Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH2:14])=[N:11][N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:34][CH2:35][O:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[NH:43][C:42](=[O:47])[CH2:41][CH2:40]3)(=O)=O)=CC=1>CN(C=O)C.O>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([NH:14][CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:44](=[CH:45][CH:46]=3)[NH:43][C:42](=[O:47])[CH2:41][CH2:40]4)=[N:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: Nc1nnc(-c2ccc(C(F)(F)F)cc2)o1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)CCC(=O)N3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OCCNc3nnc(-c4ccc(C(F)(F)F)cc4)o3)ccc2N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 5.5 %

Procedure:
To a solution of 5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-amine (0.047 g, 0.207 mmol) in DMF (2 mL) was added potassium carbonate (0.052 g, 0.376 mmol) and 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)ethyl 4-methylbenzenesulfonate (0.068 g, 0.188 mmol) and the reaction stirred at room temperature for 15 h. The temperature was then increased to 60° C. for 15 h. After cooling to room temperature, the mixture was diluted with water (5 mL), extracted with EtOAC (20 mL), dried over sodium sulfate, and evaporated. The residue was purified by preparative HPLC on a X— Terra column (10×150 mm, 5 μm) with 0-100% AcCN in 10 mM aq. NH4OAc. Solvents were evaporated under vacuum to yield 6-(2-(5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-ylamino)ethoxy)-3,4-dihydroquinolin-2(1H)-one (4.3 mg, 5.5%). 1H NMR: 400 MHz, DMSO-d6: δ 2.53 (dd, J=7.60, 8.40 Hz, 2H), 2.91 (t, J=8.00 Hz, 2H), 3.76 (t, J=5.20 Hz, 2H), 4.20 (t, J=5.20 Hz, 2H), 6.80-6.84 (m, 3H), 7.83 (d, J=8.40 Hz, 2H), 8.07 (d, J=8.00 Hz, 2H). LCMS: RT 1.79 min. LCMS (ES-API), m/z 419.0 (M+H).
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:29]2([CH3:30])[C@:16]([CH3:35])([C:17]3[C:26](=[CH:27][CH2:28]2)[C@:25]2([CH3:31])[CH:20]([C:21]([CH3:34])([CH3:33])[C:22](=[O:32])[CH2:23][CH2:24]2)[CH2:19][CH:18]=3)[CH2:15][CH2:14]1)[CH3:12])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:47](O)[CH2:48][OH:49]>C1C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])/[C:2](/[CH3:1])=[CH:8]/[CH2:9][CH2:10][C@H:11]([C@@H:13]1[C@:29]2([CH3:30])[C@:16]([CH3:35])([C:17]3[C:26](=[CH:27][CH2:28]2)[C@:25]2([CH3:31])[CH:20]([C:21]([CH3:33])([CH3:34])[C:22]4([CH2:23][CH2:24]2)[O:49][CH2:48][CH2:47][O:32]4)[CH2:19][CH:18]=3)[CH2:15][CH2:14]1)[CH3:12])[CH3:7]
Reactant: CCOC(=O)/C(C)=C/CC[C@@H](C)[C@H]1CC[C@@]2(C)C3=CCC4C(C)(C)C(=O)CC[C@]4(C)C3=CC[C@]12C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)/C(C)=C/CC[C@@H](C)[C@H]1CC[C@@]2(C)C3=CCC4C(C)(C)C5(CC[C@]4(C)C3=CC[C@]12C)OCCO5
Temperature: 25 °C

Procedure:
General Ketalization. Ketone 9E (0.257 g, 0.535 mmol, 1.0 equiv) was dissolved in benzene (27 mL). After the ketone was completely dissolved, p-toluenesulfonic acid (0.0102 g, 0.0535 mmol, 0.1 equiv) and ethylene glycol (0.298 mL, 5.35 mmol, 10 equiv) were added and the solution was heated to reflux for 20 h using a modified Dean-Stark apparatus. The mixture was then allowed to cool to room temperature, and was then concentrated using a rotary evaporator. The residue was then diluted with CH2Cl2 (30 mL) and washed with saturated sodium bicarbonate solution (3×30 mL). The organic layer was washed with a saturated brine (30 mL), dried with MgSO4, and vacuum filtered through a pad of Celite. The filtrate was concentrated with a rotary evaporator to give 10E as a pure white crystalline product (0.246 g, 88% yield). 