Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:1]1[CH:2]=[C:3]([S:7]([O:21][C:15]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[O:13][CH3:12])(=[O:9])=[O:8])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1cc(C)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)ccc1OS(=O)(=O)c1cccc(C)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of m-toluenesulfonyl chloride (0.53 g, 2.78 mmol) and 2-methoxy-4-methylphenol (0.38 g, 2.75 mmol) in DCM (10 mL) was treated with triethylamine (0.5 mL, 3.6 mmol) and stirred at ambient temperature. After 18 hours the reaction was concentrated in vacuo, the residue dissolved in 1:1 hexane:DCM, filtered, and the filtrate evaporated under high vacuum giving the title compound as a white solid (0.79 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.72 (hr s, 1H), 7.66 (br d, 1H, J=7.2 Hz), 7.45 (br d, 1H, J=7.2 Hz), 7.38 (t, 1H, J=7.6 Hz), 7.00 (d, 1H, J=8.1 Hz), 6.67 (m, 1H), 3.54 (s, 3H), 2.42 (s, 3H), 2.31 (s, 3).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][N:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([O:14]C)=[O:13])[N:3]=1.C(Cl)Cl.C[N:20]([CH:22]=[O:23])C>O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:22]([C:2]1[C:10]2[C:5](=[N:6][N:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([OH:14])=[O:13])[N:3]=1)(=[O:23])[NH2:20]
Reactant: COC(=O)Cn1nc(I)c2ccnnc21
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1nn(CC(=O)O)c2nnccc12
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-(3-iodo-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetate (675 mg, 2.12 mmol) in DMF (7.5 mL) and water (1.5 mL) was added Zn(CN)2 (274 mg, 2.33 mmol), Pd2 dba3 (194 mg, 0.21 mmol) and PdCl2(dppf).CH2Cl2 adduct (173 mg, 0.21 mmol). The reaction mixture was stirred at 100° C. for 16 h. The resulting suspension was filtered and the filtrate was evaporated under vacuum. The residue was suspended in CH3CN/MeOH 1:1, the solid was filtered off and the filtrate was purified by preparative HPLC (Macherey Nagel, VP250/40, C18 Nucleosil 100-10, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give the title compound after lyophilisation. MS (LC/MS): 222.1 [M+H]+; tR (HPLC conditions c): 1.34 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[S:21]1[CH:25]=[C:24](B(O)O)[C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]1=2>>[S:21]1[CH:25]=[C:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]1=2
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1csc2ccccc12
Product: COc1ccc2c(-c3csc4ccccc34)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and benzo[b]thiophene-3-boronic acid to give (1-benzo[b]thiophen-3-yl-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 387(MH+).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:19])C=1.C(OO)(=O)C.C(Cl)(Cl)Cl>CCOCC.C(Cl)Cl>[O:19]1[CH:4]2[CH:3]1[CH2:2][O:1][C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=Cc2ccccc2OC1
Agent: CC(=O)OO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: c1ccc2c(c1)OCC1OC21
Temperature: 25 °C

Procedure:
The compound 5 is oxidized with an oxidizing agent such as m-chloroperbenzoic acid and peracetic acid in a solvent such as chloroform, methylene chloride and ether, under cooling to room temperature to give 3,4-epoxychroman (compound 6 wherein R1, R2 and R3 are as defined above).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH3:38][O:39][C:40]([C:42]1[N:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)=[O:41].C([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:33]([O:32][C:31]([NH:30][C:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:45]3[CH:44]=[CH:43][C:42]([C:40]([O:39][CH3:38])=[O:41])=[N:47][CH:46]=3)=[CH:25][CH:24]=2)[CH2:27][CH2:28][CH2:29]1)=[O:37])([CH3:35])([CH3:34])[CH3:36]
Reactant: COC(=O)c1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cn1
Reaction time: 17 h
Yield: 94 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.090 mmol), [6-(methoxycarbonyl)pyridin-3-yl]boronic acid (32 mg, 0.18 mmol), bis (di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6 mg, 0.09 mmol), and 2M Na2CO3 aq. (0.090 mL, 0.18 mmol) in DMF (2.5 mL) was treated with microwave (160° C. for 1 hour). The reaction mixture was added potassium carbonate (30 mg, 0.22 mmol) and iodomethane (0.050 mL, 0.80 mmol) and stirred at r.t for 17 hours. The mixture was diluted with AcOEt, washed with water(×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:3) to afford the desired product (52 mg, 95%) as a pale yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.83 (d, J=2.3 Hz, 1H), 8.15 (dd, J=7.4 Hz and 1.7 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 8.02 (d, J=4.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.34 (td, J=7.4 Hz and 1.7 Hz, 1H), 7.19-7.17 (m, 3H), 6.96 (d, J=8.0 Hz, 1H), 6.80 (d, J=7.4 Hz, 1H), 6.60 (dd, J=8.0 Hz and 4.6 Hz, 1H), 6.26 (s, 1H), 5.14 (br s, 1H), 3.99 (s, 3H), 2.59-2.53 (m, 2H), 2.51-2.42 (m, 2H), 2.20-2.12 (m, 1H), 1.96-1.88 (m, 1H), 1.40 (br s, 9H). LCMS: 615 [M+H].
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]21[C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=1)[O:12][CH:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=[O:36])=[N:33][CH:34]=1>>[NH2:9][C:5]1[CH2:6][O:7][CH2:8][C:2]([F:1])([F:26])[C@@:3]2([C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:35](=[O:36])[C:32]4[CH:31]=[CH:30][C:29]([C:28]([F:38])([F:27])[F:39])=[CH:34][N:33]=4)[CH:17]=3)[O:12][CH:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10]2)[N:4]=1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(N)cc32)C(F)(F)COC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Product: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(NC(=O)c4ccc(C(F)(F)F)cn4)cc32)C(F)(F)COC1
Yield: 7 %

