Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:52]3[CH2:53][CH2:54][CH:49]([OH:48])[CH2:50][CH2:51]3)[CH:30]=[CH:29][CH:28]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2nc(-c3ccc(SC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: CC(C)(C)[Si](OC1CCNCC1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(-c2nc(-c3ccc(SC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCC(O)CC2)c1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of 500 mg (1.01 mmol) of the compound from Example 10A, 514 mg (1.51 mmol) of the compound from Example 9A, 92 mg (0.101 mmol) of tris(dibenzylideneacetone)dipalladium(0), 96 mg (0.202 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos) and 194 mg (2.02 mmol) of sodium tert-butoxide in 10 ml of toluene was heated to 80° C. under argon in a microwave oven (Biotage Initiator, dynamic control of the incident power) for 3 h. After cooling to RT, 100 ml of water were added to the reaction mixture, which was extracted three times with approx. 100 ml each time of ethyl acetate. The combined organic extracts were washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and finally freed of the solvent on a rotary evaporator. The resulting crude product, which was the corresponding silyl-protected intermediate, was purified by means of MPLC (approx. 70 g of silica gel, eluent: cyclohexane→5:1 cyclohexane/ethyl acetate). Subsequently, this product was dissolved in 3.5 ml of THF, and 3.5 ml (3.5 mmol) of a 1 M solution of tetra-n-butylammonium fluoride (TBAF) in THF were added. After this mixture had been stirred at RT for 20 min, it was concentrated on a rotary evaporator. The title compound was isolated by means of MPLC (approx. 20 g of silica gel, eluent: 2:1→1:3 cyclohexane/ethyl acetate). After concentration and drying, the product was once again stirred with pentane/diethyl ether. 65 mg (12% of theory) of the title compound were thus obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.CC1(C)C(C)(C)[O:20][B:19](B2OC(C)(C)C(C)(C)O2)[O:18]1.CC([O-])=O.[K+].Cl>CCOC(C)=O.O1CCOCC1>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:19]([OH:20])[OH:18])=[CH:3][C:4]=2[F:15])=[CH:9][CH:10]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Nc1ccc(-c2ccc(Cl)cc2F)cn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc(B(O)O)cc2F)cn1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
5-(4-Chloro-2-fluorophenyl)pyridin-2-amine (2.0 g, 9.0 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.9 g, 11.0 mmol), chloro(2-dicyclohexyl-phosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.14 g, 0.18 mmol), and KOAc (2.7 g, 27 mmol) were combined in a sealable reaction vessel under nitrogen, and then treated with anhydrous 1,4-dioxane (100 mL, sparged with nitrogen). The vessel was sealed and then heated at 80° Celsius for 16 hours. The mixture was cooled to rt, HCl (1 m, 50 mL) was added and the mixture stirred for 20 min. The mixture was then diluted with EtOAc (200 mL) and the aqueous phase was collected. The organic phase was extracted with 1 M HCl (2×75 mL). The combined aqueous phases were cooled in an icebath and the pH was adjusted to ca. 7 using solid sodium bicarbonate. The resulting precipitate was collected by filtration, washed well with water, and dried to provide the title compound (2.1 g, 98%). MS (CI): mass calcd. for C11H10BFN2O2, 232.08; m/z found, 233.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.29-8.20 (s, 2H), 8.18-8.13 (s, 1H), 7.80-7.72 (m, 1H), 7.69-7.63 (m, 1H), 7.63-7.57 (m, 1H), 7.51-7.44 (m, 1H), 6.84-6.57 (m, 3H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[C:8](B3OC(C)(C)C(C)(C)O3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[S:35][C:34]([NH2:36])=[N:33][N:32]=3)[CH:29]=2)[N:24](S(C2C=CC(C)=CC=2)(=O)=O)[CH:23]=1.CC(N)CC1C=CC=CC=1.OP(O)(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(O)C.O>[N:1]1([C:6]2[N:7]=[C:8]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[S:35][C:34]([NH2:36])=[N:33][N:32]=5)[CH:29]=4)[NH:24][CH:23]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OB(c2cccc(N3CCCC3)n2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(N)s4)ccc32)cc1
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: Nc1nnc(-c2ccc3[nH]cc(-c4cccc(N5CCCC5)n4)c3c2)s1
Temperature: 100 °C
Yield: 6.9 %

