Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.CO.[C:22]([C:24]1[N:25]=[C:26]([NH2:38])[C:27]2[N:28]([N:30]=[C:31]([C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)[CH:29]=1)#[CH:23]>O>[O:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:31]1[N:32]=[C:27]2[C:26]([NH2:38])=[N:25][C:24]([C:22]#[C:23][CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:29][N:28]2[N:30]=1
Reactant: C#Cc1cn2nc(-c3ccco3)nc2c(N)n1
Reactant: C(=Nc1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C#CC(Nc2ccccc2)c2ccccc2)cn2nc(-c3ccco3)nc12
Temperature: 40 °C

Procedure:
To a solution of benzylidene-phenyl-amine (0.05 mmol) (prepared by heating neat phenylamine (0.05 mmol) and benzaldehyde (0.05 mmol) at 60° C. for 2 hours) in a 1:1 mixture of THF (250 uL) and methanol (250 uL) was added the above 6-ethynyl-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (11 mg, 0.05 mmol). CuBr (2.2 mg, 0.015 mmol, 30 mol %) was added to the reaction mixture followed by RuCl3 (0.03 mg, 0.0015, 3 mol %) in water (50 μL). The reaction vessel was degassed and heated at 40° C., for 18 hours. After cooling, water was added and the residue was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, and concentrated in vacuo to yield a crude product, which was purified using preparative HPLC to afford 2-furan-2-yl-6-(3-phenyl-3-phenylamino-prop-1-ynyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine. 1H NMR (300 MHz, Acetone-d6) δ 8.20 (s, 1H), 7.79-7.71 (3H), 7.43-7.40(3H), 7.15-7.11(4H), 6.90-6.87(2H), 6.67-6.65 (2H), 5.70 (s, 1H), 2.55(s, 1H). MS: m/z 407 [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([OH:22])[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Si:30](Cl)([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)OC(C)(C)C)cc1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CNCCN2C(=O)OC(C)(C)C)cc1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
To a solution of (2R)-1-tert-butoxycarbonyl-2-(3-hydroxy-4-methylbenzyl)piperazine (7.73 g) and 4-dimethylaminopyridine (620 mg) in dichloromethane (90 ml) was added successively triethylamine (15.82 ml) and tert-butyldiphenylsilyl chloride (26.24 ml) at room temperature. After stirring under reflux for 27.5 hours, water (200 ml) was added to the mixture, and the mixture was extracted with dichloromethane (100 ml, 50 ml×2). The combined organic extracts were washed successively with water and brine, dried over magnesium sulfate, and evaporated under reduced pressure to give crude oil. The oil was purified with column chromatography (silica gel, 500 ml, methanol:dichloromethane 5:95) to give (2R)-1-tert-butoxycarbonyl-2-(3-tert-butyldiphenylsilyloxy-4-methylbenzyl)piperazine (12.07 g) as a solid.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([N:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]1)[CH2:5][C:6]#[N:7].[BH4-].[Na+].[OH-].[NH4+]>C1COCC1.O.O.O.O.O.O.O.[Co](Cl)Cl>[F:14][C:11]1([F:15])[CH2:12][CH2:13][N:8]([CH:4]2[CH2:5][CH2:6][NH:7][C:3]2=[O:2])[CH2:9][CH2:10]1
Reactant: COC(=O)C(CC#N)N1CCC(F)(F)CC1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NCCC1N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.5 %

Procedure:
Treat a 0° C. mixture of 3-cyano-2-(4,4-difluoro-piperidin-1-yl)-propionic acid methyl ester (3.74 g, 16.1 mmol) and cobalt (II) chloride hexahydrate (1.92 g, 8.07 mmol) in THF (50 mL) and water (25 mL) portion-wise with sodium borohydride (3.05 g, 80.6 mmol) and warm to room temperature and stir for 2 days under N2. Treat the reaction with 28% ammonium hydroxide (2 mL) and filter through hyflo. Remove the solvent from the filtrate in vacuo and dilute the residue with minimal water and brine and extract three times with 3:1 chloroform:isopropanol. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify on silica with a 0 to 10% methanol in CH2Cl2 gradient to afford 1.53 g (46%) of the titled product. Rf=0.43 (9/1 CH2Cl2/methanol, I2 stain). ES MS (m/z): 205 (M+).
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([C:8]2[N:4]3[CH2:5][CH2:6][CH2:7][C:2]([O:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:39])[F:40])[CH:33]=4)([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:3]3=[N:10][N:9]=2)[CH:16]=[CH:15][C:14]=1[C:17]1[O:21][C:20]([CH3:22])=[N:19][CH:18]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Oc2cccc(C(F)(F)F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
Ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1.0 g) was added to a mixture of 3-(trifluoromethyl)phenol (408 mg), potassium carbonate (995 mg) and DMF (10 mL) at 90° C., and the mixture was stirred for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (663 mg).
Reaction SMILES: [NH2:1][C:2]1[C:12](I)=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C.O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:12](/[CH:17]=[CH:16]/[C:15]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: Nc1c(I)cc(Br)c2c1C(=O)NC2=O
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cc(Br)c2c(c1N)C(=O)NC2=O
Yield: 70.8 %

