Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6]C=1)(=O)[CH3:2].[S:9]1[CH:13]=[CH:12][C:11]([C:14]([CH2:16][C:17]#[N:18])=[O:15])=[CH:10]1.C1(=O)CCCC1.N1CCOCC1.[S]>>[NH2:18][C:17]1[S:6][C:7]2[CH2:2][CH2:1][CH2:4][C:8]=2[C:16]=1[C:14]([C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)=[O:15]
Reactant: CC(=O)c1ccsc1
Reactant: N#CCC(=O)c1ccsc1
Agent: [S]
Solvent: C1COCCN1
Solvent: O=C1CCCC1
Product: Nc1sc2c(c1C(=O)c1ccsc1)CCC2
Yield: 71 %

Procedure:
The procedure of Example 1 was followed except that 3-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophene-3-carbonyl)acetonitrile (Steps A and B). Cyclopentanone (Aldrich), 2-(thiophene-3-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 71%; IR (KBr) cm−1: 3330, 3117, 2846, 1569, 1448, 1435, 1265, 855, 836, 757, 715; 1H NMR (CDCl3):δ2.24 (m, 4H), 2.71 (m, 2H), 6.83 (bs, 2H), 7.33 (m, 2H), 7.56 (m, 1H); yellow solid, mp: 125-127° C. (petroleum ether).
Reaction SMILES: CCN(CC)CC.[CH2:8]1[CH:12]2[CH2:13][NH:14][CH2:15][CH:11]2[CH2:10][N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].Cl[C:24]1[N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:27]=[N:26][N:25]=1>O1CCOCC1>[C:29]1([N:28]2[C:24]([N:14]3[CH2:13][CH:12]4[CH2:8][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH:11]4[CH2:15]3)=[N:25][N:26]=[N:27]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Clc1nnnn1-c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CN(c3nnnn3-c3ccccc3)CC2C1
Temperature: 115 °C

Procedure:
Et3N (5 mL) was added into a solution of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1 g) and 5-chloro-1-phenyl-1H-tetrazole (1 g) in dioxane (50 mL). The mixture was heated to 115° C. for 24 hours. The reaction was quenched with water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phase was dried over MgSO4 and concentrated to give a residue which was purified by silica gel chromatography to give tert-butyl 5-(1-phenyl-1H-tetrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH2:28][CH3:29])=[C:16]([C:22]([CH3:26])=[C:23]([Cl:25])[CH:24]=3)[C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH3:13])[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH2:28][CH3:29])=[C:16]([C:22]([CH3:26])=[C:23]([Cl:25])[CH:24]=3)[C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH3:13])[N:9]=[C:10]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)[C:3]=12
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)n2nc(I)c3c(N)ncnc32)c1OCC
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)n2nc(-c3cn[nH]c3)c3c(N)ncnc32)c1OCC
Temperature: 100 °C
Yield: 11.3 %

Procedure:
To a solution of 3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide (9.0 mg, 0.017 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.6 mg, 0.034 mmol), sodium carbonate (11 mg, 0.10 mmol) in N,N-dimethylformamide (0.1 mL)/water (51 μL) under N2 was added tetrakis(triphenylphosphine)palladium(0) (2.0 mg, 0.0017 mmol). The mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was filtered and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (0.9 mg, 10%). The product was isolated as a racemic mixture. LCMS calculated for C22H26ClN8O2 (M+H)+: m/z=469.2; Found: 469.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:25]OS(C)(=O)=O)=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:37]=1.[C:38]([O-:41])(=[S:40])[CH3:39].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:25][S:40][C:38](=[O:41])[CH3:39])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:37]=1
Reactant: CS(=O)(=O)OCC(C(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1)c1ccccc1
Reactant: CC([O-])=S
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)SCC(C(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1)c1ccccc1