Procedure:
A glass microwave reaction vessel was charged with 2-(pyrrolidin-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (46 mg, 0.17 mmol, CombiPhos Catalysts, Inc.) and 5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (060 g, 0.12 mmol) in 66% IPA in H2O (1 mL) followed by Amphos (4 mg, 6 μmol), potassium phosphate (0.077 g, 0.36 mmol). The mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 10 min. The aqueous layer was removed and the resulting mixture was concentrated in vacuo and purified by preparative HPLC. The product was dissolved in p-dioxane (1 mL) and aq. NaOH (1 M, 0.1 mL) was added. The solution was heated in a microwave at 100° C. for 10 min, and purified by preparative HPLC to give 5-(3-(6-(1-pyrrolidinyl)-2-pyridinyl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (3 mg, 8%). MS (ESI, pos. ion) m/z: 364 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 8.23 (1H, s), 8.00 (1H, s), 7.91 (1H, dd, J=9.0, 7.6 Hz), 7.65 (1H, d, J=8.6 Hz), 7.58 (1H, d, J=8.6 Hz), 7.09 (1H, d, J=7.2 Hz), 6.85 (1H, d, J=9.0 Hz), 3.60-3.68 (4H, m), 2.06-2.14 (4H, m).
Reaction SMILES: C(Cl)(Cl)Cl.[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]4[C:41]5[C:36](=[C:37]([NH2:42])[CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][C:33]4=[O:43])[CH2:26][CH2:25]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.Cl[C:45]([O:47][CH3:48])=[O:46]>C(N(CC)CC)C>[CH3:48][O:47][C:45](=[O:46])[NH:42][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:36]=1[CH:35]=[CH:34][C:33](=[O:43])[N:32]2[CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][CH:24]([N:16]([C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])[CH2:15][C:13]2[CH:12]=[CH:11][C:10]3[O:5][CH2:6][CH2:7][O:8][C:9]=3[CH:14]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.1 %

Procedure:
To 2 mL of a chloroform solution containing 80 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 45 mg of triethylamine and 42 mg of methyl chloroformate were added, and stirred at room temperature for 3 days. To the reaction mixture, 225 mg of triethylamine and 210 mg of methyl chloroformate were added, and stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; hexane:ethyl acetate=1:4], to give 40 mg of N-(1-(2-(4-((tert-butoxycarbonyl) (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yl)carbamic acid methyl ester as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(O)(=[O:15])C>C(OCC)C.O>[O:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:12]
Reactant: CC(=O)O
Reactant: Cc1ccc2oc(=O)ccc2c1
Solvent: CCOCC
Solvent: O
Product: O=Cc1ccc2oc(=O)ccc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
6-Methylcoumarin (400 mg, 2.50 mmol) was dissolved in 1.0 mL of diethyl ether, 1.0 mL of acetic acid, and 1.0 mL of water. After addition of ceric ammonium nitrate (5.5 g, 1.0 mmol) at room temperature, the reaction mixture was stirred at 100° C. for 1 h. The resulting mixture was diluted with water, and the solution was extracted with ethyl acetate. The extract was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=75/25 to 50/50) to obtain the title compound as a pale yellow powder (80 mg, 18%).
Reaction SMILES: C(OC1C=CC(N)=CC=1)C1C=CC=CC=1.N1C=CC=C1C(O)=O.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([C:41]2[CH:46]=[CH:45][CH:44]=C[N:42]=2)=[O:40])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:39]([C:41]2[NH:42][CH:44]=[CH:45][CH:46]=2)=[O:40])=[CH:36][CH:37]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccccn1
Agent: Nc1ccc(OCc2ccccc2)cc1
Agent: O=C(O)c1ccc[nH]1
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc[nH]1

