Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([CH:13]=O)[C@@H:10]([OH:15])[C@H:9]([OH:16])[C@H:7]2[N:8]=1)[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH2:17]([NH:24][CH2:13][C@H:11]1[O:12][C@H:6]2[C@H:7]([N:8]=[C:4]([NH:3][CH2:1][CH3:2])[S:5]2)[C@@H:9]([OH:16])[C@@H:10]1[OH:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C=O)O[C@@H]2S1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CNCc3ccccc3)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carbaldehyde (76.00 mg; 0.31 mmol; 1.00 eq.) in methanol (1.00 ml) was added benzylamine (0.05 ml; 0.46 mmol; 1.50 eq.), and sodium cyanoborohydride (9.70 mg; 0.15 mmol; 0.50 eq.) in 0.5 mL MeOH. The reaction was stirred at room temperature for 2 h. The desired product was isolated by prep HPLC (0% B for 10 min, then 0 to 30% B over 10 min, 0.1% TFA, 220 nm) to afford (3aR,5R,6S,7R,7aR)-5-[(benzylamino)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (12.2 mg, 12%) as a white solid (once lyophilized).
Reaction SMILES: [CH2:1]([C:3]1([CH:8]([F:13])[C:9]([NH:11][OH:12])=[O:10])OCCO1)[CH3:2].OS(O)(=O)=O>>[CH2:1]([C:3]1[O:12][N:11]=[C:9]([OH:10])[C:8]=1[F:13])[CH3:2]
Reactant: CCC1(C(F)C(=O)NO)OCCO1
Agent: O=S(=O)(O)O
Product: CCc1onc(O)c1F
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A sol. of 2-(2-ethyl-[1,3]dioxolan-2-yl)-2-fluoro-N-hydroxyacetamide (502 mg, 2.60 mmol) in cone. H2SO4 (1.2 mL) was stirred for 2 h at rt, then for 2 h at 50° C. The mixture was poured onto ice, and this mixture was extracted with EtOAc. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the title compound (280 mg, 82%). LC-MS: tR=0.66, ES+: not visible.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][O:14][C@H:15]([CH3:19])[C:16](O)=[O:17].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[C@H:15]([O:14][CH3:13])[CH3:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CO[C@H](C)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.5 g, 2.17 mmol; Example 1, Step H), (R)-2-methoxypropanoic acid (0.475 g, 4.56 mmol), BOP-Cl (1.16 g, 4.56 mmol), and triethylamine (1.51 mL, 10.9 mmol) were placed in DCM (5 mL) and stirred at room temperature for 1 hour. 3M aqueous LiOH (3 mL) was then added. The reaction was stirred for 10 minutes, then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (500:15 DCM:MeOH) to give (R)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[N:13]=[C:14]=[O:15].C1(C)C=CC=CC=1.C[O:24][C:25]([NH:27][NH2:28])=O>C1C=CC=CC=1>[Cl:8][C:6]1[C:5]([O:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]([N:13]2[C:25](=[O:24])[NH:27][NH:28][C:14]2=[O:15])=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)NN
Reactant: CCCOc1cc(N=C=O)c(F)cc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCCOc1cc(-n2c(=O)[nH][nH]c2=O)c(F)cc1Cl
Reaction time: 8 h
Yield: 115.3 %

