Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[S:3]1[C:7]([N:8]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=[N:4]1.C(=O)(O)[O-].[K+]>ClCCl>[Br:1][C:6]1[CH:5]=[N:4][S:3][C:7]=1[N:8]([C:18]([O:20][CH2:21][C:22]([Cl:23])([Cl:24])[Cl:25])=[O:19])[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: BrBr
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1ccns1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1sncc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
Bromine (85 μL, 1.7 mmol) was added to a solution of methyl N-isothiazol-5-yl-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate (150 mg, 0.370 mmol) in dichloromethane (2.0 mL) over powdered potassium bicarbonate (370 mg, 3.7 mmol) with rapid stirring at rt for 5 h. Excess bromine was quenched by the addition of 1 M aqueous NaHSO3 solution and the mixture was partitioned between water and ether. The layers were separated and the aqueous phase was extracted with additional ether (2×). The extracts were combined, dried (Na2SO4) and concentrated to give 172 mg of methyl N-(4-bromoisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:25][CH2:26][NH2:27].C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:27][CH2:26][CH2:25][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([F:22])([F:23])[F:24])[C:15]=2[F:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1cccc(C(F)(F)F)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
1 ml of 4-tert-butylbenzaldehyde (6.16 mmol), 1 g of 2-(2-fluoro-3-trifluoromethyl-phenyl)-ethylamine hydrochloride (4.1 mmol) and 567 mg of potassium carbonate (4.1 mmol) were suspended in 12 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 233 mg (6.16 mmol) of sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 1 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:4) to give 1.09 g yellow oil (75%). MS (ISP) 354.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([O:20][CH3:21])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1>CO>[CH3:1][O:2][C:3](=[O:22])[CH:4]([O:20][CH3:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: COC(=O)C(=Cc1cccc(OCc2ccccc2)c1)OC
Solvent: CO
Product: COC(=O)C(Cc1cccc(OCc2ccccc2)c1)OC
Temperature: 0 °C

