Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:20]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)NC2CC2)s1
Yield: 55 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (42 mg, 55%) which was obtained as a white solid. MS: m/e=373.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19])(=[O:12])=[O:11].[CH3:20]N(C)C=O.[OH-].[Na+].COS(OC)(=O)=O>O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH:9]([S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19])(=[O:12])=[O:11])[CH3:20]
Reactant: O=S(=O)(Cc1c(Cl)cccc1Cl)c1cccc[n+]1[O-]
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CC(c1c(Cl)cccc1Cl)S(=O)(=O)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
2-(2,6-Dichlorophenyl)methylsulfonyl pyridine 1-oxide* (1.75 g, 5.5 mmol) was added in one portion to a stirring solution of 20 mls of dimethylformamide containing 0.24 g of sodium hydroxide and 0.77 g of dimethylsulfate (6.1 mmol). The mixture was allowed to stir at room temperature for 1 h, then poured into 300 ml of rapidly stirring water whereupon a precipitate formed. The precipitate was filtered off, washed with water, and air dried to afford 1.38 g product, m.p. 179°-183° (74% yield).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12](OC)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)C.C(OCC)(=O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1csc(-c2ccccc2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCc1csc(-c2ccccc2)n1
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 86.2 %

Procedure:
In a 250 mL round-bottom flask, methyl 2-phenylthiazole-4-carboxylate (Example 3A, 1.50 g, 6.43 mmol) was dissolved in ethyl ether (40 mL). The solution was cooled down to −78° C. and treated with lithium aluminum hydride (0.75 g, 19.76 mmol) portionwise over 20 minutes. The reaction was stirred at −78° C. for 3.5 hours, then treated with 20 mL of a saturated solution of Na2SO4. The reaction was allowed to reach RT and was diluted with ethyl acetate, washed with HCl 1N (1×), brine (1×), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3×12 cm, 30% ethyl acetate/dichloromethane) to give a pale yellow oil (1.06 g) which was then distilled (bulb to bulb, bp: 110-120° C./0.2 torr) and provided the title material (0.88 g, 72%) as a clear oil. 1H NMR (CDCl3, 400 MHz): 7.95-7.90 (m, 2H) 7.45-7.40 (m, 3H) 7.16 (s, 1H) 4.82 (s, 2H) 2.34 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:8]=1.[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl-].[NH4+]>O1CCCC1>[CH:16]1([CH:12]([C:10]2[N:11]=[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:8][N:7]3[CH:9]=2)[OH:13])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=Cc1cn2cc(C(F)(F)F)ccc2n1
Reactant: Br[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1cn2cc(C(F)(F)F)ccc2n1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (2.1 g) synthesized above in tetrahydrofuran (40 mL) was added dropwise cyclohexylmagnesium bromide (1M tetrahydrofuran solution, 15 mL) at 0° C. After stirring at 0° C. for 1 hr, aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The precipitate was washed with ethanol-diisopropyl ether to give the title object compound (0.9 g, 30%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7](OC)[CH:6]=[CH:5]2.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([NH:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:6]=[CH:5]2
Reactant: NC1CCCCC1
Reactant: COc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(NC2CCCCC2)ccc2cc(Br)ccc12
Temperature: 120 °C
Reaction time: 17 h
Yield: 84 %

Procedure:
