Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[Si](C)(C)C.C(OC([NH:16][C@@H:17]([CH3:46])[CH2:18][NH:19][C:20]1[N:21]([CH2:42][C:43]#[C:44][CH3:45])[C:22]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[N:39]=[C:38]([CH3:40])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[N:25]=[CH:24][C:23]=2[N:41]=1)=O)C1C=CC=CC=1.[CH3:47]O>ClCCl>[NH2:16][C@@H:17]([CH3:46])[CH2:18][N:19]([C:20]1[N:21]([CH2:42][C:43]#[C:44][CH3:45])[C:22]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[N:39]=[C:38]([CH3:40])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[N:25]=[CH:24][C:23]=2[N:41]=1)[CH3:47]
Reactant: CO
Reactant: CC#CCn1c(NC[C@H](C)NC(=O)OCc2ccccc2)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CC#CCn1c(N(C)C[C@H](C)N)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 μl iodotrimethylsilane are added to a solution of 130 mg (S)-2-[(2-benzyloxycarbonylamino-prop-1-yl)amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 3 ml dichloromethane. After stirring at ambient temperature for 1 and 3 h, a further 100 μl of iodotrimethylsilane are added on each occasion. The solution is stirred for a further 4 h at ambient temperature and then combined with 5 ml of methanol and evaporated down. Then 1 M hydrochloric acid is added and the aqueous phase is washed twice with dichloromethane. The aqueous phase is made alkaline with sodium carbonate and extracted three times with dichloromethane. The organic extracts are dried over sodium sulphate, the solvent is removed and the residue is purified through silica gel (dichloromethane/methanol 1:0−>3:1).
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH3:26])[C:10](=[O:27])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:28][C:29]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:30]=1[CH:31]=O>C(O)(=O)C>[OH:28][C:29]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:30]=1/[CH:31]=[CH:1]/[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH3:26])[C:10](=[O:27])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc(O)ccc1O
Reactant: Cc1cc(C#Cc2ccccc2)ccc1-n1c(C)nc2ccccc2c1=O
Solvent: CC(=O)O
Product: Cc1cc(C#Cc2ccccc2)ccc1-n1c(/C=C/c2cc(O)ccc2O)nc2ccccc2c1=O
Reaction time: 8 h

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with ethynyl benzene (25a, 102 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 2-methyl-4-(phenylethynyl)benzenamine compounds (26a) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 2-methyl-4-(phenylethynyl)benzenamine (26a, 207 mg, 1 mmol) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a). Reaction of 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a, 350 mg, 1 mmol) with 2,5-dihydroxy benzaldehyde (30c, 138 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (4c) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[CH:20]=2)=[CH:8][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH2:19][CH2:18][CH2:17][CH2:16][N:15]4[CH:20]=3)=[CH:8][CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: ClCCCOc1ccc(-c2cn3c(n2)CCCC3)cc1
Product: c1cc(-c2cn3c(n2)CCCC3)ccc1OCCCN1CCCCC1
Temperature: 25 °C

