Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[C:7]2[N:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:16]=[C:17]([C:18]([NH2:20])=[O:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[Cl:28][C:29]1[N:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([NH:14][C:31]([C:30]3[C:29]([Cl:28])=[N:37][CH:36]=[CH:35][CH:34]=3)=[O:32])=[CH:9][C:8]=2[C:7]2[N:15]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[N:16]=[C:17]([C:18]([NH2:20])=[O:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc(F)cc3)c2-c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc(F)cc3)c2-c2cc(NC(=O)c3cccnc3Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
The title material from Example 24 (1.2 g, 0.0033 mol) and 2-chloro-nicotinic acid (517 mg, 0.0033 mol) were combined, under argon, in 5 mL of DMF. Diisopropyl ethyl amine (862□L, 0.00495 mol) and HATU (1.88 g, 0.00495 mol) were added and the reaction was stirred for 18 hours at room temperature. The reaction was then concentrated in vacuo, and the resulting solids were triturated with water and isolated by vacuum filtration to give the product as an off white solid. 652 mg. (MW=504.91, 39% yield). LC/MS m/z=505.7 (m+1).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([OH:16])=O)[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[F:18][C:19]1[C:20]([NH2:33])=[CH:21][C:22]2[CH:23]=[C:24]3[C:30]([CH3:32])([CH3:31])[CH2:29][CH2:28][N:25]3[C:26]=2[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:17][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:33][C:20]4[C:19]([F:18])=[CH:27][C:26]5[N:25]6[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]6=[CH:23][C:22]=5[CH:21]=4)=[O:16])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC1(C)CCn2c1cc1cc(N)c(F)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CCn2c1cc1cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (346 mg, 1.4 mmol), 6-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-amine (260 mg, 1.2 mmol) and HATU (543 mg, 1.4 mmol) in DMF (5 mL) was added triethylamine (0.40 mL, 2.9 mmol). The reaction was stirred at room temperature overnight and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (10-20% ethyl acetate-hexanes) to afford 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)cyclopropanecarboxamide (342 mg, 65%). ESI-MS m/z calc. 442.2, found 443.5 (M+1)+. Retention time 2.30 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J=7.6 Hz, 1H), 7.30-7.25 (m, 3H), 7.20 (m, 1H), 7.12 (d, J=8.2 Hz, 1H), 6.84 (d, J=11.1 Hz, 1H), 6.01 (d, J=0.5 Hz, 1H), 3.98 (t, J=6.8 Hz, 2H), 2.37 (t, J=6.8 Hz, 2H), 1.75 (dd, J=3.8, 6.9 Hz, 2H), 1.37 (s, 6H) and 1.14 (dd, J=3.9, 6.9 Hz, 2H) ppm.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[S:31]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32]1>O1CCCC1.[Cl-].[Na+].O>[C:1]1([C:7]2[N:11]([S:36]([C:33]3[CH:34]=[CH:35][S:31][CH:32]=3)(=[O:38])=[O:37])[CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccsc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccsc2)c1
Reaction time: 0.5 h

Procedure:
To a solution (10 mL) of 5-phenyl-1H-pyrrole-3-carbaldehyde (100 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 47 mg) at room temperature, and the mixture was stirred for 30 min. 15-Crown-5 (257 mg) was added dropwise, and the mixture was stirred for 30 min. (3-Thienyl)sulfonyl chloride (160 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give 5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrole-3-carbaldehyde as a colorless oil. The obtained oil was dissolved in methanol (10 mL), a 2 mol/L tetrahydrofuran solution (2.1 mL) of dimethylamine was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (47 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (30 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=4:1), and dissolved in ethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 70 mg, 45%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[N:5]=1)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][NH2:11])[N:5]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCn1ccc([N+](=O)[O-])n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCn1ccc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A solution of 206a (2.0 g, 7.0 mmol) in ethanol (30 mL) was added hydrazine hydrate (1 mL, 21 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was evaporated and the residue was purified by silica-gel eluting with 10:1 methylene chloride/methanol to give 206b as a white solid (0.8 g, 80%). MS: (M+H)+ 157.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:20]=[C:19](SCC2C=CC=C(F)C=2F)[C:18]2[N:17]=[CH:16][C:15](=[O:31])[NH:14][C:13]=2[N:12]=1.[NH2:32][C@@H:33]([CH2:35][OH:36])[CH3:34]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:20]=[C:19]([NH:32][C@H:33]([CH3:34])[CH2:35][OH:36])[C:18]2[N:17]=[CH:16][C:15](=[O:31])[NH:14][C:13]=2[N:12]=1
Reactant: O=c1cnc2c(SCc3cccc(F)c3F)nc(SCc3cccc(F)c3F)nc2[nH]1
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Yield: 11.7 %