A solution of 6-bromo-2-methoxy-1-nitronaphthalene (10.0 g, 35.6 mmol) and 8 ml of cyclohexylamine in 50 ml of dry N,N-dimethylformamide was heated with stirring at 120° C. for 17 h. The mixture was evaporated to dryness and the residue was triturated with 50 ml of ethanol at 0° C.. The solid was isolated by filtration and washed with light petroleum to give 10.4 g (84%) of 6-bromo-2-cyclohexylamino-1-nitronaphthalene. The crude product was suspended in 150 ml of 96% ethanol and hydrogenated at room temperature and 40 psi over Ni/Raney After the hydrogen uptake was completed, the reaction mixture was filtered into 50 ml of 4M hydrochloric acid and concentrated to dryness. Crude 1-amino-6-bromo-2-cyclohexylaminonaphthalene hydrochloride (9.8 g, 27.6 mmol) was taken up in 80 ml of dry tetrahydrofuran. Dry triethylamine (7.7 ml, 55.3 mmol) was added, followed by the dropwise addition of ethyloxalyl chloride (3.1 ml, 27.7 mmol) with stirring at 0° C.. The mixture was stirred over night at room temperature and finally at reflux for 4 h. The cooled mixture was filtered and the solid was washed with water and ethanol affording 5.2 g (51%) of the title compound M.p. 347.0° C. (N,N-dimethylformamide, DSC); IR (KBr): 1700 cm-1 ; 1H-NMR (DMSO-d6): 1.13-2.93 (m, 10H, 5CH2), 4.33-4.90 (m, 1H, NCH), 7.47-8.67 (m, 5H, ArH), 12.1 (broad s, 1H, NH); MS (m/z): 372 (M+, 17%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.Cl.[CH3:8][O:9][C:10](=[O:15])[C@H:11]([CH2:13][OH:14])[NH2:12].C([O-])(O)=O.[Na+]>C1COCC1>[O:6]=[C:2]([CH3:1])[CH2:3][C:4]([NH:12][C@H:11]([C:10]([O:9][CH3:8])=[O:15])[CH2:13][OH:14])=[O:5]
Reactant: COC(=O)[C@@H](N)CO
Reactant: C=C1CC(=O)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CO)NC(=O)CC(C)=O
Temperature: 25 °C
Yield: 81 %

Procedure:
10.8 g (0.13 mol) of diketene, 20 g L-serine methyl ester hydrochloride (0.13 mol) and 21.6 g (0.26 mol, 2 eq) of NaHCO3 were mixed in 1000 ml of THF at 0° C. Then the ice bath was removed and it was stirred further at room temperature. After 24 h stirring at room temperature, the reaction mixture was filtered and the residue was recrystallized from 100 ml of ethyl acetate. This gave 21.14 g (0.10 mol, 81% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]1=[O:17].Br[C:19]1[N:23]([CH:24]2[CH2:26][CH2:25]2)[C:22]2[CH:27]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)[N:28]([C:31]3[CH:36]=[C:35]([Cl:37])[C:34](=[O:38])[N:33]([CH3:39])[CH:32]=3)[C:29](=[O:30])[C:21]=2[CH:20]=1.C(Cl)Cl.CO.N>>[Cl:37][C:35]1[C:34](=[O:38])[N:33]([CH3:39])[CH:32]=[C:31]([N:28]2[C:29](=[O:30])[C:21]3[CH:20]=[C:19]([C:5]4[CH:6]=[CH:7][N:2]([CH3:1])[C:3](=[O:17])[CH:4]=4)[N:23]([CH:24]4[CH2:26][CH2:25]4)[C:22]=3[CH:27]2[C:40]2[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=2)[CH:36]=1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)cc1=O
Reactant: Cn1cc(N2C(=O)c3cc(Br)n(C4CC4)c3C2c2ccc(Cl)cc2)cc(Cl)c1=O
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Cn1ccc(-c2cc3c(n2C2CC2)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)cc1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 240 but using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (Step 242.1) and 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chlorophenyl)-1-cyclopropyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (Step 250.1). tR: 0.83 min (LC-MS 6); ESI-MS: 521.2/523.2 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH/NH3 94:5:1): Rf=0.18; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.35-0.450 (m, 1 H) 0.74-0.84 (m, 2 H) 1.12-1.25 (m, 1 H) 3.06-3.18 (m, 1 H) 3.41 (s, 3 H) 3.37 (s, 3 H) 6.30 (s, 1 H) 6.47 (dd, J=7.04, 1.95 Hz, 1 H) 6.52-6.61 (m, 1 H) 6.71 (s, 1 H) 7.30 (m, J=8.21 Hz, 2 H) 7.38 (m, J=8.60 Hz, 2 H) 7.62 (d, J=7.04 Hz, 1 H) 7.80-7.95 (m, 2 H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[N:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:44][C:45]1[CH:46]=[C:47]([NH2:56])[C:48]2[CH:49]=[N:50][N:51]([CH2:54][CH3:55])[C:52]=2[CH:53]=1>CN(C=O)C>[Br:44][C:45]1[CH:53]=[C:52]2[C:48]([CH:49]=[N:50][N:51]2[CH2:54][CH3:55])=[C:47]([NH:56][C:17]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:10])[N:16]=2)=[O:19])[CH:46]=1
