Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].C([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=C>>[CH2:17]([O:16]/[CH:5]=[CH:4]\[CH2:3][CH2:2][C:1]([O:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:6])[CH2:18][CH2:19][CH3:20]
Reactant: C=COCCCC
Reactant: C=CCCC(=O)Oc1ccccc1
Product: CCCCO/C=C\CCC(=O)Oc1ccccc1
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Following the general procedure, phenyl pent-4-enoate (50.0 mg, 0.284 mmol) was treated with butyl vinyl ether (284 mg, 2.84 mmol) and 2.5 mol % of in situ-generated complex la (71.0 μL, 0.10 M, 7.09 μmol; final substrate concentration=4.0 M) and allowed to stir for 2 h. The unpurified product is 98% Z (as determined by 400 MHz 1H NMR analysis). The resulting oil was purified by silica gel chromatography (50:1 hexanes:Et2O) to afford 8c (55.6 mg, 0.224 mmol, 79.0% yield, >98% Z isomer) as a colorless oil. IR (neat): 3040 (w), 2959 (m), 2933 (m), 2872 (m), 1759 (s), 1663 (m), 1594 (m), 1493 (m), 1374 (m), 1359 (m), 1272 (m), 1227 (m), 1195 (s), 1162 (s), 1130 (s), 1102 (s), 1072 (m); 1H NMR (400 MHz, CDCl3): δ 7.40-7.34 (2H, m), 7.25-7.19 (1H, m), 7.11-7.07 (2H, m), [diagnostic E isomer signal: 6.37 (1H, d, J=12.8 Hz)], 6.02 (1H, dt, J=6.0, 1.2 Hz), 4.43 (1H, td, J=6.8, 6.4 Hz), 3.75 (2H, t, J=6.4 Hz), 2.66-2.60 (2H, m), 2.56-2.49 (2H, m), 1.65-1.57 (2H, m), 1.46-1.35 (2H, m), 0.94 (3H, t, J=7.4 Hz); 13H NMR (100 MHz, CDCl3): δ 172.0, 150.9, 146.4, 129.4, 125.7, 121.7, 103.8, 72.2, 34.7, 32.0, 19.9, 19.1, 13.9; HRMS (ESI+) [M+H]+ calcd for C15H21O3: 249.1491, found: 249.1500.
Reaction SMILES: CCCCCC.C([Li])CCC.[F:12][C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=1.[Br:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([CH:33]=[O:34])[CH:24]=1.[Cl-].[NH4+]>C1COCC1>[Br:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([CH:33]([C:18]2[S:17][C:16]3[CH:20]=[CH:21][C:13]([F:12])=[CH:14][C:15]=3[CH:19]=2)[OH:34])[CH:24]=1
Reactant: Fc1ccc2sccc2c1
Reactant: O=Cc1cc(Br)c2ccccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1cc(Br)c2ccccc2c1)c1cc2cc(F)ccc2s1
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 1.68 ml, 2.68 mmol) was added dropwise to a solution of 5-fluorobenzo[b]thiophene (410 mg, 2.68 mmol) in THF (10 ml) and the reaction solution was stirred at the same temperature for 10 minutes. To this solution, a solution of 4-bromonaphthalene-2-carbaldehyde (600 mg, 2.55 mmol) in THF (5 ml) was added dropwise at −78° C. The obtained mixture was stirred at the same temperature for two hours, and then a saturated ammonium chloride aqueous solution was added and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (680 mg, 69%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[OH-].[K+].[C:17](=S)=[S:18].Cl>O.CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:12][C:17]([SH:18])=[N:14][N:13]=3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: S=C=S
Reactant: Cn1ccc2ccc(C(=O)NN)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ccc2ccc(-c3nnc(S)o3)cc21
Reaction time: 0.5 h

Procedure:
A mixture of 1-methyl-1H-indole-6-carboxylic acid hydrazide (2.8 g, 14.8 mmol), potassium hydroxide (0.91 g, 16.3 mmol) and methanol (50 ml) was stirred at room-temperature for 30 min. Carbon disulfide (2.25 g, 29.6 mmol) was added and the mixture was stirred for 15 h at reflux. The mixture was allowed to cool to room-temperature, water was added, pH was adjusted to 3 by adding concentrated aqueous hydrochloric acid. The crystalline product was isolated by filtration and washed with water. Yield 2.75 g (80%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH:13]([CH:15]=[CH2:16])=O>O1CCOCC1>[CH3:12][O:11][C:7]1[C:3]([C:4]([OH:6])=[O:5])=[C:2]2[C:10]([CH:13]=[CH:15][CH:16]=[N:1]2)=[CH:9][CH:8]=1
