Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]1)=[O:16])=O)(C)(C)C.[F:38][C:39]1[C:44]([O:45][CH2:46][CH3:47])=[CH:43][CH:42]=[C:41]([F:48])[C:40]=1B(O)O.C(O)(C(F)(F)F)=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[NH2:8][C:9]1[S:13][C:12]([C:40]2[C:41]([F:48])=[CH:42][CH:43]=[C:44]([O:45][CH2:46][CH3:47])[C:39]=2[F:38])=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]1)=[O:16]
Reactant: CCOc1ccc(F)c(B(O)O)c1F
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnccc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(F)c(-c2nc(C(=O)Nc3cnccc3N3CCC[C@H](N)C3)c(N)s2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
A septum sealed microwave tube was charged with (S)-tert-butyl 1-(3-(5-(tert-butoxycarbonylamino)-2-bromothiazole-4-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate (50 mg, 0.084 mmol), 2,6-difluoro-3-ethoxyphenyl-boronic acid (169 mg, 0.84 mmol), Pd(dppf)Cl2 (13.6 mg, 0.016 mmol) 1M Na2CO3 (0.6 mL, 14.1 mmol) and acetonitrile (3 mL). The mixture was irradiated for 30 min at 120 C. Upon completion of the reaction, the solvent was distilled off and the crude material was dissolved in CH2Cl2 (5 mL) and transferred to a scintillation vial. TFA (0.77 g, 6.7 mmol) was added and the mixture was stirred at room temperature for 30 min. The solvent was distilled off and the crude product was purified via reverse phase HPLC 40% to 80% MeOH in water with 0.1% NH4OH to afford (S)-5-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-2-(3-ethoxy-2,6-difluorophenyl)thiazole-4-carboxamide as a white solid (4.8 mg, 12%). 1H NMR (400 MHz, DMSO) δ 9.35 (s, 1H), 8.27-8.16 (m, 1H), 7.66 (s, 2H), 7.28 (td, J=9.2, 5.1, 1H), 7.23-7.09 (m, 2H), 4.15 (q, J=7.0, 2H), 3.06 (dd, J=41.9, 10.8, 5H), 2.65 (dd, J=15.7, 5.1, 1H), 1.89 (d, J=10.1, 1H), 1.82-1.67 (m, 2H), 1.36 (t, J=7.0, 3H). ESIMS m/z=475.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10]O)[CH:4]=1.S(Cl)([Cl:14])=O.CCOCC>C(Cl)Cl>[ClH:14].[Cl:14][CH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=1
Reactant: COc1cc(CO)ncc1C
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(CCl)ncc1C
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
28.1 g of 4-methoxy-5-methyl-2-pyridylmethanol, dissolved in 180 ml of methylene chloride, were added dropwise at 0° to 17 ml of thionyl chloride in 360 ml of methylene chloride. After stirring at room temperature for 16 hours 1400 ml of ether were added dropwise thereto while cooling and the mixture was stirred at room temperature for a further 2 hours. The separated crystals were filtered off under suction and washed with ether. There was obtained 2-(chloromethyl)-4-methoxy-5-methylpyridine hydrochloride of melting point 149°-151°.
