Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:14]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>O.CS(C)=O>[NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1ccc(C(=O)O)c(N)n1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)c1ccc(N)nc1N
Yield: 73.8 %

Procedure:
2,6-Diaminonicotinic acid (1.5 g), WSC (2.8 g), HOBt (2.0 g), ammonium chloride (1.6 g), diisopropylethylamine (7.6 g), and DMSO (45 mL) were stirred for 15 hours at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was concentrated and purified by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol=4:1). The organic layer thus obtained was concentrated and purified by NH silica gel column chromatography (ethyl acetate). Ethyl acetate and hexane were added to the residue thus obtained, and the solids were filtered off to obtain the titled compound (1.1 g).
Reaction SMILES: N[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[C:11]([CH2:13][N:14]2[C:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]4=[O:33])=[N:24][CH:25]=3)=[CH:17][N:16]=[CH:15]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[CH2:34]=O.[BH3-][C:37]#[N:38].[Na+].[OH-].[Na+]>C1COCC1>[Cl:32][C:30]1[CH:29]=[CH:28][C:27](=[O:33])[N:26]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C:18]3[N:14]([CH2:13][C:11]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:4][CH2:3][CH2:2][N:38]([CH3:37])[CH3:34])[CH:12]=4)[CH:15]=[N:16][CH:17]=3)=[CH:25][N:24]=2)[CH:31]=1
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCN
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)CCOc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2-Amino-ethoxy)-4-[5-(5-chloro-2-oxo-2H-[1,2']bipyridinyl-5'-ylmethyl)-imidazol-1-ylmethyl]-benzonitrile (L-824,459, 43 mg, 0.09 mmol) was dissolved in THF (1 mL) and CH2O (37% wt. in H2O, 14 μl, 0.18 mmol) was added. The solution was treated with NaCNBH3 (11.7 mg, 0.18 mmol) and the reaction mixture stirred at room temperature for 2 hours. 10% aqueous NaOH was added to the mixture and extracted with CH2Cl2. The water layer was extracted with CH2Cl2 (2×10 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated. Flash chromatography [8% MeOH(NH4OH 5%)/CH2Cl2 ] yielded the final product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]=O.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C1(C)C=CC=CC=1.O>[O:12]1[CH2:13][CH2:14][N:9]([CH:7]=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]1
Reactant: O=CCc1cccs1
Reactant: C1COCCN1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C(=CN1CCOCC1)c1cccs1

Procedure:
A mixture of 1.5 g of 2-thienylacetaldehyde, 1.4 mL of morpholine, and 0.012 g of p-toluenesulfonic acid hydrate in 7.5 mL of toluene is heated at reflux under a Dean-Stark Trap with azeotropic removal of water for 3 hours. The solution is cooled, neutralized by the addition of solid sodium methoxide, and concentrated in vacuo. The residue is taken up in toluene, filtered, and concentrated in vacuo to afford the desired enamine as an oil.
Reaction SMILES: C(O[C:6]([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)C)=O)(C)(C)C.[Cl:29]C1C2C(S(Cl)(=O)=O)=CC=CC=2C=NC=1.C(OC(N(C1CCNC1)C)=O)(C)(C)C.BrC1C2C(S(Cl)(=O)=O)=CC=CC=2C=NC=1.C(OC(N([C@H]1CCNC1)C)=O)(C)(C)C>>[Cl:28][C:20]1[C:19]2[C:18]([S:15]([N:12]3[CH2:13][CH2:14][CH:10]([NH:8][CH3:6])[CH2:11]3)(=[O:16])=[O:17])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:23]=[N:22][CH:21]=1.[ClH:29]
Reactant: O=S(=O)(Cl)c1cccc2cncc(Cl)c12
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Agent: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Agent: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Product: CNC1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Product: Cl

Procedure:
3-[N-(tert-Butoxycarbonyl)-N-methylamino]-1-(4-chloro-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 21) can be prepared by using 4-chloro-5-isoquinolinesulfonyl chloride and 3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example 1-3, Step A instead of 4-bromo-5-isoquinolinesulfonyl chloride and (S)-3-[N-(tert-butoxycarbonyl)-N-methyl-amino]pyrrolidine, respectively, and then used in the method of Example 1-3, Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](Cl)(=[O:13])[C:10]([Cl:12])=[O:11]>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:9](=[O:13])[C:10]([Cl:12])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CN(C(=O)C(=O)Cl)c1ccccc1
Reaction time: 1 h
Yield: 86.8 %

