Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.B(Br)(Br)Br>ClCCl.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccnc4)cc32)cc1Br
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(-c3cccnc3)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.1 %

Procedure:
In a 5 ml flask, (3,5-dibromo-4-methoxy-phenyl)-(7-pyridin-3-yl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone (35 mg, 0.069 mmol) was dissolved in dichloromethane (1 ml), and the mixture was cooled to 0□. 1.0M Boron tribromide dissolved in dichloromethane (0.4 ml, 0.415 mmol) was added thereto and then stirred at room temperature for 15 hours. n-hexane solvent was added thereto and the formed solid was filtered. The resulting solid was dissolved in methanol and concentrated. After dissolving by adding water, the mixture was adjusted to pH 6 with saturated solution of sodium hydrogen carbonate, and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was recrystallized from dichloromethane and n-hexane to obtain the target compound 52 as white solid (18 mg, 53%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8]O)[CH3:2].[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:18][CH2:2][CH2:1][O:3][CH2:4][CH2:5][O:6][CH2:7][CH3:8])=[O:17]
Reactant: NCC(=O)CCC(=O)O
Reactant: CCOCCOCCO
Agent: Cl
Product: CCOCCOCCOC(=O)CCC(=O)CN
Reaction time: 4 h

Procedure:
From diethylene glycol monoethyl ether (5.0 g; 37 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 4 h. The yield was 0.90 g (53%) of light tan solid.
Reaction SMILES: C1(CO[CH:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:21][CH:20]=2)[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1.[C:37]([OH:41])(=[O:40])[CH2:38][SH:39].B(F)(F)F.O(CC)CC>C(Cl)Cl>[C:13]1([CH2:12][O:11][CH2:10][CH:9]([S:39][CH2:38][C:37]([OH:41])=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:21][CH:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(COCC(OCc2ccccc2)c2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: O=C(O)CS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)CSC(COCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of the ether (151 mg) (Step 2) and thioglycolic acid (31 μL) in CH2Cl2 at 0° C. was added BF3 /OEt2 (117 μL) dropwise. The mixture was stirred at 0° C. for 1 h and poured onto 25% aqueous NH4OAc, extracted with CH2Cl2 and the organic phase was dried and evaporated. Chromatography on silica gel using ethyl acetate/hexane containing 0.1% AcOH afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH3:20])[CH2:15]1)=[O:13].[C:21](Cl)(=[O:23])[CH3:22]>C(OCC)(=O)C.CCCCCC>[C:21]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH3:20])[CH2:15]1)=[O:13])(=[O:23])[CH3:22]
Reactant: CC1CCCC(C(=O)c2[nH]c3cc(Cl)ccc3c2N)C1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1c(C(=O)C2CCCC(C)C2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methylcyclohexylcarbonyl)indole (Example 144) and acetyl chloride. m.p.: 202-203° C. (ethyl acetate/hexane)
Reaction SMILES: [CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:39][NH:38][CH2:37]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:45])[CH3:44])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].C(N(CC)CC)C.[CH3:65][S:66](Cl)(=[O:68])=[O:67].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:37][N:38]([S:66]([CH3:65])(=[O:68])=[O:67])[CH2:39]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:44])[CH3:45])[NH:31][CH:32]=4)=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CNC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CC2(CC1c1nc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)n5)cc4)cc3)c[nH]1)CN(S(C)(=O)=O)C2)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a solution of methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[6-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,6-diazaspiro[3.4]oct-7-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate (Example 24) (60 mg, 0.08 mmol) in anhydrous CH2Cl2 (1 mL) was added triethylamine (0.054 mL, 0.39 mmol) and the reaction was cooled to 0° C. Methanesulfonyl chloride (0.018 mL, 0.23 mmol) was added and the reaction stirred at 0° C. for 15 minutes. The solvent was removed in vacuo and the residue dissolved in methanol (1 mL) and potassium carbonate (80 mg, 0.58 mmol) was added and the reaction stirred at room temperature for 1.5 h. The reaction was partitioned between CH2Cl2 (10 mL) and water (10 mL) the organic layer was dried (MgSO4) and concentrated in vacuo to afford the title compound as a tan solid (57 mg, 86% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.50-7.86 (m, 10H) 7.33 (br. s., 2H) 5.06-5.21 (m, 1H) 4.04-4.26 (m, 2H) 3.75-4.05 (m, 6H) 3.56-3.72 (m, 6H) 3.38-3.55 (m, 2H) 2.84-3.04 (m, 3H) 2.70-2.86 (m, 1H) 2.40-2.64 (m, 1H) 2.10-2.40 (m, 3H) 1.83-2.09 (m, 2H) 1.20-1.37 (m, 2H) 1.07-1.20 (m, 2H) 0.81-1.07 (m, 12H). HRMS for C43H66N9O8S (M+H)+ calc: 858.3973. found: 858.3975. Purity (LC-MS): 86%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][N:15]=[C:16]=[O:17]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[N:12][C:16](=[O:17])[NH:15][CH3:14])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 104 °C
Reaction time: 14 h