Procedure:
A solution of 2-fluoro-4-chloro-5-n-propoxyphenyl isocyanate (1.8 g) in benzene (10 ml) was added to a toluene solution containing methoxycarbonylhydrazine (0.71 g), and the resultant mixture was allowed to stand overnight. The precipitated crystals were collected by filtration and dissolved in a 4M aqueous sodium hydroxide solution (10 ml) under heating. To the resulting solution, conc. hydrochloric acid was added, and the precipitated crystals were collected by filtration to give 2.6 g of 4-(4-chloro-2-fluoro-5-n-propoxyphenyl)urazol. M.P., 181°-182° C. IR νmax (cm-1): 3150, 1710, 1680. δ (ppm): 1.1 (3H, t), 4.0 (3H, q), 7.0 (1H, d), 7.3 (1H, d).
Reaction SMILES: CC1C=CC([N+]([O-])=O)=CC=1C=O.C(NC(C1CCNCC1)=O)(C)(C)C.[C:26]([NH:30][C:31]([CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[C:44]([N+:46]([O-])=O)[CH:43]=[CH:42][C:41]=2[CH3:49])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][C:31]([CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[C:44]([NH2:46])[CH:43]=[CH:42][C:41]=2[CH3:49])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1ccc([N+](=O)[O-])cc1CN1CCC(C(=O)NC(C)(C)C)CC1
Agent: CC(C)(C)NC(=O)C1CCNCC1
Agent: Cc1ccc([N+](=O)[O-])cc1C=O
Product: Cc1ccc(N)cc1CN1CCC(C(=O)NC(C)(C)C)CC1

Procedure:
The title compound is prepared according to the reactions described for BB-5 above starting from 2-methyl-5-nitro-benzaldehyde and piperidine-4-carboxylic acid tert-butylamide yielding after reductive amination 1-(2-methyl-5-nitro-benzyl)-piperidine-4-carboxylic acid tert-butylamide; LC-MS A: tR=0.62 min; [M+H]+=334.21 followed by reduction with stannous chloride the title compound; LC-MS A: tR=0.44 min; [M+H]+=304.28.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1.O[C:30]1[C:34]([CH:35]=[O:36])=[CH:33][N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:31]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:35]([C:34]1[C:30]([O:1][CH2:2][C:3]2[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=4[C:17]([O:19][CH3:20])=[O:18])[O:12][C:13]=3[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=2)=[N:31][N:32]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:33]=1)=[O:36]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COC(=O)c1ccccc1-c1nc(COc2ccc(CO)cc2OC)c(C)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3C=O)cc2OC)c(C)o1
Reaction time: 15 h
Yield: 64.7 %

Procedure:
To a mixture of methyl 2-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (1.06 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.58 g), tributylphosphine (0.85 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.06 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (0.99 g, yield 64%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: CO[N:3]1[C:7]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=2[N:5]=[C:4]1[C:18]([F:21])([F:20])[F:19].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(Cl)(Cl)Cl>CO>[N+:12]([C:11]1[C:6]2[NH:5][C:4]([C:18]([F:21])([F:20])[F:19])=[N:3][C:7]=2[C:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1)([O-:14])=[O:13]
Reactant: C1CCNCC1
Reactant: COn1c(C(F)(F)F)nc2c([N+](=O)[O-])cc([N+](=O)[O-])cc21
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2[nH]c(C(F)(F)F)nc2c1N1CCCCC1
Reaction time: 3 h