Reactant: COc1cccc(N)c1C(=O)O
Reactant: C=CC=O
Solvent: C1COCCO1
Product: COc1ccc2cccnc2c1C(=O)O
Temperature: 200 °C
Yield: 20.9 %

Procedure:
In 1 g separate batches a mixture of 2-amino-6-methoxybenzoic acid (11 g, 66 mmol) and acrolein (4.8 mL, 72 mmol) in 1,4-dioxane (66 mL) was heated in a microwave reactor for 20 min at 200° C. After combining the reactions, the mixture was concentrated and purified via silica gel chromatography (0-10% MeOH in DCM) to give the title compound (2.8 g, 20%). MS (ESI) mass calcd. for C11H19NO3, 203.1; m/z found 204.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH2:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:31][CH3:32]>>[CH2:30]([S:33]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:35])=[O:34])[CH2:31][CH3:32]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
[(R)-1-(Propane-1-sulfonyl)-pyrrolidin-3-yl]-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and propane-1-sulfonyl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.[F:39][CH:40]([F:55])[N:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[N:42]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:39][CH:40]([F:55])[N:41]1[CH:45]=[C:44]([C:2]2[C:7]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])[CH2:10][C:6]=3[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=2)[CH:43]=[N:42]1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: CC1(C)OB(c2cnn(C(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C(F)F)c4)c3C2=O)c(OC)c1
Yield: 89.2 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (35 mg, 0.064 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18.67 mg, 0.076 mmol) and bis(triphenylphosphine)palladium chloride (44.7 mg, 0.064 mmol) in dioxane (500 μL) and saturated aq Na2CO3 (500 μL) was heated at 85° C. for 2 h. After filtering out the solids, the solvent was removed and the residue was dissolved in MeOH and DCM and purified by preparative HPLC. The fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (36 mg, 90%). [M+H] calc'd for C31H37F3N6O5, 631. found, 631.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>CCO.C(Cl)(Cl)Cl>[CH2:12]([NH:19][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[OH:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: OC(CNCc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a cooled (0° C.) suspension of 2-bromo-1-(4-bromophenyl)ethanone (40.24 g; 0.14 mol) in EtOH (500 mL) and CHCl3 (100 mL) was added benzylamine (63 mL; 0.58 mol). After 30 minutes the ice-bath was removed and the mixture stirred for another 2 hours at RT. Subsequently the reaction mixture was cooled again to 0° C. and NaBH4 (6.26 g; 165.5 mmol) was added in small portions. The resulting mixture was stirred at 0° C. for 1 hour and thereafter another 4 hours at RT. The reaction mixture was quenched with 1M aqueous HCl (750 mL) at 0° C. and stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 1M aqueous NaOH. The organic layer was dried (Na2SO4), filtered, concentrated in vacuo. The residue was crystallized from tert-butyl methyl ether/heptanes to afford 2-benzylamino-1-(4-bromo-phenyl)-ethanol (18.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH3:11])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([OH:23])[CH2:21][NH2:22])[CH:17]=[CH:18][CH:19]=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH:22][CH2:21][CH:20]([OH:23])[C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)CCc1ccc(C)cc1