Procedure:
3-Amino-4-iodo-6-bromophthalimide (500 mg, 1.36 mmol) was dissolved in acetonitrile (25 mL), and the solution was added with methyl acrylate (0.245 mL, 2.72 mmol), palladium acetate (24 mg, 0.11 mmol) and triethylamine (1.90 mL, 13.6 mmol), followed by stirring under reflux for 5 hours under argon atmosphere. The mixture was added with methyl acrylate (0.122 mL, 1.36 mmol), palladium acetate (24 mg, 0.11 mmol) and triethylamine (1.90 mL, 13.6 mmol) and further stirred for 142 hours. The mixture was added with methyl acrylate (0.245 mL, 2.72 mmol), palladium acetate (24 mg, 0.11 mmol) and triethylamine (0.95 mL, 6.8 mmol) and further stirred for 20 hours. The reaction mixture was added with water, extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using chloroform to obtain (E)-3-amino-4-(2-methoxycarbonylvinyl)-6-bromophthalimide (313 mg, yield 71%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:33]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23]2[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:24]=2[OH:33])[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(O)c(Br)n1
Reactant: OB(O)c1ccc(C(F)(F)F)c(OCc2ccccc2)c1
Product: COC(=O)c1ccc(O)c(-c2ccc(C(F)(F)F)c(OCc3ccccc3)c2)n1
Yield: 65 %

Procedure:
According to the method described in example 4.3, starting from 4.95 g (16.7 mmol) of [3-(benzyloxy)-4-(trifluoromethyl)phenyl]boronic acid and 3.88 g (16.72 mmol) of methyl 6-bromo-5-hydroxypyridine-2-carboxylate, we obtain 4.38 g of methyl 6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-hydroxypyridine-2-carboxylate in the form of a white solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:16](I)=[CH:15][C:14]([S:18][CH3:19])=[CH:13][N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[O:23][C:24]([CH3:27])=[CH:25][CH:26]=1)#[CH:21].C(N(CC)CC)C.O>O1CCOCC1>[C:1]1([S:7]([N:10]2[C:11]3=[N:12][CH:13]=[C:14]([S:18][CH3:19])[CH:15]=[C:16]3[CH:21]=[C:20]2[C:22]2[O:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Reactant: C#Cc1ccc(C)o1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1cnc2c(c1)cc(-c1ccc(C)o1)n2S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 2-benzenesulfonylamino-5-methylthio-3-iodopyridine (203 mg) in 1,4-dioxane (5 ml), 2-ethynyl-5-methylfuran (160 mg), bistriphenylphosphine palladium dichloride (18 mg), cuprous iodide (10 mg) and triethylamine (75 mg) were added successively and the mixture was stirred in a sealed tube at 60° C. for 1 hour. After cooling, the reaction solution was poured into water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=5:1) to obtain 169 mg of the desired products as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:23])[NH:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:23])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[S:25][CH3:24])=[CH:17][C:16]=1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccccc1B(O)O
Reactant: Cc1cc(Br)ccc1NC(=O)C1CCCN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CSc1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(C)c1

Procedure:
2-(4-Bromo-2-methyl-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.07 g, 2.7 mmol), 2-(methylthio)benzene boronic acid (0.56 g, 3.3 mmol), and tetrabutylammonium bromide (322 mg, 0.13 mmol) were combined in 20 mL toluene, added 2.8 mL of a 2M aqueous Na2CO3 solution followed by tetrakistriphenylphosphine palladium(0) (0.161 g, 0.13 mmol). Heated reaction at reflux 4 hours, cooled, concentrated, redissolved in EtOAc (250 mL), washed with water (3×200 mL), brine (200 mL), dried with MgSO4, filtered, and concentrated. Purified on a silica gel column eluted with 20% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound. (0.59 g, 50%) APCI (AP−): 425.1 (M−H)−.
Reaction SMILES: Br[C:2]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([CH3:11])[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:20]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH2:11][CH:2]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:3][CH2:4][CH:5]2[NH:9][C:8](=[O:10])[CH2:7][CH2:6]2)[CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(Br)(CCC1CCC(=O)N1)O[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(-c2ccccc2)c1
Yield: 175.4 %

