Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH4+].[Cl-].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[C:23]([N+:25]([O-])=O)[C:22]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:21][C:20]=3[O:35][CH3:36])[N:13]=2)=[CH:4]1>O.C(O)C.[Fe]>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[C:23]([NH2:25])[C:22]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:21][C:20]=3[O:35][CH3:36])[N:13]=2)=[CH:4]1
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 105 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A solution of NH4Cl (0.021 g, 0.38 mmol) in water (3 mL) was added in one portion to a stirred suspension of 4-(1H-indol-3-yl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]pyrimidin-2-amine (Intermediate 67, 0.235 g, 0.51 mmol) and iron (0.171 g, 3.07 mmol) in ethanol (9 mL) and the mixture was stirred at 105° C. for 18 h. The mixture was then concentrated in vacuo and the resulting residue was dissolved in DMF (20 mL). Purification by ion exchange chromatography, using an SCX column, eluting with 0.35M methanolic ammonia in CH2Cl2 and concentration of the appropriate fractions gave the title compound (0.206 g, 94%) as a yellow solid; m/z: ES+ MH+ 430.51.
Reaction SMILES: O=C1CNCCN1.[CH2:8]([N:10]([CH2:26][CH3:27])[CH:11]([N:13]1[CH2:18][CH2:17][NH:16][C:15](=O)[CH:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:12])[CH3:9].O1CCOCC1.[OH-].[Na+]>O.CCOCC>[CH2:26]([N:10]([CH2:8][CH3:9])[CH:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:12])[CH3:27]
Reactant: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Agent: O=C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C(C)N1CCNCC1c1ccccc1
Yield: 77 %

Procedure:
89 g. of the keto piperazine prepared as described hereinabove under (a), are dissolved in 200 cc. of absolute dioxane. The solution is added to a suspension of 20 g. of lithium aluminum hydride LiAlH4 in 800 cc. of absolute ether while exposing the mixture to vibration. After addition of the keto piperazine solution is completed, the reaction mixture is boiled under reflux for 6 hours. Thereafter it is decomposed by successive treatment with 21 cc. of 15 % sodium hydroxide solution, 21 cc. of water, 63 cc. of 15 % sodium hydroxide solution, and 42 cc. of water. The decomposed reaction mixture is filtered, the solvent is removed by distillation, and the residue is distilled in a vacuum. 65 g. of a light yellow oil of the boiling point 114°-117° C./0.05 mm. Hg are obtained. This oil corresponds to the above given compound. The yield is 77 % of the theoretical yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[I-:13].[Na+].NCCCN>>[I:13][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Brc1ccc(-c2cccs2)cc1
Agent: NCCCN
Agent: [Na+]
Product: Ic1ccc(-c2cccs2)cc1
Temperature: 130 °C
Yield: 83.2 %

Procedure:
As shown in the following Reaction 9, 100 mg (0.42 mmol) of 2-(4-bromo-phenyl)-thiophene synthesized in C of Example 1-2 was melted in 5 mL of n-phentanol, and 130 mg (0.84 mmol, 2 eq) of sodium iodide and 0.004 mL (0.042 mmol, 10 mol %) of 1,3-diaminopropane was added thereto, and then the reaction solution was refluxed for 18 hours at temperature of 130° C. Next, the reaction solution was washed with aqueous ammonia, and was dehydrated with magnesium sulfate, filtered, and then distilled under reduced pressure. The compound distilled under reduced pressure was purified with a column chromatography (mobile phase: n-hexane) to obtain 100 mg of 2-(4-iodo-phenyl)-thiophene with the yield of 83.3%. NMR data of the obtained compound is as follows. [1H NMR (400 MHz, CDCl3): δ 7.52 (m, 4H), 7.33 (d, 2H), 7.10 (t, 1H)].
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)C1C=CC=CC=1.O1CCCC1>C(Cl)(Cl)Cl.[OH-].[Pd+2].[OH-].[C]>[F:16][C:13]([F:14])([F:15])[C:11]1[NH:10][C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([CH3:35])([CH3:36])[C:32]([OH:34])=[O:33])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[N:8][CH:12]=1
Reactant: CC(C)(COc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3Cc3ccccc3)cc2)cc1)C(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(COc1ccc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cc2)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 6 h
Yield: 93.6 %

