Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1.C([BH3-])#N.[Na+]>CO.O>[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:24][CH:23]=1)[CH2:8]2
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(Cc1ccc(C(F)(F)F)cc1)CC2
Reaction time: 2.5 h
Yield: 50.9 %

Procedure:
A solution of the product from Example 5 (1 g, 3.24 mmol) and α,α,α-trifluro-p-tolualdehyde (1.22 g, 7 mmol) in 2:1 MeOH/H2O (50 mL) was treated with sodium cyanoborohydride (0.56 g, 9 mmol) portionwise under nitrogen and stirred for 2.5 hours. The precipitate was filtered, washed with hexane and dried to give the title compound (0.71 g, 51% yield) as a yellow solid, mp=119-120° C.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH2:5][CH2:4]1)=O.[Cl-].[CH3:20][O:21]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH:20]([CH2:1][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH2:5][CH2:4]1)=[O:21]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=CC[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Reaction time: 0.5 h

Procedure:
11.5 g of 1-((trans-4-formylcyclohexyl)methoxy)-2,3-difluorobenzene was dissolved in 50 mL of THF, and 18.6 g of methoxymethyl triphenylphosphonium chloride was added thereto. To this solution, the THF (20 mL) solution containing 6.1 g of potassium-t-butoxide was added dropwise at an internal temperature of 5 to 20° C., and the solution was stirred for 30 min. 10 mL of water was added thereto, and the solvent was evaporated under reduced pressure. Hexane and 50% methanol aqueous solution were added thereto, and the organic layer was fractioned. This organic layer was washed with 50% methanol aqueous solution and saturated saline, and subjected to column chromatography. After evaporating the solvent under reduced pressure, the residue was dissolved in 70 mL of THF, and 70 mL of 10% hydrochloric acid was added thereto, followed by reflux with heating for 2 hours. To the solution, water and ethyl acetate were added, and the organic layer was fractioned, washed with saturated saline 3 times, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby obtain 8.2 g of 1-((trans-4-(formylmethyl)cyclohexyl)methoxy)-2,3-difluorobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:31]([F:34])([F:33])[F:32])=[CH:10]/[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH:19]([NH:23][C:24](=[O:30])[CH2:25][CH:26]([O:28][CH3:29])[CH3:27])[CH2:18][CH2:17]3)=[N:12][OH:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:31]([F:34])([F:32])[F:33])=[CH:10]/[C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH:19]([NH:23][C:24](=[O:30])[CH2:25][CH:26]([O:28][CH3:29])[CH3:27])[CH2:18][CH2:17]3)=[N:12][O:13][C:42](=[O:44])[CH3:43])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: COC(C)CC(=O)NC1CCc2cc(C(/C=C(/c3cc(Cl)cc(Cl)c3)C(F)(F)F)=NO)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(C)CC(=O)NC1CCc2cc(C(/C=C(/c3cc(Cl)cc(Cl)c3)C(F)(F)F)=NOC(C)=O)ccc21
Temperature: 25 °C
Yield: 72.1 %

Procedure:
0.5 g of N-[5-{(Z)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-hydroxyimino-2-butenyl}-indane-1-yl]-3-methoxybutyric acid amide and 0.22 g of triethylamine were dissolved in 10 ml of tetrahydrofuran, and 0.1 g of acetyl chloride was added to the resulting solution under ice-cold conditions, followed by stirring at room temperature for one night. The reaction solution was poured into ice-water, extracted with ethyl acetate, washed with saturated brine, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=7/3 (volume ratio)) to obtain 0.39 g of the target compound. Yield was 69%.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1.Cl.CO[C:16](=N)[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.O.Cl>CO>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]2[NH:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][C:7]=3[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COC(=N)C=Cc1ccc(OC)c(OC)c1
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc2[nH]c(C=Cc3ccc(OC)c(OC)c3)nc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.7 %

