Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(F)(F)F.[CH2:23](O)C=C>C(N(CC)CC)C>[CH2:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[CH:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])[CH:1]=[CH2:23]
Reactant: C=CCO
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CCN(CC)CC
Product: C=CCOCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
Using the procedure of Step A of Example 8, 27.2 g of 7-amino-cephalosporanic acid, 170 ml of the etherate of boron trifluoride, 136 ml of allyl alcohol and 115 ml of triethylamine were reacted and the 9 g of raw product was purified successively twice with hot hydrochloric acid and ammonium hydroxide to obtain 4.72 g of 3-allyloxymethyl-7-amino-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH2:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH:19][S:30]([CH3:29])(=[O:32])=[O:31])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](NS(C)(=O)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 575.9 %

Procedure:
A solution of 39 (0.10 g, 0.26 mmol), methanesulfonyl chloride (0.08 mL, 1.03 mmol), NEt3 (0.04 mL, 0.28 mmol) and a catalytic amount of DMAP in CH2Cl2 (50 mL) was stirred at room temperature for 2 h. The mixture was washed with 2N HCl (30 mL), 2N NaOH (30 mL), and H2O (30 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a crude solid. The crude solid was purified by column chromatography (eluent: 2% MeOH/CH2Cl2) to afford 0.7 g (56%) of 42 as a white crystalline solid, mp 262-265° C. (EtOAc/n-hexanes); 1H NMR (CDCl3); δ 1.09 (3H, s); 1.46 (3H, s); 1.60 (3H, m); 1.79 (1H, dd, J=2.7, 9.6); 2.07 (2H, m); 2.18 (1H, m); 2.21 (1H, s); 2.50 (2H, m); 2.75 (1H, dd, J=3.6, 13.2); 2.99 (3H, s); 3.72 (3H, s); 4.15 (1H, m); 5.34 (1H, d, J=5.4); 5.55 (1H, dd, J=5.1, 11.4); 6.38 (1H, dd, J=0.9, 1.2); 7.41 (1H, dd, J=1.5, 1.8); 7.43 (1H, dd, J=0.9, 1.5).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[CH:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>C1COCC1.C(Cl)Cl>[C:30]1([C:27]2[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=2)[CH:31]=[CH:32][C:33]([NH:36][C:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:11]2)=[O:38])=[CH:34][CH:35]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-biphenyl isocyanate: ESMS m/e: 513.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([B:8]([C:20]2[C:25]([F:26])=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:21]=2[F:30])[C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[C:6]([F:31])[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34].CCOCC.[F:40][C:41]1[C:46]([Li:47])=[C:45]([F:48])[C:44]([F:49])=[C:43]([F:50])[C:42]=1[F:51]>CCCCCC>[F:26][C:25]1[C:20]([B-:8]([C:46]2[C:45]([F:48])=[C:44]([F:49])[C:43]([F:50])=[C:42]([F:51])[C:41]=2[F:40])([C:7]2[C:2]([F:1])=[C:3]([F:34])[C:4]([F:33])=[C:5]([F:32])[C:6]=2[F:31])[C:9]2[C:10]([F:19])=[C:11]([F:18])[C:12]([F:17])=[C:13]([F:16])[C:14]=2[F:15])=[C:21]([F:30])[C:22]([F:29])=[C:23]([F:28])[C:24]=1[F:27].[Li+:47]
Reactant: [Li]c1c(F)c(F)c(F)c(F)c1F
Reactant: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: CCOCC
Solvent: CCCCCC
Product: Fc1c(F)c(F)c([B-](c2c(F)c(F)c(F)c(F)c2F)(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Product: [Li+]

Procedure:
The obtained tris(pentafluorophenyl)boron (41 mmol) was reacted with an ether solution of pentafluorophenyllithium (41 mmol) in hexane, to isolate lithium tetrakis(pentafluorophenyl)borate as a white solid product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][F:28].O>C(Cl)(Cl)Cl>[F:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1
Reactant: FCCCBr
Reactant: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: FCCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.1 %

