Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[C@@H:31]([CH:32]=[O:33])[CH2:30][O:29][C@@H:28]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:40][C:41]1[CH:46]=[C:45]([CH2:47][CH2:48][N+:49]([O-:51])=[O:50])[CH:44]=[C:43]([F:52])[CH:42]=1>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[C@@H:31]([C@@H:32]([OH:33])[C@@H:48]([N+:49]([O-:51])=[O:50])[CH2:47][C:45]2[CH:46]=[C:41]([F:40])[CH:42]=[C:43]([F:52])[CH:44]=2)[CH2:30][O:29][C@@H:28]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](C=O)CO1
Reactant: O=[N+]([O-])CCc1cc(F)cc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)[N+](=O)[O-])CO1
Reaction time: 0.33 h
Yield: 30.1 %

Procedure:
Add tetrabutylammonium fluoride (18.32 mL, 18.32 mmol, 1.0 M in tetrahydrofuran) to (2R,5R)-2-(2,2-dimethylpropoxy)-5-formylmorpholine-4-carboxylic acid tert-butyl ester (5.02 g, 16.66 mmol) and 1,3-difluoro-5-(2-nitroethyl)-benzene (3.43 g, 18.32 mmol) in tetrahydrofuran (28 mL) at −10° C. and stir 20 minutes. Pour into ice cold saturated aqueous sodium chloride and extract with ethyl acetate. Wash with 0.1 N aqueous citric acid and saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 20:80 to 30%:70 diethyl ether:hexanes) to give a mixture of 2 diastereomers (3.66 g, 75:25 mixture) which are separated using chiral chromatography to give the desired compound (˜2.45 g, 34.0%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.O[NH:14][C:15](=[NH:24])[C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([CH3:23])[CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([C:8]2[O:10][N:24]=[C:15]([C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([CH3:23])[CH:17]=3)[N:14]=2)[N:7]=1
Reactant: COc1cc(Br)nc(C(=O)O)c1
Reactant: Cc1cc(C(=N)NO)cc(C)n1
Product: COc1cc(Br)nc(-c2nc(-c3cc(C)nc(C)c3)no2)c1
Yield: 10.3 %

Procedure:
2-Bromo-6-[3-(2,6-dimethyl-4-pyridinyl)-[1,2,4]oxadiazol-5-yl]-4-methoxy-pyridine (24 mg) is prepared following the general method for the preparation of 3,5-dipyridyl-[1,2,4]oxadiazoles starting from 6-bromo-4-methoxy-pyridine-2-carboxylic acid (150 mg, 0646 mmol) and N-hydroxy-2,6-dimethyl-isonicotinamidine (107 mg, 0.646 mmol); LC-MS: tR=0.76 min, [M+1]+=360.91.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1>>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:18][CH:19]=2)=[O:24])=[CH:26][CH:27]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 10.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (341 mg) and 4-t-butylphenyl 4-hydroxyphenyl ketone (775 mg) obtained in Example 30 were mixed and stirred at 150° C. for 15 minutes. The reaction mixture was then purified by column chromatography on silica gel eluting with hexane/acetone to obtain 72 mg of the title compound (yield: 11%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.[OH-].[Na+].P([O-])(O)(O)=[O:49].[K+].[F-].[F-].[F-].[F-].[F-].[F-].N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C=O)C.O.C1COCC1.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([NH2:20])=[O:49])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:22]=[C:23]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH2:29][CH2:30]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(=O)(=O)C(F)(F)F)CC2)c2nc(-c3c(F)cccc3F)c3cc(C#N)ccc3c21
Reactant: O=P([O-])(O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(NC2CCN(S(=O)(=O)C(F)(F)F)CC2)c2nc(-c3c(F)cccc3F)c3cc(C(N)=O)ccc3c21
Reaction time: 3 h