Procedure:
300 mg (1.5 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulfoximide in 8 ml toluene and 4 ml petroleum ether 60/80 are treated with 0.097 ml (1.65 mmol) methyl isocyanate. The mixture is stirred in a pressure tube at 104° C. for 5 hours and at room temperature for 14 hours. The suspension is filtrated to give 302 mg (corresponding to 78% of theor.) of the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:7]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cccc(CNCc2ccc(C)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(CN(Cc2ccc(C)cc2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
To a solution of (3-{[(4-methyl-benzyl)-amino]-methyl}-phenyl)-acetic acid ethyl ester (119 mg, 0.401 mmol) and triethylamine (0.61 mL, 0.726 mmol) in CH2Cl2 (2 mL) at 0° C. was added methanesulfonyl chloride (0.031 mL, 0.405 mmol). The reaction was stirred at room temperature for 2.5 h and 1N HCl was added. The product was extracted into CH2Cl2 (3×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by medium pressure chromatography (3:1 hexanes:EtOAc) to provide the title compound (101.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.13–7.36 (m, 8H), 4.27–4.30 (m, 4H), 4.14 (q, 2H), 3.60 (s, 2H), 2.74 (s, 3H), 2.33 (s, 3H); MS 376 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Br:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH:25][C:26]([C:28]3([O:31][CH3:32])[CH2:30][CH2:29]3)=[O:27])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1.CC#N.O>CCCCO.O>[Br:15][C:16]1[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[C:18]2[C:24]([NH:25][C:26]([C:28]3([O:31][CH3:32])[CH2:30][CH2:29]3)=[O:27])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COC1(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)CC1
Solvent: CC#N
Solvent: O
Solvent: CCCCO
Product: COC1(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)CC1
Temperature: 160 °C
Yield: 33.2 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (366 mg, 1.83 mmol) was added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methoxycyclopropanecarboxamide (200 mg, 0.61 mmol) in n-BuOH (3 mL). The resulting mixture was heated in a sealed tube at 160° C. for 24 hours. The cooled mixture was diluted with water (40 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over MgSO4 and filtered, and the filtrate was concentrated. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-85% CH3CN/water, 25CV) to give (R)-tert-butyl 1-(5-bromo-3-(1-methoxycyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (103 mg, 33% yield) as a solid. LCMS (APCI+) m/z 510 (M+2H)+, Retention time=3.84 minutes.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[S:6][C:7]=1[NH2:8].N1C=CC=CC=1.Cl[S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C1COCC1.CCOC(C)=O>[CH3:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[S:6][C:7]=1[NH:8][S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=1)(=[O:22])=[O:21]
Reactant: Cc1c(N)sc2ccccc12
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(NS(=O)(=O)c2ccc(C(=O)O)cc2)sc2ccccc12
Temperature: 5 °C
Reaction time: 72 h
Yield: 84.6 %