Procedure:
The condensation of (2RS,4R)-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepine]-3′,6-diamine (intermediate C4.3) and 5-trifluoromethyl-pyridine-2-carboxylic acid yielded the title compound (7% yield) as a light brown solid. MS (ISP): m/z=532.8 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
1-tert-Butyloxycarbonyl-4-hydroxymethylpiperidine (2.8 g) was dissolved in dimethylformamide (10 ml), followed by stirring for 30 minutes. To the mixture was added p-fluoronitrobenzene (2.1 g), followed by stirring at room temperature overnight. Aqueous saturated solution of sodium bicarbonate was added to the mixture which was extracted with methylene chloride (50 ml×3). The combined organic layer was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue thus obtained was purified by silica gel column chromatography (developing solvent: hexane/ethylacetate=5/1 (v/v)) to obtain 1-tert-butyloxycarbonyl-4-[(4-nitrophenyloxy)methyl]piperidine (1.9 g) as pale yellow crystals, m.p. 130°-131° C.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH3:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1>CN1C(=O)CCC1.CCOCC>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:4][CH3:5])[C:14]#[N:15])=[CH:9][CH:8]=1
Reactant: CCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCC(C#N)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 51.2 %

Procedure:
A mixture of NaH (4.0 g, 99 mmol) in 50 mL NMP stirred at 0° C., was treated dropwise with a mixture of bromoethane (11 g, 99 mmol) and 2-(4-chlorophenyl)acetonitrile (15 g, 99 mmol) in 20 mL ether. The mixture was stirred at room temperature for 2 hours, cooled to 0° C., and quenched carefully with H2O. The resulting mixture was neutralized with 10% HCl to a pH of 5. The mixture was extracted with ether (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 5% EtOAc/hexane to give 9.1 g of the product as a pale yellow oil.
Reaction SMILES: [OH-].[K+].Cl.[CH:4]1([CH2:7][NH2:8])[CH2:6][CH2:5]1.Cl[CH2:10][C:11]1[N:15]2[C:16]3[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=3[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[N:19][CH2:20][C:14]2=[N:13][N:12]=1.[I-].[K+]>O1CCCC1>[CH:4]1([CH2:7][NH:8][CH2:10][C:11]2[N:15]3[C:16]4[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=4[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:19][CH2:20][C:14]3=[N:13][N:12]=2)[CH2:6][CH2:5]1
Reactant: ClCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Reactant: NCC1CC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccccc1C1=NCc2nnc(CNCC3CC3)n2-c2ccccc21

Procedure:
In the manner given in Example 3, a solution of potassium hydroxide and (cyclopropylmethyl)amine hydrochloride is treated with a solution of 1-(chloromethyl)-6-(o-chlorophenyl)-4-H-s-triazolo[4,3-a][1,4]benzodiazepine and potassium iodide in tetrahydrofuran to give 1-[[(cyclopropylmethyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][C:9]([Br:16])=[CH:8]2>[OH-].[Na+]>[Br:16][C:9]1[CH:10]=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][C:5]([CH2:4][C:3]([OH:17])=[O:2])=[C:14]([F:15])[CH:13]=2
Reactant: COC(=O)Cc1cc2cc(Br)cnc2cc1F
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1cc2cc(Br)cnc2cc1F
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A suspension of (3-bromo-7-fluoro-quinolin-6-yl)-acetic acid methyl ester (13.9 g, 46.6 mmol) in 72 mL of aqueous NaOH (2N) was heated to reflux for 2 hrs then cooled to r.t. The mixture was washed with dichloromethane (50 mL×2) and the aqueous phase acidified with 5N hydrochloric acid to pH 4. The white precipitate was collected via filtration, washed with water and dried. 11.0 g of the title compound was obtained as white powder in 83.3% yield. 1H NMR (DMSO-d6): δ 12.64 (s, 1H), 8.94˜8.95 (d, 1H), 8.72˜8.72 (m, 1H), 7.94˜7.97 (d, 1H), 7.77˜7.81 (d, 1H), 3.85 (s, 2H). LC-MS: 283.9 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:21]=[C:20]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[OH:23])[CH:19]=[CH:18][N:17]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:21]=[C:20]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[OH:23])[CH:19]=[CH:18][N:17]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(C(O)c2cccc(C(F)(F)F)c2)ccn1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCCCC2)cc1-c1cc(C(O)c2cccc(C(F)(F)F)c2)ccn1
Reaction time: 5 h
Yield: 0.9 %