Solvent: c1ccccc1
Product: Cc1ccc(CCC(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
A mixture of 4-(4-Methylphenyl)butan-2-one (1.62 g) and 2-(3-chlorophenyl)-2-hydroxyethanamine (1.71 g) was refluxed in benzene under Dean & Stark conditions for 4 h. The solvent was removed under reduced pressure, replaced with methanol (100 ml) and sodium borohydride (2 g) added portionwise. The solvent was evaporated under reduced pressure, the residue partitioned between water and ether and the ether layer dried (MgSO4). Removal of the solvent gave an oil which was chromatographed on Kieselgel 60. Elution with 1% methanol-chloroform gave the title compound as an 11:89 mixture of diastereoisomers, mp 75-106 (hexane).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([C@@H:23]([OH:25])[CH3:24])=[CH:19][C:18]=4[Cl:26])[CH2:13][C@H:12]3[CH3:27])[NH:7][C:6]=2[CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.BrC1C2N=C(N3CCN(C4N=CC([C@H](O)C)=CC=4Cl)C[C@H]3C)NC=2C=C(C(F)(F)F)C=1.[F:63][C:64]1[CH:65]=[C:66](B(O)O)[CH:67]=[C:68]([F:71])[C:69]=1[F:70]>>[Cl:26][C:18]1[CH:19]=[C:20]([C@@H:23]([OH:25])[CH3:24])[CH:21]=[N:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:8]2[NH:9][C:10]3[C:2]([C:66]4[CH:65]=[C:64]([F:63])[C:69]([F:70])=[C:68]([F:71])[CH:67]=4)=[CH:3][C:4]([C:28]([F:31])([F:29])[F:30])=[CH:5][C:6]=3[N:7]=2)[C@H:12]([CH3:27])[CH2:13]1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: C[C@H](O)c1cnc(N2CCN(c3nc4c(Br)cc(C(F)(F)F)cc4[nH]3)[C@H](C)C2)c(Cl)c1
Agent: C[C@@H]1CN(c2ncc([C@@H](C)O)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1
Product: C[C@H](O)c1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(-c5cc(F)c(F)c(F)c5)c4[nH]3)[C@H](C)C2)c(Cl)c1

Procedure:
The diastereoisomeric mixture of (1S)-1-{6-[(3R)-4-(4-bromo-6-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-ethanol and (1R)-1-{6-[(3R)-4-(4-bromo-6-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-ethanol (416 mg, 0.8 mmol, Example 166a) reacted with 3,4,5-trifluorophenylboronic acid (282 mg, 1.6 mmol, Lancaster) under the conditions of Example 158 to give the title compound as a mixture of diastereoisomers. Separation of the mixture by preparative HPLC on a Chiralcel OD column, eluting with 9:1 hexane/EtOH afforded the fast running title compound. The configuration (1S) was assigned at random. (ESI, neg. ion) m/z: 570 (M−1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].C>C1COCC1.O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2nc3ccc(C(=O)O)cc3[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2nc3ccc(C(=O)O)cc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-methoxycarbonyl-phenyl)-3H-benzoimidazole-5-carboxylic acid (4.1 g) in THF (15 mL) and water (18 mL) and LiOH (1.74 g) was stirred for 16 hours at room temperature and then mixed with hot water (100 mL) and charcoal. The mixture was filtered and the filtrate was diluted with ice and water (100 mL) and acidified with conc. HCl. The crude diacid was filtered, washed with water and ether and then recrystallized from THF and MeOH. Yield 3.3 g; TLC single spot [CH2Cl2—CH3OH (9:1)].