Procedure:
673 mg (corresponding to 2.0 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 25 mL of N,N-dimethylformamide, and 831 mg (corresponding to 6.0 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 275 μL (corresponding to 3.0 mmol) of 1-bromo-3-fluoropropane, and then stirred at room temperature for 24 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: chloroform), and further by recycle preparative HPLC(HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 349 mg (corresponding to 0.881 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 1-5, Step 3).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]1([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][C:23](O)([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])=[CH:28][C:27]=3[F:43])[CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[C:10]1([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][C:23]([F:7])([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])=[CH:28][C:27]=3[F:43])[CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(C2(F)CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethylaminosulfur trifluoride (DAST, 0.65 mL) in dry methylene chloride (49 mL) at −78° C. under N2 is added a solution of 4-hydroxy-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step 1, 2.25 g) in dry methylene chloride (47 mL) over 2 mins. The resulting mixture is stirred at −78° C. for 1 hr and at ambient temperature for 30 mins and is then adjusted to pH 8 with saturated aqueous sodium bicarbonate (50 mL), diluted with water (50 mL), and the layers are separated. The organic phase is washed with water (25 mL) and saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on silica gel (230-400 mesh, 150 g), eluting with methanol/methylene chloride (0.5/99.5). Those fractions with an Rf=0.27 by TLC (ethyl acetate/hexane, 25/75) are pooled and concentrated to give the title compound (contaminated with approx. 15% of the elimination side product). An analytical sample is prepared by radial chromatography (1000 m silica gel rotor, ethyl acetate/hexane (20/80) eluent), mp 116-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:10]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[S:11][CH:12]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:11][CH:12]=2)=[C:4]([O:27][CH3:28])[CH:3]=1
Reactant: CCOC(=O)CCc1scc(-c2ccc(Cl)cc2OC)c1-c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(Cl)ccc1-c1csc(CCC(=O)O)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a solution of ethyl 3-(4-(4-chloro-2-methoxyphenyl)-3-(4-hydroxyphenyl)thiophen-2-yl)propanoate (220 mg, 0.53 mmol) in EtOH (5 mL) was added NaOH (42 mg, 1.06 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water, neutralized to pH=4-5, extracted with EtOAc, and concentrated to give 3-(4-(4-chloro-2-methoxyphenyl)-3-(4-hydroxyphenyl)thiophen-2-yl)propanoic acid (Scheme II, 12, X1=4-hydroxyphenyl, X2=4-chloro-2-methoxyphenyl) (127.42 mg, yield 62%). 1H NMR (DMSO-d6 400 MHz): δ 9.36 (br, 1H), 7.25 (s, 1H), 7.01 (d, J 8.0 Hz, 1H), 6.91-6.88 (m, 2H), 6.79 (d, J=8.4 Hz, 2H), 6.64 (d, J=8.4 Hz, 2H), 3.40 (s, 3H), 2.92 (t, J=7.2 Hz, 2H), 2.47 (t, J=7.2 Hz, 2H); MS (ESI): m/z [M+1]+=389.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH:12]1[N:16]=[CH:15][N:14]([C:17](N2C=NC=C2)=[O:18])[CH:13]=1.CNC(NC)=[S:27]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[N:14]([CH3:13])[C:15](=[S:27])[N:16]([CH3:12])[C:10]1=[O:11]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CNC(=S)NC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1c(=S)n(C)c(=O)n(-c2ccc(F)cc2F)c1=O
Temperature: 62.5 °C
Reaction time: 3 h

Procedure:
31 g of 2,4-difluorophenyl isocyanate and 64.9 g of carbodiimidazole were added in succession to 20.8 g of N,N′-dimethylthiourea in 500 ml of toluene and 1 ml of triethylamine. This mixture was stirred first for 3 hours at 60-65° C. and then for 12 hours at 80-85° C. After cooling to room temperature, the mixture was washed three times with 100-ml-portions of water, and the organic phase was dried over sodium sulfate. After distillation of the low-boiling fractions, 48 g of the desired product of melting point 156-159° C. remained.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:12]([C:22](=O)[CH3:23])=[CH:13][C:14]([F:21])=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO.C(#N)C>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:12]([CH:22]([NH2:31])[CH3:23])=[CH:13][C:14]([F:21])=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1cc(F)c2cccnc2c1N1CCN(C2CCC2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(F)c2cccnc2c1N1CCN(C2CCC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[8-(4-cyclobutylpiperazin-1-yl)-5-fluoroquinolin-7-yl]ethanone (16 mg, 0.049 mmol) and ammonium acetate (37.7 mg, 0.489 mmol) in methanol (0.27 mL) and acetonitrile (0.28 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (6 mg, 0.01 mmol) was added. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C19H26FN4 (M+H)+: m/z=329.2; Found: 329.2.
Reaction SMILES: [CH2:1]([C@@:5]1([CH2:24][CH3:25])[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]>CCCCCC.CCOC(C)=O>[CH2:1]([C@@:5]1([CH2:24][CH3:25])[NH:11][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@]1(CC)CSc2cc(OC)ccc2C(c2ccccc2)=N1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCC[C@]1(CC)CSc2cc(OC)ccc2[C@@H](c2ccccc2)N1
Yield: 41.7 %