Reaction SMILES: [C:1]([O:4][CH:5]([C:23](=[O:34])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:31]=[N+]=[N-])[CH:6]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][OH:10])(=[O:3])[CH3:2]>C(O)C.[Ni]>[C:1]([O:4][CH:5]([C:23](=[O:34])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH2:31])[CH:6]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][OH:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCN=[N+]=[N-]
Agent: [Ni]
Solvent: CCO
Product: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCN
Reaction time: 4 h

Procedure:
In a hydrogenation apparatus, a suspension of 1.12 g of 2,3,4-triacetoxy-1-{2-[2-(2-azido-ethoxy)ethoxy]acetyl}-5-hydroxypentyl acetate and 1.0 g of Raney-Nickel in 100 ml of ethanol is shaken under an atmosphere of hydrogen for 4 h. The reaction solution is filtered and concentrated. The residue contains 23:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8].C([O-])([O-])=O.[Na+].[Na+].[Cl:16][C:17]1[C:18]([Cl:26])=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[C:18]([Cl:26])[CH:19]=2)[C:7]=1[NH2:8]
Reactant: Nc1c(Br)cncc1Br
Reactant: OB(O)c1cccc(Cl)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1c(Br)cncc1-c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 3,5-dibromo-4-amino-pyridine 1 (4.0 g, 15.87 mmol), Pd(PPh3)4 (0.91 g, 0.78 mmol) and aqueous solution of Na2CO3 (23.8 ml, 2M ) in toluene (80 ml ) is added to a solution of dichlorobenzene boronic acid (6.23 g, 46.4 mmole) in ethanol (24 ml). The mixture is refluxed for 14 h., diluted with ethyl acetate and washed with saturated NH4Cl solution. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel to give 2.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([Si:11]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[O:12][C@@H:13]1[C@@H:17]([CH2:18][O:19]C(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)[O:16][C@@H:15]([N:43]2[CH:51]=[C:49]([CH3:50])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[CH2:14]1)([CH3:10])[CH3:9].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH:55]([Si:11]([CH:8]([CH3:10])[CH3:9])([CH:52]([CH3:54])[CH3:53])[O:12][C@@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C@@H:15]([N:43]2[CH:51]=[C:49]([CH3:50])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[CH2:14]1)([CH3:56])[CH3:57]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[Si](C(C)C)(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cn([C@H]2C[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 94.2 %

Procedure:
1.6 ml of trifluoroacetic acid were added dropwise to a solution of 1.861 g (2.655 mmol) of 3'-O-triisopropylsilyl-5'-O-(4,4'-dimethoxytrityl)thymidine [prepared as described in step (a) above] in 80 ml of chloroform, whilst cooling in an ice bath and stirring. The resulting mixture was stirred for 10 minutes and then 2 ml of pyridine were added. The reaction mixture was washed twice, each time with 100 ml of a 5% w/v aqueous solution of sodium hydrogencarbonate and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel (70-230 mesh), using methylene chloride containing 4% by volume of methanol as the eluent, to give 0.9965 g (yield 94%) of the title compound.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 102.5 %

Procedure:
To a solution of (3S)-3-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (5.33 g, 15.0 mmol) (obtained as described in Reference Example 53(3)) in dimethylformamide (159 ml) was added sodium azide (1.07 g, 16.5 mmol), and the mixture was stirred in an oil bath (100° C.) for 3.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed successively with 10% aqueous sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:2) as the eluant to afford (3R)-3-azido-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (4.48 g, yield 100%) as a colorless oil.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[Cl:19][CH2:20][CH2:21][C:22]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][CH:9]=2)[CH2:18][CH2:17]1)=[O:23]
Reactant: O=C(Cl)CCCl
Reactant: c1cc(N2CCNCC2)ccc1C1CCCCC1
Product: O=C(CCCl)N1CCN(c2ccc(C3CCCCC3)cc2)CC1

Procedure:
A target compound (2.2 g, 6.569 mmol) was yielded as white solid in the same manner as Reference Example 13 by reacting 1-(4-cyclohexylphenyl)piperazine (2.01 g, 8.224 mmol) with 3-chloropropionyl chloride (0.79 mL, 8.224 mmol) and purifying by separation through column chromatography (EtOAc:hexane:CH2Cl2, 1:1:5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.N1CCCC1>CO.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8](=[O:10])[CH2:9][C:16]3([O:11][C:4]=2[CH:3]=1)[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]3