Procedure:
A mixture of 4-methoxy-1,2-phenylenediamine dihydrochloride (1.55 g; 7.3 mmol) and methyl-(3,4-dimethoxy)-cinnamoimidate hydrochloride (1.9 g; 7.3 mmol) in methanol (50 mL) was stirred at ambient temperature for 72 hours. The methanol was concentrated to 25 mL. A yellow solid was separated by filtration. The solid was suspended in MeOH (10 mL), and treated with hydrogen chloride. The precipitate that formed was collected to obtain 515 mg (21% yield) of the title compound as a mono-hydrochloride, hydrate, yellow solid, m.p. 246-249° C. Anal. Calcd. for C18H18N2O3HCl. H2O: C, 61.72, H, 5.20; N, 7.79. Found: C, 61.61; H, 5.37; N, 7.84 . Mass spectrum: (EI; M+) m/z 310. 1H-NMR (DMSO-d6; 400 MHz) δ14.8 (broad s,1H), 8.3-8.5(d,1H), 7.62-7.63 (d, 1H), 7.3 (d,1H), 7.21-7.23 (dd 1H), 7.2 (d, 2H), 7.07-7.16(m, 3H), 3.86-3.88 (d, 6H), 3.82-3.84 ppm (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCCCCCN1CCN(CCCCCNC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCCN1CCN(CCCCCN)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of {5-[4-(5-tert-butoxycarbonylamino-pentyl)-piperazin-1-yl]-pentyl}-carbamic acid tert-butyl ester (329 mg, 0.72 mmol) in DCM (10 mL) is treated with trifluoracetic acid (1 mL). The reaction was left to stir at RT for 4 days and then the solvent is removed in vacuo. The material was used crude and conversion was assumed quantitative to produce 5-[4-(5-amino pentyl)-piperazin-1-yl]-pentylamine.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Li][CH2:14][CH2:15][CH2:16][CH3:17].BrCCCC>C1COCC1>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:12][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1
Reactant: Cc1cc(C)c2c(n1)N(C)CC2
Reactant: [Li]CCCC
Solvent: CCCCBr
Solvent: C1CCOC1
Product: CCCCCc1cc(C)c2c(n1)N(C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 225 mg (1.39 mmol) of 1,4,6-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 4 mL of THF was added 1.39 mL (2.22 mmol, 1.6 M in hexanes) of n-BuLi followed by 157 μL (1.46 mmol) of 1-bromobutane at −78° C. The reaction mixture was slowly warmed to room temperature and stirred for another 16 h. The reaction mixture was quenched by the addition of 10 mL of sat aq NH4Cl at 0° C. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (25 3.2 cm). Elution with 10:1 hexanes/ethyl acetate gave the product as a yellow oil: yield 0.20 g (66%); silica gel TLC Rf 0.15 (8:1:1 hexanes/ethyl acetate/MeOH); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=7.2 Hz), 1.30-1.36 (m, 4H), 1.66 (quint, 2H, J=7.6 Hz), 2.08 (s, 3H), 2.55 (t, 2H, J=8.0 Hz), 2.81 (t, 2H, J=8.0 Hz), 2.88 (s, 3H), 3.38 (t, 2H, J=8.0 Hz) and 6.13 (s, 1H); 13C NMR (CDCl3) δ 14.1, 18.0, 22.6, 24.4, 29.6, 31.8, 33.3, 38.0, 52.5, 112.4, 118.2, 141.1, 159.1 and 163.7; mass spectrum, m/z 218.2 (M+) (theoretical 218.3); mass spectrum (APCI), m/z 219.1864 (M+H)+ (C14H23N2 requires 219.1861).
Reaction SMILES: O1CCCCC1[N:7]1[C@@H:10]([CH2:11][CH2:12][O:13]C2CCCCO2)[C@H:9]([CH2:20][CH2:21][O:22][O:23][C:24]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:25])[C:8]1=[O:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.P([O-])([O-])([O-])=O>CO>[N+:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:24]([O:23][O:22][CH2:21][CH2:20][C@H:9]2[C@H:10]([CH2:11][CH2:12][OH:13])[NH:7][C:8]2=[O:36])=[O:25])=[CH:32][CH:31]=1)([O-:35])=[O:34]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)OOCC[C@@H]1C(=O)N(C2CCCCO2)[C@H]1CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)OOCC[C@@H]1C(=O)N[C@H]1CCO
Reaction time: 2 h

Procedure:
A solution of trans-1-(2-tetrahydropyranyl)-3-(1-p-nitrobenzylcarbonyldioxyethyl)-4-[2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone in methanol at 25° C. is treated with 0.1 molar equivalent of p-toluenesulfonic acid monohydrate. The solution is stirred for a period of 2 hours and then neutralized with 1M pH7 phosphate buffer. The product is extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give trans-3-(1-p-nitrobenzylcarbonyldioxyethyl)-4-(2-hydroxyethyl)-2-azetidinone. The cis diastereoisomers are obtained in an analogous manner.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:14][C:13](=[O:15])[NH:12][NH:11][C:10](=[O:16])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][CH:25]=1>C1C=CC=CC=1>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:14][C:13](=[O:15])[N:11]([N:12]=[CH:30][C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=3)[C:10](=[O:16])[CH2:9]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)CC(=O)NN1
Reactant: Cc1cccc(C=O)n1
Solvent: c1ccccc1
Product: Cc1cccc(C=NN2C(=O)CN(C(c3ccccc3)c3ccccc3)CC2=O)n1