Procedure:
This compound was prepared from 4-benzyloxyaniline (4.0 g, 17 mmol) and pyrrole-2-carboxylic acid (1.98 g, 17.8 mmol), using the same method used to prepare pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide. The product was purified by flash chromatography, on silica gel, using 5% methanol in DCM as the eluant, to give the product as a colorless solid, 2.6 g (50%). MS m/z 293 (MH+). 1H NMR(DMSO-d6) δ 5.04 (s, 2H), 6.13 (m, 1H), 6.95-7.05 (m, 4H), 7.28-7.45 (m, 5H), 7.65 (d, 2H), 9.7 (s, 1H) and 11.65 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][CH2:38][C@H:39]2[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]2)[C:34]([F:52])=[CH:33][N:32]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][CH2:38][C@H:39]4[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:40]4)[C:34]([F:52])=[CH:33][N:32]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CNc2nc(Cl)ncc2F)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a degassed solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.71 g, 1.65 mmol), (R)-tert-butyl 3-((2-chloro-5-fluoropyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate, 11a, (1.19 g, 3.60 mmol) and aqueous K2CO3 (2.48 mL of 2 M solution, 4.97 mmol) in THF (30 mL) was added bis(tri-tert-butylphosphine)palladium(0) (0.17 g, 0.33 mmol). The reaction mixture was degassed for an additional 15 min. The mixture was stirred at room temperature for 4 hours, concentrated in vacuo, and the resulting crude residue was purified by silica gel chromatography (10%-80% EtOAc/hexanes) to afford the desired product, 11b.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:13]=1[O:14][CH:15]1[CH2:18][N:17](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16]1>C(Cl)Cl>[Cl:11][C:12]1[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][C:13]=1[O:14][CH:15]1[CH2:16][N:17]([C:1]([Cl:4])=[O:2])[CH2:18]1
Reactant: O=C(Cl)Cl
Reactant: FC(F)(F)c1ccc(Cl)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2cc(C(F)(F)F)ccc2Cl)C1
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 13.5 g (0.14 mol) of phosgene and 19.4 g (0.14 mol) of potassium carbonate in 300 mL of methylene chloride was stirred under nitrogen while cooling in an ice bath. The cold reaction mixture was treated with a solution of 47.6 g (0.114 mol) of 3-[2-chloro-5-(trifluoromethyl)phenoxy]-1-(diphenylmethyl)azetidine in 100 mL of methylene chloride added dropwise. After stirring for 16 hr as the reaction mixture warmed to ambient temperature, it was again cooled in an ice bath while small pieces of ice were added to destroy the excess phosgene. The methylene chloride solution was decanted from the inorganic salt paste, dried by filtering through Whatman PS paper and concentrated in vacuo (58 g). The residue was triturated with 600 mL (3×200 mL) of petroleum ether, decanting the petroleum ether each time. The residue was then triturated with boiling hexanes and allowed to cool. The insoluble oil was separated using a separating funnel yielding 24 g of oily product (67%). A sample was distilled in a Kugelrohr apparatus (136°-150° C. @ 2 mm Hg) yielding a clear oil which slowly solidified on standing, mp 40°-45°.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].Cl.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:18]1[CH:19]=[CH:20][C:15]([CH3:21])=[CH:16][CH:17]=1)=[O:12]
Reactant: O=C(Cl)CCCCCBr
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CCCCCBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (1.3 g) was added to a solution of 6-bromohexanoyl chloride (2 g) in toluene (20 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure to give 2.76 g of 6-bromo-1-(4-methylphenyl)-1-hexanone.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.[OH-].[Na+]>CO>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH2:21][C:9]1[C:10]([O:17][CH:18]([F:19])[F:20])=[N:11][C:12]2[C:7]([C:8]=1[CH3:30])=[C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3Cl)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Cc2ccc(Cl)cc2Cl)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12

Procedure:
A solution of [3-(2,4-dichlorobenzyl)-2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.071 g), methanol (10 mL), and 5.0 M aqueous sodium hydroxide solution (0.15 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the pH of the residue adjusted to 4 by the addition of glacial acetic acid. The mixture was diluted in ethyl acetate, washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and methanol (1:0 to 1:1 by volume) to afford title compound as a white solid, 0.040 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][C:4](=[O:16])[C:3]=1[C:17]#[N:18].Cl.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:36])=[C:32]([NH:34][NH2:35])[CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[NH2:18][C:17]1[N:34]([C:32]2[CH:33]=[C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:29]=[CH:30][C:31]=2[CH3:36])[N:35]=[C:2]2[C:11]3[CH:10]=[C:9]([O:12][CH3:13])[C:8]([O:14][CH3:15])=[CH:7][C:6]=3[NH:5][C:4](=[O:16])[C:3]=12
Reactant: Cc1ccc(OCc2ccccc2)cc1NN
Reactant: COc1cc2[nH]c(=O)c(C#N)c(Cl)c2cc1OC
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2[nH]c(=O)c3c(N)n(-c4cc(OCc5ccccc5)ccc4C)nc3c2cc1OC
Temperature: 80 °C
Reaction time: 24 h
Yield: 74.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (53 mg), 5-benzyloxy-2-methylphenylhydrazine hydrochloride (53 mg), triethylamine (84 μl) and ethanol (5 ml) was stirred at 80° C. for 24 hours. After cooling, 10% citric acid was added thereto, extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography to obtain the target compound (68 mg).
Reaction SMILES: CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.B.CSC.[CH2:26]([O:33][C:34]1[C:39]2[NH:40][C:41](=[O:43])[S:42][C:38]=2[C:37]([C:44](=[O:47])[CH2:45][Br:46])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C1COCC1>[CH2:26]([O:33][C:34]1[C:39]2[NH:40][C:41](=[O:43])[S:42][C:38]=2[C:37]([C@@H:44]([OH:47])[CH2:45][Br:46])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)sc12
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CSC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1[nH]c2c(OCc3ccccc3)ccc([C@@H](O)CBr)c2s1
Reaction time: 72 h
Yield: 69.8 %

