl chloroformate (0.32 mL, 2.31 mmol) over 2 min, then the mixture stirred vigorously for min. The aqueous layer was extracted with EtOAc (10 mL), then the combined organics washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to leave a yellow-brown oil. FCC, using 0-30% EtOAc in cyclohexane, gave the title compound as a white foam (337 mg, 41%). LCMS (Method 3): Rt 4.81 min, m/z 531, 533 [MH+].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: C1COCCN1
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2s1
Solvent: CS(C)=O
Product: O=C(c1ccc(Oc2nccnc2N2CCOCC2)cc1)c1nc2ccccc2s1
Temperature: 100 °C

Procedure:
To a solution of benzo[d]thiazol-2-yl(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (185 mg, 0.503 mmol) in DMSO (2 mL) was added morpholine (219 μl, 2.52 mmol). The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was partitioned between EtOAc and brine. The precipitate formed was collected by filtration, washed with EtOAc and water, dried to provide benzo[d]thiazol-2-yl(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone as light-yellow solid. MS (ESI, pos. ion) m/z: 419.0. IC50 (uM) ++.
Reaction SMILES: N.C([O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:26])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])=[CH:13][CH:12]=2)[CH2:7]1)(=O)C>CO>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:17](=[O:26])[C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][C@H:6]([OH:5])[CH2:7]2)=[CH:12][CH:13]=1
Reactant: CC(=O)O[C@H]1CCN(c2ccc(C(=O)Nc3ccccc3N)cc2)C1
Agent: N
Solvent: CO
Product: Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
Ammonia gas was bubbled into a solution of compound 159 (300 mg, 0.88 mmol) in methanol (10 mL) at 0° C. for 5 min. The reaction mixture was then stirred for 3 hrs at r.t. and concentrated. The residue was purified by flash chromatography using a gradient 75-100% EtOAc in hexanes as an eluent, to afford title compound 160 (135 mg, 51% yield). 1H NMR: (MeOH-d4) δ(ppm): 7.91 (s, 1H), 7.86 (d, 2H, J=7.0 Hz), 7.16 (d, 1H, J=7.8 Hz), 7.05 (t, 1H, J=7.2 Hz), 6.89 (d, 1H, J=8.0 Hz), 6.76 (t, 1H, J=7.6 Hz), 6.62 (d, 2H, J=9.0 Hz), 4.56 (m, 1H), 3.54 (m, 2H), 3.46 (m, 1H), 2.98 (s, 1H), 2.85 (s, 1H), 2.17 (m, 1H), 2.05 (m, 1H), LRMS (ESI): (calc): 297.15 (found) 298.1 (MH+).
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClCCCl.[C-:14]#[N:15].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:3]1([CH:2]([OH:9])[CH2:1][C:14]#[N:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCCl
Product: N#CCC(O)c1ccccc1

Procedure:
The procedure of Experiment 1 was repeated employing 1.0 g of racemic styrene oxide, 4 ml of 1,2-dichloroethane, 2 ml of water, 596 mg of potassium cyanide, and 267 mg of tetrabutylammonium bromide. After 6 hours of heating at reflux, the reaction mixture was cooled and worked up extracting with methylene chloride. Proton nuclear magnetic resonance analysis indicated the desired product contaminated with the phase transfer catalyst.
Reaction SMILES: [Li+].[Cl-].C[Mg+].[Br-].[CH2:6](OCC)C.[O:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[OH:11][C:12]1([CH3:6])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC1(O)CCN(C(=O)OC(C)(C)C)C1
Yield: 83.8 %