Procedure:
A 450 mg. portion of 1-methoxy-4,6-dinitro-2-(trifluoromethyl) benzimidazol was dissolved in methanol, and 150mg. of piperidine was added at room temperature. The reaction mixture was constantly stirred, and the progress of the reaction was monitored by thin-layer chromatography. After about 3 hours, the solvent was evaporated under vaccum, and the residue was taken up in water and acidified to pH 3. The mixture was then extracted with ethyl acetate, and the product was isolated by chromatography of the organic layer, using chloroform as the eluent. The product was recrystallized from ethanol-water, and was identified as 4,6-dinitro-7-piperidino-2-(trifluoromethyl) benzimidazole, m.p. 207° -209° C., by nuclear magnetic resonance analysis and elemental microanalysis, the results of which follow. The yield was about 70 mg.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C@H:14]([CH2:15][C:16]([C:18]2[CH:22]=[C:21]([CH2:23][CH3:24])[N:20]([CH3:25])[N:19]=2)=O)[N:13]([C:26](=P(CCCC)(CCCC)CCCC)[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[C:12]1=[O:46])[CH3:10])(C(C)(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:23]([C:21]1[N:20]([CH3:25])[N:19]=[C:18]([C:16]2[CH2:15][C@@H:14]3[C@@H:11]([C@H:9]([OH:8])[CH3:10])[C:12](=[O:46])[N:13]3[C:26]=2[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH:22]=1)[CH3:24]
Reactant: C=CCOC(=O)C(N1C(=O)[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)c1cc(CC)n(C)n1)=P(CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1=C(c2cc(CC)n(C)n2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
Allyl 2-{(3R,4S)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-[2-(5-ethyl-1-methylpyrazol-3-yl)-2-oxoethyl]azetidin-2-on-1-yl}-2-(tri-n-butylphosphoranylidene)acetate (1.94 g) in toluene (650 ml; 3 mgs/ml) was heated under reflux for a total of 7 h. T.l.c. analysis showed only a small amount of unreacted starting material. The solution was concentrated and purified by silica gel chromatography, eluting with 5% then 10% acetone/ethyl acetate. The product was obtained as an off white, crystalline solid. Trituration with ether, followed by filtration gave the title compound as a colourless crystalline solid, (356 mg; 30%); (Found: M+, 345.1689. C18H23N3O4 requires M 345.1689); nmax (CH2Cl2) 3603, 1774, 1716, 1599(w) and 1542(w) cm−1; dH(CDCl3) 1.28 (3H, t, J7.4 Hz), 1.36 (3H, d, J6.3 Hz), 1.85 (1H, d, J5.0 Hz), 2.61 (2H, d, J7.4 Hz), 3.19 (1H, dd, J2.8,6.7 Hz), 3.27 (1H, dd, J9.0,18.5 Hz), 3.59 (1H, dd, J9.8, 18.5 Hz), 3.84 (3H, s), 4.24 (2H, m), 4.79 (2H, m), 5.27 (1H, m), 5.46 (1H, m), 6.01 (1H, m) and 7.02 (1H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]([C:20]#[N:21])=[N:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][C:17]([C:20]#[N:21])=[N:18][N:19]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nnc(C#N)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nnc(NC2CCNCC2)s1
Temperature: 0 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
To a stirred solution of 4-(5-cyano-[1,3,4]thiadiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (D5) (0.973 g, 3.12 mmol) in dichloromethane (55 ml), at 0° C., was added trifluoroacetic acid (3 ml). The reaction mixture was stirred at 0° C. for 1 h. and at room temperature for 18 h. more. After this period, the reaction mixture was extracted with a saturated solution of sodium carbonate. The aqueous layer was extracted with ethyl acetate (2×25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo to yield D6 (0.60 g, 92%) as a solid. C8H11N3S requires 209. Found 210 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCCCC1.C(OCC)C>O1CCCC1.O>[C:11]1([CH:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:1]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Li]c1ccccc1
Reactant: c1ccc2ncccc2c1
Solvent: O
Solvent: CCOCC
Solvent: C1CCCCC1
Product: C1=CC(c2ccccc2)Nc2ccccc21
Temperature: 2 °C
Yield: 42.2 %

Procedure:
30 g of quinoline were dissolved in 100 ml tetrahydrofuran. The solution was cooled to 2° C., then 19.6 g of phenyllithium in the form of a 2M solution in a 70:30 mixture of cyclohexane and diethyl ether were added over the course of 2 hours while the temperature was maintained between 0° and 2° C. The reaction mixture was then allowed to warm to room temperature. To work up the reaction mixture it was added to water and then extracted with diethyl ether. The ether phase was washed with water until neutral, dried and concentrated. 50 g of crude product were obtained, which was purified by chromatography on a silica gel column using toluene as the eluent. 20.3 g of 1,2-dihydro-2-phenylquinoline having a melting point of 75° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)COc1ccc(O)cc1
Reactant: BrCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OCCCCc2ccccc2)cc1
Reaction time: 3 h
Yield: 75.5 %