Procedure:
The mixture of 3-({4′-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]biphenyl-4-yl}oxy)-2,2-dimethylpropanoic acid (830 mg), 20% palladium hydroxide-carbon (850 mg) and tetrahydrofuran (20 mL) was stirred at 60° C. under hydrogen atmosphere for 6 hours. Nitrogen gas was passed through the reaction mixture, and the mixture was diluted with chloroform. The mixture was filtered by using a membrane filter, and the filtrate was washed with tetrahydrofuran, methanol and chloroform. The filtrates were combined, and n-hexane and propanol were added to the residue obtained by concentrating the same under the reduced pressure. The precipitated solid was collected by filtration to obtain 3-({4′-[5-(trifluoromethyl)-1H-imidazol-2-yl]biphenyl-4-yl}oxy)-2,2-dimethylpropanoic acid (635 mg).
Reaction SMILES: Br[C:2]1[C:3]([N:9](CC2C=C(OC)C=C(OC)C=2)[CH2:10][CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:8][C:5]1[N:4]=[C:3]2[C:2]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][CH2:10][NH:9]2)=[CH:7][N:6]=1
Reactant: CNC(=O)CCN(Cc1cc(OC)cc(OC)c1)c1nc(Cl)ncc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CCNc2nc(Cl)ncc21
Reaction time: 8 h

Procedure:
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-[(3,5-dimethoxyphenyl)methyl]amino]-N-methyl-propanamide (Intermediate 97; 83 mg, 0.23 mmol) was taken up in DCM (1 mL) and TFA (1 mL) and stirred for 30 minutes. A further addition of TFA (1 mL) was made and stirring continued overnight. The reaction mixture was diluted with DCM (25 mL) and poured directly onto a SCX-3 cartridge (2 g). The cartridge was washed through with methanol (50 mL). Products were eluted with 2M ammonia in methanol and ammoniacal eluant evaporated to dryness to afford the title compound as an off white solid (34 mg, 70%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.C([Sn](CCCC)(CCCC)[C:37]1[CH:42]=[N:41][CH:40]=[CH:39][N:38]=1)CCC>CN(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>[CH3:21][C:5]1[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[N:7][C:2]([C:37]2[CH:42]=[N:41][CH:40]=[CH:39][N:38]=2)=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:4]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cnccn2)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.5 %