Procedure:
The product of Step B (83 mg) and piperidine (1.0 mL) were heated at 100° C. for 1.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (2×10 mL) and the organic portions combined and washed with brine (10 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (35 mg). 1H-NMR (CDCl3) δ 7.61 (m, 2H), 7.16 (s, 1H), 6.92 (m, 2H), 4.01 (m, 4H), 2.84 (t, J=6.0 Hz, 2H), 2.72 (m, 6H), 2.00 (m, 6H), 1.68 (m, 4H), 1.56 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2([C:39]([F:42])([F:41])[F:40])[O:28][N:27]=[C:26]([C:29]3[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[C:31]([CH3:38])[CH:30]=3)[CH2:25]2)[CH:20]=[C:21]([Cl:23])[CH:22]=1>ClCCl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([C:26]3[CH2:25][C:24]([C:19]4[CH:20]=[C:21]([Cl:23])[CH:22]=[C:17]([Cl:16])[CH:18]=4)([C:39]([F:42])([F:41])[F:40])[O:28][N:27]=3)=[CH:30][C:31]=2[CH3:38])=[N:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(N)nc1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ccc(C#N)cn1
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In a solution of 0.39 g of 2-amino-5-cyanopyridine and 0.71 g of pyridine in 20 mL of dichloromethane, a solution of 1.31 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 in 20 mL of dichloromethane was added dropwise. After the completion of the addition dropwise, it was continued to stir at the same temperature further for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, precipitated insoluble material was removed through silica gel column, and the solvent was distilled off under reduced pressure. The residual solid was washed with diisopropyl ether to obtain 1.11 g of the aimed product as colorless resinous substance.
Reaction SMILES: [C:1]([C:4]1[C:5]([F:25])=[C:6]([N:10]([CH2:22][O:23][CH3:24])[S:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:26][Si:27](OS(C(F)(F)F)(=O)=O)([CH3:29])[CH3:28]>C(Cl)Cl>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[S:11]([N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([O:3][Si:27]([CH3:29])([CH3:28])[CH3:26])=[CH2:2])[C:5]=1[F:25])[CH2:22][O:23][CH3:24])(=[O:13])=[O:12]
Reactant: COCN(c1cccc(C(C)=O)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C)c1cccc(N(COC)S(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
100 mg (0.27 mmol) of N-(3-acetyl-2-fluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide were dissolved in 4 mL of dry DCM under nitrogen atmosphere. The solution was cooled to 0° C. and 94 μL (0.65 mmol) of TEA and 106 μL (0.54 mmol) of trimethylsilyl-trifluoromethansulfonate were added. The solution was stirred 15 min at the same temperature and then diluted with DCM and washed rapidly with brine. The organic layer was dried over Na2SO4 and evaporated giving 2,5-difluoro-N-(2-fluoro-3-{1-[(trimethylsilyl)oxy]ethenyl}phenyl)-N-(methoxymethyl)benzenesulfonamide as a clear oil. The latter was re-dissolved in 4 mL of dry DCM under nitrogen atmosphere and 58 mg (0.32 mmol) of N-bromosuccinimide were added at 0° C. After 30 min the reaction was complete. The mixture was diluted with DCM and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated to give the title compound, which was used without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([BH3-])#N.[Na+].CC(O)=O>CO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)=[CH:10][C:3]=1[O:2][CH3:1])#[N:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(CC=O)ccc1C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Reaction time: 0.17 h

Procedure:
2-(Methyloxy)-4-(2-oxoethyl)benzonitrile (200 mg, 1.142 mmol), tert-butyl piperazine-1-carboxylate (532 mg, 2.85 mmol), and SODIUM CYANOBOROHYDRIDE (717 mg, 11.4 mmol) were combined in a 50 mL Flask and dissolved in MeOH. The resulting mixture was then stirred for 10 minutes followed by addition of few drops of AcOH. The mixture was stirred for overnight. The reaction mixture was concentrated to dryness, re-dissolved in EtOAc and washed with saturated NaHCO3 solution, brine, and the organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue purified by MPLC to yield the title compound. LC-MS (IE, m/z): 346 [M+1]+;
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[Br:15])([CH3:7])[CH3:6]>C(O)(=O)C>[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[C:10]([CH3:14])[C:9]=1[Br:15])([CH3:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C(C)C)c1Br
Solvent: CC(=O)O
Product: Cc1c([N+](=O)[O-])ccc(C(C)C)c1Br
Temperature: 90 °C