Procedure:
Reacting 5-diphenylmethyl-3,7-diketo-1,2-dihydro-1,2,5-triazepine with 6-methylpyridine-2-carboxaldehyde in the presence of benzene at reflux temperature and a reaction time of 4 hours to afford 1-diphenylmethyl-4-(6-methyl-2-pyridylmethyleneamino)-3,5-diketopiperazine;
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:10]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][C:18]=2[CH3:27])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]([O:38]C(C)(C)C)=[O:37]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:10]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19]([CH2:35][C:36]([OH:38])=[O:37])[C:18]=2[CH3:27])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1[nH]c2ccc(Cl)cc2c1C1=NN(Cc2ccccc2)C(=O)C(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C2=NN(Cc3ccccc3)C(=O)C(C)(C)C2)c2cc(Cl)ccc2n1CC(=O)O
Temperature: 80 °C

Procedure:
The product of step b) (˜0.3 mmol) was dissolved in 5 mL DMF and treated with K2CO3 (1 mmol, 138 mg) and t-butyl bromoacetate (1 mmol, 195 mg). After heating to 80° C. for ½ h, the reaction was cooled, diluted with EtOAc and washed 5× water. The reaction was concentrated, dissolved in EtOH (5 mL) and treated with 1.4 mL of 1M NaOH. After heating to 80° C. for ½ h, the reaction was acidified with 3 M HCl and extracted into DCM (3×).
Reaction SMILES: FC(F)(F)C(O)=O.[O-:8][C:9]#[N:10].[Na+].NN.[CH2:14]([O:18][C:19]1[CH:20]=[C:21]([N:25]([CH2:27][C:28]([O:30]C)=O)[NH2:26])[CH:22]=[CH:23][CH:24]=1)[CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[CH2:14]([O:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:27][C:28](=[O:30])[NH:10][C:9](=[O:8])[NH:26]2)[CH:22]=[CH:23][CH:24]=1)[CH2:15][CH2:16][CH3:17]
Reactant: N#C[O-]
Reactant: CCCCOc1cccc(N(N)CC(=O)OC)c1
Agent: NN
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1cccc(N2CC(=O)NC(=O)N2)c1
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1.2 ml, 15.5 mmol) was added to a suspension of sodium cyanate (1.17 g, 18.0 mmol) and hydrazine (Intermediate 47 1.30 g, 5.15 mmol) in toluene (17 ml) at room temperature and stirred for 2 h. The reaction was quenched with sodium bicarbonate solution, extracted with ethyl acetate and washed with sodium bicarbonate, water and brine, dried (Na2SO4) and concentrated to afford the urea intermediate as a brown oil. A portion of this crude urea (0.65 g, 2.2 mmol) was taken up in methanol (10 ml) and treated with sodium methoxide (0.48 g, 8.8 mmol) at room temperature for 2 h. The reaction was quenched (pH 6.5 buffer), extracted with ethyl acetate, washed with water followed by brine, dried (Na2SO4) and concentrated to afford a red oil which was triturated with ether to afford a pale brown solid (105 mg, 18%), m.p. 100°-105°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:18])=[C:8]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1)(=[O:3])[CH3:2].O.[Se](=O)=[O:21].C>O1CCOCC1>[F:18][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[O:21])=[CH:9][C:8]=1[C:10]1[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[Se]=O
Reactant: CC(=O)c1ccc(F)c(-c2ccccc2C#N)c1
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1cc(C(=O)C=O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5′-Acetyl-2′-fluorobiphenyl-2-carbonitrile (0.31 g, 1.3 mmol) was suspended in 1,4-dioxane (4.75 ml) and water (0.25 ml) and warmed to 60° C. to solubilise the starting material. The solution was then cooled to ambient temperature, selenium dioxide (0.17 g, 1.55 mmol) added and the mixture heated under reflux for 2 h. The mixture was then allowed to cool to 60° C., activated charcoal (1 g) added and the mixture stirred for 30 min. The mixture was then allowed to cool to ambient temperature, filtered through a glass fibre filter paper and the solid washed with 1,4-dioxane (10 ml) and the filtrate evaporated to give crude 2′-fluoro-5′-(2-oxoacetyl)biphenyl-2-carbonitrile which was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1.[CH3:20][N:21](C=O)C>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N>[C:20]([C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1)#[N:21]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(C#N)cc2C1
Temperature: 80 °C