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CN1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCC2(CC1)CC(=O)c1ccc(F)cc1O2
Reaction time: 0.5 h

Procedure:
A stirred solution of 4′-fluoro-2′-hydroxyacetophenone (15.97 g), 1-methyl-4-piperidone (12.74 cm3) and pyrrolidine (4.325 cm3) in methyl alcohol (250 cm3) was heated to reflux under nitrogen. After 0.5 h, further pyrrolidine (4.33 cm3) was added and, after another 0.5 h, the solution was allowed to cool. The reaction mixture was then evaporated under reduced pressure to give an oil, which was dissolved in dichloromethane (400 cm3). This solution was washed with water (3×400 cm3), dried (Na2SO4) and evaporated to give an oil (25.7 g). Flash chromatography on silica (eluting with dichloromethane-methyl alcohol-33% aqueous ammonia=380:20:1) gave the purified product as an oil (14.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1.C(Cl)(C(Cl)=O)=O.[CH3:24][N:25]([CH3:40])[CH2:26][CH2:27][N:28]([CH3:39])[C:29]1[S:30][C:31]2[CH:37]=[C:36]([NH2:38])[CH:35]=[CH:34][C:32]=2[N:33]=1>>[ClH:1].[CH3:24][N:25]([CH3:40])[CH2:26][CH2:27][N:28]([CH3:39])[C:29]1[S:30][C:31]2[CH:37]=[C:36]([NH:38][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:14][CH:13]=3)=[O:17])[CH:35]=[CH:34][C:32]=2[N:33]=1.[CH3:24][N:25]([CH3:40])[CH2:26][CH2:27][N:28]([CH3:39])[C:29]1[S:30][C:31]2[CH:37]=[C:36]([NH:38][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][CH:11]=3)=[O:16])[CH:35]=[CH:34][C:32]=2[N:33]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4Cl)cc3)cc2s1
Product: Cl

Procedure:
The title compound is prepared by following Method C, using 2′,4′-dichloro-biphenyl-4-carboxylic acid (6.40 g, 23.97 mmol), (COCl)2 (7.0 mL, 79.9 mmol) and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (4.0 g, 15.9 mmol) top afford 2′,4′-dichloro-biphenyl-4-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-amide (4.19 g, 54%). The material is dissolved in THF (100 mL), and followed by addition of 1.0 M HCl in EtOH (8.5 mL). The resulting solid is collected to give the 4.27 g (93%) of the hydrochloride salt. LC/MS, Retention time=5.17 min; (m/z): calcd for C25H24Cl2N4OS 499.5; found: 499.0.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH:10]([OH:12])[CH2:9][C@H:5]1[C:6]([OH:8])=O)(=[O:3])[CH3:2].CN1CCOCC1.ClC(OC)=O.[NH2:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30](=[O:39])[C:31]([C:36]([OH:38])=[O:37])=[CH:32][NH:33]2)=[CH:28][CH:27]=1.C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl>[C:1]([N:4]1[CH2:11][CH:10]([OH:12])[CH2:9][CH:5]1[C:6]([NH:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30](=[O:39])[C:31]([C:36]([OH:38])=[O:37])=[CH:32][NH:33]2)=[CH:28][CH:27]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(O)C[C@H]1C(=O)O
Reactant: Nc1ccc2c(=O)c(C(=O)O)c[nH]c2c1
Agent: COC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(O)CC1C(=O)Nc1ccc2c(=O)c(C(=O)O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A mixture of 6.41 g (37 mmol) of N-acetyl-4-hydroxy-L-proline, 4.07 ml (37 mmol) of N-methyl morpholine, 2.87 ml (37 mmol) of methyl chloroformate, and 90 ml of dichloromethane is stirred at -10° to -20° for 30 minutes. A mixture of 4.08 g (20 mmol) of 7-amino-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 8.4 ml (60 mmol) of triethylamine, 7.6 ml (60 mmol) of chlorotrimethylsilane, and 100 ml of dichloromethane is stirred at room temperature for 30 minutes and then is cooled to -30°. The cold mixed anhydride is added to the cold silylated quinoline and is stirred with cooling for 4 hours and overnight at room temperature. The reaction mixture is evaporated to dryness and the residue is treated with water and 1 N hydrochloric acid. The solid is filtered to give 5.30 g of 7-[[(1-acetyl-4-hydroxy-2-pyrrolidinyl)carbonyl]amino]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].CNC([OH:29])C.[CH2:30]([N:32]([CH2:35]C)CC)[CH3:31]>C1COCC1>[OH:29][CH2:31][CH2:30][N:32]([CH3:35])[C:10](=[O:11])[C:9]1[CH:13]=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])[CH:6]=[CH:7][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Reactant: CNC(C)O
Solvent: C1CCOC1
Product: CN(CCO)C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 38.9 %

Procedure:
5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoyl chloride (7 g, 0.0184 mole) was added over 1 hr to a solution of N-methylaminoethanol (2.8 g, 0.0372 mole), triethylamine (3.7 g, 0.0368 mole) and THF (30 ml) at 25°-38°. The resulting mixture was heated to and held at reflux for 1.5 hrs., cooled and concentrated. The residue was taken into 400 ml of ether, washed three times with water, dried over MgSO4 and concentrated to 7.8 g of crude product. Kugelrohr distillation under reduced pressure afforded 3.0 g of pure N-(2-Hydroxyethyl)-N-methyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzamide as a gum; nmr (CDCl3) δ 2.95-3.08 (2S, 3H); 3.22-3.82 (m) 4.74 (s, 1H), 7.04-8.52 (m, 6H); ir (CHCl3) 3640, 3420, 1648 Cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(OO)=[O:14].CC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Brc1cnc2ccccc2c1
Reactant: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Br)cc2ccccc21
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of 3-Bromoquinoline 5 (2.08 g, 10 mmol) in CHCl3 (5 ml) was added CH3CO2OH (5 ml, 32% solution in dilute HOAc, 20 mmol) and the mixture was stirred overnight. Acetone (3 ml) was added and the mixture was stirred an additional 15 min then poured into saturated NaHCO3 (aq) and extracted with CH2Cl2. The combined extracts were dried (K2CO3) and concentrated to yield pure 6 (2.26 g, 100%) as a tan solid. 1H NMR d (d=delta) (ppm): 7.7 dd (CH atom), 7.8 m (2 CH atom), 7.9 s (CH atom), 8.6 s (CH atom), 8.7 d (CH atom).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.CC1C=CC(S(O)(=O)=O)=CC=1.O.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1
Reactant: C1=COCCC1
Reactant: Brc1cccc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Brc1cccc2c1cnn2C1CCCCO1
Yield: 80.1 %

Procedure:
A mixture of 4-bromo-1H-indazole (0.5 g, 2.53 mmol), p-TsOH.H2O (50 mg, 0.25 mmol), and 3,4-dihydro-2H-pyran (0.64 g, 7.61 mmol) in THF (20 mL) was degassed then heated to reflux overnight. After the solvent was removed, the residue was partitioned between DCM (300 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (0.5 to 1% MeOH) to afford 570 mg (81%) of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (196) as yellow solid: MS (ESI) m/z=282.2 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:12](=[O:14])[NH:30][CH2:29][C:28]([F:32])([F:31])[F:27])[CH2:10][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)NCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
To a stirred solution of 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (10.0 g, 49.7 mmol) in CH2Cl2 (80 mL) was added EDC.HCl (13.8 g, 71.8 mmol) followed by 2,2,2-trifluoroethylamine (8.21 g, 82.8 mmol) and 4-(dimethylamino)pyridine (7.31 g, 59.8 mmol). The reaction mixture was stirred at ambient temperature for 18 h, taken up in 300 mL of EtOAC, then washed with aq. 10% HCl (3×), aq. 10% K2CO3 (2×) and aq. sat. NaCl (1×). The organic phase was dried (MgSO4) and concentrated in vacuo to afford the title compound as a white solid (11.8 g, 84%): mp 166-167° C.; 1H NMR (400 MHz, DMSO-d6) rotamers δ 8.43 (s, 0.3H), 8.20 (s, 0.7H), 7.41 (s, 0.7H), 7.11 (s, 0.3H), 3.84 (dt, J=9.9, 4.9 Hz, 2H), 1.38 (d, J=11.4 Hz, 9H), 1.24 (q, J=4.3 Hz, 2H), 0.92 (q, J=4.3 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −70.57; 13C NMR (101 MHz, DMSO-d6) rotamers δ 172.82, 155.37, 124.64 (q, J=281 Hz), 78.29, 40.18 (q, J=34 Hz), 35.43, 34.70, 28.05, 27.84, 17.28, 16.62.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[N:3]1[CH2:23][CH2:22][C:6]2([NH:10][C:9](=[O:11])[CH:8]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:7]2=[O:21])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].O>O1CCCC1>[CH2:36]([O:35][C:33](=[O:34])[O:21][C:7]1[C:6]2([CH2:5][CH2:4][N:3]([N:2]([CH3:1])[CH3:24])[CH2:23][CH2:22]2)[NH:10][C:9](=[O:11])[C:8]=1[C:12]1[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=1[CH3:18])[CH3:37]
Reactant: Cc1cc(C)c(C2C(=O)NC3(CCN(N(C)C)CC3)C2=O)c(C)c1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)NC12CCN(N(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
97 mg 8-Dimethylamino-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione (from Step 4) and 45 mg triethylamine are dissolved in 15 ml tetrahydrofuran, and the mixture cooled in an ice bath. Then, 33 mg ethyl chloroformate is added at 0° C. The mixture is allowed to warm to room temperature, and stirred for 2 hours. Then water is added and the mixture extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and the solvent evaporated. The crude product is purified by chromatography on silica gel, with ethyl acetate/methanol/triethylamine (90:5:5) as a solvent, yielding 79 mg Carbonic acid 8-dimethylamino-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester as a solid, mp 162-166° C. 1H-NMR (CDCl3): 7.20 ppm (s, broad, 1H), 6.83 ppm (s, 2H), 4.02 ppm (q, 2H), 3.05 ppm (m, 2H), 2.54 ppm (m, 2H), 2.40 ppm (s, 6H), 2.25 ppm (m, 5H), 2.17 ppm (s, 6H), 1.70 ppm (m, 2H), 1.10 ppm (t, 3H).