Procedure:
A solution of ethyl (4-hydroxyphenoxy)acetate (0.49 g, 2.5 mmol), 4-phenylbutyl bromide (0.59 g, 2.8 mmol), potassium carbonate (0.69 g, 5.0 mmol) and potassium iodide (30 mg, 0.50 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 30 min., and further at 50° C. for 3 hrs. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated brine. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (0.62 g, yield 76%). oil.
Reaction SMILES: [CH:1]1([N:4]([CH:20]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][CH3:38])=[O:36])[CH:23]=2)[CH3:21])[C:5]([C@@H:7]2[O:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(=O)([O-])O.[Na+]>ClCCl.CO>[CH:1]1([N:4]([C:5]([C@@H:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH:20]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:36])[O:37][CH3:38])[CH:23]=2)[CH3:21])[CH2:3][CH2:2]1
Reactant: COC(=O)NCCCn1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)c2cccnc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)NCCCn1cc(C(C)N(C(=O)[C@H]2CNCCO2)C2CC2)c2cccnc21
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of t-butyl (2R)-2-({cyclopropyl[1-(1-{3-[(methoxycarbonyl)amino]propyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]amino}carbonyl)morpholin-4-carboxylate (116 mg) and 2,6-lutidine (0.077 mL) in dichloromethane (2 mL) was added trimethylsilyltriflate (0.099 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Then, thereto were added aqueous sodium hydrogen carbonate solution and methanol (2.0 mL) under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: ethyl acetate→ethyl acetate/methanol=9/1) to give methyl {3-[3-(1-{cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino}ethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl}carbamate (50 mg) as a colorless oil. Methyl {3-[3-(1-{cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino}ethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl}carbamate (40 mg) was separated by CHIRALPAK IC (eluent: n-hexane/ethanol/diethylamine=50/50/0.1; instrument: Waters 302 (600E system)) into diastereomers to give methyl {3-[3-((1R)-1-{cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino}-ethyl-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl}carbamate (18 mg) as a colorless oil and methyl {3-[3-((1S)-1-{cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino}-ethyl-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl}carbamate (18 mg) as a colorless oil.
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:30]Br)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][NH:33][CH3:34]>>[C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:30][N:33]([CH3:34])[CH3:32])=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](NC(=O)c1c(CBr)n(-c2ccccc2)c(=O)c2ccccc12)c1ccccc1
Reactant: CNC
Product: CC[C@H](NC(=O)c1c(CN(C)C)n(-c2ccccc2)c(=O)c2ccccc12)c1ccccc1
Reaction time: 0.17 h

Procedure:
A mixture of 3-bromomethyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide (70 mg, 0.147 mmol) and dimethylamine (1 ml of 33% solution in abs. ethanol, excess) was kept at 50° C. for 10 min and then evaporated in vacuo. The residue was dissolved in methanol and passed through SCX cation exchange column (1 g, RSO3H form). Uncharged impurities were eluted with methanol and the product was eluted with 4M NH3 in methanol to give 53 mg of colourless glass-like solid. It was further purified by flash chromatography on SiO2 (5 g, gradient 1,2-dichloroethane—10% ethyl acetate in 1,2-dichloroethane) to give 45 mg of colourless solid. Yield 70%. LC-MS (m/z) 440.1 (MH+); tR=0.88. 1H NMR (250 MHz, DMSO-d6, T=333 K): 0.92 (t, 2H), 1.83 (two overlapping m, 2H), 1.66 (s, 6H), 2.96 and 3.08 (two d of CHAHBN, 2H), 4.96 (q, 1H), 7.19-7.56 (m, 12H), 7.68 (t, 1H), 8.21 (d, 1H), 8.75 (d, 1H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=[CH:31][O:32][CH3:33])[C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([C@@H:18]2[O:9][C@H:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=[CH:31][O:32][CH3:33])[C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC=C(C(=O)OC)c1ccccc1C=Cc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC=C(C(=O)OC)c1ccccc1[C@@H]1O[C@H]1c1ccccc1
Yield: 57.7 %