Procedure:
To a degassed solution of 0.20 g (0.44 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) in 8.0 ml of DMF was added 0.051 g (0.044 mmol) of tetrakis-(triphenylphosphine)-palladium and the reaction mixture was stirred for 20 min at RT. Then, 0.49 g (1.32 mmol) of 2-tributylstannanyl-pyrazine were added and the reaction was heated up to 100° C. After 6 hours, it was cooled down to RT, poured into crashed ice and extracted three times with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.11 g (50%) of the title compound as yellow oil. MS: 496.2 (MH−).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[C@H:10]([CH2:25][O:26]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][O-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[C@H:10]([CH2:25][O:26][CH3:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[O-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2NC(=O)c2[nH]c(C)c(Cl)c2Cl)cc1
Agent: [Na+]
Solvent: CO
Product: COC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Cis-tert-butyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1-carboxylate (Intermediate 72; 325 mg) was dissolved in 5 ml of a 30 wt % MeOH solution containing NaOMe and an additional 5 ml of dry MeOH. The homogeneous reaction was stirred at room temperature for 2 days. Upon reacting, solids began to precipitate from solution. The reaction was concentrated to a solid residue, re-dissolved in EtOAc and washed with saturated NH4Cl (2×10 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The residual material was purified by flash column chromatography eluting with (1:1 EtOAc/hexanes) to give the title compound (192 mg). MS (ES)(MH+): 420 for C19H27Cl2N3O4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[Mg].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].[NH4+].[Cl-]>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([CH:19]([C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=2)[OH:20])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1cccc(C2OCCO2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 1.0 mL aliquot of 2-(3-bromophenyl)-1,3-dioxolane is added into magnesium (610 mg; 25 mmol) and THF (5 mL) under Argon. After the reaction is started, the residue of 2-(3-bromophenyl)-1,3-dioxolane (total: 5.73 g; 25 mmol) in THF (20 mL) is added dropwise into the reaction mixture. The resulting solution is stirred at room temp for six hours, and then at 50-60° C. for 20 hours. After the mixture is cooled, a solution of 3-(trifluoromethyl)-benzaldehyde (4.35 g; 25 mmol) in THF (20 mL) is added dropwise and the reaction is stirred at room temp for 24 hours. A saturated solution of NH4Cl (50 mL) is added and stirred for 30 minutes. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×100 mL). The organic layers are combined and dried over anhydrous Na2SO4. The solvent is removed and the residue is purified by column chromatography on silica gel. Eluting with ethyl acetate/hexanes (20:80) provide a colorless oil (3.23 g; 40%) as (3-(1,3-dioxolan-2-yl)phenyl)[3-(trifluoromethyl)phenyl]-methan-1-ol: MS 307.0 (M−17).
Reaction SMILES: [NH2:1][C:2]1([C:5]([O:7][CH3:8])=[O:6])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]I>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[N:1]1([C:2]2([C:5]([O:7][CH3:8])=[O:6])[CH2:4][CH2:3]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)C1(N)CC1
Reactant: ICCCCCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: COC(=O)C1(N2CCCCC2)CC1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 1-aminocyclopropane-1-carboxylate (0.50 g, 4.35 mmoles), powdered potassium carbonate (2.40 g, 17.4 mmoles), and tetrabutylammonium bromide (0.140 g, 0.43 mmoles) in anhydrous acetonitrile (12 mL) was treated with 1,5-diiodopentane (1.70 g, 5.22 mmoles). The mixture was stirred for three days at 90° C. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on an Alltech pre-packed silica gel column eluting with ethyl acetate to afford the title compound. MS (DCI) m/z 184 (M+H)+. Vaidyanathan, G.; Wilson, J. W. J. Org. Chem. 1989, 54, 1810-1815.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]([NH2:34])=[O:33])[CH2:28][CH2:27]2)=[N:24][CH:25]=1.[N+](C1C=CC(N2CCC(C(N)=O)CC2)=NC=1)([O-])=O.CCO.C1COCC1.CCOC(C)=O.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C.[Pd]>[C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][CH:29]([C:32]([NH2:34])=[O:33])[CH2:28][CH2:27]4)=[N:24][CH:25]=3)=[O:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C1CCN(c2ccc(N)cn2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Yield: 26 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3.42 g, 12.6 mmol), 5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid amide (which was the product from the catalytic hydrogenation of 5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid amide: 2.93 g, 12.6 mmol, 200 mL EtOH/THF/EtOAc mixture, 50 psi H2, 7 hr, with 300 mg of Pd/C 10%), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.89 g, 15.1 mmol) and DMAP (catalytic) in anhydrous DMF (25 mL) was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (400 mL) and washed with aqueous ammonium chloride (saturated, 200 mL), sodium bicarbonate (saturated, 200 mL with addition of brine to clear emulsion) and brine (100 mL). The aqueous ammonium chloride was extracted with ethyl acetate (200 mL) which was subsequently washed with brine (100 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and tritrated from boiling ethyl acetate to give 5′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid amide (1.5 g, 26%) as a light brown solid. LCMS calcd for C22H20F3N5O3 (m/e) 459, obsd 460 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:21]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)([CH3:20])[CH2:9][O:10][C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:14])=O)[C:5]([F:34])=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:20])[CH2:9][O:10][C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:14])=[N:21]2)[C:5]([F:34])=[CH:4][CH:3]=1
Reactant: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1nc(Br)ccc1F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@]1(c2nc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 148.7 %

Procedure:
A suspension of (R)-2-[(R)-2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(4-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide (8.43 g, 14.70 mmol) and triethylamine (5.12 ml, 36.8 mmol) in 85 ml DCM was cooled to 0-5° C. Trifluoroacetic anhydride (2.49 ml, 17.64 mmol) was added dropwise over 30 min. Additional triethylamine (1.54 ml, 11.07 mmol) and trifluoroacetic anhydride (0.75 ml, 5.29 mmol) were added to complete the reaction. The reaction mixture was quenched by addition of 14 ml aqueous ammonia (25%) and 14 ml water. The emulsion was stirred for 15 min, more water and DCM were added and the layers were separated. The organic layer was dried with MgSO4 H2O, filtered and evaporated. Purification by column chromatography on a silica gel (hexanes/10-25% EtOAc) gave 8.09 g of the title compound as a yellow resin.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=2[CH:23]=[CH:22]1.C(=O)([O-])O.[Na+].C(O)C>O.C1(C)C=CC=CC=1>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]5[N:11]=[CH:12][CH:13]=[CH:14][C:8]=5[C:6]=4[N:7]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: Clc1nc(N2CCOCC2)c2sc3ncccc3c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc(-c2nc(N3CCOCC3)c3sc4ncccc4c3n2)c2cc[nH]c2c1
Temperature: 120 °C