Procedure:
A 12-L 4-neck flask equipped with an overhead mechanical stirrer, N2 inlet/outlet adapter, and thermocouple was charged with THF (3.26 L) and compound 757-A (326 g, 1.6 mol) followed by pyridine (265 mL, 3.3 mol). The reaction mixture was cooled to 5° C. using a ice bath, to which was added a solution of 4-(chlorosulfonyl)benzoic acid (396 g, 1.8 mol) dissolved in THF (2.44 L), drop-wise. The reaction was allowed to stir at ambient temperature for 72 h, diluted with EtOAc (4 L), washed with 1N HCl (1 L), brine (1 L), the organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by triturating with EtOAc/heptane (1:1/1 L). The slurry was filtered, washed with heptane (2×250 mL) and dried in a vacuum oven at 40° C. for 18 h to afford 470 g of compound 306-C as a white solid. 1H-NMR (DMSO-d6): δ 13.51 (br s, 1H), 10.65 (br s, 1H), 8.12 (d, 2H), 7.86 (d, 2H), 7.83-7.79 (m, 1H), 7.66-7.63 (m, 1H), 7.37-7.33 (m, 1H), 2.03 (s, 3H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C(O)(=O)C.N1CCCCC1>CC(O)C>[C:3]([C:2](=[CH:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=1)[C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])=[O:6])(=[O:4])[CH3:5]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: O=Cc1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(=O)C(=Cc1cccc(Cl)c1)C(=O)OCCC#N

Procedure:
1.00 g (6.45 mmol) of 2-cyanoethyl acetoacetate and 730 μl (6.44 mmol) of 3-chlorobenzaldehyde were stirred in the presence of a catalytic amount of acetic acid and piperidine in 100 ml of 2-propanol at room temperature overnight. The solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=4[CH:18]=[CH:17][C:16]4[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:15]3=4)[C:11](=[O:31])[NH:10][C:9]2=[O:32])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:34][O:35][C:36](=[O:42])[C@@H:37]1[CH2:41][CH2:40][CH2:39][NH:38]1>>[CH3:25][C:23]1[CH:22]=[CH:21][C:20]2[CH:14]([C:12]3[C:11](=[O:31])[NH:10][C:9](=[O:32])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:38]5[CH2:39][CH2:40][CH2:41][C@H:37]5[C:36]([O:35][CH3:34])=[O:42])[N:7]=4)[CH:13]=3)[C:15]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:16]=3[CH:17]=[CH:18][C:19]=2[CH:24]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: COC(=O)[C@@H]1CCCN1c1nccc(-n2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=O)[nH]c2=O)n1

Procedure:
The subtitle compound was prepared from the product of example 8 step (ii) (0.3 g) and L-proline methyl ester hydrochloride (0.56 g) by the method of example 10 step (ii). Purification was by chromatography eluting with 5% methanol in chloroform. Yield 0.3 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:31]1[S:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>CN1C(=O)CCC1>[S:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[NH:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1
Reactant: Clc1nc2ccccc2s1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(CNc2nc3ccccc3s2)cn(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 115 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (40 mg, 0.140 mmol), N,N-diisopropylethylamine (74.0 mg, 100 μL, 0.567 mmol) and 2-chlorobenzothiazole (31 mg, 0.181 mmol) in NMP (0.5 mL) was heated at 115° C. in a sealed tube. After 2 hr., LCMS indicated the desired product to be present with some remaining starting material and minor impurities. Heating continued overnight. In the morning, more 2-chlorobenzothiazole (12 mg, 0.070 mmol) was added. Heating continued for another 24 hr. The reaction mixture was concentrated under a stream of nitrogen, and the crude product was purified by preparative reverse phase HPLC. The desired product 3-(benzothiazol-2-ylaminomethyl)-7-chloro-1-phenyl-1H-quinolin-4-one (13 mg, 22%) was obtained an off-white solid. MS calcd. for C23H16ClN3OS [(M+H)+] 418.1, obsd. 418.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=1>>[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:25][CH:24]=1
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: CNc1ccc(-c2ccn3c(=O)c(C(=O)OC)cc(C4CC4)c3c2C)cc1
Yield: 89.4 %

