Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([CH3:21])[NH:14][C:13]([CH3:23])([CH3:22])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:36](Cl)=[O:37].C(Cl)(=O)C1C=CC=CC=1>C(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([CH3:21])[N:14]([C:36]([C:35]1[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:33]([O:32][CH3:31])[CH:34]=1)=[O:37])[C:13]([CH3:22])([CH3:23])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1cc2c(cc1OCc1ccccc1)CC(C)(C)NC2C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Product: COc1cc2c(cc1OCc1ccccc1)CC(C)(C)N(C(=O)c1cc(OC)c(OC)c(OC)c1)C2C
Temperature: 25 °C
Reaction time: 21 h
Yield: 58 %

Procedure:
To a solution of 244 (467 mg, 1.5 mmol) in DCM (10 ml) was added triethyl amine (0.42 ml) and 3,4,5-trimethoxybenzoyl chloride (520 mg, 2.3 mmol). The reaction mixture was stirred at rt for 21 h. TLC analysis indicated the presence of starting material so the reaction mixture was heated in the microwave for 5 min at 60° C. and for 15 min at 80° C. A further 0.5 eq of benzoyl chloride was added and the reaction mixture was heated in the microwave at 80° C. for 15 min. Water (20 ml) was added, the layers separated and the aqueous layer extracted with DCM (3×60 ml). The combined organic phases were washed with sat. aq. sodium hydrogen C(Ar)bonate (60 ml) and brine (60 ml), dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 20 g, EtOAc/hex then Hex/DCM) afforded the title compound (440 mg, 58%) as a colourless foam. mp 175-177° C. 1H NMR (270 MHz; CDCl3) 1.32 (3H, d, J=6.9 Hz, CH3CH), 1.39 (3H, s, CH3), 1.87 (3H, s, CH3), 2.53 (1H, d, J=15.3 Hz, one of CH2), 3.27 (1H, d, J=15.3 Hz, one of CH2), 3.82 (6H, s, 2×OCH3), 3.86 (3H, s, OCH3), 3.88 (3H, s, OCH3), 4.69 (1H, q, J=6.9 Hz, CHCH3), 5.04 (2H, ABq, J=12.1 Hz, CH2Ph), 6.47 (3H, s, 3×CH), 6.75 (1H, s, CH), 7.25-7.41 (5H, m, 5×CH, phenyl). 13C NMR (100 MHz; CDCl3) 23.43 (CH3), 25.28 (CH3), 29.40 (CH3), 44.18 (CH2), 56.18 (4×OCH3), 57.68 (C), 60.92 (CH), 71.38 (CH2), 102.51 (CH), 111.45 (CH), 112.36 (CH), 127.09 (C), 127.28 (CH), 127.87 (CH), 128.49 (CH), 130.61 (C), 135.07 (C), 136.09 (C), 137.89 (C), 146.88 (C), 149.06 (C), 153.41 (C), 170.97 (C). LC/MS (ES+) tr=1.03 min, m/z 528.27 (M++Na). HPLC tr=2.38 min (>99%). Anal. Calcd. for C30H35NO6: C 71.27, H 6.98, N 2.77. Found: C 71.1, H 6.99, N 2.70%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24]>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[C:23]([F:24])[CH:22]=2)[S:6]1(=[O:16])=[O:15]
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(F)c(F)c1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (474 mg) was coupled to 3,4-difluorophenylboronic acid to provide 3-(3-chloropropyl)-1-(3,4-difluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (92 mg):
Reaction SMILES: [C:1]([CH2:3][S:4]([N:7]([CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8])(=[O:6])=[O:5])#[N:2].[H-].[Na+].[CH2:24]([N:31]1[C:39]2[C:34](=[CH:35][C:36](Br)=[CH:37][CH:38]=2)[C:33]([CH2:41][C@H:42]2[CH2:46][CH2:45][CH2:44][N:43]2[CH3:47])=[CH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1.COCCOC.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:24]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([CH:3]([C:1]#[N:2])[S:4]([N:7]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:8])(=[O:5])=[O:6])=[CH:37][CH:38]=2)[C:33]([CH2:41][C@H:42]2[CH2:46][CH2:45][CH2:44][N:43]2[CH3:47])=[CH:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN1CCC[C@@H]1Cc1cn(Cc2ccccc2)c2ccc(Br)cc12
Reactant: CN(C(c1ccccc1)c1ccccc1)S(=O)(=O)CC#N
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CN1CCC[C@@H]1Cc1cn(Cc2ccccc2)c2ccc(C(C#N)S(=O)(=O)N(C)C(c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.2 %