10Z was prepared by an analogous procedure in 83% yield. (6R,E)-Ethyl-2-methyl-6-((10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-1,2,4,5,6,10,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17-yl)hept-2-enoate (10E): mp 75-79° C. IR (KBr) νmax 3047, 2963, 2924, 2898, 2888, 1705, 1652, 1197, 1141, 1101, 1098, 1050, 1028, 964, 952 cm−1. 1H NMR (CDCl3) δ 6.75 (dt, J=1.3, 7.5 Hz, 1H), 5.45 (m, 1H), 5.31 (d, J=6.3 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.96 (m, 3H), 3.88 (m, 1H), 2.27-2.17 (m, 2H), 2.11-1.84 (m, 8H), 1.81 (d, J=1.1 Hz, 3H), 1.75-1.31 (m, 7H), 1.29 (t, J=7.1 Hz, 3H), 1.22-1.1 (m, 2H), 1.04 (s, 3H), 1.02 (s, 3H), 0.92 (d, J=6.5 Hz, 3H), 0.88 (s, 3H), 0.86 (s, 3H), 0.60 (s, 3H). 13C{1H} (CDCl3) δ 168.3, 145.9, 142.8, 142.5, 127.4, 120.2, 116.0, 113.1, 64.9, 64.7, 60.4, 50.8, 50.3, 47.4, 43.8, 41.8, 37.8, 37.0, 36.2, 34.9, 34.0, 31.5, 27.9, 27.2, 25.7, 25.6, 23.1, 22.9, 22.7, 20.4, 18.3, 15.6, 14.3, 12.3. HRMS calcd for C34H5304 (M+H)+525.3938. found 525.3922.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([CH:35]=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O:39][C:40](=[O:42])[CH3:41])C>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:35][C:29]1[CH:30]=[CH:31][C:32]([CH2:41][C:40]([OH:42])=[O:39])=[CH:33][CH:34]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccccc1
Product: O=C(O)Cc1ccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
Prepared using the procedure in Example 56 except using 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol instead of 4-(3-hydroxyphenyl)-8-(trifluoromethyl) quinolin-3-yl](phenyl)methanone and 4-bromomethyl-phenyl)-acetic acid ethyl ester as the halide. MS (ESI) m/z 528.
Reaction SMILES: [C:1]([C:6]1[CH:7]=C2[C:12](=[CH:13][CH:14]=1)[NH:11]C(=S)C2C)([O:3][CH2:4][CH3:5])=[O:2].[CH3:17][C:18](C)([O-:20])[CH3:19].[K+].[O:23]1CCCC1>>[C:1]([C:6]1[CH:7]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:19](=[O:23])[C:18]2=[O:20])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)C(=S)N2
Agent: [K+]
Product: CCOC(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reaction time: 18 h
Yield: 60 %

Procedure:
According to the general procedure, 4.06 g of 5-carboethoxy-3-methylthiooxindole and an E.Q. of sublimed potassium t-butoxide in 250 ml of dry tetrahydrofuran was stirred and aerated for 6 h at 0° C. and 18 h at 25° C. Acidification with 1.35 ml of conc. hydrochloric acid in 25 ml of water, followed by extraction with ether and normal workup (vide supra), gave a yellow solid which was recrystallized from ethyl acetate to yield 2.20 g (60%) of 5-carboethoxyisatin, mp 205°-206° C. EXAMPLE 3: 5-Methylisatin
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:11])=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:11]
Reactant: CCOC(=O)[C@H](Cc1cccc(OC)c1)NC(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cccc(OC)c1)NC(=O)CN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100-mL round-bottomed flask was added ethyl N-(tert-butoxycarbonyl)glycyl-3-methoxyphenylalaninate (812 mg, 2.13 mmol) and trifluoroacetic acid (5 mL, 67.3 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 30 min. The solvent was removed in vacuo to give crude ethyl glycyl-3-methoxyphenylalaninate trifluoroacetate as a viscous oil which was used without purification.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:15]=3)[C:10]([C:22]3[N:23]=[N:24][N:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[O:34])=[CH:29][CH:28]=4)[CH:26]=3)=[N:9]2)=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O.O>[N:35]1([C:33]([C:30]2[CH:31]=[CH:32][C:27]([N:25]3[CH:26]=[C:22]([C:10]4[C:11]5[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:12]=5)[NH:8][N:9]=4)[N:23]=[N:24]3)=[CH:28][CH:29]=2)=[O:34])[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(OCCCO)ccc32)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(OCCCO)cc34)nn2)cc1)N1CCOCC1