Procedure:
Methyl 8-(4-(methylamino)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (74 mg, 0.25 mmol) and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (71 mg, 0.31 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (81 mg, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7](=[O:16])[C:8](=[CH:12][O:13][CH2:14][CH3:15])[C:9](=[O:11])[CH3:10])=[O:5])[CH3:2].[CH2:17]([O:19][C:20]([O:23][CH2:24][CH3:25])=[CH:21][CH3:22])[CH3:18]>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20]1([O:23][CH2:24][CH3:25])[C@@H:21]([CH3:22])[C@H:12]([O:13][CH2:14][CH3:15])[C:8]([C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:16])=[C:9]([CH3:10])[O:11]1)[CH3:18].[CH3:17][CH2:18][CH2:12][CH2:8][CH2:9][CH3:10]
Reactant: CC=C(OCC)OCC
Reactant: CCOC=C(C(C)=O)C(=O)NC(=O)OCC
Solvent: Cc1ccccc1
Product: CCCCCC
Product: CCOC(=O)NC(=O)C1=C(C)OC(OCC)(OCC)[C@@H](C)[C@@H]1OCC
Temperature: 40 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
N-Ethoxycarbonyl-2-ethoxymethylene-3-oxobutanamide (2.3 g) was dissolved in toluene (15 ml) and treated dropwise with 1,1-di-ethoxyprop-1-ene (2 g). The mixture was stirred at 40° C. for 2 hours and evaporated to dryness. The residual oil was purified by medium pressure liquid chromatography on K60 silica using ethyl acetate/petroleum ether b.p. 60°-80° C. 15/85 v/v and 20/80 v/v as eluting solvents, to give after trituration with n-hexane trans-2,2-diethoxy-3,6-dimethyl-4-ethoxy-N-ethoxycarbonyl-3,4-dihydro-2H-pyran5-carboxamide (0.6 g) m.p. 84°-7° C. The n.m.r. spectrum in deuterochloroform displayed the --CH(OEt)-- signal at 3.9 ppm (doublet of quartets, 1H J=3 Hz and 1 Hz), which is indicative of the trans arrangement of the 3 and 4 substituents.
Reaction SMILES: [P:1]([O:13]CCCC)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].COC(=O)[O-].[CH3:23][NH+:24]1[CH2:28][CH:27]([CH3:29])[N:26]([CH3:30])[CH:25]1[CH3:31].O>CO>[CH2:9]([O:8][P:1]([O-:13])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2])[CH2:10][CH2:11][CH3:12].[CH3:23][NH+:24]1[CH2:28][CH:27]([CH3:29])[N:26]([CH3:30])[CH:25]1[CH3:31]
Reactant: CCCCOP(=O)(OCCCC)OCCCC
Agent: CC1C[NH+](C)C(C)N1C
Agent: COC(=O)[O-]
Solvent: CO
Solvent: O
Product: CCCCOP(=O)([O-])OCCCC
Temperature: 100 °C
Reaction time: 20 h