Procedure:
To a stirred solution of 1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (from step (c), 18.79 g, 62.6 mmol) in a mixture of toluene (60 ml) and ethylene glycol dimethylether (20 ml) at 0-5° C. under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil) (4.6 g, 115 mmol) portionwise, maintaining the temperature below 5° C. Upon completion of the addition, the dark brown solution was warmed to ambient temperature over a 30 min period, before tetrakis(triphenylphosphine) palladium(0) (3.61 g, 3.1 mmol) was added in one portion. A solution of (R)-1-benzyl-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (from Example 1(d), 19.74 g, 52 mmol) in toluene (20 ml) was then added dropwise to the brown slurry and the mixture was warmed to reflux. Reflux was maintained for 2 hr after which time the dark brown solution was cooled to ambient temperature. The reaction mixture was then poured into water (250ml) and extracted with ethyl acetate (3×100 ml). The organic extracts were combined and evaporated in vacuo to yield a brown oil. This was re-dissolved in absolute ethanol (80 ml) and stirred for 18 hr over which time precipitation occurred. The solid seas filtered and dried in vacuo at 50° C. overnight to yield the subtitle compound (22 g, 70%) as a cream solid. m.p. 152-155° C.
Reaction SMILES: [NH2:1][C:2]([CH2:40][CH3:41])([CH2:38][CH3:39])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[C:42](Cl)(=[O:44])[CH3:43].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:38]([C:2]([NH:1][C:42](=[O:44])[CH3:43])([C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4])[CH2:40][CH3:41])[CH3:39]
Reactant: CCC(N)(CC)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)(NC(C)=O)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1

Procedure:
A solution of 2-Amino-2-ethyl-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.100 g, 0.178 mmol), acetyl chloride (0.014 g, 0.178 mmol) and DIEA (0.069 g, 0.534 mmol) were stirred at room temperature in DCM (3 ml) for 2 hours. Solvent was removed and compound was purified by RP-HPLC to yield 0.072 g (67%). 1H NMR (400 MHz, CDCl3) 7.67 (m, 1H), 7.40-7.29 (m, 2H), 7.18 (m, 2H), 7.09 (m, 1H), 6.99 (m, 2H), 4.60 (m, 1H) 4.04 (br, 2H), 3.32-3.23 (m, 4H), 2.74 (m, 2H), 2.57 (s, 3H), 2.36 (m, 2H), 2.20 (m, 2H), 2.01 (s, 3H), 1.92 (m, 6H), 1.82-1.63 9 (m, 10H), 0.78 (br, 5H). ES-LCMS m/z 602 (M+1).
Reaction SMILES: [C:1]([C:3]([CH:18]([CH3:20])[CH3:19])([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH2:4][CH2:5][CH:6]=O)#[N:2].[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][NH2:30])=[CH:25][CH:24]=1.[BH4-].[Na+]>C(O)C>[CH:18]([C:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)([CH2:4][CH2:5][CH2:6][NH:30][CH2:29][CH2:28][O:27][C:26]1[CH:31]=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[C:1]#[N:2])([CH3:20])[CH3:19]
Reactant: COc1ccc(C(C#N)(CCC=O)C(C)C)cc1OC
Reactant: COc1ccc(OCCN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(OCCNCCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
A solution of 3.96 g of 4-cyano-4-isopropyl-4-(3,4-dimethoxyphenyl)butyraldehyde and 2.00 g of 2-(4-methoxyphenoxy)ethylamine in 50 ml of ethanol was refluxed for 1 hour. To the solution was added 0.55 g of sodium borohydride under ice-cooling, and the solution was stirred for 30 minutes at room temperature. The solvent was removed and the residue was dissolved in 10% hydrochloric acid and washed with ether. The aqueous layer was made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue was chromatographed on silica gel using chloroform as an eluent to give 2.93 g of the desired compound as a pale yellow oil.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:17])[NH:6][C:7]1[N:8]([CH3:16])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH:20]([Si:23]([CH:56]([CH3:58])[CH3:57])([CH:53]([CH3:55])[CH3:54])[O:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:36]3[CH:37]=[C:38]([O:41][C@H:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[C@@H:45]([NH2:52])[CH2:44][CH2:43]4)[CH:39]=[CH:40][C:35]3=[N:34][N:33]=2)[CH2:28][CH2:27]1)([CH3:22])[CH3:21].CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:52][C@@H:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:42]([O:41][C:38]3[CH:39]=[CH:40][C:35]4[N:36]([C:32]([N:29]5[CH2:28][CH2:27][CH:26]([CH2:25][O:24][Si:23]([CH:20]([CH3:22])[CH3:21])([CH:56]([CH3:58])[CH3:57])[CH:53]([CH3:55])[CH3:54])[CH2:31][CH2:30]5)=[N:33][N:34]=4)[CH:37]=3)[CH2:43][CH2:44]2)=[O:17])[N:8]([CH3:16])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5C)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Yield: 58.8 %