Reactant: CCn1ncc2c(N)cc(Br)cc21
Reactant: Cc1cccc(C(=O)O)n1
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: CCn1ncc2c(NC(=O)c3cccc(C)n3)cc(Br)cc21
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
DIPEA (0.161 ml, 0.93 mmol) was added to 6-methyl-2-pyridinecarboxylic acid (available from Fluorochem, 51 mg, 0.37 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (174 mg, 0.46 mmol) in DMF (3 ml). The reaction was stirred for 30 mins under nitrogen then 6-bromo-1-ethyl-1H-indazol-4-amine (100 mg, 0.42 mmol) was added and the reaction was stirred overnight. The solvent was evaporated and water (5 ml) was added before extraction into DCM (2×20 ml). The compound was loaded onto an aminopropyl cartridge (20 g), eluted with 10% MeOH in DCM and evaporated to dryness. The residue was purified by silica chromatography, eluting with 0-50% ethyl acetate in DCM over 60 mins. Appropriate fractions were evaporated to give the title compound (107 mg).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([NH2:16])=O)=[N:6]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C1COCC1>[C:14]([C:7]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]([CH2:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[F:1])[N:6]=1)#[N:16]
Reactant: NC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: N#Cc1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
36.1 g (133 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide from Example 3A are dissolved in 330 ml of THF, and 27 g (341 mmol) of pyridine are added. Then, over the course of 10 minutes, 47.76 ml (71.66 g, 341 mmol) of trifluoroacetic anhydride are added, during which the temperature rises to 40° C. The mixture is stirred at room temperature overnight. It is then added to 1 l of water and extracted three times with 0.5 l of ethyl acetate each time. The organic phase is washed with saturated sodium bicarbonate solution and with 1N hydrochloric acid, dried with magnesium sulphate and concentrated in a rotary evaporator.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])[CH3:2]
Reactant: CCOC(=O)/C=C/c1cccc(C(=O)O)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of (E)-3-(3-ethoxy-3-oxoprop-1-en-1-yl)benzoic acid (8.60 g) in ethanol (500 mL) was added 10% palladium-activated carbon (4.10 g) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 3 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (8.70 g) as a white amorphous solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:2]2[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=2)[CH2:30][CH2:31]1)[CH3:19]
Reactant: CCc1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-ethyl-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 4-[4-(2-ethyl-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=412.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[C:22]([O:30][C@H:31]([C@@H:34]([C@@H:44]([CH2:54][O:55][C:56](=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[O:45][C:46](=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[O:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)C=O)(=O)C1C=CC=CC=1.[Pb].[Ar].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C.CCOCC.CCOC(C)=O.CCOC(C)=O.CCCCCCC>[C:36]([O:35][C@@H:34]1[C@H:44]([O:45][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@H:54]([O:55][C:56](=[O:63])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:22][O:30][C@H:31]1[N:12]1[CH:13]=[C:8]([CH2:7][CH2:6][N:5]2[C:4](=[O:16])[C:3]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]3[C:1]2=[O:21])[C:9](=[O:15])[NH:10][C:11]1=[O:14])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c(=O)[nH]c1=O
Reactant: O=C[C@H](OC(=O)c1ccccc1)[C@H](OC(=O)c1ccccc1)[C@@H](COC(=O)c1ccccc1)OC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Ar]
