Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([NH2:31])=[O:30])=[CH:22][CH:21]=1.[OH-].[Na+]>Cl.CN1C(=O)CCC1.O>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][C:29]([NH2:31])=[O:30])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: NC(=O)CCCc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)CCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 120 °C
Yield: 37.3 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol), 4-(4-aminophenyl)butanamide (0.071 g, 0.40 mmol) and conc. HCl (2 drops) in NMP (3 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 2 h. The reaction mixture was cooled, diluted with water (5 mL) then treated with 2M aqueous sodium hydroxide until pH˜8 affording a solid. The solid was isolated by filtration and purified by chromatography on silica using dichloromethane/methanol (10:0 to 19:1) as eluent followed by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford 4-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)butanamide (0.050 g, 37%) as a white solid. MW=405.92. 1H NMR (DMSO-d6, 500 MHz) δ 8.07 (s, 1H), 7.91 (t, J=2.0 Hz, 1H), 7.74 (dt, J=7.5, 1.5 Hz, 1H), 7.46-7.38 (m, 2H), 7.25 (br s, 1H), 7.22-7.15 (m, 5H), 6.71 (br s, 1H), 2.91 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.55 (t, J=7.5 Hz, 2H), 2.08 (quin, J=7.5 Hz, 4H), 1.79 (quin, J=7.5 Hz, 2H); ESI MS m/z 406 [M+H]+. Treatment with 1.25M HCl in methanol afforded the title compound (0.053 g, 99%) as an off-white solid. MW=442.38. M.p. 108-111° C. 1H NMR (DMSO-d6, 500 MHz) δ 11.91 (br s, 1H), 8.84 (br s, 1H), 7.91-7.88 (m, 1H), 7.74-7.69 (m, 1H), 7.54-7.47 (m, 2H), 7.27-7.22 (m, 5H), 7.11 (br s, 1H), 6.72 (br s, 1H), 3.01 (t, J=7.5 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.57 (t, J=7.5 Hz, 2H), 2.15 (quin, J=7.5 Hz, 2H), 2.09 (t, J=7.5 Hz, 2H), 1.80 (quin, J=7.5 Hz, 2H); ESI MS m/z 406 [M+H]+.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:18])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:6]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([CH2:2][C@H:3]([OH:18])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:6]=1)=[N+:20]=[N-:21]
Reactant: CCC(CC)COc1cccc(C[C@@H](O)CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCC(CC)COc1cccc(C[C@@H](O)CN=[N+]=[N-])c1

Procedure:
Treatment of (R)-1-chloro-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol with sodium azide following the method used in Example 66 gave (R)-1-azido-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:14]([O:16][C:17]1[C:18](=O)[C:19](=[O:24])[C:20]=1[O:21]CC)[CH3:15]>>[CH3:13][O:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([NH:1][C:18]3[C:19](=[O:24])[C:20](=[O:21])[C:17]=3[O:16][CH2:14][CH3:15])[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: COc1cc(N)c2ncccc2c1
Product: CCOc1c(Nc2cc(OC)cc3cccnc23)c(=O)c1=O
Yield: 28.9 %