Procedure:
A solution of (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (US 20040192653, 90 mg, 0.273 mmol), Intermediate 14e (150 mg, 0.273 mmol) and DIPEA (71 μL, 0.409 mmol) in dioxane (2 mL) was heated at 60° C. for 48 h. The reaction mixture was cooled and diluted with DCM (5 mL). The organic layer was washed with water (3×5 mL), passed through a phase separator and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound (117 mg, 59%). LCMS (Method 3): Rt: 5.12 min, m/z 729 [MH+].
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([N+:17]([O-:19])=[O:18])=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[CH:10]2)(=O)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:25][CH:24]=1>>[C:32]([O:31][C:30](=[O:36])[NH:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:7]2[C:8]([N+:17]([O-:19])=[O:18])=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[N:12][CH:11]=[CH:10]3)=[CH:28][CH:27]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2cnccc12
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3cnccc3c2[N+](=O)[O-])cc1
Yield: 26.3 %

Procedure:
By using 5-nitroisoquinolin-6-yl trifluoromethanesulfonate (258 mg, 0.8 mmol), and tert-butyl 4-aminophenylcarbamate (250 mg, 1.2 mmol), the title compound (80 mg, yield 26%) was obtained as red crystals in the same manner as that of Example 1, (1).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[O:3][CH2:4][CH2:5][N:6]([CH2:14][CH3:15])[C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:1][Si:2]([CH3:17])([CH3:16])[O:3][CH2:4][CH2:5][N:6]([CH2:14][CH3:15])[C:7]1[CH:12]=[CH:11][C:10]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:9][CH:8]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCN(CCO[Si](C)(C)C)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CCO[Si](C)(C)C)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture containing 10.9 g, that is 30 mmole, 4-[(2-trimethylsiloxyethyl)ethylamino]iodobenzene from the previous step, 1.0 g, that is 1.4 mmole bis(triphenylphosphine)palladium(II) chloride from Aldrich Chemical Co., and 74 mg, that is 0.75 mmole cuprous chloride, from Aldrich Chemical Co. in 50 m triethylamine was stirred and degassed under nitrogen for 15 minutes. Next 3.5 g, that is, 36 mmole trimethylsilylacetylene from Aldrich chemical Co. was added with vigorous mechanical stirring at room temperature and the final mixture was stirred at 80° C. for 1 hour. The cooled reaction mixture was filtered, diluted with ethyl ether and extracted with dilute HCL. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The dark residue was flash column chromatographed on silica gel with 4% ethyl acetate-hexane to give 9.2 g of yellow oil at a 92% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[Br:12]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: Nc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 22 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50% yield, 97.5% AUC). Other impurities were a bromo-regioisomer (1.4% AUC) and a di-bromo adduct (1.1% AUC). 1H NMR (500 MHz, DMSO) δ 8.19 (1H, d, J=8.1 Hz), 7.06 (br. s, 2H), 6.64 (d, 1H, J=14.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17](=O)[C:18]([CH3:24])([CH3:23])[C:19]([NH:21][NH2:22])=[O:20])=[N:9]2)=[N:6][CH:7]=1.O.NN.[CH2:29](O)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]3[C:18]([CH3:24])([CH3:23])[C:19](=[O:20])[N:21]([CH3:29])[N:22]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C(=O)NN)C(=O)c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Reactant: CCO
Agent: NN
Solvent: O
Product: CN1N=C(c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)C(C)(C)C1=O
Temperature: 80 °C
Yield: 86 %