Yield: 29.3 %

Procedure:
A solution of 3-[(1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)oxy]propan-1-ol (43 mg; 0.08 mmol; 1.0 eq.) and anisole (124 mL, 1.13 mmol, 15 eq.) in TFA (2 mL) and water (2.7 mL) was stirred at RT for 48 h. Reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give the title compound as a brown gum (10.5 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.35 (s, 1H), 8.15 (d, J=8.6 Hz, 2H), 7.77-7.72 (m, 1H), 7.69 (d, J=8.6 Hz, 2H), 7.52 (d, J=9.0 Hz, 1H), 7.10 (dd, J=9.0, 2.4 Hz, 1H), 4.61 (t, J=5.2 Hz, 1H), 4.21-4.06 (m, 2H), 3.78-3.24 (m, 10H), 2.02-1.82 (m, 2H). HPLC (max plot) 97.2%; Rt %2.63 min. UPLC/MS: (MS+) 449.1, (MS−) 447.1.
Reaction SMILES: [H-].[Na+].Cl[CH2:4]/[CH:5]=[C:6](/[CH3:13])\[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11].[CH2:14]([O:16][CH2:17][PH:18]([CH2:20][P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])=[O:19])[CH3:15].[I-].[CH3:30][CH2:31]OCC>CN(C=O)C>[CH2:14]([O:16][CH2:17][PH:18]([CH:20]([P:21](=[O:28])([O:22][CH2:23][CH3:24])[O:25][CH2:26][CH3:27])[CH2:30][CH2:31][CH2:4]/[CH:5]=[C:6](/[CH3:13])\[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[O:19])[CH3:15]
Reactant: CC(C)=CCC/C(C)=C\CCl
Reactant: CCOC[PH](=O)CP(=O)(OCC)OCC
Reactant: CCOCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC[PH](=O)C(CCC/C=C(/C)CCC=C(C)C)P(=O)(OCC)OCC
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 123 mg (5.13 mmol) of sodium hydride in 10 mL of DMF at 0° C. under argon was added 1.32 g (5.13 mmol) of Example 1, Part A [(ethoxymethylphosphinyl)methyl]phosphonic acid, diethyl ester in 5 mL of DMF dropwise over 20 minutes. The mixture was stirred for 0.5 hours and was treated with 1.00 g (3.42 mmol) of Part A iodide in 3 mL of DMF. The reaction was stirred at 0° C. for 1 hour then at room temperature for 48 hours, at which time the reaction was diluted with ether and quenched with saturated NH4Cl. The organic layer was washed with water, brine, dried (MgSO4) and evaporated to provide 1.10 g of a pale yellow oil. Flash chromatography was performed on 100 g of silica gel eluted with 49.5:49.5:1 acetone/ethyl acetate/methanol (1 liter) followed by 45:45:10 acetone/ethyl acetate/methanol. Pure product fractions were combined and evaporated to provide 600 mg (43%) of title ester as a pale yellow oil, a mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[N:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1>CO>[OH2:4].[N:7]1[CH:12]=[CH:11][C:10]([CH:13]=[N:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[CH:9][CH:8]=1
Reactant: COC(=O)NN
Reactant: O=Cc1ccncc1
Solvent: CO
Product: COC(=O)NN=Cc1ccncc1
Product: O
Temperature: 25 °C
Yield: 198.5 %

Procedure:
A solution of 2.70 gm (0.03 mole) of methyl carbazate, 3.21 gm (0.03 mole) of 4-pyridinecarboxaldehyde and 50 ml of anhydrous methanol is refluxed 8 hr. The hot solution is filtered. The filtrate is diluted with water to the cloud point and cooled to room temperature. The mixture is chilled in the refrigerator. The crystals are collected, washed with water and dried to yield 5.87 gm (99%) of the title compound having a melting point of 159.6° C. (decomp.).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([OH:34])[C:32]#[CH:33])=[CH:27][CH:26]=1>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]([OH:34])[C:32]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:33]=2)=[CH:29][CH:30]=1
Reactant: C#CC(O)c1ccc(Br)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1C(O)c1ccc(Br)cc1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and 1-(4-bromophenyl)prop-2-yn-1-ol. MS (+ESI) m/z: 483.0.