Procedure:
In a procedure identical to Example 10, Step 1, 8-amino-6-methoxyquinoline (2.00 g, 11.48 mmol) was reacted with 3,4-diethoxy-3-cyclobutene-1,2-dione (1.70 mL, 11.48 mmol) to give 0.99 g (29%) of product: 1H NMR (DMSO-d6) δ10.21 (s, 1H), 8.75 (dd, 1H), 8.29 (dd, 1H), 7.61 (m, 2H), 7.17 (d, 1H), 4.76 (q, 2H), 3.90 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([O:12][CH2:13][CH2:14][CH3:15])[CH:4]=1.[F:16][B-:17]([F:20])([F:19])[F:18].[CH2:21]([O+](CC)CC)[CH3:22]>ClCCl>[F:16][B-:17]([F:20])([F:19])[F:18].[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[NH:9])[O:8][CH2:21][CH3:22])=[C:5]([O:12][CH2:13][CH2:14][CH3:15])[CH:4]=1
Reactant: CCCOc1cc(OC)ccc1C(N)=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCOc1cc(OC)ccc1C(=N)OCC
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 4-methoxy-2-propoxybenzamide (15 g) and triethyloxonium tetrafluoroborate (0.08 mol) in dichloromethane (180 ml) was stirred at ambient temperature for about 60 hours. The reaction mixture was evaporated under reduced pressure and the residue was washed with diethyl ether to yield crude ethyl 4-methoxy-2-propoxybenzimidate tetrafluoroborate, 20.52 g which was used without further purification.
Reaction SMILES: C1C=CC2NC(C(O)=O)=CC(=O)C=2C=1.NOCC(O)=O.[CH:21]1[CH:22]=[CH:23][C:24]([NH2:35])=[C:25]([C:27]([CH2:29][CH:30]([NH2:34])[C:31]([OH:33])=[O:32])=[O:28])[CH:26]=1>>[CH:21]1[CH:22]=[CH:23][C:24]([NH2:35])=[C:25]([C:27]([CH2:29][C@H:30]([NH2:34])[C:31]([OH:33])=[O:32])=[O:28])[CH:26]=1
Reactant: Nc1ccccc1C(=O)CC(N)C(=O)O
Agent: NOCC(=O)O
Agent: O=C(O)c1cc(=O)c2ccccc2[nH]1
Product: Nc1ccccc1C(=O)C[C@H](N)C(=O)O

Procedure:
In order to establish that the kynurenic acid measured in striatal ECF was synthesized in the CNS rather than transported into the CNS from the periphery, we examined the ability of aminooxyacetic acid (AOAA), an established inhibitor of kynurenine transaminase, to inhibit the kynurenic acid surge produced by peripheral infusion of L-kynurenine. We designed a model with internal controls to negate the effects of variable L-kynurenine absorption from the periphery. Dialysis probes were implanted bilaterally into the striata of five rats. Initially, both probes were infused with artificial ECF. After 1.5 hours of pre-baseline perfusion, three consecutive 30 minute baseline fractions were collected from each probe. After the last fraction was collected, artificial ECF containing either 1.0 mM (N=3 rats) or 2.0 mM (N=2 rats) AOAA was perfused through one probe, while the contralateral probe was perfused with artificial ECF alone, as a control. Both probes were perfused for 1.5 hours (three consecutive 30 minute fractions). After the last fraction was collected L-kynurenine (75 mg kg−1) was administered peripherally via an intraperitoneal route. Dialysis fractions were then collected, at 30 minute intervals, for the next 3.0 hours. Ipsi-lateral (AOAA perfused) and contralateral (control) fractions were analyzed for kynurenic acid.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH2:17]>C(O)C>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1cc(F)cc(F)c1
Solvent: CCO
Product: O=C(O)C1CCN(c2cc(F)cc(F)c2)C1=O
Yield: 47.8 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 3,5-difluoroaniline (0.575 g; 4.36 mmol) in ethanol (3 mL). 1-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid 0.167 g (48%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[F-].[K+].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1B(O)O.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCCC1.O.CC(O)C>[F:10][C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]([C:15]2[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=2[F:20])=[CH:9][CH:8]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: N#Cc1cc(F)ccc1Br
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)ccc1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A suspension of 2-bromo-5-fluorobenzonitrile (10.0 g, 50 mmol), potassium fluoride (9.59 g, 165 mmol) and 2,6-difluorophenylboronic acid (9.87 g, 62.5 mmol) in tetrahydrofuran (120 ml) and water (15 ml) was degassed with nitrogen for 30 min. Tris(dibenzylidineacetone)dipalladium(0) (916 mg, 1.0 mmol) and tri-tert-butylphosphine (10% w/w solution in hexane, 0.5 ml) were added and the mixture stirred at ambient temperature for 18 h. The black solution was washed with 1N sodium hydroxide solution (2×100 ml), and the aqueous phase was re-extracted with diethyl ether (100 ml). The organic layers were combined, washed with brine (50 ml), filtered through a glass microfibre filter paper then evaporated to give an orange solid. The solid was suspended in 2-propanol (120 ml) and heated to 70° C. to aid dissolution. The solution was left to cool to ambient temperature then water (120 ml) was added dropwise over 1 h. The resulting solid was collected by filtration, washed with 2-propanol/water (1:1, 30 ml) then dried under vacuum to give 4,2′,6′-trifluorobiphenyl-2-carbonitrile (9.92 g, 85 %) as a grey solid: δH (360 MHz, CDCl3) 7.06 (2H, t, J 7.9), 7.38–7.52 (4H, m).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].C(OC([NH:30][C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=O)(C)(C)C>>[NH2:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]3[C@@H:14]3[CH2:16][C@@H:15]3[F:17])=[C:3]([CH3:22])[C:2]=2[F:1])[CH2:32]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: Cc1c(F)c(N2CC[C@@H](N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 66.1 %