Procedure:
The product of example 2, step (g) (2.3 g) and D-alaninol (5 g) were microwaved at 150° C. for 5 min. The resulting solution was partitioned between ethyl acetate and aqueous ammonium chloride and the organic layer was washed with ammonium chloride (2×50 ml). The organic layer was evaporated to dryness and purified twice by silica gel chromatography using first 20:1 DCM:methanol and then 1:1 DCM:ethyl acetate to yield the titled compound (220 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.S(Cl)(Cl)=O.[CH3:15]O>>[CH3:15][O:9][C:8]([C@H:5]1[CH2:6][CH2:7][C@@H:3]([NH2:2])[CH2:4]1)=[O:10]
Reactant: CO
Reactant: N[C@H]1CC[C@@H](C(=O)O)C1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of (1R,3S)-3-aminocyclopentanecarboxylic acid hydrochloride (2.5 g, 15.09 mmol) in dry methanol (10 ml) under N2 at 0° C. was added thionyl chloride (5.51 ml, 75 mmol) dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was concentrated in vacuo. The resultant residue was washed with anhydrous diethyl ether (3×30 ml) and dried under high vacuum to afford of (1S,3R)-3-aminocyclopentanecarboxylic acid methyl ester (2.65 g 98%) as the hydrochloride salt that was used in a subsequent reaction without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1B(O)O>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: COc1ccc(OC)c(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2,5-dimethoxyphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 366.0 (M+H)+, retention time 1.36 minutes.
Reaction SMILES: [N+](=[C:3](P(=O)(OC)OC)C(=O)C)=[N-].[N:13]1([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]=O)=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CO.C(OCC)C>[CH2:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:20][CH:21]=1)[CH2:26][C:27]#[CH:3]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: O=CCCc1ccc(CN2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#CCCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
815 mg (4.2 mmol) dimethyl (1-diazo-2-oxo-propyl)-phosphonate is added to a mixture of 760 mg (3.5 mmol) 3-(4-pyrrolidin-1-ylmethyl-phenyl)-propionaldehyde and 970 mg (7.0 mmol) K2CO3 in 100 mL dry MeOH under an argon atmosphere and stirred overnight at RT. The reaction mixture is diluted with diethyl ether, the organic phase is washed with saturated, aqueous NaHCO3 solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[OH:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:17]I>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[O:16][CH3:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(O[C@@H]2CCC[C@@H]2O)cc1Cl
Reactant: CI
Product: CO[C@H]1CCC[C@H]1Oc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
2-Chloro-4-(cis-2-hydroxy-cyclopentyloxy)-benzonitrile (76 mg, 0.32 mmol) was added to a flame dried round bottom flask under nitrogen containing 2 mL of dry DMF and 8.5 mg of 60% sodium hydride as an oil dispersion (0.35 mmol). The reaction was stirred at room temperature for 1 h, after which time methyl iodide (54 mg, 0.38 mmol) was added. The mixture was stirred for 16 h, quenched by the dropwise addition of 5 mL of water, and extracted with ether (2×). The combined organic phases were washed with brine, dried (MgSO4), concentrated and purified by reverse phase HPLC (Shimadzu) to give 35 mg of the title compound. GC/MS: 251 (M/Z for C13H14ClNO2)—
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[CH3:28][N:29]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:34][CH:31]4[CH2:32][CH2:33][N:29]([CH3:28])[CH2:30]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Reactant: CN1CCC(N)C1
Product: CN1CCC(NC(=O)c2c(C(N)=O)nc3n2CCOc2cc(F)c(C#CC(C)(C)O)cc2-3)C1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.06 g) was reacted with 1-methylpyrrolidin-3-amine similar to as described in Example 2 to afford 15.9 mg of (±)9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(1-methylpyrrolidin-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 456 (M)+. 1H NMR (400 MHz, DMSO) δ 11.49 (d, J=6.5 Hz, 1H), 8.59 (d, J=8.5 Hz, 1H), 8.35 (s, 1H), 7.84 (s, 1H), 7.01 (d, J=10.6 Hz, 1H), 5.48 (s, 1H), 5.07-4.91 (m, 2H), 4.62-4.45 (m, 2H), 4.42-4.24 (m, 1H), 2.75-2.67 (m, 1H), 2.64-2.55 (m, 1H), 2.43-2.34 (m, 2H), 2.24-2.14 (m, 1H), 1.68-1.56 (m, 1H), 1.50 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Br-].Cl.O1CC[CH2:17][CH2:16]1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]([OH:8])[CH:16]=[CH2:17])[CH:9]=1
Reactant: C1CCOC1
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Br-]
Product: C=CC(O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: -78 °C
Yield: 73 %