Procedure:
This compound was prepared following the procedure of Synthetic Example 1(n), using the product (54.4 g) from step (e). Chromatography on silica gel, using hexane:EtOAc (9:1) as eluant, gave the title product (22.8 g) as an orange oil. 1H NMR consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[Cl:10][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: OB(O)c1ccccc1F
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: Nc1c(F)cc(-c2ccccc2F)cc1Cl
Yield: 74.4 %

Procedure:
The title compound (0.392 g) was prepared from 4-bromo-2-chloro-6-fluoroaniline (0.5 g, 2.2 mmol) and 2-fluorophenylboronic acid (0.363 g, 2.6 mmol) as a pale-yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.51 (td, J 1.7, 7.8, 1H), 7.38-7.32 (m, 1H), 7.28 (s, 2H), 7.27-7.22 (m, 2H), 5.62 (s, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:17]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:28](Cl)=[O:29])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:10]=1.Cl>O1CCCC1.O>[OH:3][NH:2][C:28](=[O:29])[CH:27]=[CH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17](=[O:19])(=[O:18])[NH:16][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:21]=1
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.31 g, 4.40 mmol) in tetrahydrofuran (5 ml) a saturated NaHCO3 solution (6.8 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-{3-[(pyridin-3-ylmethyl)-sulfamoyl]-phenyl}-acryloyl chloride (16b) (0.29 g, 0.86 mmol) in tetrahydrofuran (5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into water, the obtained solution was acidified with 2N HCl to pH˜5 of the reaction medium and extracted with ethyl acetate. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was washed with hot ethyl acetate and methanol affording the title compound (0.12 g, 37%). M.p. 191° C. 1H NMR (DMSO-d6, HMDSO) δ: 4.05 (2H, d, J=6.4 Hz); 6.56 (1H, d, J=16.0 Hz); 7.16-8.05 (7H, m); 8.16-8.49 (3H, m); 9.12 (1H, br s); 10.80 (1H, br s). HPLC analysis on Symmetry C18 column: impurities 8% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 10:90; sample concentration 0.4 mg/ml; flow rate 1.3 ml/min; detector UV 270 nm). Anal. Calcd for C15H15N3O4S containing 0.5% of inorganic impurities, %: C, 53.77; H, 4.51; N, 12.54. Found, %: C, 53.72; H, 4.33; N, 12.41.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:27](O)=[O:28])[C:14]3[C:19]([CH3:20])=[N:18][N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:15]=3[N:16]=2)=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][NH:49][C@H:48]([CH2:52][C:53]([F:56])([F:55])[F:54])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl.O>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:27]([C:13]2[C:14]3[C:19]([CH3:20])=[N:18][N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:15]=3[N:16]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=3)[CH:12]=2)=[O:28])[C@H:48]([CH2:52][C:53]([F:55])([F:56])[F:54])[CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CC(F)(F)F)C1
Reactant: COCOc1ccc(-c2cc(C(=O)O)c3c(C)nn(C4CCCCO4)c3n2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(-c2cc(C(=O)N3CCN(C(=O)OC(C)(C)C)C[C@H]3CC(F)(F)F)c3c(C)nn(C4CCCCO4)c3n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48 %