Procedure:
A mixture of 123 mg of (2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridin-4-yl)(3-(trifluoromethyl)phenyl)methanol 5.2b, 30 mg of moist 10% Pd/C, and 3 mL of methanol was stirred under a hydrogen atmosphere for 5 h. The mixture was filtered and the solvent was evaporated to provide 1.05 mg of product. MS (ES, m/z) 428.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:7]=2[CH:6]=1)=[O:4].[Br:16]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([Br:16])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(OC)cccc2s1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2c(OC)ccc(Br)c2s1

Procedure:
The title compound was prepared as an off-white solid (m.p. 112° C.) according to the literature by treatment of 4-methoxy-benzo[b]thiophene-2-carboxylic acid methyl ester with bromine in chloroform at 0° C. to 20° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[O:9])=[N:6][CH:7]=1.Cl.[CH3:18][C:19]1([CH3:38])[C:23]([CH3:25])([CH3:24])[O:22][B:21]([C:26]2[CH:27]=[N:28][N:29]([C:31]3([CH2:35][C:36]#[N:37])[CH2:34][NH:33][CH2:32]3)[CH:30]=2)[O:20]1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:36]([CH2:35][C:31]1([N:29]2[CH:30]=[C:26]([B:21]3[O:22][C:23]([CH3:25])([CH3:24])[C:19]([CH3:38])([CH3:18])[O:20]3)[CH:27]=[N:28]2)[CH2:34][N:33]([C:2]2[N:3]=[CH:4][C:5]([C:8]([NH:10][C@@H:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[O:9])=[N:6][CH:7]=2)[CH2:32]1)#[N:37]
Reactant: CC1(C)OB(c2cnn(C3(CC#N)CNC3)c2)OC1(C)C
Reactant: C[C@H](NC(=O)c1cnc(Cl)cn1)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1)C(F)(F)F
Temperature: 100 °C
Yield: 97 %

Procedure:
A mixture of 5-chloro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide (254 mg, 1.00 mmol), {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (325 mg, 1.00 mmol) and N,N-diisopropylethylamine (401 μL, 2.30 mmol) in 1,4-dioxane (5.0 mL) was heated at 100° C. for 2 h. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (gradient: 20-80%) to afford the desired product (0.49 g, 97%). LCMS cacld. for C22H28BF3N7O3 (M+1)+: m/z=506.2. Found: 506.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:20]=[C:21]([C:22]([O:24]C)=[O:23])[C:4]=2[N:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:4]=2[N:3]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
A mixture of methyl 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxylate (170 mg, 0.41 mmol) and LiOH (172 mg, 4.1 mmol) in THF (15 mL) and water (10 mL), was stirred at 50° C. for 1 h. Then the pH of the reaction mixture was neutralized with 1N aq. HCl. Then the mixture was stirred at rt for 1 h, filtered to give the desired product (150 mg, 91%), as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.51 (s, 3H), 3.07 (t, 4H, J=4.8 Hz), 3.70 (t, 4H, J=4.8 Hz), 6.09 (s, 2H), 6.38 (d, 1H, J=7.8 Hz), 7.32-7.46 (m. 3H), 7.60-7.73 (m, 2H), 7.87 (d, 1H, J=7.8 Hz), 8.02 (d, 1H, J=8.4 Hz), 8.23 (d, 1H, J=8.1 Hz); LC-MS: m/e=402 [M+1]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Na+].[CH3:16][S:17]([O-:19])=[O:18]>CS(C)=O>[CH3:16][S:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: Oc1cnc(-c2ccc(Br)cc2)nc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-c2ncc(O)cn2)cc1
Yield: 24.5 %