Procedure:
Step-2: 3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-dimethyl-3-oxopropanehydrazide: A mixture of step-1 intermediate (2.40 g, 5.53 mmol) and hydrazine hydrate (0.87 mL, 27.6 mmol) in ethanol (30 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and the solvent was then evaporated under vacuum. The residue was triturated with toluene to obtain 2.0 g (86%) of title compound as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H, D2O exchangeable), 8.72 (d, J=2.0 Hz, 1H), 8.38 (dd, J=2.0 & 8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.54 (s, 1H), 1.42 (s, 6H); ESI-MS (m/z) 420, 422 [(MH)+, Br79,81].
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[CH:8]1[C:17]2[CH:16]=[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]3=[CH:13][N+:12]=2[CH:11]=[CH:10][CH:9]=1.F[P-](F)(F)(F)(F)F.C1C2CC3C=CC=CC=3C[N+]=2C=CC=1>[N+](C)([O-])=O.C(O)(C)C.C(Cl)Cl>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[CH2:8]1[C:17]2[CH:16]=[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]3=[CH:13][N+:12]=2[CH:11]=[CH:10][CH2:9]1
Reactant: c1ccc2c[n+]3ccccc3cc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)Cc1cccc[n+]1C2
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Solvent: CC(C)O
Product: C1=C[n+]2cc3ccccc3cc2CC1

Procedure:
A mixture of 6 g (0.0196 mol) of benzo[b]quinolizinium hexafluorophosphate and 5.12 g (0.023 mol) of 4-(3-furyl)-6,7-dihydrothianaphthene in 100 mL of nitromethane was heated to reflux for 14 h, cooled, and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL), filtered, and the filtrate was concentrated in vacuo, the residue was dissolved in ether, and the ether solution was cooled to yield 11 g of 6,11[5',']-4'-(3-furyl)-4',5',6',7'-tetrahydrothianaphthyl]6,11-dihydrobenzo[b]quinolizinium hexafluorophosphate as a gray solid, (1:1.03 mixture of isomers). The gray solid, product was dissolved in 500 mL of isopropanol/methylene chloride (3:2) on a steam-bath while distilling 150 mL of methylene chloride and cooled to afford 6,11[[5',4']-4'-(3-furyl)-4',5',6',7'-tetrahydrothianaphthyl]6,11]-dihydrobenzo[b]quinolizinium hexafluorophosphate, (Formula I: R1 =R2 =R3 =R7 =H; ##STR56## R5 =3-furyl; X- =PF6- ; and Formula I: R1 =R2 =R4 =R7 =H; ##STR57## R6 =3-furyl; X-=PF6-), as a tan solid (1:1 mixture of isomers).
Reaction SMILES: [CH3:1][C:2]1([CH3:48])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([NH:35][C:36]([NH:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([N+:45]([O-])=O)[CH:40]=5)=[O:37])[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1>CCO.CCOC(C)=O.[Pt]=O>[NH2:45][C:41]1[CH:40]=[C:39]([NH:38][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]3[CH2:13][C@@H:12]([C:10]4[CH:9]=[CH:8][C:6]5[O:7][C:2]([CH3:1])([CH3:48])[O:3][CH2:4][C:5]=5[CH:11]=4)[O:16][C:15]3=[O:17])[CH:30]=2)=[O:37])[CH:44]=[CH:43][CH:42]=1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc([N+](=O)[O-])c5)c4)C(=O)O3)ccc2O1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(N)c5)c4)C(=O)O3)ccc2O1
Yield: 99.8 %