Procedure:
5-Hydroxy-2-nitrobenzaldehyde (6.0 g) is dissolved in dry tetrahyrofuran (90 ml) and thereto is added dropwise vinylmnagnesium bromide (2.3 equivalents) with stirring at −78° C. The temperature of the reaction mixture is raised gradually. After completion of the reaction, 1N HCl is added to the reaction mixture, and the mixture is extracted with ethyl acetate, and the organic layer is separated, washed with an aqueous saturated saline solution, dried over sodium sulfate, and then distilled off the solvent. The residue is purified with a silica gel column chromatography to give 1-(5′-hydroxy-2′-nitrophenyl)-2-propen-1-ol (5.09 g) as yellowish brown powders.
Reaction SMILES: [C:1]([C:4]1([NH:7][C:8]([C:10]2([NH:13][C:14]([C:16]3[N:20]4[C@@:21]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=5)([CH3:33])[C:22](=[O:32])[N:23]([C:24]5[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=5)[C:19]4=[N:18][CH:17]=3)=[O:15])[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5]1)(=[S:3])[NH2:2].[CH2:43](OC(OCC)CBr)[CH3:44].Cl.O1CCOCC1>CC(C)=O>[S:3]1[CH:44]=[CH:43][N:2]=[C:1]1[C:4]1([NH:7][C:8]([C:10]2([NH:13][C:14]([C:16]3[N:20]4[C@@:21]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=5)([CH3:33])[C:22](=[O:32])[N:23]([C:24]5[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=5)[C:19]4=[N:18][CH:17]=3)=[O:15])[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5]1
Reactant: CCOC(CBr)OCC
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(C(N)=S)CC4)CC3)n21
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5nccs5)CC4)CC3)n21
Temperature: 25 °C
Yield: 30.9 %

Procedure:
To a solution of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [1-(1-thiocarbamoyl-cyclo-propylcarbamoyl)-cyclopropyl]-amide (92 mg, 0.15 mmol) in 1.5 mL of acetone was added bromoacetaldehyde diethyl acetal (0.089 mL, 0.59 mmol) and HCl in dioxane (4 M, 0.002 mL, 0.01 mmol). The reaction mixture was heated at reflux for 15 h, and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 25 mL of ethyl acetate and washed with 10 mL of saturated NaHCO3 solution. The organic phase was washed with water and brine (10 mL each), dried over Na2SO4, filtered, and concentrated in vacuo to yield a pale brown oil. The crude product was purified by flash chromatography on silica gel (1-5% MeOH in CH2Cl2), to furnish 30 mg (31%) of the title compound as a pale brown foam, m/z 646.7 [M+1]+.
Reaction SMILES: Br[O-].[Na+].BrBr.[OH-].[Na+].[C:8]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]=1[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([O:30][CH2:31][CH2:32][Br:33])=[CH:22][CH:21]=1)(=[O:10])C.S(=O)(O)[O-:35].[Na+]>O.O1CCOCC1>[C:8]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]=1[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([O:30][CH2:31][CH2:32][Br:33])=[CH:22][CH:21]=1)([OH:10])=[O:35]
Reactant: O=S([O-])O
Reactant: CC(=O)c1c(-c2ccc(OCCBr)c3ccccc23)oc2ccccc12
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(-c2ccc(OCCBr)c3ccccc23)oc2ccccc12
Reaction time: 1 h