Procedure:
A solution of 3-(3-benzyloxy-phenyl)-2-methoxy-acrylic acid methyl ester (Example 291, Step 2) (3.96 g) in methanol (10 mL) was placed in a round bottom flask equipped with a reflux condenser. The mixture was cooled to 0° C. and Mg turnings (6.45 g) were added. The mixture was initially stirred vigorously and then further stirred at room temperature for about an hour. The solvent was evaporated under vacuum, and 100 mL of diethyl ether were added to the resulting solid. HCl (3N, 100 mL) was added and the solution was stirred for one minute. The organic layer was separated from the slurry, and 100 mL of diethyl ether and HCl (3N, 100 mL) were added to the remaining slurry. The procedure was repeated until the entire solid was dissolved. The combined ethereal extracts were washed with brine and dried over MgSO4. Concentration of the mixture afforded a yellow oil which was about 90% pure bye NMR. 1H-NMR (CDCl3, 200.15 MHz): 7.45–7.17 (m, 6H), 6.88–6.81 (m, 3H), 5.05 (s, 2H), 3.97 (dd, 1H, J=7.3, 5.4), 3.72 (s, 3H), 3.34 (s, 3H), 3.00 (d, 1H, J=5.1), 2.99 (d, 1H, J=7.8).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[OH:10].P(Br)(Br)[Br:12]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:12])=[CH:4][C:3]=1[OH:10]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Br)c(O)c1
Solvent: ClC(Cl)Cl
Product: Oc1cc(CBr)ccc1Br
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a suspension of 2-bromo-5-hydroxymethylphenol 71 (5.17 g, 25.5 mmol) in chloroform (100 mL) at 0° C. was added a solution of PBr3 (1.21 g 12.7 mmol) in chloroform (60 mL) over 30 min. The resultant solution was stirred at 0° C. for 1 h, and then was warmed to room temperature and stirred for an additional 1.75 h. After this time, the reaction mixture was poured into ice water and extracted with dichloromethane (2×). The organic layers were dried over Na2SO4, filtered, and the filtrate was purified by silica gel chromatography (eluent: dichloromethane:EtOAc, 95:5) to give 72. 1H NMR (400 MHz CDCl3) δ: 4.40 (s, 2H), 5.52 (s, 1H), 6.85 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.06 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H). MS (EI) m/z (M−H−) 263.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([CH3:16])=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC(O)=O.C1C(=O)N([Br:28])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([CH3:16])=[C:14]([Br:28])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2scc(C)c2CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)N1CCc2sc(Br)c(C)c2CC1
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
The product of step (g) (337 mg, 1.4 mmol) was dissolve in 10 mL of 1:1 CHCl3:HOAc and treated with NBS (301 mg, 1.7 mmol). After stirring for ½ hour, the reaction was diluted with DCM and washed with water (50 mL) and 1M NaOH (2×50 mL). The crude product was purified by silica gel chromatography to give 235 mg of the sub-title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.CSC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cc1ccccc1Br)NCc1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: Brc1ccccc1CCNCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2-Bromophenyl)-N-(phenylmethyl)acetamide was dissolved THF (0.2 M), followed by addition of BH3.DMS (3 eq), and the reaction was heated to reflux with stirring. After 2 hrs, the mixture was cooled to room temerature, and quenched with excess 10% HCl. The mixture was heated to reflux for 1 hr, and then cooled to room temperature. After washing with EtOAc, the aqueous phase was made alkaline with 10% sodium carbonate, and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with EtOAc to afford a colorless solid. EI-MS m/z 290/292 (M+H)+
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:16][CH2:15][C:13](=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].CCN(S(F)(F)[F:23])CC>C1COCC1>[C:2]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:16][CH2:15][C:13]([F:23])=[CH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CC=C(F)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
4-N-Boc-aminomethyl cyclohexanone (4.95 g, 21.8 mmol) was dissolved in THF (80 mL). DAST (4.3 mL, 32.7 mmol) was added dropwise and the solution was stirred at 50° C. for 5 h. The solvent was concentrated and the product purified by flash chromatography on silica gel using hexanes/EtOAc (3:1) as eluent. Yield: 1.62 g (30%). 1H NMR (400 MHz, CDCl3) δ 1.36-1.42 (m, 1 H), 1.44 (s, 9 H), 1.70-1.80 (m, 2 H), 1.82-1.90 (m, 1 H), 2.09-2.17 (m, 1 H), 2.17-2.29 (m, 2 H), 3.04-3.11 (m, 2 H), 4.61 (s, 1 H), 5.11-5.19 (m, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Cl>CN(C)C=O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.8 %

Procedure:
3-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N,N-dimethylformamide (60 mL). 2-Picolyl chloride hydrochloride (4.44 g, 27.1 mmol) was added to this suspension, and stirred for 14 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1-1:1) to obtain the title compound (2.98 g, 57%).
Reaction SMILES: [C:1]([C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:13]=3)[C:8]=2[CH:7]=[C:6]([CH:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)[CH:5]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCCl>[N:19]1([C:17]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]4[CH:7]=[C:6]([CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]=4[NH:15]3)=[CH:10][CH:11]=2)=[O:18])[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: NC(=O)c1cc(C2CCNCC2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Yield: 54.4 %

Procedure:
tert-Butyl 4-(1-carbamoyl-7-(morpholine-4-carbonyl)-9H-carbazol-3-yl)piperidine-1-carboxylate (Example 393, 50 mg, 0.099 mmol) was dissolved in 1,2-Dichloroethane (3 ml) and trifluoroacetic acid (1 ml, 12.98 mmol) and stirred for 1 hour at room temperature. Evaporation of volatiles and purification by reversed phase preparative HPLC, followed by filtration of product containing fractions through a PHENOMENEX® Strata-X cartridge (2 g adsorbent), a wash with Methanol, and elution with 2M NH3 in MeOH gave 21.9 mg 7-(morpholine-4-carbonyl)-3-(piperidin-4-yl)-9H-carbazole-1-carboxamide. MS (ESI) m/e−=405 and m/e=407 consistent with [M−H]− and [M+H]+. HPLC retention time 7.61 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA). 1H NMR (CD3OD) δ ppm 8.21 (s, 1H), 8.20 (d, 1H, J=8.0), 7.87 (d, 1H, J=1.5), 7.69 (s, 1H), 7.27 (dd, 1H, J=8.0, 1.5), 3.90-3.50 (b, 8H), 3.23 (br. d., 2H, J˜12), 2.91 (m, 1H), 2.83 (m, 2H), 1.97 (br. d., 2H, J˜12), 1.85 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][CH2:35][CH3:36])=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[O-]CC.[Na+]>C(O)C>[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][CH2:35][CH3:36])=[C:27](/[CH:28]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CCCOc1c(C=O)cccc1OC
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)cccc1OC
Yield: 47.9 %