Reaction SMILES: Br[C@@H:2]([CH2:6][CH3:7])[C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:15][O:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][NH2:21]>C(#N)C>[CH3:15][O:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][NH:21][C@@H:2]([C:3](=[O:4])[NH2:5])[CH2:6][CH3:7]
Reactant: CC[C@H](Br)C(N)=O
Reactant: COC(=O)CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC[C@@H](NCCCC(=O)OC)C(N)=O
Temperature: 60 °C
Reaction time: 43 h

Procedure:
A mixture of (S)-2-bromobutyramide (IIh) (optical purity>98.4%; 0.25 g, 1.5 mmol), potassium carbonate (1.1 g, 8.0 mmol, 5 equiv.) and methyl-4-aminobutyrate hydrochloride (0.46 g, 3.0 mmol, 2 equiv.) is diluted in 5 ml (15 vol.) of acetonitrile and heated at 60° C. for until complete conversion. After 43 hours (GC: >90% conversion), the mixture is cooled to room temperature and filtered. The cake is rinsed with acetonitrile (20 ml) and the combined filtrates are concentrated to dryness under reduce pressure. The crude product is used directly in the subsequent step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[Cl:27])[N:23]=[CH:22][N:21]=[C:20]2[NH:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][C:34](=O)[CH2:33]1)=[O:31]>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[Cl:27])[N:23]=[CH:22][N:21]=[C:20]2[NH:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH:34]([N:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([OH:15])[CH:9]([CH3:14])[CH2:10]2)[CH2:33]1)=[O:31]
Reactant: O=C1CCN(C(=O)CNc2ncnc3cc(Cl)c(Cl)cc23)C1
Reactant: C[C@H]1CNCC[C@]1(O)c1ccc(F)cc1
Product: CC1CN(C2CCN(C(=O)CNc3ncnc4cc(Cl)c(Cl)cc34)C2)CCC1(O)c1ccc(F)cc1

Procedure:
2-(6,7-dichloroquinazolin-4-ylamino)-1-(3-(4-(4-fluorophenyl)-4-hydroxy-3-methylpiperidin-1-yl)pyrrolidin-1-yl)ethanone was prepared as a mixture of 4 isomers from (3S,4R)-4-(4-fluorophenyl)-3-methylpiperidin-4-ol (prepared via general procedure O, AA) and 1-(2-(6,7-Dichloroquinazolin-4-ylamino)acetyl)pyrrolidin-3-one (Preparation #32) according to general procedure E then purified via chiral preparative NP-HPLC (isocratic 2.5% methanol:2.5% ethanol:95% heptane:0.1% diethylamine modifier at 16 mL/min, room temperature; UV detection monitored at 265 nm; Daicel AD-H column, 20×250 mm, 5 um particle) to yield two products. Product A eluted at Rt 7.5-11 min. Product B eluted at Rt 11-15 min. Product A has a positive optical rotation and product B has a negative optical rotation. Product A was further separated via chiral preparative NP-HPLC (isocratic 10% methanol:10% ethanol:80% heptane:0.1% diethylamine modifier at 14 mL/min, room temperature; UV detection monitored at 265 nm; Daicel OD-H column, 20×250 mm, 5 um particle) to yield two isomers. Isomer 1 eluted at Rt 14-16.3 min. Isomer 2 eluted at Rt 16.3-19 min. Both isomers have positive optical rotation. The absolute stereochemistry of the isomers was not assigned. Isomers 1 & 2: RP-HPLC (Table 1, Method a) Rt 1.99 min; m/z: (M+H)+ 532. Product B was further separated via chiral preparative NP-HPLC (isocratic 10% methanol:10% ethanol:80% heptane:0.1% diethylamine modifier at 14 mL/min, room temperature; UV detection monitored at 265 nm; Daicel OD-H column, 20×250 mm, 5 um particle) to yield two isomers. Isomer 3 eluted at Rt 13.3-16 min. Isomer 4 eluted at Rt 16.3-19 min. Both isomers have negative optical rotation. The absolute stereochemistry of the isomers was not assigned. Isomers 3 & 4: RP-HPLC (Table 1, Method a) Rt 1.92 min; m/z: (M+H)+ 532.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])[CH2:4]1)#[N:2].C(O)(=[O:21])C>Cl.O>[C:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[O:11])[CH2:4]1)(=[O:21])[NH2:2]
Reactant: N#CN1CCCC(CC(=O)c2ccc(F)cc2)C1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: NC(=O)N1CCCC(CC(=O)c2ccc(F)cc2)C1

Procedure:
1-Cyano-3-(4-fluorophenacyl)piperidine (Example 19), 21.5 g, was dissolved in a mixture of 150 ml of glacial acetic acid, 30 ml of concentrated aqueous hydrochloric acid, and 70 ml of water. The resulting solution, under a nitrogen atmosphere, was heated on a steam-bath for 16 hours. The reaction solution was distilled under reduced pressure, the residue was diluted with water, and the resulting solution was made alkaline with 3 N sodium hydroxide. Upon extracting the alkaline aqueous solution with ethyl ether, solid precipitated and was isolated by filtration and washed with ether. The solid, 6.7 g, was recrystallized once from aqueous acetone and then four times from acetone/diethyl ether, to give 1-carbamoyl-3-(4-fluorophenacyl)piperidine, mp 136°-137.5°. The following elemental analysis was obtained:
Reaction SMILES: OS([C:5]([F:8])([F:7])[F:6])(=O)=O.Cl.[C:10]([S:13][CH2:14][C:15]1[CH2:16][CH2:17][CH2:18][C:19]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:20]=2[C:21]=1[CH3:22])(=[NH:12])[NH2:11].[C:28](=O)([OH:30])[O-:29].[Na+]>C(O)(C(F)(F)F)=O>[Br:27][C:24]1[CH:25]=[CH:26][C:19]2[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH2:14][S:13][C:10]([NH2:11])=[N:12][C@:21]3([CH3:22])[C:20]=2[CH:23]=1.[C:28]([OH:30])([C:5]([F:8])([F:7])[F:6])=[O:29]
Reactant: CC1=C(CSC(=N)N)CCCc2ccc(Br)cc21
Reactant: O=C([O-])O
Reactant: O=S(=O)(O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C[C@]12N=C(N)SC[C@H]1CCCc1ccc(Br)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triflic acid (1.33 mL, 15.0 mmol) was added to flask charged with a stirred solution of (2-bromo-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate, HCl from step E3 (540 mg, 1.5 mmol) in TFA (5.0 mL) at 0° C. The reaction mixture was allowed to warm to rt and stir for 6 h. The reaction contents were carefully added to a swirled mixture of ice and excess solid sodium bicarbonate. After gas evolution had ceased, the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using preparatory HPLC (SunFire PrepC18 OBD 10 mm, 50×250 mm column, 90% MeOH/10% water/0.1% TFA-90% MeOH/10% water/0.1% TFA, linear gradiant over 34 min, 50 ml/min) to afford (4aS,11bS)-10-bromo-11b-methyl-4,4a,5,6,7,11b-hexahydrobenzo[6,7]cyclohepta[1,2-d][1,3]thiazin-2-amine, TFA (77 mg, 0.18 mmol, 12% yield) as a white solid. LCMS (M+H)+=327.0. 