Procedure:
To a solution of 5-[3-bromo-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (750 mg, 1.76 mmol) in DME (15 mL) was added phenylboronic acid (236 mg, 1.93 mmol). Palladium acetate (26.8 mg, 0.120 mmol) and tri-o-tolylphosphine (39.5 mg, 0.130 mmol) were added, followed by a solution of Na2CO3 (373 mg, 3.52 mmol) in water (1.8 mL). The reaction mixture was heated under reflux for 24 h. The reaction mixture was cooled and the volatiles were removed in vacuo. The residue was diluted with brine and EtOAc. The aqueous solution was washed with EtOAc (3×) and the combined organic extracts were dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography eluting with a solvent gradient (1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 5-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-pyrrolidin-2-one (717.3 mg). 1H NMR (CDCl3) δ7.57 (m, 2H), 7.43 (m, 2H), 7.33 (m, 3H), 7.11 (m, 2H), 5.78 (m, 1H), 3.91 (m, 1H), 3.59 (m, 1H), 2.76 (m, 2H), 2.27 (m, 3H), 1.73-1.38 (m, 5H), 0.83 (s, 9H), −0.03 (d, 3H), −0.16 (d, 3H); MS 424.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[C:16]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH3:16][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(O)n(-c2cc(C#N)ccn2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc(C)nn1-c1cc(C#N)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
To a solution of 2-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (200 mg, 1 mmol) and K2CO3 (276 mg, 2 mmol) in DMF was added MeI (213 mg, 1.5 mmol) dropwise at −20° C. The mixture was warmed to 0° C. and stirred for 3 h. Water was added, and the reaction mixture was extracted with EtOAc, then washed with water and brine. The organic phase was dried, concentrated, and purified by prep-HPLC to afford the title compound (50 mg). [M+H] Calc'd for C11H10N4O, 215; Found, 215.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH2:10]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[N:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][C:11]2=[O:15])=[CH:3][CH:4]=1
Reactant: Ic1ccncc1
Reactant: CN1CCNC(=O)C1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCN(c2ccncc2)C(=O)C1
Temperature: 110 °C
Yield: 23.6 %

Procedure:
A mixture of 4-iodopyridine (218 mg, 1.06 mmol), 4-methyl-2-piperazinone (106 mg, 0.929 mmol), K3PO4 (425 mg, 2.00 mmol) and 1,2-trans-diaminocyclohexane (0.050 mL, 0.41 mmol) in anhydrous dioxane (3.0 mL) was degassed with Ar before being charged with CuI (40 mg, 0.21 mmol). The mixture in a sealed tube was heated at 110 ° C. overnight. The mixture was purified by a prep-TLC using MeOH/CH2Cl2 (10/90) as solvents to give 1-(pyridin-4-yl)-4-methyl-2-piperazinone (42 mg). MS 192.5 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([NH:10][C@@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[OH:17])[S:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([OH:2])[CH:19]=[CH:18][C:6]=2[N:7]=1
Reactant: COc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.2 %

Procedure:
To the solution of (1R,2R)-2-(6-methoxybenzo[d]thiazol-2-ylamino)cyclohexanol (1.06 g, 3.81 mmol) in 16 ml of DCM was added 1 M boron tribromide in DCM (8 ml, 8 mmol) slowly at 0° C. The reaction solution was stirred at room temperature for 2 hours. Removal of all solvent in vacuo, followed by quenching with water (ca. 30 ml) and diluted NaHCO3 solution, and extraction of aqueous phase with ethyl acetate (3×100 ml) and drying of combined organic extracts over Na2SO4 and subsequent removal of ethyl acetate in vacuo yielded the desired product (1.16 g) as pink solid. The residue was purified by flash column chromatography to give 2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (1.0 g, 3.78 mmol) as brown solid. ES/MS m/z 265.1 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C.[CH2:28]([O:30][CH:31]([O:35][CH2:36][CH3:37])[CH2:32][CH2:33][NH2:34])[CH3:29]>ClCCl.O>[CH2:28]([O:30][CH:31]([O:35][CH2:36][CH3:37])[CH2:32][CH2:33][NH:34][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19])[CH3:29]
Reactant: CCOC(CCN)OCC
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(CCNc1c([N+](=O)[O-])cnc2ccccc12)OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
Potassium carbonate (19.9 g, 144 mmol) was added to a mixture of 4-chloro-3-nitroquinoline (30 g, 144 mmol) and dichloromethane (150 mL). The reaction mixture was sparged with nitrogen. Triethylamine (21.8 g, 216 mmol) was added dropwise. The reaction mixture was cooled to 0° C. then a solution of 3,3-diethoxypropylamine (25.4 g, 173 mmol) in dichloromethane (50 mL) was added dropwise over a period of 15 minutes. The reaction mixture was stirred at room temperature for 3 hours. Dichloromethane and water (200 mL) were added. The layers were separated. The organic layer was washed with brine (×2). The combined aqueous layers were extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 45 g of N-(3,3-diethoxypropyl)-3-nitroquinolin-4-amine.
Reaction SMILES: [C:1](=[N:9][OH:10])(Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12][C:13]([CH3:15])=O.C(N(CC)CC)C.C(OCC)(=O)C>C(O)C.C(Cl)Cl>[CH3:18][O:17][C:11]([C:12]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][O:10][C:13]=1[CH3:15])=[O:16]
Reactant: ON=C(Cl)c1ccccc1
Reactant: COC(=O)CC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccccc2)noc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.7 %