Procedure:
A hundred milligrams of 6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 120 mg of (R)-3-t-butoxycarbonylaminopyrrolidine were reacted in the same manner as in Example 7, and the reaction mixture was worked up similarly to yield 80 mg of the titled compound as a grayish white to yellowish white substance.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[NH:24][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: COc1cnc(-c2ccccn2)nc1Cl
Product: COc1cccc(Nc2nc(-c3ccccn3)ncc2OC)c1

Procedure:
The title compound was prepared from 4-chloro-5-methoxy-2-(2-pyridinyl)pyrimidine (100 mg, 0.451 mmol) and m-anisidine (51 μl, 0.451 mmol) similar to Example 13 and isolated as a tan oily liquid (63 mg, 45%). 1H NMR (CDCl3): 8.76–8.74 (m, 1H), 8.37 (dd, J=1.1, 8.0 Hz, 1H), 8.05 (s, 1H), 7.79–7.73 (m, 2H), 6.65–6.62 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [O:1]1[CH2:3][C:2]21[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:7]=[CH:6][C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]2=1.[NH2:18][NH2:19]>>[NH:18]([CH2:3][C:2]1([OH:1])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[NH2:19]
Reactant: C1=Cc2ccccc2C2(CO2)c2ccccc21
Reactant: NN
Product: NNCC1(O)c2ccccc2C=Cc2ccccc21

Procedure:
A mixture of 10.5 g. of spiro [dibenzo[a,d]cycloheptene-5,2'-oxirane] and 100 ml. of anhydrous hydrazine is refluxed for 3 hours, the resulting mixture evaporated in vacuo to about 50 ml., cooled, the resulting crystals filtered off and washed generously with water. The crude solid is taken up in methylene chloride, extracted with water and then with saturated sodium chloride solution, dried and evaporated in vacuo. The residue is crystallized from ethyl acetate to obtain 5-hydrazinomethyl-5H-dibenzo[a,d]cyclo-hepten-5-ol, m.p. 128°-131° C.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22]([CH3:25])(=[O:24])=[O:23]>CN(C)C=O.O>[F:21][C:19]1[CH:20]=[CH:15][C:16]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:17]([NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: Nc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(F)cc1Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.8 %

Procedure:
Naphthalen-1-amine (0.89 g, 4.7 mmol) and 60% NaH in oil (0.24 g, 6.1 mmol) were stirred in N,N-dimethylformamide (5 mL) for 15 min at 0° C. and for 30 min at room temperature. 2,4-Difluoro-1-(methylsulfonyl)benzene (0.67 g, 4.7 mmol), was added to the reaction as a solid. The reaction was allowed to stir at room temperature for 16 h. The reaction was poured in water and extracted with ether. After removal of solvent the crude was purified on silica chromatography in 10% ethyl acetate in hexanes to obtain 0.56 g of product (0.36 mg, 38% yield). 1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 7.89 (m, 3H), 7.54 (m, 5H), 6.79 (t, 1H), 6.48 (d, 1H), 3.22 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([NH:8][NH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)=[O:7])#[N:2].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].C(OCC)(=O)C.ClCCl>ClC(Cl)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:7][C:23](=[O:24])[N:9]([C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=3)[N:8]=2)[CH:20]=[CH:21][CH:22]=1)#[N:2]
Reactant: COC(=O)c1ccc(NNC(=O)c2cccc(C#N)c2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2nc(-c3cccc(C#N)c3)oc2=O)cc1
Yield: 98 %