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]3[CH2:19][NH:20][CH2:21][CH2:22][N:11]3[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH2:31][CH3:32].Cl>C(Cl)(Cl)Cl.CCOCC>[C:3]1([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]3[CH2:19][N:20]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:21][CH2:22][N:11]3[CH2:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCC(=O)Cl
Reactant: c1ccc([C@@H]2CN3CCNC[C@H]3c3ccccc32)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(=O)N1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
To a stirred solution is cis-1,3,4,6,7,11b-hexahydro-7-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride (7.0 g, 0.20 m) and triethylamine (8.4 g, 0.08 m) in chloroform (100 ml) maintained at 0° under nitrogen was added dropwise propionyl chloride (2.9 g, 0.031 m). The mixture was allowed to warm to ambient temperature and stirred for 16 hours, then treated with 10% HCl (50 ml). The layers were separated and the organic phase washed with 10% HCl (2×50 ml), water (50 ml), and dried over MgSO4. Evaporation of the solvent gave a solid residue, which was slurred with ether and filtered to give 2.1 g cis-1,3,4,6,7,11b-hexahydro-7-phenyl-2-propionyl-2H-pyrazino[2,1-a]isoquinoline, m.p. 250°-251° . An additional 3.2 g of good purity product was recovered from the ether to give a total of 5.3 g (82%).
Reaction SMILES: [Li]C(CC)C.CN(CCN(C)C)C.[CH3:14][O:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].[Br:29]C(Cl)(Cl)C(Cl)(Cl)Br>C1CCCCC1.C1COCC1>[Br:29][C:21]1[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=[C:16]([O:15][CH3:14])[C:17]=1[C:18]([OH:20])=[O:19]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COc1cc(C(F)(F)F)cc(Br)c1C(=O)O
Temperature: -75 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To −75° C. cooled THF (70 ml) was added dropwise 36 ml (50.0 mmol) of a 1.4 M sec-BuLi solution in cyclohexane within 5 minutes keeping the temperature below −70° C. 7.5 ml (50.0 mmol) TMEDA were added dropwise at temperature below −70° C. within 5 minutes. A solution of 5.0 g (22.71 mmol) 2-methoxy-4-(trifluoromethyl)benzoic acid (commercial) in THF (25 ml) was added dropwise at over a period of 20 minutes. The dark green solution was stirred at −75° C. for 2 hours. A solution of 29.6 g (90.84 mmol) 1,2-dibromotetrachloroethane in THF (30 ml) was added dropwise. The off-white suspension was stirred at −75° C. for 1 hour and then allowed to warm to room temperature. The yellow solution was quenched by dropwise addition of 60 ml water under ice bath cooling. The mixture was diluted with ethyl acetate (70 ml) and water (30 ml). The aqueous layer was extracted with ethyl acetate (50 ml), acidified with HCl 25% and extracted with ethyl acetate (3×50 ml). The extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was stirred in heptane, filtered and dried. The solid was recrystallized from heptane (7 ml) and ethyl acetate (2 ml) to provide 815 mg (12%) of the title compound as a white solid. MS (m/e): 298.9 (M−H).