Procedure:
A solution of N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-N′-(3-nitrophenyl)urea (0.976 g) in EtOH (12 ml) and EtOAc (12 ml) was hydrogenated over platinum oxide (0.020 g) for 2 h. The mixture was filtered through celite and washed with EtOH. Solvent evaporation in vacuo gave the title compound (0.93 g). LCMS RT=3.48 min, ES+ve 633 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(C)(C)C.Cl.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29][NH2:30])=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl>C1COCC1.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:30][CH2:29][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CC(=O)O)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)NCCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A solution of 4-methoxybenzeneacetic acid (8.3 g) in dry THF (250 ml) was treated with triethylamine (6.9 ml) and wooled in a salt/ice-bath with stirring under a nitrogen atmosphere. Pivaloyl chloride (6.1 ml) was added and stirring continued for 1 h. A further aliquot of triethylamine (6.9 ml) was added followed by p-nitrophenethylamine hydrochloride (10 g). The resultant suspension was warmed to room temperature and stirred for 19.5 h (overnight). The reaction mixture was acidified to pH 1 using hydrochloric acid solution (2N; 30 ml) and the resultant solution was extracted with EA (1×250 ml, 1×100 ml). The combined organic extracts were washed with 8% NaHCO3 solution (200 ml), dried (MgSO4) and evaporated under reduced pressure to give a brown oil. Purification by `flash` chromatography, ER:CH2Cl2 (4:1) gave the title compound as a pale yellow solid (7.4 g) m.p. 109°-110°.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(CC)CC)C.C([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])(=O)C>C(#N)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:24](=[O:23])[C:25]([F:28])([F:27])[F:26])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OCC(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 24 h

Procedure:
To a suspension of 4-nitrobenzylamine hydrochloride (10.0 g) and triethylamine (22.2 ml) in acetonitrile (100 ml) was added trifluoroethyl acetate (12.6 ml) at room temperature and the mixture was stirred for 24 hours. The solvent was removed under reduced pressure, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were collected by filtration. The crystals were washed with hexane, to give N-(4-nitrobenzyl)trifluoroacetoamide (12.79 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:18])[CH2:16][CH3:17])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Br:19]Br.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.Br.C(O)(=O)C>[Br:19][CH:16]([CH3:17])[C:15]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:18]
Reactant: CCC(=O)c1ccc(-c2ccccn2)c(OC)c1
Reactant: BrBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1cc(C(=O)C(C)Br)ccc1-c1ccccn1
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-one (120 mg, 0.5 mmol) in benzene (1 mL) and 30% HBr/Acetic acid (1 mL) was cooled to 0° C. and was treated with a solution of bromine (0.024 mL, 0.5 mmol) in benzene (0.5 mL) over 1 h. The reaction was stirred for an additional 30 min, then poured into an iced solution of saturated aqueous NaHCO3 (100 mL), and the product was extracted into ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated to afford 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.CCOCC>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:31])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 ml). Benzoyl chloride (0.03 ml, 0.29 mmol) was added dropwise and the reaction was stirred at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 19 (33 mg, 40% yield) as a pale yellow solid. LC-MS (M+H=312, obsd.=312).