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccccn4)c23)C1

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide (194 mg, 0.579 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.348 g, 1.74 mmol) in n-BuOH (2 mL) was stirred at 149° C. for 24 hours in a sealed tube and concentrated in vacuo. The residue obtained was dissolved in ethyl acetate (20 mL) and successively washed with water (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+) on Biotage SP4 unit eluting with gradient of 10-90% CH3CN/water to provide (R)-tert-butyl 1-(5-bromo-3-(picolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate. This material was dissolved in DCM (3 mL), treated with TFA (0.5 mL) and stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo. The resulting residue was dissolved in DCM (1 mL) and treated with 2N HCl in ether (3 mL). The solid formed was collected by filtration and dried to give (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide hydrochloride (0.022 g, 0.0419 mmol, 7% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.90 (br s, 1H), 11.35 (br s, 1H), 8.87 (d, 1H), 8.36 (br s, 3H), 8.31 (s, 1H), 8.21-8.11 (m, 3H), 7.74 (t, 1H), 4.04-3.94 (m, 1H), 3.76-3.67 (m, 1H), 3.58-3.48 (m, 1H), 3.43-3.34 (m, 1H), 3.08-3.00 (m, 1H), 2.44-2.37 (m, 1H), 2.27-2.14 (m, 1H), 1.90-1.81 (m, 1H), 1.63-1.51 (m, 1H); LCMS (APCI+) m/z 415.1, 417 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:16](=[O:27])[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=4)[CH2:14]3)[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])([OH:28])[CH:9]([OH:37])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Cl-].[NH4+]>CO.[Zn]>[C:38]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:16](=[O:27])[CH2:17][C:18]4[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=4)[CH2:14]3)[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])([OH:28])[CH:9]([OH:37])[CH2:8]2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccc([N+](=O)[O-])cc3)CC21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccc(N)cc3)CC21
Temperature: 25 °C
Yield: 74.9 %

Procedure:
To a solution of 1 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(4-nitrophenyl)acetyl]perhydro-4,5-isoindolediol in 3.3 cm3 of methanol, maintained at a temperature of 50° C., are added 33 cm3 of water, 4.6 g of ammonium chloride and 2.2 g of zinc powder. The reaction mixture is brought to reflux for 30 minutes, cooled to room temperature and then washed with twice 50 cm3 of dichloromethane. The organic phase is separated off after settling, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 70 cm3 of 1N hydrochloric acid. The organic phase is extracted with twice 50 cm3 of ethyl acetate. The aqueous phase is basified with 1N sodium hydroxide and the organic phase is then extracted with 3 times 100 cm3 of ethyl acetate. It is separated off after settling, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The meringue-like product obtained is crystallized in 20 cm3 of isopropyl ether. 0.71 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(4-aminophenyl)acetyl]perhydro-4,5-isoindolediol is obtained, melting at 188° C.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][CH2:37][C:38]#[N:39])[CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([CH:30]2[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][CH2:37][C:38]#[N:39])[CH2:31]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: N#CCCC1CCCC(Nc2c(N)cnc3ccsc23)C1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCCC(CCC#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A mixture of (2R)-2-hydroxypropanamide (194 mg, 2.18 mmol) and triethyloxonium tetrafluoroborate (0.41 g, 2.2 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 1 h and then concentrated. A mixture of 3-{3-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}propanenitrile (131 mg, 0.436 mmol) and the above made reagent in ethanol (4.7 mL) was heated at reflux for 2 h. The mixture was filtered, diluted with MeOH and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (60 mg, 39%). LCMS calculated for C19H23N4OS (M+H)+: m/z=355.2. Found: 355.0.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH2:19])[C:16]([O:20][CH3:21])=[C:15]([NH2:22])[N:14]=2)=[N:6]1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C=O)C>[NH2:19][C:17]1[N:18]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])[N:6]=2)[N:14]=[C:15]([NH:22][C:34](=[O:36])[CH3:35])[C:16]=1[O:20][CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1NC(C)=O