Procedure:
An ethanol solution of freshly prepared benzoyl chloride oxime (14.0 g, 90 mmol) (100 mL) was added dropwise, at 5° C. to methyl acetoacetate (11.18 g, 96 mmol) and triethyl amine (13 mL, 103 mmol) in ethanol (50 ml) After stirring for 12 hr at ambient temperature, the solution was diluted with CH2Cl2, washed with 1N HCl. saturated NaHCO3, brine, dried over MgSO4 and evaporated to give amber oil. Flash chromatography (silica) with 10% ethyl acetate in hexanes afforded the title compound (7.56 g, 39% yield) as a white solid: MS m/z MH+218 (100); 1H NMR (CDCl3) δ 2.78 (s, 3H), 3.81 (s, 3H), 7.45–7.55 (m, 3H), 7.65–7.69 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:24])=[CH:4][C:3]=1[NH:25][C:26]([C:28]1([C:31]([O:33]CC2C=CC=CC=2)=[O:32])[CH2:30][CH2:29]1)=[O:27].CO.[H][H].[CH2:45]([N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[CH3:46]>O1CCCC1.[Pd]>[CH2:45]([N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[CH3:46].[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:24])=[CH:4][C:3]=1[NH:25][C:26]([C:28]1([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]1)=[O:27]
Reactant: [H][H]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)N1CC[C@H](O)C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Benzyl 1-[({2,5-difluoro-4-[(2-{[((S)-3-hydroxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylate (156.8 mg) was dissolved in tetrahydrofuran and methanol (1:1) (4 ml) under a nitrogen atmosphere. 10% palladium on carbon (60.4 mg) was added, and the air in the reaction vessel was replaced by hydrogen, and the mixture was stirred at room temperature for 19 hours. The air in the reaction vessel was replaced by nitrogen, and triethylamine (0.0991 ml) was added, and the mixture was stirred for 30 minutes. The catalyst was removed by filtration, and washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (174.9 mg, quant.) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>COCCOC.O.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>[CH:17]1([O:16][C:10]2[CH:15]=[CH:14][C:13]([C:2]3[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=3)=[CH:12][CH:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OB(O)c1ccc(OC2CCCCC2)cc1
Reactant: Nc1ncc(F)cc1Br
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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ncc(F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (54.5 mg) was added to a suspension of 3-bromo-5-fluoropyridin-2-amine (300 mg), 4-(cyclohexyloxy)phenylboronic acid (449 mg) and sodium carbonate (333 mg) in DME (15 mL) and water (3 mL) and the mixture was stirred at 100° C. under nitrogen for 2 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and washed with IPE to give the title compound (366 mg) as a yellow solid.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH:8]([O:21][CH3:22])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH:28]=[O:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.C1C=CC=CC=1.O>[CH3:22][O:21][CH:8]([O:7][CH3:6])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[C:10]=1[CH:28]([OH:29])[C:27]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=1
Reactant: COc1cc(C(OC)OC)cc(OC)c1OC
Reactant: COc1ccc(C=O)cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C(O)c2c(C(OC)OC)cc(OC)c(OC)c2OC)cc1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
136 ml of a 1.6M n-butyl lithium solution in hexane are added to a solution of 48.5 g of 3,4,5-trimethoxybenzaldehyde dimethyl acetal in 485 ml of benzene under stirring at 0° C. for about 20 minutes. The mixture is further stirred at 0° C. for 30 minutes, and 33.2 g of 3,4-dimethoxybenzaldehyde are added thereto. After stirring the mixture at 0° to 10° C. for 2 hours, 485 ml of water and 16 g of citric acid are added thereto. After shaking the mixture, the organic layer is separated therefrom, washed with water and evaporated under reduced pressure to remove solvent. 78.5 g of 2-(3,4-dimethoxy-α-hydroxybenzyl)-3,4,5-trimethoxybenzaldehyde dimethyl acetal are thereby obtained as a yellow oil.