Procedure:
A solution of sodium hypobromite, prepared by adding 2.45 g. (0.45 mol.) of bromine to a cooled (0°) solution of 4.5 g. (0.1125 mol.) of sodium hydoxide in 40 ml. of water, was added to a solution of 6.1 g. (0.015 mol.) of 3-acetyl-2-[4-(2-bromoethoxy)naphthyl]benzofuran in 60 ml. of dioxane and the mixture was shaken for 12 hours. Sodium bisulfite was added to the reaction mixture, water was added and the mixture was extracted twice with ether. The aqueous phase was acidified with hydrochloric acid, the resulting precipitate was digested on a steam bath for 1 hour, cooled to 0° and collected by filtration to give 3-carboxy-2-[4-(2-bromo-ethoxy)naphthyl]benzofuran, m.p. 260°-265° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:14][C@@H:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:16]([O:18]C)=O)[C:5]([CH2:12]O)=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[Cl:11].S(Cl)(Cl)=O.[F:29][C:30]([F:34])([F:33])[CH2:31][NH2:32].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[C:7]([Cl:11])[C:6]=2[C:5]2[CH2:12][N:32]([CH2:31][C:30]([F:34])([F:33])[F:29])[C:16](=[O:18])[C@H:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:14][C:4]=2[CH:3]=1
Reactant: COC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Cl)c2c1CO)C(=O)OC
Reactant: NCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 46 %

Procedure:
(S)-Dimethyl 2-((7-bromo-3-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (450 mg, 1.072 mmol) was dissolved in thionyl chloride (2.0 M in dichloromethane) (5.0 mL, 10.00 mmol). Reaction stirred at room temperature for 2.5 hours. Mixture was concentrated by roto-vap. Residue was dissolved in ethyl acetate. Material was washed twice with aqueous sodium bicarbonate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Residue (430 mg, 0.982 mmol) was dissolved in acetonitrile (15 mL). 2,2,2-Trifluoroethylamine (400 μl, 5.03 mmol) was added to the mixture followed by potassium carbonate (195 mg, 1.411 mmol). Mixture was warmed to reflux and held with stirring for 30 minutes. Mixture was cooled to room temperature. Mixture was filtered over celite. Filtrate was concentrated by roto-vap. Residue was dissolved in toluene (15 mL). Acetic acid (500 μl, 8.73 mmol) was added to the mixture. Reaction was warmed to reflux and held with stirring for 14 hours. Mixture was cooled to room temperature. Mixture was diluted with ethyl acetate. Material was washed twice with aqueous sodium bicarbonate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as white solid in 46% yield. MS (M−H)−=467.9.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1.C(N(C(C)C)C(C)C)C.O>O1CCCC1>[CH:31]1([C:34]([NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][C:12]4[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=4)[C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=4)=[O:16])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc2s1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[4-(trifluoromethyl)phenyl]benzamide (215 mg, 0.50 mmol) produced in Example A25(v), cyclopropanecarbonyl chloride (210 mg, 2.00 mmol) and N-ethyl-N-isopropylpropane-2-amine (518 mg, 4.00 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (220 mg, 88%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:40])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C@@H:36]([OH:39])[CH2:37][OH:38])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:40])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C@@H:36]([OH:39])[CH2:37][OH:38])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(C[C@@H](O)CO)S(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(C[C@@H](O)CO)S(=O)(=O)c3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-25 (100 mg) and lithium hydroxide (20 mg) were added to tetrahydrofuran (5 ml) and water (2 ml), and the same manner to Example 2-12 was conducted to give the titled compound as a white solid. Yield: 58 mg (60%); MS APCI+ve 567 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:18]([F:30])[CH:17]=1)[CH2:9][CH2:8]2)=[O:4].[OH-].[Na+].CO>O>[CH3:28][N:27]([CH3:29])[C@@H:24]1[CH2:25][CH2:26][N:22]([C:19]2[CH:20]=[CH:21][C:16]([N:10]3[CH2:9][CH2:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=4)[C:11]3=[O:15])=[CH:17][C:18]=2[F:30])[CH2:23]1
Reactant: COC(=O)c1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N(C)C)C3)c(F)c1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(C(=O)O)ccc4C3=O)cc2F)C1

Procedure:
A mixture of 2-[4-((R)-3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester (0.80 g), sodium hydroxide (78 mg), methanol (20 mL) and water (10 mL) was boiled under reflux for 2 hours and then concentrated. The product with the molecular weight of 397.45 (C22H24FN3O3) was obtained in this way; MS (ESI): 398 (M+H+).