Procedure:
N-methylaniline (1.0 g) was dissolved in toluene (10 mL). Under cooling with ice, oxalyl chloride (4.07 mL) was added thereto, and the temperature of the mixture was lowered to room temperature, followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, to thereby give the title compound (1.06 g, 86.8%) as a brown oil. The compound was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2C(=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)NC=[C:5]2[CH:14]([CH3:16])[CH3:15].I[CH3:18].[H-].[Na+].[CH3:21][N:22]([CH:24]=O)[CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:23](=[C:9]([C:11]([O:13][CH3:18])=[O:12])[CH:10]=1)[N:22]([CH3:21])[CH:24]=[C:5]2[CH:14]([CH3:16])[CH3:15]
Reactant: CI
Reactant: CN(C)C=O
Reactant: CC(C)c1c[nH]c2c(C(=O)O)cc(Br)cc12
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)cc2c(C(C)C)cn(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a stirred solution of 5-bromo-3-(1-methylethyl)-1H-indole-7-carboxylic acid (15 g, 53.2 mmol) in DMF (100 mL) at 0° C. was added iodomethane (13.25 mL, 212.7 mmol) followed by sodium hydride (2.8 g, 122.3 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo to dryness. The residue was diluted with water and ethyl acetate. The organic layer was separated and dried, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: 8% EtOAC in pet. ether) to afford methyl 5-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylate (10.58 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, 6H, J=6.4 Hz), 3.10-3.19 (m, 1H), 3.74 (s, 3H), 3.92 (s, 3H), 7.22 (s, 1H), 7.58 (s, 1H), 7.95 (s, 1H). MS (ES)+m/e 310.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[N:22]=[C:23]([CH:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]5)[NH:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:41](OC(N1CCC(C2NC(C3C=C(C=CC=3C)C(O)=O)=C(C)N=2)(C)CC1)=O)(C)(C)C.C(OC(N1CCC(C2NC(C3C=C(C=CC=3C)C(O)=O)=C(C)N=2)CC1)=O)(C)(C)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[NH:22][C:23]([C:27]5([CH3:41])[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:29][CH2:28]5)=[N:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2(C)CCN(C(=O)OC(C)(C)C)CC2)nc1C
Agent: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(C)CCN(C(=O)OC(C)(C)C)CC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 182.3, except 3-(2-(1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 185.2) was used in place of 3-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 182.2).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])O)O)=O.CN1[C:18](=[O:19])[CH2:17]CC1.C(OC(=O)C)(=O)C>CN(C1C=CN=CC=1)C.O>[C:18]([O:12][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1)(=[O:19])[CH3:17]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CN1CCCC1=O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OCc1ccc(C=O)o1
Temperature: 110 °C