Procedure:
Nitric acid (30 mL, fuming) is added slowly to an ice-cold solution of 2-isopropyl-6-methyl-bromobenzene (10 g, 213 mmol) in acetic acid (60 mL). The mixture is heated 1 h at 90° C. and cooled to room temperature. The reaction mixture is poured into 200 mL ice-water and extracted with CH2Cl2 (3×60 mL). The combined extracts are washed with 1 N NaOH (3×40 mL) and then water (40 mL), dried (Na2SO4), and concentrated to yield crude 2-isopropyl-6-methyl-5-nitro-bromobenzene which is dissolved in AcOH (75 mL)/EtOH (75 mL). To this is added Fe power (5.3 g, 95 mmol) and the mixture is refluxed for 2 h. The mixture is cooled to room temperature, diluted with water, and neutralized with solid Na2CO3. The mixture is extracted with EtOAc, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 3-bromo-4-isopropyl-2-methyl-aniline. A solution of NaNO2 (798 mg, 12 mmol) in H2O (10 mL) is added dropwise at 0° C. to a slurry of 3-bromo-4-isopropyl-2-methyl-aniline (2.4 g, 11 mmol) in HBF4 (15 mL)-H2O (15 mL), and the mixture is stirred for 1 h at 0° C. The resulting solid is filtered, washed with cold water and then Et2O, and dried under reduced pressure to yield the diazonium salt as a beige solid. The diazonium salt is added in one portion to mixture of KOAc (1.5 g, 15 mmol) and 18-C-6 (98 mg, 0.37 mmol) in ethanol-free CHCl3 (70 mL) at room temperature. The mixture is stirred for 1 h and the resulting solid is removed by filtration. The filtrate is washed with water, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 4:1) to yield 4-bromo-5-isopropyl-1H-indazole. 1H NMR (CDCl3) 8.03 (br s, 1H), 7.41 (d, 1H), 7.35 (d, 1H), 3.55 (m, 1H), 1.24 (d, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])[CH3:2].C(N1CCOCC1)C.[CH3:26][C:27]([CH3:32])([CH3:31])[C:28](Cl)=[O:29]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH:11][C:28](=[O:29])[C:27]([CH3:32])([CH3:31])[CH3:26])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Reactant: CC(C)(C)C(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(NC(=O)C(C)(C)C)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
3 g (12.97 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 100 ml of THF, 1.6 ml (1.49 g, 12.97 mmol, 1 eq) of N-ethylmorpholine and 1.56 f (12.97 mmol, 1 eq) of trimethylacetylchloride are added and the resulting mixture is stirred overnight at RT. The solvent is removed in vacuo and the crude material obtained (3.8 g, Yield: 93%) is used in the following steps without further purification.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([O:16][CH3:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:29][N:30](C)[C:31](C1CN(C)C(=O)C=1O)=O>>[CH3:17][O:16][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:6]([C:5]1[CH2:29][N:30]([CH3:31])[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccccc1C)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1ccccc1C)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 61 %

Procedure:
2-Hydroxy-3-[methoxy-(2-methylbenzyl)-carbamoyl]-acrylic acid methyl ester (Compound 56-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (61% yield); mp 153–154° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.39 (3H, s, CH3), 3.13 (3H, s, NCH3), 3.67 (3H, s, OCH3), 4.19 (2H, s, NCH2), 4.95 (2H, s, NCH2), 7.2–7.3 (4H, m, aromatics), 11.7 (1H, broad s, OH). Anal. calcd for C15H18N2O4: C, 62.05; H, 6.24; N, 9.65. Found: C, 61.79; H, 6.30; N, 9.58.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:16])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[C:9]2[CH3:15])[CH:2]=[CH2:3].[C:17]([O-])(=[O:19])[CH3:18].[Na+].C(OC(=O)C)(=O)C>O>[C:17]([O:16][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[C:13]2[C:8]([C:9]([CH3:15])=[CH:10][C:11](=[O:14])[O:12]2)=[CH:7][CH:6]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: C=CCc1c(O)ccc2c(C)cc(=O)oc12
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C=CCc1c(OC(C)=O)ccc2c(C)cc(=O)oc12
Reaction time: 4 h
Yield: 94 %

Procedure:
A solution of 8-allyl-7-hydroxy-4-methylcoumarin (61.0 g, 0.282 mol) and a few pinches of anhydrous sodium acetate in boiling acetic anhydride (480 ml.) was allowed to relux for four hours with magnetic stirring. The cooled brown mixture was then poured into water (1750 ml.) with magnetic stirring. The mixture was allowed to stir for half an hour. A brown precipitate was collected by filtration, washed with water, and dried in vacuo to obtain 7-acetoxy-4-methyl-8-allylcoumarin (68.5 g. 94% yield), mp. 98.8°-99.8° C. (lit.2 87°-87.5° C.).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([CH:9]=[CH:10][CH2:11]Cl)=[N:5][CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:11][CH:10]=[CH:9][C:4]3[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Cc1cccnc1C=CCCl
Reactant: Nc1nc2c(s1)CCNCC2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1cccnc1C=CCN1CCc2nc(N)sc2CC1
Yield: 45 %