Agent: [Pb]
Solvent: CC#N
Solvent: CCCCCCC
Solvent: CCOCC
Product: O=C(O[C@@H]1[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)CO[C@H]1n1cc(CCN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1=O)c1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
7.00 g (24 mmol) of 32 and 13.6 g (24 mmol) of 33 were suspended in 120 ml of acetonitrile in a 250 ml three-necked flask, equipped with an argon lead-in, internal thermometer and septum. Firstly 12.2 ml (50 mmol) of BSA and, after stirring for 30 min, a further 7 ml (28 mmol) of BSA were then added by means of syringe. After heating to 40° C. for a short time, the reaction mixture clarified. 13 ml (72 mmol) of TMSOTf were added by means of syringe at room temp. After one hour, no product formation was yet observed (TLC checking, AcOEt/n-heptane 1:1). A further 13 ml (72 mmol) of TMSOTf were therefore added. Subsequently, the reaction mixture was heated to 50° C. After stirring at 50° C. for 2.5 h (TLC checking), the mixture was cooled to RT., [lacuna] onto an ice-cold mixture of 250 ml of AcOEt and 190 ml of satd. NaHCO3 solution and intensively extracted by stirring for 10 min. It was again washed with 100 ml of NaHCO3 solution and the aqueous phases were again extracted with 100 ml of AcOEt. The dil. org. phases were dried using MgSO4 and the solvents were removed in vacuo in a rotary evaporator. After drying in an oil pump vacuum, 20.9 g of crude product were obtained. Chromatography on silica gel (h=25 cm, f=5 cm, AcOEt/n-heptane 1:1) yielded a TLC-uniform, foamy product, which was digested using Et2O. Filtration and drying in an oil pump vacuum afforded 15 g (86%) of 34.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][C:8](OC)=O)[C:3](OC)=O.[NH2:12][C@H:13]([CH3:16])[CH2:14][OH:15]>>[CH3:1][C@H:2]1[CH2:7][CH2:8][N:12]([C@H:13]([CH3:16])[CH2:14][OH:15])[CH2:3]1
Reactant: COC(=O)C[C@H](C)C(=O)OC
Reactant: C[C@@H](N)CO
Product: C[C@H]1CCN([C@H](C)CO)C1

Procedure:
The title compound was synthesized as described in Intermediate 11 using (S)-dimethyl 2-methylsuccinate and (R)-2-aminopropan-1-ol as starting materials. 1H NMR (CDCl3): δ 3.60 (dd, 1H), 3.58 (br s, 1H), 3.40 (dd, 1H), 2.89 (dd, 1H), 2.72 (m, 2H), 2.63 (m, 1H), 2.24 (m, 1H), 2.17 (dd, 1H), 2.00 (m, 1H), 1.35 (m, 1H), 1.04 (m, 6H); MS: 144.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17]C3CCCCO3)[CH:14]=[C:15]([F:16])[C:7]1=2)[CH3:2].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([F:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(F)c21
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(F)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of ethyl-2-(4-fluoro-1-hydroxy-6-(tetrahydro-2H-pyran-2-yloxy)-1,3-dihydro benzo[c][1,2]oxaborol-3-yl)acetate (0.34 g, 1.0 mmol) in THF (10 mL) was added dropwise concentrated hydrochloride acid (0.2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and quenched by addition of sat. aqueous NaHCO3 (20 mL). The resulting mixture was extracted with EtOAc(2×30 mL). The combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/PE=1/4) to give the title compound as a light yellow solid (180 mg, Yield: 70.9%). 1H NMR (400 MHz, DMSO-d) δ 9.93 (s, 1H), 9.40 (s, 1H), 6.94-6.94 (d, J=1.6 Hz, 1H), 6.65-6.68 (m, 1H), 5.49-5.52 (m, 1H), 4.00-4.08 (m, 2H), 2.94-2.99 (m, 1H), 2.38-2.44 (m, 1H), 1.13-1.20 (m, 3H). MS (ESI) m/z=255 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc(OC[C@H](CC3CCCCC3)NC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](COc1ccc(-c2ccc(C(=O)O)cc2)cc1)CC1CCCCC1
Yield: 81.7 %

Procedure:
A solution of methyl (S)-4-[4-[2-(tert-butoxycarbonylamino)-3-cyclohexylpropyloxy]phenyl]benzoate (0.28 g) in a mixed solvent of methanol (14 ml) and tetrahydrofuran (3 ml) was treated with 1N-sodium hydroxide aqueous solution, and the mixture was refluxed for 16 hours. After cooling, water was added to the mixture, and the acidity of the mixture was adjusted to pH 1 with 1N-hydrochloric acid. The resulting precipitate was filtered, washed with water and dried under reduced pressure to give (S)-4-[4-[2-(tert-butoxycarbonylamino)-3-cyclohexylpropyloxy]phenyl]benzoic acid (222 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@H:12]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13]([NH2:15])=[O:14].CCN(C(C)C)C(C)C.O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:15])=[O:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NC(=O)[C@H](N)CC1CCCCC1
Reactant: N#Cc1ccc(F)cc1Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N[C@H](CC2CCCCC2)C(N)=O)cc1Br
Yield: 63.4 %

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile (200 mg, 1.00 mmol), (R)-2-amino-3-cyclohexylpropanamide (280 mg, 1.64 mmol) and DIEA (0.500 mL, 2.87 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with 0-70% EtOAc in hexane to give (R)-2-(3-bromo-4-cyanophenylamino)-3-cyclohexylpropanamide (222 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[C:27]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])(=[O:29])[CH3:28]
Reactant: COc1ccc(CO)cc1C(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(C)=O)cc1C(=O)OCc1ccccc1
Yield: 99 %

Procedure:
Next, benzyl 5-hydroxymethyl-2-methoxybenzoate and 100 ml of methylene chloride were mixed and, after pyridine (660 ml, 8.16 mmol), acetic anhydride (460 ml, 4.88 mmol) and N,N-dimethylaminopyridine (25 mg, 0.205 mmol) were added under stirring and cooling with ice, the mixture was stirred overnight. The reaction mixture was washed with 1 mol/l hydrochloric acid, aqueous solution of sodium hydrogencarbonate and brine, then dried over anhydrous sodium sulfate and concentrated to obtain 1.27 g (99%) of the title compound as a colorless oil.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][CH:8]=[C:7](C(C)(C)C)[C:6]=1[OH:15])(C)(C)C.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>S(=O)(=O)(O)O>[CH:10]1[C:9]([C:19]2[CH:20]=[CH:21][C:16]([OH:22])=[CH:17][CH:18]=2)=[CH:8][CH:7]=[C:6]([OH:15])[CH:5]=1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Product: Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
A starting material which was a mixture of 3,3',5,5'-tetra-t-butyl-4,4'-diphenoquinone (1.0 g) and 2,6-di-t-butylphenol (1.0 g) was subjected to reaction at 180° C. for 1 hour in a nitrogen gas atmosphere using 10 ml of phenol as a solvent and 0.05 g of sulfuric acid as a catalyst. p,p'-biphenol was produced in an amount of 0.49 g (yield, 54.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([NH2:39])[CH:37]=2)[CH:32]=[N:31]1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:39][C:36]3[CH:37]=[C:38]4[C:33]([CH:32]=[N:31][NH:30]4)=[CH:34][CH:35]=3)=[O:23])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Reactant: Nc1ccc2cn[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc5cn[nH]c5c4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a mixture of 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (82 mg, 0.2 mmol) and 1H-indazol-6-amine (27 mg, 0.2 mmol) in 5 mL of DCM was added EDCI (80 mg, 0.6 mmol) followed by N-methylimidazole (50 mg, 0.6 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc to give 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(1H-indazol-6-yl)benzamide (30 mg, 28%) as white solid. 1H NMR (300 MHz, DMSO): δ 12.96 (s, 1H), 10.57 (s, 1H), 10.15 (s, 1H), 9.42 (s, 1H), 8.99 (s, 1H), 8.63 (d, 1H, J=8.1 Hz), 8.33 (s, 1H), 8.12 (d, 1H, J=7.8 Hz), 8.03 (s, 1H), 7.87 (s, 1H), 7.76-7.70 (m, 2H), 7.57 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 7.45 (dd, 1H, J1=8.7 Hz, J2=1.5 Hz), 7.01 (d, 1H, J=9.0 Hz), 3.84 (s, 3H), 3.74 (s, 3H). LC-MS: 524 [M+H]+, tR=1.52 min. HPLC: 97.61% at 214 nm, 97.19% at 254 nm, tR=4.75 min.