Procedure:
39.4 kg (219 mol) of D-fructose and 5.9 kg of dried acidic Dowex® 50WX8-200 ion exchanger (styrene-divinylbenzene copolymer resin with SO3H groups, obtainable from The Dow Chemical Company, Midland, U.S.A.) in the H form were introduced with stirring into 90 l of NMP and heated to 110° C. for 6 h. After cooling, the reaction mixture was filtered and washed with 8 l of NMP. The filtrate was admixed with stirring with 390 g (3.2 mol) of 4-(N,N-dimethylamino)pyridine and 20.5 1 (217 mol) of acetic anhydride at 20-25° C. within 1 h. After continuing the reaction for 1 h, the brown reaction mixture was freed of the solvent at 90-100° C. under reduced pressure (of 50-10 mbar). After cooling, the residue was admixed with 160 l of MtBE, 60 1 of water and 4 kg of activated carbon. The suspension was filtered though Celite®. After the phase separation, the solvent of the filtrate was distilled off at 50° C. under reduced pressure (20 mbar) and the residue was fractionally distilled under reduced pressure at 106-110° C./5 mbar.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[O:4][N:3]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1[NH2:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:22][C:21]1[C:16]([NH:15][C:10]([C:7]2([C:5]3[O:4][N:3]=[C:2]([CH3:1])[CH:6]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:17][CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:20]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: Cc1cc(C2(C(=O)O)CC2)on1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2(C(=O)Nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3N)CC2)on1
Temperature: 40 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
1-(3-Methylisoxazol-5-yl)cyclopropanecarboxylic acid (40 mg, 0.24 mmol), (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (86 mg, 0.24 mmol), and diisopropylethylamine (200 μL, 1.2 mmol) were combined and dissolved in N,N-dimethylformamide (1.25 mL). O-Benzotriazole-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HBTU) (109 mg, 0.287 mmol) was added and the reaction mixture was stirred at 40° C. for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. A saturated aqueous solution of sodium bicarbonate was added. The organics were collected and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-12% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridine-3-yl)-1-(3-methylisoxazol-5-yl)cyclopropanecarboxamide (56 mg, 53%). MS (ES+) (M+H) 439.2; LCMS retention time 1.94 min (Method L).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10].[OH-].[Li+]>C1COCC1.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cccc(-c2nccs2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2nccs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
Preparation H11, Step 4: A solution of 0.6 g (0.0027 mol) of methyl 3-(thiazol-2-yl)benzoate in 6 ml of THF and 1.2 ml of water was charged with 0.11 g (0.0046 mol) of lithium hydroxide. The reaction mixture was stirred at RT overnight. THF was removed and the aqueous layer was washed with ether and acidified with 1.5 N HCl. The solid product was extracted with ethyl acetate. The organic layer was washed with brine and concentrated to afford 3-(thiazol-2-yl)benzoic acid (0.4 g) as an off white solid obtained. 1H NMR (400 MHz, CDCl3): 7.45 (d, 1H), 7.63 (m, 1H), 8.0 (d, 1H), 8.22 (d, 1H), 8.30 (d, 1H), 8.79 (s, 1H). MS found: (M−H)−=204.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([N:18]([C:20]4[CH:25]=[CH:24][N:23]=[C:22](Cl)[N:21]=4)[CH3:19])=[CH:17][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:29][S:30]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([N:18]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:38][C:37]5[CH:39]=[CH:40][C:34]([CH2:33][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:35][CH:36]=5)[N:21]=4)[CH3:19])=[CH:17][C:10]=3[N:9]=2)=[CH:27][CH:28]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccc(Cl)cc1)n2C)c1ccnc(Cl)n1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Product: CN(c1ccc2c(c1)nc(NCc1ccc(Cl)cc1)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N2-(4-Chloro-benzyl)-N5-(2-chloro-pyrimidin-4-yl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (103 mg, 0.25 mmol) and 4-[(methylsulfonyl)methyl]aniline (46 mg, 0.25 mmol) as a white solid (61 mg, 41%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.20 (s, 1H), 7.76-7.80 (m, 3H), 7.36-7.43 (m, 5H), 7.24 (d, J=8.1 Hz, 2H), 7.08 (d, J=1.8 Hz, 1H), 6.85 (dd, J=8.1 and 1.8 Hz, 1H), 5.63 (d, J=6.0 Hz, 1H), 4.58 (d, J=5.7 Hz, 2H), 4.34 (s, 2H), 3.58 (s, 3H), 3.43 (s, 3H), 2.85 (s, 3H). MS (ESI) m/z=562 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([Li])CCC.[B:30](OC(C)C)([O:35]C(C)C)[O:31]C(C)C.Cl>CCOCC.CCCCCC.C1(C)C=CC=CC=1>[C:15]1([N:8]([C:5]2[CH:4]=[CH:3][C:2]([B:30]([OH:35])[OH:31])=[CH:7][CH:6]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Under an ambient atmosphere of argon gas, cooling a solution prepared by mixing 18.7 g of N-(4-bromophenyl)-N-phenyl-1-naphthylamine, 100 milliliter of dried ethyl ether and 100 milliliter of dried toluene down to a temperature of −78° C., a hexane solution of 1.6M normal butyllithium in an amount 32.8 milliliter was dripped into the cooled solution. The reacted solution was stirred for 1 hour while warming up to a temperature of 0° C. Cooling the reacted solution down to the temperature of −78° C. again, a solution prepared by dissolving 23.5 g of boric acid triisopropyl into dried ether in an amount of 50 milliliter was dripped down to the cooled solution. The resultant solution was further stirred at a room temperature for 5 hours. Adding 100 milliliter of 1 N hydrochloric acid and after stirring the resultant solution for 1 hour, a water layer was removed. After drying an organic layer with a use of magnesium sulfate, the solvent was distillated away under a reduced pressure. Refining a resultant solid by means of a silicagel column chromatography, 10.2 g of 4-(N-1-naphthyl-N-phenylamino)phenylboronic acid was obtained.
Reaction SMILES: [CH2:1]1[O:23][C:4]2([CH2:9][CH2:8][C:7](O)([C:10]3[C:19]4[O:18][CH2:17][CH2:16][O:15][C:14]=4[C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.C[Si]([C:28]#[N:29])(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]1[O:23][C:4]2([CH2:9][CH2:8][C:7]([C:28]#[N:29])([C:10]3[C:19]4[O:18][CH2:17][CH2:16][O:15][C:14]=4[C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: COc1ccc(C2(O)CCC3(CC2)OCCO3)c2c1OCCO2
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2(C#N)CCC3(CC2)OCCO3)c2c1OCCO2
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
To a solution of Compound 2a (0.49 g, 1.5 mmol) obtained in Step A in dichloromethane (4.9 mL), trimethylsilyl cyanide (0.26 mL, 1.9 mmol) was added at −78° C., then boron trifluoride-ethyl ether complex (0.20 mL, 1.6 mmol) was added dropwise, and the mixture was stirred for 10 minutes, followed by stirring at room temperature for 10 minutes. A saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=2/1) to give Compound 2 (0.30 g, 61%)as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:19]1[C:20]2[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[S:25][C:21]=2[N:22]=[CH:23][N:24]=1>O1CCCC1>[CH3:30][CH:28]([C:26]1[S:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([O:1][CH:2]3[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]3)[C:20]=2[CH:27]=1)[CH3:29]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: CC(C)c1cc2c(Cl)ncnc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(OC3CCC(NC(=O)OC(C)(C)C)CC3)ncnc2s1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (3.3 g, 15.33 mmol, 1.10 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of sodium hydride (800 mg, 33.33 mmol, 2.36 equiv) in portions at 0-5° C. The resulting solution was stirred for 2.5 h at room temperature. To this was added a solution of commercially available 4-chloro-6-(propan-2-yl)thieno[2,3-d]pyrimidine (3.0 g, 14.10 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) at 5-10° C. The resulting solution was stirred overnight at room temperature. The reaction mixture was cooled to 5-10° C. with a water/ice bath. The reaction was then quenched by the addition of 100 mL of water. The resulting mixture was concentrated under vacuum. The solids were collected by filtration. This resulted in 4.8 g (87%) of tert-butyl N-(4-[[6-(propan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]cyclohexyl)carbamate as a yellow solid. MS: m/z 392 (M+H)+.
Reaction SMILES: O1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[CH2:27]([SH:31])[CH2:28][CH2:29][SH:30].B(F)(F)F>>[S:30]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2][S:31][CH2:27][CH2:28][CH2:29]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: SCCCS
Agent: FB(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CSCCCS4)c(F)c2)C(=O)O1