Procedure:
Methyl 4-[2-(3-cyanobenzoyl)hydrazino]benzoate (0.59 g, 2.0 mmol) and carbonyldiimidazole (0.49 g, 3.0 mmol) are stirred at 80° C. in dichloroethane (20 mL) overnight, and the mixture is then subjected to chromatography directly (silica gel, 1:9 ethyl acetate-dichloromethane) to provide methyl 4-[5-(3-cyanophenyl)-2-oxo-1,3,4-oxadiazol-3(2H)-yl]benzoate (0.63 g, 98%). MS (ES+) m/z: 322.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)[CH:12]=[C:11]([C:31]([C:33]2[CH:43]=[C:42]([CH3:44])[C:36]3[N:37]([CH3:41])[C:38](=[O:40])[O:39][C:35]=3[CH:34]=2)=[O:32])[CH:10]=1)C1C=CC=CC=1.Cl.N1C=CC=CC=1>>[CH3:41][N:37]1[C:36]2[C:42]([CH3:44])=[CH:43][C:33]([C:31]([C:11]3[CH:12]=[C:13]([N:15]4[CH2:16][CH2:17][CH:18]([N:21]5[C:29]6[C:24](=[N:25][CH:26]=[CH:27][CH:28]=6)[NH:23][C:22]5=[O:30])[CH2:19][CH2:20]4)[NH:14][C:9](=[O:8])[CH:10]=3)=[O:32])=[CH:34][C:35]=2[O:39][C:38]1=[O:40]
Reactant: Cc1cc(C(=O)c2cc(OCc3ccccc3)nc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c2)cc2oc(=O)n(C)c12
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)[nH]c(=O)c2)cc2oc(=O)n(C)c12

Procedure:
20 mg (0.034 mmol) 1-[6′-benzyloxy-4′-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one in 0.10 g (0.87 mmol) pyridine hydrochloride were kept in a melt for 4 min. After cooling the mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[O:19]1[CH:23]=[N:22][N:21]=[C:20]1[C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>>[OH:28][C:24]([C:20]1[O:19][CH:23]=[N:22][N:21]=1)([CH3:25])[C:26]#[C:27][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: C#CC(C)(O)c1nnco1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Product: CC(O)(C#Cc1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2)c1nnco1
Yield: 3 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1,3,4-oxadiazol-2-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (3.1 mg, 3%).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[Cl:26][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7])[N:9]=1
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(Sc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(Cl)c2cc(Sc3ccccc3)ccc2c1O

Procedure:
194 mg of 1-chloro-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.5 mmol) were reacted with glycine and sodium methylate analogously to Example D-1 g). 168 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.17 (t, 1H), 8.24 (d, 1H), 7.51 to 7.79 (m, 7H), 4.00 (d, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13]1)=[O:9].CCN(C(C)C)C(C)C.CS(C)=O.N1C=CC=CC=1.S(=O)(=O)=O>C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]([CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:16][CH2:17]1)=[O:9])=[O:1]
Reactant: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)NCc1cccc(CO)c1
Agent: O=S(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1cccc(CNC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
To a flask was added biphenyl-2-ylcarbamic acid 1-[2-(3-hydroxymethylbenzyl carbamoyl)ethyl]piperidin-4-yl ester (0.33 g, 0.68 mmol; prepared as described in Preparation 12), DCM (5 mL), DIPEA (0.47 mL, 2.7 mol) and DMSO (0.2 mL, 2.7 mol). Using an ice bath, the mixture was cooled to about −10° C. and sulfur trioxide pyridine-complex (0.32 g, 2.0 mol) was added. The reaction was stirred at −10° C. for 0.75 hour. Before removing the ice-bath, the reaction was quenched by adding water (5 mL). The aqueous layer was separated and the organic layer was washed with water (2×5 mL), 1.0N NaHSO4(aq) (2×5 mL), 1.0N NaHCO3(aq) (1×5 mL) and brine (0.5 L) and then dried over MgSO4 and filtered to provide the title compound which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[Li]CCCC.CC([O:21][B:22](OC(C)C)[O:23]C(C)C)C.Cl.COC1C(C(F)(F)F)=C(B(O)O)C=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[C:4]([C:9]([F:10])([F:11])[F:12])=[CH:5][CH:6]=[CH:7][C:8]=1[B:22]([OH:23])[OH:21]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccccc1C(F)(F)F
Agent: COc1cccc(B(O)O)c1C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(B(O)O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of 1-methoxy-2-(trifluoromethyl)benzene (6.30 g, 35.8 mmol) in THF (150 mL) was added n-BuLi (21.0 ml, 2.50 M hexane solution, 53.7 mmol), and the mixture was stirred at room temperature for 1 hr. The solution was cooled to −78° C., tris(1-methylethyl)borate (8.08 g, 43.0 mmol) was added, and the mixture was stirred at −78° C. for 0.5 hr. The reaction solution was allowed to cool to room temperature and stirred for 16 hr. The mixture was acidified with 1M hydrochloric acid and extracted with ethyl acetate (300 mL). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a mixture (6.52 g, yield 83%) of [2-methoxy-3-(trifluoromethyl)phenyl]boronic acid and [3-methoxy-2-(trifluoromethyl)phenyl]boronic acid.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>>[CH3:8][C:7]1[S:6][C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[C:2]1[S:13][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:1]=1
Reactant: COC(=O)c1cc(C(N)=S)c(C)s1
Reactant: O=C(CBr)c1ccccc1
Product: COC(=O)c1cc(-c2nc(-c3ccccc3)cs2)c(C)s1