Procedure:
The title compound was prepared by condensation of Intermediate 15 (400 mg, 1.225 mmol) with 3-methoxy-2-propoxybenzaldehyde (333 mg, 1.716 mmol) in the presence of sodium ethoxide (176 mg, 2.301 mmol) in ethanol (25 ml) according to the procedure outlined in Example 24 to give 295 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7.2 Hz, 3H), 1.53 (q, J=6.9 Hz, 2H), 3.31 (s, 1H), 3.77 (s, 3H), 3.80 (s, 1H), 6.91-6.99 (m, 4H), 7.40-7.46 (m, 4H), 7.50 (d, J=4.8 Hz, 1H), 7.95-8.07 (m, 2H); ESI-MS (m/z) 503.51 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C:7]1[N:8]([C:12]2[N:13]=[C:14]([CH2:39][CH2:40][CH3:41])[N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[C:16]=2[C:17]([O:19]C)=[O:18])[CH:9]=[CH:10][CH:11]=1)C(F)(F)F.Cl.[OH-:43].[Na+]>O>[C:17]([C:16]1[N:15]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:35][N:36]=[N:37][N:38]=3)=[CH:26][CH:27]=2)[C:14]([CH2:39][CH2:40][CH3:41])=[N:13][C:12]=1[N:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:2]([OH:43])=[O:1])([OH:19])=[O:18]
Reactant: [OH-]
Reactant: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCc1nc(-n2cccc2C(=O)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 120.4 %

Procedure:
Methyl 4-[2-(1-oxo-2,2,2-trifluoroethyl)-1H-pyrrol-1-yl]-2-propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylate (Example 13, 0.8 g) was dissolved in a solution sodium hydroxide (1.68 g) in water (14 mL) and the resulting solution refluxed overnight. After cooling in an ice bath, conc HCl was added dropwise until the pH of the mixture was between 3-4. The insoluble product was collected by filtration, washed several times with water, and dried under reduced pressure overnight at room temperature to afford 0.85 g of the title compound 1H-NMR (DMSO-d6) δ 7.8 7.5 (m, 4H), 7.3-7.0 (m, 5H), 6.9 (m, H), 6.3 (m, 1H), 5.7 (s, 2H), 2.6 (t, 2H), 1.7 1.4 (m, 2H), 0.9 (t, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[N:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1.C[Si]([N:33]=[C:34]=[S:35])(C)C>C1C=CC=CC=1.O>[N:19]1[C:28]2[CH:27]([C:34](=[S:35])[NH2:33])[CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)N=C=S
Reactant: c1cnc2c(c1)CCCC2
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: NC(=S)C1CCCc2cccnc21
Reaction time: 1 h

Procedure:
A solution of di-isopropylamine (33.3g, 0.33 mol) in benzene (150 ml) was cooled in ice and treated with 9% w/v butyl-lithium in hexane (237 ml, 0.33 mol). After 45 minutes the solution was treated with 5,6,7,8-tetrahydroquinoline (39.9 g, 0.3 mol) dropwise with stirring. After 1.5 hours trimethylsilyl-isothiocyanate (43.2 ml. 0.3 mol) was added and the resulting solution was allowed to stand at 0° C for 0.5 hours and at room temperature for 1 hour. Water (50 ml.) was added to the solution of 5,6,7,8-tetrahydroquinoline-8-(N-lithio-N-trimethylsilyl) thiocarboxamide causing hydrolysis to 5,6,7,8-tetrahydroquinoline-8-(N-trimethylsilyl)thiocarboxamide and subsequent hydrolysis to the title compound, and the resulting mixture acidified with 2N HCl. The acid solution was separated, washed with ethyl acetate and the pH was adjusted to 9 with solid sodium carbonate. Extraction with chloroform followed by drying of the extract over MgSO4, filtration and evaporation gave a thick gum which crystallised on trituration with n-hexane. Recrystallisation from methanol gave 5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (16g, 30%) m.p. 160°. The hydrochloride was prepared by dissolution of the free base in hot isopropyl alcohol adding ethereal HCl solution and allowing to crystallise. m.p. 263°-4°. (Found: C, 52.6; H, 6.0; N, 12.2. C10H12N2S, HCl requires C, 52.5; H, 5.7; N, 12.3%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:12]2[N:13]([CH2:22][OH:23])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CCOC(C)=O.CCCCCC>[CH2:1]([O:8][C:9]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:12]2[N:13]([CH2:22][O:23][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CCCN(CO)c2c1cc(OCc1ccccc1)c1ccccc21
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C1CCCN(COS(C)(=O)=O)c2c1cc(OCc1ccccc1)c1ccccc21
Yield: 92.1 %