Procedure:
Under Ar(g), to a mixture of compound 5 (14.97 mg, 0.049 mmol), indole-4-boronic acid (8.70 mg, 0.054 mmol), dichloro-bis(triphenylphosphine)palladium (II) (1.81 mg, 0.0026 mmol) and sodium hydrogen carbonate (12.50 mg, 0.15 mmol) was added ethanol (0.75 mL) followed by toluene (1.25 mL) and then water (0.35 mL). The reaction was then heated in a microwave at 120° C. (300 W) for 1 h. The reaction nl/xtuvevvas then cooled to rt, and was partitioned between CH2Cl2 and water, and the organic layer was then separated, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 0:1-1:99) MeOH/CH2Cl2) furnished A (1 mg, 0.0026 mol, 5%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([NH:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[C:34]1([S:40]([N:43]2[CH:47]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:45]=[N:44]2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.ClCCl.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:17][C:15]1[N:14]=[C:13]([NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:12]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:46]4[CH:45]=[N:44][N:43]([S:40]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)(=[O:42])=[O:41])[CH:47]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)(=[O:27])=[O:26])[CH:9]=2)[CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(NC3CCCCC3)c2)c2cc(Br)cnc21
Reactant: CC1(C)OB(c2cnn(S(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnc3c(c2)c(-c2cc(Cl)nc(NC4CCCCC4)c2)cn3S(=O)(=O)c2ccccc2)cn1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
A solution of Example 171a (0.158 g, 0.29 mmol), 1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.100 g, 0.29 mmol), catalytic amount of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) and saturated sodium bicarbonate solution (2 mL) in 8 mL dimethylformamide was heated at 65° C. for 2 hours. The material was cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel using flash chromatography (20% ethyl acetate/hexane) to afford 0.11 g of the title compound. m/z 673.6 (ESI, M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:18]([Br:19])=[C:17]([O:20]COC)[CH:16]=[C:15]([O:24]COC)[C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][Si](C=[N+]=[N-])(C)C.CCCCCC.C(O)(=O)C>CO>[CH3:28][O:14][C:12](=[O:13])[C:11]1[C:15]([OH:24])=[CH:16][C:17]([OH:20])=[C:18]([Br:19])[C:10]=1[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COCOc1cc(OCOC)c(C(=O)O)c(COCc2ccccc2)c1Br
Solvent: CC(=O)O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1c(O)cc(O)c(Br)c1COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
The above-obtained 2-(benzyloxymethyl)-3-bromo-4,6-bis(methoxymethoxy)benzoic acid (16 mg, 0.036 mmol) was dissolved in methanol (2 mL) and the obtained mixture was further added with 2.0 mol/L trimethylsilyldiazomethane-hexane solution (0.30 mL, 0.60 mmol) followed by stirring at a room temperature for 1 hour. After adding acetic acid (0.050 mL) to the reaction mixture, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol (4 mL) and the obtained solution was added with concentrated hydrochloric acid (0.10 mL) followed by stirring at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by preparative thin-layer chromatography (chloroform/methanol=20/1) to obtain Compound 10 (11 mg, 82%).
Reaction SMILES: O1CCCC1.CS(C)=O.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[N+:25]([O-:27])=[O:26])=[CH:19][CH:18]=1.C(O)(=O)C.[BH4-].[Na+]>O>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N+:25]([O-:27])=[O:26])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(CCc2ccco2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])CCc1ccc(CCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
To a mixed tetrahydrofuran-dimethyl sulfoxide (1:1, 10 mL) solution of 4-(2-furan-2-yl-ethyl)-((E)-2-nitro-vinyl)-benzene (554 mg, 2.28 mmol) described in Manufacturing Example 80-1-5 and acetic acid (0.5 mL) was added sodium borohydride (129 mg, 3.42 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 10 minutes at room temperature. Water was added dropwise into this reaction solution at room temperature while cooling appropriately. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (t-butylmethyl ether:heptane=5:95) to obtain the title compound (300 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.CS(O)(=O)=O.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:12]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([C:8]([CH3:10])([CH3:9])[C:6]=2[CH:7]=1)[C:13]3=4
Reactant: CC(C)(O)c1cc(Br)ccc1-n1c2ccccc2c2ccccc21
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)c2cc(Br)ccc2-n2c3ccccc3c3cccc1c32
Temperature: 60 °C

Procedure:
16.4 g (43.6 mmol) of 2-(5-bromo-2-carbazol-9-ylphenyl)propan-2-ol are dissolved in 1200 ml of degassed toluene, a suspension of 40 g of polyphosphoric acid and 28 ml of methanesulfonic acid is added, and the mixture is heated at 60° C. for 1 h. The batch is cooled, and water is added. A solid precipitates out and is dissolved in methylene chloride/THF (1:1). The solution is carefully rendered alkaline using 20% NaOH, the phases are separated and dried over MgSO4. The solid obtained is washed by stirring with heptane. Yield: 14.8 g (40 mmol), 95% of theory, purity according to 1H-NMR about 95%.