Procedure:
Prepared from 3-(3-methyl-2-pyridyl)allyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 45% of theory, Melting point: 188°-190° C. (ether).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]1[CH:21]=[C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([NH:33][C@H:34]4[CH2:39][NH:38][C@H:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)=[O:32])[CH:29]=3)[NH:24][N:23]=2)[CH:19]=[CH:18][N:17]=1.[F:44][C:45]1[CH:52]=[CH:51][CH:50]=[C:49]([O:53][CH3:54])[C:46]=1[CH:47]=O>CO>[F:44][C:45]1[CH:52]=[CH:51][CH:50]=[C:49]([O:53][CH3:54])[C:46]=1[CH2:47][N:38]1[CH2:39][C@H:34]([NH:33][C:31]([C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[C:20]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:15])[CH:21]=2)=[O:32])[CH2:35][CH2:36][C@H:37]1[C:40]([O:42][CH3:43])=[O:41]
Reactant: COc1cccc(F)c1C=O
Reactant: COC(=O)[C@@H]1CC[C@@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CN1Cc1c(F)cccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
SODIUM TRIACETOXYBOROHYDRIDE (6.46 g, 30.5 mmol) was added to a stirred mixture of (2S,5R)-methyl 5-(3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamido)-piperidine-2-carboxylate (2 g, 5 mmol) and 2-Fluoro-6-Methoxy-Benzaldehyde (4.70 g, 30.5 mmol) in MeOH (100 ml) and the mixture was stirred at room temperature for overnight. The reaction LCMS gave M+H at 532. The reaction was rotovap to dryness and the residue was purified by column chromatography on silica gel Biotage 40M, eluting with 5% MeOH/NH3(2M)CH2Cl2 to give desired product as a brown solid (2 g, 3.76 mmol, 74.0% yield).
Reaction SMILES: C1([Br:7])CCCCC1.[Br-].[CH:9]1([N+:15]([CH3:28])([CH3:27])[CH:16]2[CH2:21][CH:20]([CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:18][C:17]2([OH:26])[CH3:25])[CH2:14][CH2:13]C[CH2:11][CH2:10]1>>[Br-:7].[CH:9]1([N+:15]([CH3:28])([CH3:27])[CH:16]2[CH2:21][CH:20]([CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:18][C:17]2([OH:26])[CH3:25])[CH2:14][CH2:13][CH2:11][CH2:10]1
Reactant: CC(C)C1CCC(C)(O)C([N+](C)(C)C2CCCCC2)C1
Reactant: BrC1CCCCC1
Agent: [Br-]
Product: CC(C)C1CCC(C)(O)C([N+](C)(C)C2CCCC2)C1