Procedure:
Following the general procedure detailed for 84, 91 (0.029 g, 0.074 mmol, 1 equiv) was treated with Et3N (0.052 mL, 0.371 mmol, 5 equiv) and CH3SO2Cl (0.017 mL, 0.148 mmol, 2 equiv). Radial chromatography (SiO2, 1 mm plate, 50% EtOAc-hexane) furnished 93 (0.032 g, 0.035 g theoretical, 91%) as a white solid: mp 130-132° C.; 1H NMR (500 MHz, CDCl3) major rotamer δ 8.40 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.61-7.35 (m, 7H), 6.63 (s, 1H), 5.27-5.17 (m, 2H), 4.51-4.33 (m, 4H), 3.60 (s, 3H), 2.86-2.81 (m, 1H), 2.54 (s, 3H), 2.32-2.23 (m, 1H), 2.07-2.04 (m, 1H), 1.76-1.70 (m, 2H); 13C NMR (125 MHz, CDCl3) major rotamer δ 155.3, 153.7, 139.5, 136.6, 133.1, 128.6 (2C), 128.0 (2C), 127.7, 127.6, 127.3, 125.4, 124.3, 123.4, 122.8, 106.9, 71.1, 70.1, 53.0, 48.3, 36.8, 36.2, 26.7, 24.5; IR (film) νmax 3063, 3022, 2938, 2858, 1701, 1593 cm−1; FABHRMS (NBA) m/z 470.1648 (M+H+, C25H27NO6S requires 470.1637).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:10][C:9]#[N:12])=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: Oc1ccc(F)cc1
Product: N#CCCOc1ccc(F)cc1
Yield: 85 %