Procedure:
7.2 g of m-chloroperbenzoic acid (about 50% pure) are added to a solution of 10.2 g of methyl 2-[2-(2-phenylethenyl)phenyl]-3-methoxyacrylate in 80 ml of methylene chloride. The reaction mixture is refluxed for two days and then the precipitate is filtered off with suction and the filtrate is washed twice with saturated sodium bicarbonate solution and water. The isolated organic phase is dried over sodium sulfate and concentrated, and the residue is recrystallized from methyl tert-butyl ether. 6.2 g (58%) of methyl trans-2-[2-(3-phenyl-2-oxiranyl)phenyl]-3-methoxyacrylate are obtained of melting point 110°-113° C.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=O)C.[BrH:23]>O>[BrH:23].[BrH:23].[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([NH:12][CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[S:14][C:15]=2[CH:21]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccc(Cl)cc3s2)CC1
Agent: Br
Solvent: O
Product: Clc1ccc2nc(NC3CCNCC3)sc2c1
Yield: 99 %

Procedure:
A solution of 4-(6-chloro-benzothiazol-2-ylamino)-piperidine-1-carboxylic acid ethyl ester (2.60 g, 7.65 mmol) in hydrobromic acid 48% in water (60 mL) was heated to reflux for 18 h. Removal of hydrobromic acid under reduced pressure and precipitation from ethanol (50 mL) provided 3.26 g (99%) of the title compound which was used directly in the next step. 1H NMR (400 MHz, DMSO): δ 1.69-1.79 (m, 2H), 2.14-2.17 (m, 2H), 3.01-3.09 (m, 2H), 3.32-3.35 (m, 2H), 4.06 (br s, 1H), 7.31 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 8.52 (br s, 1H), 8.62 (br s, 1H), 9.00 (br s, 1H). MS (ISP): 266.0 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[N:4]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30](I)[CH:29]=1)[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26].[N:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.CC(O)C(O)C.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.O.C(O)C>[CH3:1][O:2][C:3](=[O:39])[N:4]([CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:23])[CH3:24])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26])[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:43]2[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=2)[CH:29]=1
Reactant: COC(=O)N(Cc1cc(I)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(O)C(C)O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: COC(=O)N(Cc1cc(-c2ccncc2)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C

Procedure:
Methyl[3-iodo-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 119, 20 mg, 0.03 mmol) and pyridine-4-boronic acid (4.6 mg, 0.04 mmol) were placed in a microwave tube in a microwave tube, and dissolved with dimethyl ethylene glycol (170 μL). Next, 2M Na2CO3 (38 μL), ethanol (42 μL), and water (56 μL) were added. The solution was degassed with nitrogen for 2 minutes. Pd(PPh3)4 (3.5 mg, 0.003 mmol) was added and the solution was degassed with nitrogen again for 2 minutes. The solution was sealed and placed in a microwave reactor. The wattage was set for 60 W until the temperature reached 150° C. and then the temperature was held at 150° C. for twenty minutes. The mixture was then cooled to room temperature, poured into H2O (10 mL), and extracted with EtOAc (30 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 5% to 80% EtOAc/hexanes afforded methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl)}[3-pyridin-4-yl-5-(trifluoromethyl)benzyl]carbamate. Rf=0.40 (75% EtOAc/hexanes). LCMS=617.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 8.54 (broad singlet, 2H), 7.70 (s, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.35 (d, J=8.0, 1H), 7.28 (s, 1H), 7.06 (d, J=8.0, 1H), 7.02 (dd, J=2.0 Hz, 8.5, 1H), 6.89 (m, 2H), 6.83 (d, J=2.0, 1H), 6.58 (d, J=8.5, 1H), 4.45 (broad singlet, 2H), 4.13 (broad singlet, 2H), 3.38 (s, 3H), 3.23 (s, 3H), 2.65 (m, 1H), 1.12 (d, J=7.0 Hz, 6H).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccnc1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1cccnc1
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)pyridin-3-sulfonamide (19 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.