1H NMR (500 MHz, methanol-d4) δ 7.43 (dd, J=8.1, 2.1 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 3.17-3.06 (m, 1H), 2.96 (dd, J=12.1, 3.1 Hz, 1H), 2.89 (dd, J=15.4, 5.6 Hz, 1H), 2.80 (t, J=12.4 Hz, 1H), 2.57-2.39 (m, 2H), 2.08 (dd, J=14.8, 4.0 Hz, 1H), 1.94-1.86 (m, 1H), 1.84 (s, 3H), 1.67-1.48 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22]>CC(C)=O.O>[CH3:1][N:2]([C:21](=[O:22])[CH2:20][Cl:19])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccccc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1N(C)C(=O)CCl
Reaction time: 1 h

Procedure:
25 Grams of methyl o-methylaminobenzoate was dissolved in 125 ml of acetone, to this solution was added a solution prepared by dissolving 20.92 g of potassium carbonate in 60 ml of water. Under an ice-cooled condition, 17.95 g of chloroacetyl chloride was added dropwise thereto, then the reaction mixture was stired at a room temperature for 1 hour. Acetone was removed by distillation, the residue obtained was extracted with chloroform, then the chloroform layer was washed with water, dried and the solvent was removed by distillation. The residue thus obtained was purified by a silica gel column chromatography to obtain 16.80 g of N-methyl-o-methoxycarbonyl-α-chloroacetanilide in the form of colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.C1N=CN([C:26](N2C=NC=C2)=[O:27])C=1.[F:33][C:34]([F:50])([F:49])[CH:35]([NH:38][C:39]1[N:40]=[CH:41][C:42]2[CH2:48][CH2:47][NH:46][CH2:45][C:43]=2[N:44]=1)[CH2:36][OH:37]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][C:26]([N:46]2[CH2:47][CH2:48][C:42]3[CH:41]=[N:40][C:39]([NH:38][CH:35]([CH2:36][OH:37])[C:34]([F:33])([F:49])[F:50])=[N:44][C:43]=3[CH2:45]2)=[O:27])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCC(Nc1ncc2c(n1)CNCC2)C(F)(F)F
Reactant: C[C@@H](N)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)N1CCc2cnc(NC(CO)C(F)(F)F)nc2C1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 185 (21.0 mg, 0.111 mmol) in DCM (1 mL) at RT under nitrogen was added sequentially DIPEA (38.5 μL, 0.221 mmol) neat by syringe followed by CDI (17.9 mg, 0.111 mmol) neat as a solid. After stirring for 30 min, the solution was added by pipet to a flask containing solid 354 (29 mg, 0.111 mmol). The reaction was stirred at RT under nitrogen overnight. The reaction was diluted to 30 mL with DCM and washed sequentially with 2 N HCl (2×30 mL) with 2N HCl and satd. aq. NaHCO3 (2×30 mL). The organics were dried (MgSO4), filtered and concentrated to a yellow foam. The crude product was purified by SiO2 chromatography (Biotage 12S) eluting with EtOAc. The product containing fractions were pooled and concentrated to afford 10 mg (19%) of I-92 as a yellow residue: 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.39 (m, 2H), 7.17 (dd, 1H), 5.57 (d, 1H), 4.97 (m, 1H), 4.91 (m, 1H), 4.75 (d, 1H), 4.36 (s, 2H), 3.96 (m, 2H), 3.65 (m, 2H), 2.69 (dd, 2H), 1.48 (d, 6H); MS m/z (APCI-pos) M+1=478.5.