Procedure:
Dissolve 0.3 g (0.56 m mole) of 8-chloro-11-[1-(2-methanesulfonyloxy-1-phenylethylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo-[5,6]cyclohepta-[1,2-b]pyridine (Formula 5.6 of Example 83) in 5 mL of DMF and add 0.2 g (0.6 m mole) of cesium thioacetate (preparation described in Synthetic Communications, 13, 553, 1983). Stir the reaction at 80° C. for twenty hours then concentrate under vacuo. Purify the residue by silica gel chromatography using 70% EtOAc and 30% hexane as the solvent. The product is obtained as a light brown solid, mp=92.7°-93° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: Oc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5-hydroxyaniline (42 mg, 0.290 mmol) similar to Example 108 and isolated as a brown solid (3 mg, 4%). 1H NMR (CDCl3): 8.68 (dd, J=1.8, 4.5 Hz, 2H), 8.13 (dd, J=1.8, 4.2 Hz, 2H), 7.99 (d, J=2.7 Hz, 1H), 7.34 (s, 1H), 7.33 (d, J=8.7 Hz, 1H), 6.98 (s, 1H), 6.73 (dd, J=2.7, 8.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([NH:19][CH2:20][C:21](O)=[O:22])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:22])[CH2:20][NH:19][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
Methyl 4-amino-benzoate (3.58 g, 23.70 mmol) and N-Boc glycine (4.15 g, 23.70 mmol) were stirred in DMF (50 mL) at room temperature. BOP (11.52 g, 26.07 mmol) was added followed by the addition of DIEA (6.18 mL, 35.55 mmol). The resulting mixture was stirred at rt for 1.5 h. It was quenched with sat'd NaHCO3 and EtOAc. The organic layer was washed with H2O, brine (3×), dried (MgSO4), and concentrated to dryness to give 4-(2-tert-butoxycarbonylamino-acetylamino)-benzoic acid methyl ester (7.18 g, yield: 98%). 1H NMR (CDCl3) δ 9.16 (s, br, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 3.98 (s, 2H), 3.89 (s, 3H), 1.45 (s, 9H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]6[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=56)[CH:23]=[CH:22][N:21]=4)=[C:12]([O:35][CH3:36])[CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:11]=[C:12]([O:35][CH3:36])[C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]6[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=56)[CH:23]=[CH:22][N:21]=4)=[CH:14][C:15]=3[NH2:16])[CH2:6][CH2:7]2)[CH2:3]1
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Yield: 32.6 %

Procedure:
A mixture of N-{4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 133, 400 mg, 0.82 mmol), iron (273 mg, 4.89 mmol) and NH4Cl (30.5 mg, 0.57 mmol) in ethanol (12 mL) and water (4 mL) was heated at reflux for 4 h and then stirred at r.t.overnight. Part-purification by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia provided crude material that was concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 provided impure product as a brown gum. Further purification by FCC, eluting with 0-2% 7N methanolic ammonia in CH2Cl2 provided the title compound (123 mg, 33%) as a brown gum; m/z: ES+ MH+ 461.26.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[C:25]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1)#[N:26]>C(O)(C)C>[ClH:2].[C:25]([C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:29]([F:34])[CH:28]=1)#[N:26]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(C#N)cc3F)ncnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
5M Isopropanolic hydrogen chloride (1.5 ml) was added to a solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (202 mg, 0.6 mmol), (prepared as described for the starting material in Example 18), and 4-cyano-2-fluoroaniline (100 mg, 0.72 mmol), (U.S. Pat. No. 4,120,693), in isopropanol (5 ml) heated at 50° C. The mixture was then heated at 80° C. for 2 hours, allowed to cool to ambient temperature and left standing overnight. The resulting precipitate was collected by filtration and the solid was then partitioned between methylene chloride and water and 1M aqueous sodium hydroxide solution (0.8 ml) was added. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/methanol (94/6). The purified solid was dissolved in methylene chloride and 2.2M ethereal hydrogen chloride was added. The precipitated product was collected by filtration, washed with ether and dried under vacuum to give 4-(4-cyano-2-fluoroanilino)-6-methoxy 7-(3-morpholinopropoxy)quinazoline hydrochloride (125 mg, 39%).
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[F:15][C:16]1[CH:41]=[CH:40][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27][CH2:28][C:29]3([C:37](Cl)=[O:38])[CH2:35][CH:34]4[O:36][CH:31]([CH2:32][CH2:33]4)[CH2:30]3)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.Cl>ClCCl>[OH:3][NH:2][C:37]([C:29]1([CH2:28][S:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:19]3[CH:40]=[CH:41][C:16]([F:15])=[CH:17][CH:18]=3)=[CH:22][CH:23]=2)[CH2:35][CH:34]2[O:36][CH:31]([CH2:32][CH2:33]2)[CH2:30]1)=[O:38]
Reactant: NO
Reactant: O=C(Cl)C1(CSc2ccc(Oc3ccc(F)cc3)cc2)CC2CCC(C1)O2
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NO)C1(CSc2ccc(Oc3ccc(F)cc3)cc2)CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0° C. is treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture is allowed to warm to ambient temperature overnight. This mixture is then cooled to 0° C. and treated with a solution of (15.1 mmol) of the product from Step F in 73 mL of dichloromethane causing an exotherm to about 8° C. This mixture is stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction is then treated with 50 mL of 2N aqueous hydrochloric acid and is stirred at ambient temperature for one hour. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). The organic phase is then concentrated to yield the title compound.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([NH:20][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: OC[C@H]1O[C@@H](NCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 48 h