Procedure:
A mixture of 11.2 g of 4-fluorophenol, 26.5 g of acrylonitrile and 4.9 g of cupric hydroxide was refluxed for 8 hours with stirring, and then acrylonitrile and 4-fluorophenol were removed from the mixture under reduced pressure. After diluting the obtained residue with ether and filtering solid, the ether layer was successively washed with 10% aqueous solution of sodium hydroxide and 2N hydrochloric acid and dehydrated with anhydrous magnesium sulfate. Ether was distilled away to give 14.02 g of colorless liquid of 3-(4-fluorophenoxy)propionitrile (yield: 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[C:11]3[S:17][CH:18]=[CH:19][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8].C([Li])CCC.CCCCCC.[I:31]I>O1CCCC1.COC(C)(C)C.C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][CH2:14][NH:13][C:12](=[O:16])[C:11]3[S:17][C:18]([I:31])=[CH:19][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: II
Reactant: O=C1NCCC(c2ccc(Cl)c(Cl)c2)c2ccsc21
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1NCCC(c2ccc(Cl)c(Cl)c2)c2cc(I)sc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a stirring solution of 4-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one (1.05 g, 3.36 mmol) in tetrahydrofuran (30 mL) at −78° C. was added a solution of n-butyllithium in hexane (2.5 M, 6.73 mL, 16.82 mmol) in rapid drops under an atmosphere of argon. The reaction solution became purplish after ˜2 ml had been added and became intensely purple by the end of the addition. The reaction solution was stirred at −78° C. for 30 minutes then iodine (7.95 g, 31.3 mmol) was added as a solid in a single portion with good stirring—the purple color was instantly quenched to give a reddish brown mixture. The resulting mixture was stirred at −78° C. for 5 minutes then the dry ice/acetone bath was removed and the reaction was allowed to warm to rt with stirring for one hour. A saturated sodium bisulfate solution (150 mL) was added to the reaction mixture with good stirring—most of the color faded to give a lemon yellow mixture. Ethyl acetate was added and the mixture was transferred to a separatory funnel. The organic layer was separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with saline, dried over sodium sulfate, filtered, and concentrated to leave crude product as a light orange solid. The crude product was stirred with DCM—most solids did not dissolve. The mixture was sonicated well, diluted with t-butyl methyl ether, and the white precipitate was isolated on a fritted funnel. It was washed it with additional TBME and air-dried to leave 787 mg product as a white powder. The filtrate was evaporated to leave an orange residue which was purified using column chromatography on silica gel (80 g RediSep column, gradient 0% ethyl acetate in hexane to 100% ethyl acetate in hexane over 30 minutes) to give 440 mg additional product as a white solid. Total yield 1.227 g (83% yield). LCMS: (FA) ES+ 438, 440. 1H NMR (400 MHz, DMSO) δ 8.27-8.20 (d, J=4.5 Hz, 1H), 7.61-7.53 (d, J=8.3 Hz, 1H), 7.47-7.42 (d, J=2.0 Hz, 1H), 7.09-7.02 (dd, J=8.3, 2.1 Hz, 1H), 6.81-6.75 (s, 1H), 4.51-4.41 (dd, J=8.6, 5.3 Hz, 1H), 3.22-3.05 (d, J=5.5 Hz, 2H), 2.27-2.14 (m, 1H), 2.09-1.99 (m, J=7.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O.P(Cl)(Cl)([Cl:18])=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]=[C:3]([Cl:18])[C:2]([F:15])([F:14])[F:1])=[CH:7][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(NC(=O)C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(N=C(Cl)C(F)(F)F)cc1
Temperature: 82 °C
Yield: 117.6 %

Procedure:
Ten grams (45.6 mmol) of 2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide, 4.92 g (32.0 mmol) of phosphorus oxychloride, 9.23 g (91.2 mmol) of triethylamine, and 50 ml of acetonitrile were introduced into a 200 ml flask and reacted for 19 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 30 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 8.94 g of N-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 82.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[C:12]([O:22][CH3:23])[CH:11]=3)=[N:7][C:6]=2[CH:24]=1.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:25]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[C:12]([O:22][CH3:23])[CH:11]=3)=[N:7][C:6]=2[CH:24]=1)#[N:26]
Reactant: CN(C)C=O
Reactant: COc1cc(-c2nc3cc(Br)ccc3o2)ccc1-c1ccccn1
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(-c2nc3cc(C#N)ccc3o2)ccc1-c1ccccn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 1 mL of degassed DMF was added 5-bromo-2-(3-methoxy-4-pyridin-2-ylphenyl)-1,3-benzoxazole (622 mg, 1.63 mmol), zinc cyanide (115 mg, 0.98 mmol), tris(dibenzylideneacetone)-dipalladium (0)-chloroform complex (30 mg, 0.029 mmol), and 1,1′-bisdiphenylphosphinoferrocene (41 mg, 0.073 mmol). The reaction mixture was degassed with argon for an additional 10 min and heated at 120° C. under an argon atmosphere for 20 h. The mixture was cooled to 80° C., 4 mL of a 4:1:4 saturated NH4Cl:NH4OH:H2O solution was added dropwise, and the mixture cooled to rt and stirred overnight. The mixture was cooled to −9° C. and filtered, the solid washed with 5 mL of a 4:1:5 sat. NH4Cl:NH4OH:H2O solution followed by 5 mL H2O, and dried under vacuum to a dark yellow solid. The crude solid was purified by column chromatography (20–80% EtOAc/hexanes) to give 5-cyano-2-(3-methoxy-4-pyridin-2-ylphenyl)-1,3-benzoxazole as a tan solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.72 (d, 1H), 8.47 (d, 1H), 8.09–7.85 (m, 7H), 7.40 (ddd, 1H), 4.01 (s, 3H); MS (ESI) 328 (M+H)+.