Procedure:
To a suspension of 0.80 g of 6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid in 12 ml of DCM were added 1 ml of Hünig's base, 0.48 g of BEP and 0.50 g of (R)-3-(2,2,2-trifluoroethyl)-piperazine-1-carboxylic acid tert-butyl ester. The reaction was stirred at r.t. for 2 d. For workup it was diluted with water and DCM and the layers were separated. The organic layer was washed with water twice, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 0.58 g (60%) of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:10]=[C:11]([C:15](OC)=[O:16])[CH:12]=[N:13][CH:14]=1)[CH3:8]>C1COCC1>[CH2:7]([C:9]1[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[N:13][CH:14]=1)[CH3:8]
Reactant: CCc1cncc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cncc(CO)c1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a suspension of LAH (1.92 g, 50.85 mmol) in anhydrous THF 40 mL at 0° C. was added dropwise a solution of methyl 5-ethylpyridine-3-carboxylate (4.20 g, 25.42 mmol) in THF (50 mL). After stirring for 1 hour, the reaction mixture was slowly quenched with 15% NaOH and then diluted with water. Ethyl acetate was added, the reaction mixture was stirred for 10 minutes, and the precipitate was filtered off. The solid was washed with ethyl acetate (3×100 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, and evaporated to provide (5-ethylpyridin-3-yl)methanol as a thick oil (3.31 g, 95% yield), which was used in the next step without any further purification; M+137.18.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([OH:11])([CH2:8][CH:9]=[CH2:10])[CH2:5][CH:6]=[CH2:7].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][CH2:2][CH2:3][C:4]([OH:11])([CH2:8][CH:9]=[CH2:10])[CH2:5][CH:6]=[CH2:7])[CH3:20])=[CH:15][CH:14]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: C=CCC(O)(CC=C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(O)(CC=C)CCN[C@@H](C)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-(2-chloro-ethyl)-hepta-1,6-dien-4-ol (7.87 g), (S)-1-(4-bromo-phenyl)-ethylamine (13.52 g), K2CO3 (9.34 g), KI (8.23 g), and acetonitrile (150 mL) is stirred at reflux temperature overnight. After cooling to room temperature, the mixture is concentrated under reduced pressure and water is added to the residue. The resulting mixture is extracted with ethyl acetate (3×), and the combined extracts are washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→0:1) to afford the title compound as an oil. Yield: 8.36 g (55% of theory); Mass spectrum (ESI+): m/z=338/340 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([NH:19][C@H:20]([C:23]4[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[N:26]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:24]=4)[CH2:21][CH3:22])=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CN.C1COCC1.C[CH2:49][N:50](C(C)C)C(C)C>CN(C=O)C.[Cl-].[NH4+]>[CH3:32][S:29]([C:27]1[CH:28]=[C:23]([C@@H:20]([NH:19][C:17]([C:16]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[O:18])[CH2:21][CH3:22])[CH:24]=[C:25]([NH:50][CH3:49])[N:26]=1)(=[O:30])=[O:31]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cc(OS(=O)(=O)C(F)(F)F)nc(S(C)(=O)=O)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cc(NC)nc(S(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
To a stirred solution of trifluoromethanesulfonic acid 4-((S)-1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-6-methanesulfonyl-pyridin-2-yl ester (0.08 g, 0.13 mmol) in DMF (2 mL) was added a 2.0 M solution of methylamine in THF (0.150 mL, 0.30 mmol) followed by DIPEA (0.05 mL, 0.3 mmol). After 16 hours, the mixture was diluted with saturated aqueous ammonium chloride (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulfate and concentrated onto silica gel. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([N+:11]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[NH4+:14].[OH-]>CCO.CCOC(C)=O.C(O)(=O)C.[Zn]>[NH2:14][C:8]1[C:7]([NH2:11])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: N#Cc1cc([N+](=O)[O-])c(F)cc1F
Reactant: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)c(N)cc1F
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-difluoro-5-nitrobenzonitrile (CAS #: 67152-20-9) (5.0 g, 27.2 mmol) in EtOH (100 mL) was added NH4OH (100 mL) slowly at room temperature. The mixture was stirred for 30 min, then concentrated under reduced pressure to about 100 mL. The yellow product was filtered and washed with water, and then dried. To a solution of the residue (3.96 g, 22 mmol) in EtOAc (150 mL) and acetic acid (25 mL) was added zinc (14.3 g, 219 mmol). The mixture was stirred at room temperature for 2 hour. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite®. The Celite® pad was washed with EtOAc. The filtrate was concentrated, and the residue was dissolved in MeOH (50 mL) and NH4OH (100 mL). The mixture was then concentrated to around 100 mL and the mixture was left standing at room temperature overnight. The precipitate was filtered and washed with water, and then dried to give the title compound. MS (ESI+) m/z 152.1 (M+H).
Reaction SMILES: OC1C=CC=C2C=1N=CC=C2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19].[OH:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31](O)=O)[CH:27]=[CH:26]2.O=O.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[S:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:31]1[C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[C:21]([OH:20])[CH:22]=[CH:23][CH:24]=2)[N:29]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)c1ccc2cccc(O)c2n1
Agent: O=O
Agent: Oc1cccc2cccnc12
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: Oc1cccc2ccc(-c3nc4ccccc4s3)nc12
Temperature: 40 °C

Procedure:
To introduce a benzo[d]thiazol group into an 8-hydroxyquinoline compound, 2-aminothiophenol (123 mg, 1.1 mmol) and 8-hydroxyquinoline-2-carboxylic acid (189 mg, 2 mmol) were dissolved in dry toluene (30 ml) with blown nitrogen to prevent oxidation which is caused by oxygen in air. The solution was heated to 40° C. and phosphorus trichloride (0.1 ml, 1.1 mmol) was slowly added thereto. Then, the reaction solution was heated at 100° C. for 24 hours and allowed to cool. The reaction mixture was extracted with a 20% aqueous sodium carbonate solution, distilled water and dichloromethane, dried and recrystallized with dichloromethane and hexane to yield 2-(benzo[d]thiazol-2-yl)quinolin-8-ol, the compound of Formula 1 as a light green solid (yield: 75%).