Procedure:
50 g of D-glucose were dissolved in 1,000 ml of hot ethanol and, after addition of 89 g of benzylamine, the mixture was left at room temperature for 48 hours. It was then cooled with ice and the product was precipitated with petroleum ether. The product was filtered off with suction, washed with ether and dried in vacuo. 1H-NMR in CD3OD: δ=7.33, broad singlet, phenyl-H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.P(Br)(Br)[Br:11]>C(Cl)Cl>[Br:11][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccnc(Cl)c1
Solvent: ClCCl
Product: Clc1cc(CBr)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
(2-chloropyridin-4-yl)methanol (1.1 g, 7.3 mmol) is dissolved in 20 mL DCM; flushed with argon and cooled to 0° C. PBr3 (0.76 mL; 8.1 mmol) is added drop wise via a syringe (solution turned cloudy) and reaction mixture is stirred at RT for 3 h. Cooled to 0° C. and quenched with 5 mL water. The reaction mixture is adjusted to pH 7 by the addition of 2M K2CO3. The aqueous and organic layer are separated and the aqueous layer is extracted 3× with EtOAc. The organic layers are combined, dried over anhydrous sodium sulfate, filtered and deposited on silica. Column chromatography on silica gel (pre-washed with 1% NEt3), using a solvent gradient from hexanes to EtOAc lead to the isolation of the product as pale pink crystals (700 mg, 50% yield based on recovered starting material).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](Cl)=[CH:7][CH:8]=1)(=O)[CH3:2].[Cl:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.C1(=O)CCCCC1.N1CCOCC1.[S]>>[NH2:20][C:19]1[S:5][C:6]2[CH2:2][CH2:1][CH2:4][CH2:8][C:7]=2[C:18]=1[C:16]([C:14]1[S:15][C:11]([Cl:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: CC(=O)c1ccc(Cl)s1
Reactant: N#CCC(=O)c1ccc(Cl)s1
Agent: [S]
Solvent: C1COCCN1
Solvent: O=C1CCCCC1
Product: Nc1sc2c(c1C(=O)c1ccc(Cl)s1)CCCC2
Yield: 76 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-chlorothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-chlorothiophene-2-carbonyl)acetonitrile (Steps A and B). Cyclohexanone (Aldrich), 2-(5-chlorothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 76%; IR (KBr) cm−1: 3349, 3237, 3131, 2911, 1577, 1547, 1430, 1281, 1006, 765; 1H NMR (CDCl3):δ 1.59 (m, 2H), 1.65 (m, 2H), 2.35 (t, 2H, J=5.8 Hz), 2.55 (t, 2H, J=5.8 Hz), 6.07 (bs, 2H), 6.88 (d, 1H, J=4 Hz), 7.16 (d, 1H, J=4 Hz); yellow solid, mp: 173–175° C. (petroleum ether).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].[Br:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18]Br>C(#N)C>[Br:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18][NH:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: NCCCO
Reactant: Fc1ccc(Br)c(CBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: OCCCNCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Hunig's base (1.3 eq) and 3-aminopropan-1-ol (1.3 eq) were added to a solution of 2-bromo-5-fluoro-benzyl bromide (1 eq) in acetonitrile (0.6 M) and the resulting mixture stirred at RT under nitrogen for 12 h. Concentrated in vacuo to give 3-(((2-bromo-5-fluorophenyl)methyl)amino)propan-1-ol as a clear oil. EI-MS m/z 262, 264 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[OH:27][CH2:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([CH2:28][OH:27])[CH:34]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: OCc1cccc(B(O)O)c1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccc(CO)c3)cc1OCC2)c1ccccc1Cl