Procedure:
By analogues procedure using cyclohexyl bromide there was also prepared cyclohexyl dimethyl (1-hydroxy-p-menth-2-yl) ammonium bromide.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][NH:29][CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:15])[F:14])[C:5]=12.C(N(CC)CC)C.[CH3:40][C@H:41]1[CH2:43][O:42]1>C(O)(C)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][N:29]([CH2:40][C@@H:41]([OH:42])[CH3:43])[CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:14])[F:15])[C:5]=12
Reactant: C[C@H]1CO1
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a mixture of 5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitrile dihydrochloride (20 mg, 0.04 mmol, racemic intermediate from Example 129, Step 2) and triethylamine (18 μL, 0.13 mmol) in isopropyl alcohol (0.1 mL) was added (S)-(−)-methyloxirane (9.1 μL, 0.13 mmol). The resulting mixture was stirred at 90° C. for 5 h. The crude mixture was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to 2.5 mg (10%) of give the desired product. The product was isolated as a mixture of diastereomers. LCMS calculated for C23H28F2N7O2 (M+H)+: m/z=472.2; Found: 472.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:40][O:41][CH3:42])[C:4]([CH3:39])=[C:5]([C:28]([O:30]COC(=O)C(C)(C)C)=[O:29])[CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9]>C(OC(C)C)(C)C.O>[CH3:39][C:4]1[N:3]([CH2:40][O:41][CH3:42])[C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17])=[O:9])[C@@H:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:5]=1[C:28]([OH:30])=[O:29]
Reactant: COCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: CC(C)OC(C)C
Solvent: O
Product: COCN1C(C)=C(C(=O)O)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
In 20 ml of isopropyl ether saturated with water was dissolved 1.2 g of bis(pivaloyloxymethyl) 1,4-dihydro -2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate obtained in Example 1 or 2 as a substrate. To the substrate solution was added 300 mg of Lipase B, and the reaction system was stirred at room temperature for 3 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1/2) to obtain 0.9 g (yield: 95%) of (S)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl)-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1C(C2C=C3C(=CC=2)C=C(CCOS(C)(=O)=O)C=C3)=CC=C(C)[N:3]=1.[CH3:26][C:27]1[C:32]([C:33]2[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=2)[CH:39]=[C:38]([CH2:43][CH2:44][OH:45])[CH:37]=[CH:36]3)=[CH:31][CH:30]=C(C)N=1>>[OH:45][CH2:44][CH2:43][C:38]1[CH:37]=[C:36]2[C:41](=[CH:40][CH:39]=1)[CH:42]=[C:33]([C:32]1[CH:31]=[CH:30][C:1]([C:2]#[N:3])=[CH:26][CH:27]=1)[CH:34]=[CH:35]2
Reactant: Cc1ccc(-c2ccc3cc(CCO)ccc3c2)c(C)n1
Reactant: Cc1ccc(-c2ccc3cc(CCOS(C)(=O)=O)ccc3c2)c(C)n1
Product: N#Cc1ccc(-c2ccc3cc(CCO)ccc3c2)cc1
Yield: 97 %

Procedure:
Methanesulfonic acid 2-[6-(2,6-dimethyl-pyridin-3-yl)-naphthalen-2-yl]-ethyl ester The compound was prepared by the method in Example 3B substituting 2-[6-(2,6-dimethyl-pyridin-3-yl)-naphthalen-2-yl]-ethanol in place of 4-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-benzonitrile (0.9763 g, 97% yield). 1H NMR (CD3OD, 300 MHz), δ 8.09–8.05 (m, 1H), 7.99–7.87 (m, 2H), 7.82–7.79 (m, 1H), 7.66–7.62 (m, 1H), 7.53–7.44 (m, 2H), 7.22–7.13 (m, 1H), 4.57–4.52 (t, J=7.5 Hz, 2H), 4.08 (s, 3H), 3.27–3.19 (t, J=7.5 Hz, 2H). MS (DCI-NH3) [M+H]+ at 356.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[C:36]([Cl:40])=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:6][C:32](=[O:33])[C:31]1[CH:35]=[C:36]([Cl:40])[C:37]([Cl:39])=[CH:38][C:30]=1[NH:29][S:26]([C:22]1[C:19]2=[N:20][S:21][N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid as in Example 1, Part C. HPLC: RT=10.74 min. MS (ESI−): mass calcd. for C23H16BrCl2FN4O5S2, 662.34; m/z found, 659/661 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.16 (s, 1H), 8.36 (dd, J=7.1, 0.8, 1H), 8.24 (dd, J=8.8, 0.8, 1H), 7.86 (s, 1H), 7.74 (dd, J=8.8, 7.1, 1H), 7.33 (s, 1H), 7.30-7.27 (m, 1H), 7.06 (t, J=8.3, 1H), 7.03-6.98 (m, 1H), 6.53 (d, J=7.1, 1H), 4.93 (q, J=5.8, 1H), 3.22 (s, 3H), 3.24-3.11 (m, 2H).