Procedure:
2-[4-(Methylsulfonyl)phenyl]-5-pyrimidinol (0.19 g, 40%) was prepared as a light brown solid from 2-(4-bromophenyl)-pyrimidin-5-ol (0.50 g, 1.89 mmol), methanesulfinic acid sodium salt (0.73 g, 80%, 5.68 mmol) and Cul (1.08 g, 5.68 mmol) in DMSO (15 mL) in a manner similar to Example 83, Step 2. The crude product was purified by chromatography on a silica gel column eluted with 2:4:0.1 EtOAc/CH2Cl2/MeOH to give 0.116 g 2-[4-(methylsulfonyl)phenyl]-5-pyrimidinol as a light brown solid. Impure fractions were combined and further purified by chromatography on a silica gel column eluted with 2:6:0.1 EtOAc/CH2Cl2/MeOH to give additional 0.075 g of 2-[4-(methylsulfonyl)phenyl]-5-pyrimidinol as a light brown solid (40% yield overall). 1H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.60-8.40 (m, 4H), 8.00 (d, 2H, J=8.5 Hz), 3.23 (s, 3H); LRMS (ESI), m/z 251 (M+H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:34])[N:24]([CH2:31][CH2:32][CH3:33])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:20]=[C:19]([Cl:35])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:35][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH2:31][CH2:32][CH3:33])[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:34]
Reactant: CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCOCC1
Reaction time: 2 h

Procedure:
A solution of (2-{3-chloro-5-[propyl-(tetrahydro-pyran-4-yl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.070 g) in a mixture of dichloromethane (2 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.048 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: C([Li])CCC.[NH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:13][C:14]1[N:15]=[C:16](S(C)(=O)=O)[N:17]=[N:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:13][C:14]1[N:15]=[C:16]([NH:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:17]=[N:18][C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NN1CCCCC1
Reactant: Cc1nc(S(C)(=O)=O)nnc1-c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(NN2CCCCC2)nnc1-c1ccccc1
Reaction time: 2 h
Yield: 41.6 %

Procedure:
n-Butyllithium (25 g/250 ml solution in hexane) (28.5 ml) was added dropwise to a stirred solution of N-aminopiperidine (4.12 g) in tetrahydrofurane (40 ml) at -78° C. and the stirring was continued for 2 hours at room temperature. A solution of 5-methyl-3-methylsulfonyl-6-phenyl-1,2,4-triazine (5 g) in tetrahydrofuran (100 ml) was added dropwise to the above obtained solution at -78° C. in 70 minutes with stirring and the stirring was continued for 30 minutes at the same temperature. The reaction mixture was washed with water and brine, and then extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated. The resulting residue was dissolved in chloroform and extracted with an aqueous solution of 6N-hydrochloric acid. The extract was made alkaline with an aqueous solution of potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and evaporated. Thus obtained crude product (3.82 g) was purified by chromatography on silica gel (100 g) using a mixture of benzene and ethyl acetate (2:1) as an eluent and recrystallized from diisopropyl ether to give crystals of 5-methyl-6-phenyl-3-piperidinoamino-1,2,4-triazine (2.25 g).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C@@H:7]([C:20]2[O:21][C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH2:6]1)(=O)C.C[O-].[Na+].Cl>CC#N.CO>[C:25]1([C:23]2[N:24]=[C:20]([C@H:7]3[CH2:6][C@H:5]([OH:4])[CH2:9][N:8]3[C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[O:21][C:22]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)O[C@H]1C[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1C[C@@H](O)C[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of benzyl (2R, 4S)-4-acetoxy-2-(4,5-diphenyloxazol-2-yl)pyrrolidine-1-carboxylate (1.49 g) in MeCN (15 mL) was added 28% sodium methylate in MeOH (0.72 mL) at 5° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 1N HCl (3.8 mL) under ice-cooling, and extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogen carbonate solution, water and brine, dried (MgSO4), and evaporated in vacuo. The residue was purified by silica gal column chromatography (hexane-EtOAc, 1:3 elution) to give benzyl (2R, 4S)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate (980.8 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([O:21]C)=[O:20])[C:10]([S:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[C:10]([S:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCCSC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCSC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 65 h
Yield: 99.3 %

Procedure:
To a solution of 8.52 g (25.7 mmol) of N-tert-butoxycarbonyl-3-(4-pentenylthio)-L-valine, methyl ester in 200 mL of tetrahydrofuran at room temperature was added a solution of 1.10 g (26.2 mmol) of lithium hydroxide monohydrate in 50 mL of water. The resulting mixture was stirred at room temperature for 65 hours. To the reaction mixture then was added 28 mL of 1.00N hydrochloric acid. The mixture was diluted with diethyl ether, washed with water (3×) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 8.10 g of N-tert-butoxycarbonyl-3-(4-pentenylthio)-L-valine as a colorless oil. NMR (300 MHz, CDCl3): δ 5.75 (d of d of t, 1H, J=17.2, 10.3, 6.6 Hz), 5.40 (br s, 1H), 5.05-4.94 (m, 2H), 4.28 (br s, 1H), 2.56 (m, 2H), 2.13 (quart., 2H, J=7.3Hz), 1.63 (quint., 2H, J=7.3Hz), 1.44 (s, 9H), 1.39 (s, 3H), 3 H).