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.3 mmol) with 1,3-propanedithiol (0.330 mmol), BF3.etherate (catalytic) in tetrahydrofuran (10 ml) at 70-80° C. for 14 hours followed by silica gel column chromatographic purification to provide title compound in 50% yield.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.C([NH:14][C:15](=[CH2:20])[C:16]([O:18][CH3:19])=[O:17])(=O)C>>[Cl:10][C:7]1[CH:6]=[C:3]2[C:2]([CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[N:14]=[CH:4]2)=[CH:9][CH:8]=1
Reactant: O=Cc1cc(Cl)ccc1Br
Reactant: C=C(NC(C)=O)C(=O)OC
Product: COC(=O)c1cc2ccc(Cl)cc2cn1
Yield: 25 %

Procedure:
methyl 7-chloro-isoquinoline-3-carboxylate was prepared using the procedure described in example 12A: 2-bromo-5-chlorobenzaldehyde was reacted with methyl 2-acetamidoacrylate at 110° C. for 24 hours to yield methyl 7-chloro-isoquinoline-3-carboxylate (25%) as brown solid.
Reaction SMILES: [I:1]I.[CH2:3]([N:7]([CH2:14][CH2:15][CH2:16][CH3:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH3:6].C([O-])(O)=O.[Na+].CCOCC>O>[I:1][C:11]1[CH:12]=[CH:13][C:8]([N:7]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][CH:10]=1
Reactant: CCCCN(CCCC)c1ccccc1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCCCN(CCCC)c1ccc(I)cc1
Temperature: 12.5 °C
Yield: 70.7 %

Procedure:
Iodine (7.88 g, 31 mmol) was added portionwise to a mixture of N,N-dibutylaniline (7 g, 34 mmol) and NaHCO3 (2.87 g, 34 mmol) in water (25 mL) with stirring at 10-15° C. After 1 h the mixture was poured into Et2O (200 mL), washed with water (100 mL), Na2S2O3 (2×100 mL), water (2×100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using hexane as eluent. The first fraction was collected and the solvent removed under reduced pressure to give the title compound (7.26 g, 71%) as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][CH:24]=[CH:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[S:23][CH:24]=[CH:25][C:16]=12
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: N#Cc1cnc2sccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3sccc23)c(Cl)cc1Cl
Yield: 21.4 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (300 mg, 1.57 mmol) and 60% sodium hydride (70 mg, 1.75 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 30 minutes The solution is cooled and 4-chlorothieno[2,3-b]pyridine-5-carbonitrile (150 mg, 0.8 mmol) [Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14, 807 (1977)] is added. The reaction mixture is heated at reflux for 3.5 hours. The resultant black solution is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2:3 ethyl acetate:hexane. The fractions containing product are combined and concentrated. Diethyl ether is added and the insoluble material is collected by filtration to provide 60 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[2,3-b]pyridine-5-carbonitrile as a tan solid, mp 197-199° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.38 (s, 1H), 7.68 (d, J=5.7 Hz, 1H), 7.76 (s, 1H), 7.81 (d, J=5.7 Hz, 1H), 8.43 (s, 1H), 9.80 (s, 1H); MS 348.2 (M−H)−.