Temperature: 100 °C

Procedure:
50 mg of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxy pyrimidine-4,6-diamine 1-6-1 were suspended in 0.7 mL DMF. After addition of 14 mg of triethylamine (0.14 mmol, 1.0 eq.) and 14 mg of acetic anhydride (0.14 mmol, 1.0 eq.), the resulting reaction mixture was heated for three h at 100° C. For completition of reaction further 4 mg of triethylamine (0.04 mmol, 0.3 eq.) and 4 mg of acetic anhydride (0.04 mmol, 0.3 eq.) were added and the mixture was heated over night at 100° C. After cooling and dilution with water, the crude product was extracted with DCM and was purified by flash chromatography yielding 25 mg (0.063 mmol, 45%) of analytically pure target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:21][C:20]3[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17](Cl)=[N:16][C:15]=3[CH:14]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[NH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:19]2[C:20]3[S:21][C:13]([CH2:12][N:9]4[CH2:10][CH2:11][N:6]([S:3]([N:2]([CH3:29])[CH3:1])(=[O:5])=[O:4])[CH2:7][CH2:8]4)=[CH:14][C:15]=3[N:16]=[C:17]([C:34]3[CH:35]=[CH:36][C:31]([NH2:30])=[N:32][CH:33]=3)[N:18]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CN(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CN(C)S(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-sulfonic acid dimethylamide was reacted with 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in General Procedure A. Purification on silica yielded 111. NMR (CDCl3): 2.50-2.54 (4H, m, CH2), 2.74 (6H, s, Me), 3.21-3.24 (4H, m, CH2), 3.75 (2H, s, CH2), 3.78-3.82 (4H, m, CH2), 3.95-3.98 (4H, m, CH2), 4.58 (2H, br s, NH2), 6.50 (1H, d, J 8.6, Ar), 7.17 (1H, s, Ar), 8.38 (1H, dd, J 8.6 and 1.8, Ar) and 9.12 (1H, d, J 1.8, Ar). MS: (ESI+): MH+=519.34.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](Cl)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3.[F:18][C:19]([F:26])([F:25])[C@H:20]([NH2:24])[CH:21]([CH3:23])[CH3:22]>O1CCOCC1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]([NH:24][C@@H:20]([C:19]([F:26])([F:25])[F:18])[CH:21]([CH3:23])[CH3:22])=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3
Reactant: CC(C)[C@@H](N)C(F)(F)F
Reactant: Clc1nc2ccnc(Cl)c2c2cc(Br)ccc12
Solvent: C1COCCO1
Product: CC(C)[C@@H](Nc1nc2ccnc(Cl)c2c2cc(Br)ccc12)C(F)(F)F
Temperature: 150 °C

Procedure:
To a solution of dried 9-bromo-1,6-dichlorobenzo[c]-1,6-naphthyridine (0.80 g, 2.46 mmol) in dioxane (16 mL) was added (2R)-1,1,1-trifluoro-3-methylbutan-2-amine (2.4 g, 17.2 mmol) and heated to 150° C. for 24-48 hrs. The reaction was concentrated to dryness to give 9-bromo-1-chloro-N-[(1R)-2-methyl-1-(trifluoromethyl)propyl]benzo[c]-1,6-naphthyridin-6-amine. LRMS (ESI) calc'd for (C17H15BrClF3N3) [M+H]+, 432.0; found 432.0.
Reaction SMILES: [H-].[Na+].[C:3]([NH:22][CH2:23][CH2:24][CH2:25][OH:26])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:27][CH2:28][C:29]1[C:30]([CH2:35]Br)=[CH:31][CH:32]=[CH:33][CH:34]=1.O>C1COCC1>[Br:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][O:26][CH2:25][CH2:24][CH2:23][NH:22][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: BrCc1ccccc1COCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a suspension of NaH (909 mg/22.7 mmol) in THF (50 ml) was added 3-(tritylamino)-1-propanol, and the solution was stirred at reflux temperature for 2 hours. To the solution was added α,α′-dibromo-o-xylene, and the solution was stirred at reflux temperature for 16 hours. After cooling, the mixture was poured into water. The whole was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, 200-350 mesh/hexane:ethyl acetate=100:0-20:1) to afford a yellow oil (4.84 g/51%).