Procedure:
A mixture of 1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 73) (2.67 g, 8.14 mmol), zinc cyanide (1.715 g, 16.27 mmol) and tetakis(triphenylphosphine)palladium(0) (1.410 g, 1.220 mmol) in DMF (30 ml) was heated at 80° C. overnight. Additional tetakis(triphenylphosphine)palladium(0) (700 mg) was added and the yellow suspension heated at 80° C. for a further 5 hrs. The cooled reaction mixture was diluted with EtOAc/water, separated, and organics dried over anhydrous magnesium sulphate and evaporated. The crude was purified by flash chromatography eluting with EtOAc/iso-hexane 1:9. The combined fractions were evaporated to give the title compound (2.01 g) as a yellow solid. 6H (CDCl3, 400 MHz): 1.42 (9H, br.s), 3.81 (2H, t), 4.09 (2H, m), 4.43 (1H, s), 4.51 (1H, s), 7.09 (1H, m), 7.47-7.59 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:34]2[C:29]([F:28])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1F
Reactant: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)cn1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl({5-bromo-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (463 mg), (2-fluoropyridin-3-yl)boronic acid (172 mg), sodium carbonate (260 mg) and tetrakis(triphenylphosphine)palladium (176 mg), the title compound was obtained as a pale-yellow oil (yield 293 mg, 45%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:23])=[N:6][CH:7]=1.NC1C(F)=CC(C2CCN(C(OC(C)(C)C)=O)CC2)=C(C)C=1>CC(O)C.Cl>[Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:23])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C)CC4)cc3F)ncc2Cl)n[nH]1
Agent: Cc1cc(N)c(F)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
A mixture of 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Intermediate 1, 132 mg, 0.54 mmol) and tert-butyl 4-(4-amino-5-fluoro-2-methylphenyl)piperidine-1-carboxylate (Intermediate 19, 166 mg, 0.54 mmol) in 2-propanol (15 mL) was treated with conc. aqueous HCl (14 drops). The mixture was sealed and heated in a microwave at 130° C. for 60 min. The mixture was concentrated to afford 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as yellow solid. A portion of the crude product was purified with preparative RP-HPLC to afford 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid; ESMS m/z 416.1 (M+H+).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:17][C:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.[OH-].[Na+]>C(Cl)Cl.O>[OH:9][CH2:8][C@H:7]([NH:10][C:21]([C:18]1([Br:17])[CH2:20][CH2:19]1)=[O:22])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)C1(Br)CC1
Reactant: N[C@@H](CO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(N[C@@H](CO)c1ccccc1)C1(Br)CC1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
739 mg of D-(−)-α-phenylglycinol is dissolved in 27 ml of methylene chloride, and 678 mg of sodium carbonate is added to 11 ml of water and 1.09 g of acid chloride 107 at room temperature. It is stirred overnight and then mixed with methanolic sodium hydroxide solution, the organic phase is separated, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.09 g of (1R)-1-bromocyclopropanecarboxylic acid-2-hydroxy-1-phenylethylamide 110 is isolated as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:26])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:16]2[CH:17]=[CH:18][C:13]([C:12]3[O:11][N:10]=[C:9]([CH3:20])[C:8]=3[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=2)=[CH:31][CH:30]=1)[CH3:23]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)(C)C)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:29]1([C:32](O)=O)[CH2:31][CH2:30]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[CH:29]1([C:32]2[O:24][C:23]([C:22]3[CH:21]=[CH:20][C:19]([O:18][C@H:15]4[CH2:16][CH2:17][C@H:12]([C:10]([N:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[O:11])[CH2:13][CH2:14]4)=[CH:28][CH:27]=3)=[N:25][N:26]=2)[CH2:31][CH2:30]1
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NN)cc3)CC2)CC1
Reactant: O=C(O)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(-c4nnc(C5CC5)o4)cc3)CC2)CC1

Procedure:
A mixture of 80 mg (0.21 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid hydrazide, 0.02 ml (0.26 mmol) of cyclopropanecarboxylic acid and 2 ml of phosphorus oxychloride was refluxed for 2 hr. To the mixture, 1N NaOH solution was added. The mixture was extracted with AcOEt, washed with saturated NaHCO3 solution, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 19:1. The combined product fractions were evaporated to dryness to yield 56 mg (56%) of the title compound. MS (m/e): 439.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH2:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:22][S:31]([CH3:30])(=[O:33])=[O:32])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of C—[(R)-7-(3-Fluoro-benzenesulfonyl)-chroman-2-yl]-methylamine (0.28 g, 0.871 mmol) in methylene chloride (10 mL) was added triethylamine (0.363 mL, 0.26 mmol.) and methanesulfonyl chloride (0.071 g, 0.915 mmol) The mixture was stirred at room temperature for two hours, and was then quenched by addition of water. The mixture was extracted with methylene chloride, and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the residue by flash chromatography (hexanes:EtOAc 1:1) gave 0.296 g of N-[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-methanesulfonamide as a foam. MS (M+H)=400.