Procedure:
A solution of 200 mg (0.93 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted with 185 mg (0.93 mmol) of 2-bromoacetophenone in a manner similar to Example 8, step (a) to give, after purification by preparative thin layer chromatography eluting with hexanes:ethyl acetate 7/3 (v:v), a mixture of methyl 5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate and methyl 4-cyano-5-methylthiophene-2-carboxylate (96 mg, 36%) as a solid.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[CH3:11][O:12][NH2:13]>C(O)C>[CH3:11][O:12][N:13]=[C:3]([CH2:2][Br:1])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CON
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CBr)=NOC
Yield: 80 %

Procedure:
Ethyl bromopyruvate (80% purity), 38.9 g (200 mmol as calculated on an assumption of 100% purity) was dissolved in 100 ml of ethanol. At room temperature, 16.6 g (200 mmol) of methoxyamine hydrochloride was added to the solution, followed by heating under reflux for 2 hours. After reaction had been completed, ethanol was distilled away, and 200 ml of ethyl acetate was added to the residue. The reaction product was washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. Filtration and subsequent distillation to remove the solvent gave 36.9 g (165 mmol) of ethyl 2-methoxyimino-3-bromopropionate as a light yellow oily matter. The yield was 80%. The product synthesized was subjected to the next reaction without purification.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH:11]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2Br)[CH2:6]1)(=[O:4])=[O:3].C([O-])([O-])=O.[Cs+].[Cs+].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:13]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:7]1[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]1
Reactant: OB(O)c1ccccc1
Reactant: COCCCOC(c1ccccc1Br)C1CCCN(S(C)(=O)=O)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COCCCOC(c1ccccc1-c1ccccc1)C1CCCN(S(C)(=O)=O)C1
Temperature: 120 °C

Procedure:
A tube designed for a microwave reactor was charged with 1-methanesulfonyl-3-((3-methoxypropoxy)(2-bromophenyl)methyl)piperidine (200 mg, 0.0.476 mmol, 1.0 equiv), PdCl2(dppf) (21 mg, 0.0.238 mmol, 0.05 equiv), Cs2CO3 (511 mg, 1.57 mmol, 3.3 equiv), phenylboronic acid (87 mg, 0.714 mmol, 1.5 equiv) and 4 mL of 1,4-dioxane. The tube was sealed and the resulting yellow solution degassed by three evacuates/N2 backfill cycles, then placed in a microwave reactor and heated to 120° C. for 15 min. The contents were transferred to a flask and volatile materials removed in vacuo. The residue was partitioned between CH2Cl2 and water. The yellow organic layer was washed with brine, dried over Na2SO4 and evaporated. The product was purified by flash chromatography on 4 g silica, eluting with 0 to 50% EtOAc in hexanes. 3-(Biphenyl-2-yl(3-methoxypropoxy)methyl)-1-(methylsulfonyl)piperidine was isolated as an off white solid (82 mg, 91%). 1H NMR (CDCl3) δ 0.8-1.8 (m, 8H), 2.25-2.5 (m, 4H), 2.85 (s, 3H), 3.25-3.55 (m, 4H), 3.25 (s, 3H), 3.55 and 3.62 (bd, 1H), 4.08 and 4.13 (d, 1H), 7.07-7.56 (m, 9H).