Procedure:
Following the procedure of Example 93, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and 3-hydroxymethylphenylboronic acid were reacted to give 201. MS: (ESI+) 476.16
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([CH2:36][OH:37])[CH:30]=1>CN1CCCC1=O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:2]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)=[O:5])=[C:31]([CH2:36][OH:37])[CH:30]=1
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Reactant: OCc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1Oc1ccc(F)cc1CO
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 1.2 %

Procedure:
2-Fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (625.3 mg, 2.08 mmol), potassium carbonate (287.9 mg, 2.08 mmol) and 4-fluoro-2-(hydroxymethyl)phenol (296 mg, 2.08 mmol) were added to 1-methylpyrrolidin-2-one (3.0 mL) and the reaction was stirred at 80° C. for 10 minutes. The reaction was filtered and the compound was purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modifier to yield 2-[4-fluoro-2-(hydroxymethyl)phenoxy]-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (157) (10.3 mg, 1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 10.66 (s, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.41-7.27 (m, 2H), 7.24-7.12 (m, 1H), 7.12-7.07 (m, 1H), 7.04 (s, 1H), 6.80 (d, J=2.1 Hz, 1H), 6.43 (dd, J=7.3, 2.2 Hz, 1H), 4.47 (s, 2H) ppm. ESI-MS m/z calc. 422.09. found 423.2 (M+1)+; Retention time: 1.32 minutes (3 minutes run).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12].[CH:15](=O)[CH3:16].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:15][CH3:16]
Reactant: CC=O
Reactant: CON(C)C(=O)c1ccc(F)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNc1cc(F)ccc1C(=O)N(C)OC
Reaction time: 1.5 h

Procedure:
To a solution of N-methoxy-N-methyl-2-amino-4-fluoro-benzamide (0.20 g, 1.01 mmol), acetaldehyde (86 μL, 1.53 mmol), and AcOH (87 μL, 2.1 mmol) in dichloromethane (20 mL) was added sodium triacetoxyborohydride (430 mg, 2.03 mmol) at 5° C. The mixture was stirred for 90 minutes at the same temperature and then 40 minutes at room temperature. The reaction was quenched by adding water. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-4-fluoro-2-ethylamino-benzamide quantitatively.
Reaction SMILES: CI.[Mg].Br[C:5]1[C:13]2[O:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:20](=[O:22])=[O:21].Cl>O1CCCC1>[C:14]1([C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:20]([OH:22])=[O:21])[C:13]=3[O:12][CH:11]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=O
Reactant: Brc1cccc2c(-c3ccccc3)coc12
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: O=C(O)c1cccc2c(-c3ccccc3)coc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3)-(i) 2.4 ml of methyl iodide are added dropwise to a solution of 3.9 g of magnesium in 16 ml of tetrahydrofuran and the mixture is stirred at room temperature for 20 minutes. A solution of 11.0 g of 7-bromo-3-phenylbenzofuran in tetrahydrofuran is added dropwise to the mixture and the mixture is refluxed for 4 hours. After cooling, the reaction mixture is poured to dry ice, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate to give 6.31 g of 3-phenylbenzofuran-7-carboxylic acid as pale yellow prisms.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH2:56]([O:58][C:59](=[O:71])[C@H:60]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=1)[NH2:61])[CH3:57]>CS(C)=O>[CH2:56]([O:58][C:59](=[O:71])[C@@H:60]([NH:61][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[N:9][C:10]=2[CH:15]=1)=[O:17])[CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=1)[CH3:57]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(C#N)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
The carboxylic acid of example 2 (0.060 g, 0.20 mmol) and TBTU (1.3 equiv., 0.26 mmol, 0.084 g) were dissolved in DMSO (0.6 mL) and DIEA (5 equiv., 1.0 mmol, 0.18 mL) was added followed by (S)-4-cyanophenylalanine ethyl ester hydrochloride (1.3 equiv., 0.26 mmol, 0.065 g). The mixture was stirred at room temperature for 1 h and quenched with water. The precipitated solid was collected by filtration, washed with water and dried. The title amide (0.081 g) was obtained as a beige solid.