Procedure:
A solution of [(R)-tetrahyro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c] [1,3,2]-oxazaborole] (22 μl of 1M in toluene) in dry THF(1 ml) was cooled to −5° C., stirring under nitrogen. Borane-methyl sulfide complex (2M solution in THF, 11 μl) was added and stirred for 10 min at −5° C. A solution of 4-(benzyloxy)-7-(bromoacetyl)-1,3-benzothiazol-2(3H)-one (47 mg) in dry THF (1.5 ml) was added dropwise and then another 66 μl of borane-methyl sulfide complex (2M solution in THF). The reaction mixture was left for 72 h at less than 5° C. and then partitioned between 2N HCl and ethyl acetate. The organic solution was dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a 5 g silica SPE cartridge, eluting with a stepped gradient of 10% to 25% ethyl acetate-cyclohexane mixtures to give the title compound (33 mg). LCMC RT=3.19 min.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:22])[CH2:12][N:13](C)[C:14](=O)OC(C)(C)C)=[CH:7][CH:6]=1)[CH3:3]>Cl.O1CCOCC1>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:22])[CH2:12][NH:13][CH3:14])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(C(O)CN(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CNCC(O)c1ccc(CN(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.8 %

Procedure:
To a solution of HCl-dioxane (20 mL, 4.0 M HCl in dioxane) was added tert-butyl 2-{4-[(dimethylamino)methyl]phenyl}-2-hydroxyethyl(methyl)carbamate (124 mg, 0.40 mmol). The mixture was stirred at room temperature for 16 hours. The solvent and HCl was evaporated. After treated with high vacuum for 15 minutes, the residue was dissolved in methanol (2 mL) and treated with resin (BioRad 50w×2, 0.20 g) for 3 hours. The resin was collected by filtration and washed with methanol. The product on the resin was washed off with NH4OH/CH3OH (20 mL, 10% ammonium hydroxide aqueous solution (Aldrich, 29.4% NH3) in methanol). The solution was concentrated to dryness, and treated with high vacuum to give the title compound (89 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[C:14]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)=[O:9]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cc(Cl)ccc1O
Yield: 72.1 %

Procedure:
Using 5-chlorosalicylic acid and 4-fluoro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[NH2:8][C:9](=[N:11][C:12]([C:14]1[CH:26]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[C:16]=2[CH:15]=1)=[O:13])[NH2:10]>C(O)C>[ClH:1].[ClH:1].[NH2:10][C:9]([NH2:8])=[N:11][C:12]([C:14]1[CH:26]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[C:16]=2[CH:15]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c3ccccc3c3ccc(C(=O)N=C(N)N)cc32)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(N)=NC(=O)c1ccc2c3ccccc3n(C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 0.6 ml portion of 4 M hydrogen chloride/ethyl acetate was added to 4.4 ml ethanol solution of 201 mg tert-butyl 4-(2-{[(diaminomethylene)amino]carbonyl}-9H-carbazol-9-yl)piperidine-1-carboxylate which had been synthesized in the same manner as in Example 1, followed by stirring overnight at room temperature. The thus precipitated-solid was collected by filtration and washed with EtOH to obtain 125 mg of N-(diaminomethylene)-9-piperidin-4-yl-9H-carbazole-2-carboxamide dihydrochloride as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=3[CH3:30])[CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:31])[O:4][N:3]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:65]1[CH2:70][CH2:69][CH2:68][CH2:67][CH:66]1[O:71][CH2:72][CH2:73]O>O1CCCC1>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:73][CH2:72][O:71][CH:66]4[CH2:67][CH2:68][CH2:69][CH2:70][O:65]4)=[CH:25][C:24]=3[CH3:30])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: OCCOC1CCCCO1
Reactant: Cc1cc(O)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCOC2CCCCO2)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 50 °C

Procedure:
An aliquot of tetrahydrofuran (THF) (1 mL) containing 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(4-hydroxy-2-methylphenyl)-N-isobutylbenzenesulfonamide (50 mg, 0.112 mmol) and DIAD (0.048 mL, 0.247 mmol) was added to triphenylphosphine (64.9 mg, 0.247 mmol). The reaction mixture was sealed and left to stir for 10 minutes before addition of 2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol (0.015 mL, 0.112 mmol). The sealed reaction mixture was then heated to 50° C. over night. LCMS showed the formation of the product. LCMS (M+1) 572, RT 1.4 mins. Used without further purification in next reaction.