Procedure:
By adding 62 parts of tributyl phosphate to the above-described methanol solution of 46 parts of 1,2,3,4-tetramethylimidazolinium methylcarbonate salt, followed by addition of 5.4 parts of water and stirring at 100° C. for 20 hours, tributyl phosphate was hydrolyzed and a salt exchange reaction was carried out to obtain a methanol solution of 1,2,3,4-tetramethylimidazolinium dibutyl phosphate monoanion. The above-described solution was heated under reduced pressure of 1.0 kPa or less at 50° C. to distill methanol until no distillate of methanol was observed. Thereafter, the temperature was raised from 50° C. to 100° C. and heating was continued for 30 minutes to distill and remove monomethyl carbonate (HOCO2CH3), methanol, and carbon dioxide (slight amounts of methanol and carbon dioxide are formed by thermal decomposition of monomethyl carbonate. Hereinafter, these are abbreviated as by-products). Thus, 1,2,3,4-tetramethylimidazolinium dibutyl phosphate monoanion, electrolyte (C-1), was obtained. The yield was 99 parts (yield based on the weight of 46 parts of 1,2,3,4-tetramethylimidazolinium methyl carbonate salt; hereinafter the same shall apply). The molecular weight of the electrolyte (C-1) was 280.
Reaction SMILES: [CH3:1][Mg]Br.C[C:5]1([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11]>O1CCCC1>[F:20][C:17]([F:18])([F:19])[C:12]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([CH3:1])[OH:11])([OH:21])[C:13]([F:15])([F:14])[F:16]
Reactant: CC1(C(O)(C(F)(F)F)C(F)(F)F)CCCCC1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCCCC1C(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a flame-dried, nitrogen-purged, 250 mL 3-neck roundbottom flask with 50 mL, pressure-equalized addition funnel and stirbar was added 48 mL of methyl magnesium bromide (143 mmol, 2.1 eq., 3 M in ethyl ether). A degassed solution of 18 g methyl 2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)cyclohexanone (IX) (68 mmol, 1 eq.) in 60 mL anhydrous tetrahydrofuran was charged to the addition funnel and added dropwise to the reaction over the course of 1 hour at room temperature. The reaction was stirred at room temperature for 14 hours, after which it was cooled to 0° C. and carefully quenched with dilute hydrochloric acid solution until the pH was less than 5.0. The reaction solution was neutralized with saturated aqueous sodium bicarbonate until the pH was greater than 8. The product was extracted into ethyl ether and the organic phase washed with brine and dried over magnesium sulfate, filtered, concentrated in vacuo, and stored over a small amount of sodium bicarbonate. Crude 1H and 19F NMR indicated only 42% conversion to a single isomer. The reaction was repeated again and the conversion driven to 69% by NMR. The crude product was taken on to the next step without further purification.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH2:7]([N:10]1[C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[N:13][CH2:12][C:11]1=[O:29])[CH:8]=[CH2:9].[OH2:30]>CC(C)=O>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]2[N:10]([CH2:7][CH:8]([OH:2])[CH2:9][OH:30])[C:11](=[O:29])[CH2:12][N:13]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:15]=2[CH:20]=1
Reactant: C=CCN1C(=O)CN=C(c2ccccc2F)c2cc(Cl)ccc21
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(O)CO
Reaction time: 0.17 h

Procedure:
A solution of 16 g of potassium permanganate in 300 ml of water was added dropwise within 15 minutes at 10°C to a solution of 33.0 g of 1-allyl-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 300 ml of acetone. After the potassium permanganate addition, the solution is stirred for a further 10 minutes. Then the mixture is filtered off by vacuum from the precipitated manganese dioxide and the manganese dioxide is washed with acetone. Subsequently the acetone is distilled off on a rotary evaporator. The remaining aqueous phase is extracted with ethyl acetate; the ethyl acetate solution is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is chromatographed on silica gel with ethyl acetate/methanol (9:1). The pure fractions are combined and evaporated. Crystallization from ethyl acetate yields pure 7-chloro-1-(2,3-dihydroxypropyl)-5-(2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 117°-118°C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6](Cl)[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.[OH-].[NH4+:13]>O1CCOCC1>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([NH2:13])[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1
Reactant: [NH4+]
Reactant: Clc1nccc2c(Br)csc12
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc2c(Br)csc12
Temperature: 140 °C
Yield: 14.6 %

Procedure:
To a solution of 3-bromo-7-chlorothieno[2,3-c]pyridine (200 mg, 0.805 mmol) in 1,4-dioxane (2.6 mL) was added 28% ammonium hydroxide (2.2 mL, 22 mmol). The mixture was heated in a microwave at 140° C. for 6 h and then concentrated. The residue was suspended in water (15 mL) and extracted with 5% methanol:dichloromethane (5×10 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification by ISCO chromatography (0 to 5% methanol:dichloromethane) afforded 27 mg (15%) of the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J=5.8 Hz, 1 H), 7.58 (s, 1 H), 7.18 (d, J=5.6 Hz, 1 H), 4.87 (br. s., 2 H); MS (ESI): 229.04, 231.00 [M+H]+; HPLC tR=2.19 min (ZQ3, polar—4 min).