Procedure:
To a 30 L reaction kettle was added 4 L dry THF at −10° C. After stirring, to the mixture were added ZnCl2 (118 g, 0.86 mol) and LiCl (402 g, 9.5 mol). After half an 0.5 hour, to the resulting mixture was slowly added a solution of MeMgBr (3 mol/L) in diethyl ether (6.4 L, 19.2 mol) dropwisely. The stirring was continued for half an hour. To the resulting mixture was slowly added a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1600 g, 8.6 mol) in THF dropwisely. After the completion of reaction by HPLC detection, to the system was dropwisely added a saturated NH4Cl solution to quench off the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate as a pale yellow solid (1450 g) in a yield of 83.8%.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]([O-:10])(C)[CH3:8].[K+].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1.C1OC1C>CCCCCC.C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[C:14]=1[CH2:6][CH:7]([OH:10])[CH3:8]
Reactant: Fc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)[O-]
Agent: CC1CO1
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)Cc1c(F)cccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.5 M of n-BuLi in hexane (4.4 mL) was added to THF (10.0 mL) at −78° C. under nitrogen, followed by the addition of 1.0 M of KOtBu in THF (11 mL). The mixture was stirred at −78° C. for 30 min, then 1-fluoro-3-(trifluoromethyl)benzene (1.5 g, 9.1 mmol) in THF (5 mL) was added slowly, and the resulting mixture was stirred at this temperature for 30 min. Then a solution of propylene oxide (640 mg, 11 mmol) in THF (5 mL) was added at −78° C. The mixture was allowed to slowly warmed to rt and stirred overnight. The mixture was quenched with water (10 mL), and then extracted with EtOAc (50 mL). The organic phase was washed with brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield a brown oil. The crude material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to give the desired product as a yellow solid. 1H NMR (CD3OD, 400 MHz): δ=1.22 (d, J=6.3 Hz, 3H), 2.90-2.97 (m, 1H), 3.06-3.13 (m, 1H), 4.05-4.13 (m, 1H), 7.37-7.44 (m, 1H), 7.47 (td, J=7.9, 5.7 Hz, 1H), 7.54-7.59 (m, 1H). 1H NMR (CDCl3, 400 MHz): δ=1.30 (d, J=6.1 Hz, 3H), 1.41 (d, J=6.1 Hz, 1H), 2.93-3.07 (m, 1H), 4.08-4.17 (m, 1H), 7.23-7.27 (m, 1H), 7.29 (s, 1H), 7.30-7.37 (m, 1H), 7.48 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH:20][C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1)=[O:22])=[O:6])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[CH:1]([NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1)=[O:22])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Oc3ccccc3)cc2C(=O)NC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(C(=O)O)cc1
Reaction time: 20 h
Yield: 94.3 %

Procedure:
A solution of 34D (80 mg, 0.19 mmol) in THF (2 mL) was treated with 1 N NaOH (0.4 mL). The resulting solution was stirred for 20 hours. The reaction mixture was treated with 1 N HCl (0.6 mL) and partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was washed with brine (20 mL), dried (Na2SO4), and concentrated to afford 34E (75 mg, 94%). HPLC retention time: 4.34 minutes (YMC S-5 ODS-A 4.6×50 mm, 10% to 90% MeOH/H2O w/0.2% H3PO4, 4 minute gradient).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14](=[O:18])[C:15]([NH2:17])=[CH:16][C:9]=2[C:8](=[O:19])[CH:7]=1)=[O:5])C.[OH-].[K+].Cl>>[NH2:17][C:15]1[C:14](=[O:18])[CH:13]=[CH:12][C:10]2[NH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8](=[O:19])[C:9]=2[CH:16]=1
Reactant: CCOC(=O)c1cc(=O)c2cc(N)c(=O)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Nc1cc2c(=O)cc(C(=O)O)[nH]c2ccc1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 6-amino-4,7-dihydro-4,7-dioxo-1H-cyclohepta[b]pyridine-2-carboxylic acid ethyl ester (0.73 g, described in Example 3) and 2N potassium hydroxide (15 ml) is stirred at room temperature for 16 hr. Hydrochloric acid (10%) is added until the solution is acidic. The crystalline precipitate is collected and washed with water and acetone to give the title compound, mp > 270° C.