Procedure:
A 30 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 272 mg of 5-(2,6-difluorophenyl)-3-{[1-(trifluoromethanesulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile, 10 ml of ethanol, 5 ml of THF and 0.611 ml of 9.3N NaOH. After 2 h of reflux, the mixture is cooled, and 50 ml of a 1M aqueous solution of potassium dihydrogen phosphate are poured in. The product is extracted with AcOEt, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated to dryness under RP. The crude solid obtained is dissolved in 4 ml of DMF and than 275 mg of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoride (BOP), 84 mg of 1-hydroxybenzotriazole (HOBT), 44 mg of ammonium chloride and 2 ml of N,N-diisopropylethylamine (DIPEA) are added. After 3 h at RT, the mixture is poured into water, extracted with AcOEt, and washed with saturated aqueous NaCl solution. Drying of MgSO4, filtering and concentration under RP give 300 mg of 5-(2,6-difluorophenyl)-3-{[1-(trifluoromethanesulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide. MS (E/I): m/z=684 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=2[F:32])[C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.CCN(C(C)C)C(C)C.[CH3:62][N:63]([CH3:65])[NH2:64]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH:64][N:63]([CH3:65])[CH3:62])=[O:29])=[CH:25][C:24]=2[F:32])[C@@H:12]2[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C)N
Reactant: CC1(C)CCNC(=O)[C@H](N(Cc2ccc(C(=O)O)cc2F)S(=O)(=O)c2ccc(Cl)cc2)C1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)NC(=O)c1ccc(CN([C@@H]2CC(C)(C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid (0.15 g, 0.30 mmol) was dissolved in DMF (20 ml) and treated with 2-(2-pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) (0.1 g, 0.33 mmol), Hünig's base (0.15 ml, 0.90 mmol) and N,N-dimethyl hydrazine (0.07 ml, 0.90 mmol). After 1 h the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and washed with NaHCO3, KHSO4/K2SO4, brine, dried (Na2SO4) filtered anconcentrated under reduced pressure. Crystallisation from isopropyl acetate yielded 4-chloro-N-[4-(N′,N′-dimethyl-hydrazinocarbonyl)-2-fluoro-benzyl]-N-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-benzenesulfonamide as a crystalline solid: δ 0.12 g; MS: m/e=525.4 (MH+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH3:10].Br[CH2:23][CH:24]([CH3:26])[CH3:25]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:10]
Reactant: CC(C)CBr
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(C)C)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 87.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (21.2 mL of a 0.31 M stock solution, 6.14 mmol) cooled to −78° C. was treated with (4-chloro-phenyl)-acetic acid ethyl ester (1.11 g, 5.58 mmol) in tetrahydrofuran/hexamethylphosphoramide (13.9 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of 1-bromo-2-methyl-propane (1.81 mL, 16.7 mmol) in hexamethylphosphoramide (1 mL). The mixture was stirred at −78° C. for 3 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organics layers dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-4-methyl-pentanoic acid ethyl ester (1.24 g, 87.1%) as a white solid: mp 34-35° C.; EI-HRMS m/e calcd for C14H19ClO2 (M+) 254.1074, found 254.1069.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]=2[CH:11]=[C:12](Br)[CH:13]=1)=[O:4].[CH3:22][N:23](C=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[Zn]>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]=2[CH:11]=[C:12]([C:22]#[N:23])[CH:13]=1)=[O:4]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Br)cc2c1ccn2-c1ccc(F)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)c1cc(C#N)cc2c1ccn2-c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromo-1-(4-fluorophenyl)-1H-indole-4-carboxylic acid methyl ester (1.50 g, 4.30 mmol), Pd2(dba)3 (393.5 mg, 0.43 mmol), Zn(CN)2 (622 mg, 5.30 mmol), dppf (249.48 mg, 0.45 mmol) and Zn (196.11 mg, 3.00 mmol) in DMF (30 mL) is degassed with argon for 5 minutes. The mixture is warmed at 120° C. After 3 hours, the mixture is diluted with saturated aqueous ammonium chloride (30 mL) and extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with EtOAc-hexanes (20:80) to afford 6-cyano-1-(4-fluorophenyl)-1H-indole-4-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:29][C:30]1[C:31]([F:40])=[C:32]2[C:38]([NH2:39])=[CH:37][NH:36][C:33]2=[N:34][CH:35]=1.[Li+].[OH-].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:29][C:30]1[C:31]([F:40])=[C:32]2[C:38]([NH:39][C:1](=[O:6])[CH:2]([CH3:4])[CH3:3])=[CH:37][NH:36][C:33]2=[N:34][CH:35]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
Isobutyric acid (306 mg, 3.48 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (885 mg, 3.48 mmol) and triethylamine (880 mg, 8.69 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (400 mg, 1.74 mmol) in DCM (200 mL). The reaction was stirred at room temperature for 1 hour, and then 3M aqueous LiOH (4 mL) was added. The reaction as stirred for 1 hour, and then saturated aqueous Na2CO3 was added (200 mL). The aqueous phase was extracted 3 times with DCM (200 mL). Then the combined organic phases were dried over MgSO4 and concentrated to dryness. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 20-100% CH3CN/water gradient; 20 CV) to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (158 mg, 30% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.03 (br s, 1H), 9.40 (s, 1H), 8.34 (d, 1H), 7.56 (d, 1H), 2.69-2.62 (m, 1H), 1.12 (d, 6H); LCMS (APCI+) m/z 299.9, 301.9 (M+H)+, Retention time=3.02 minutes (Method 3).
Reaction SMILES: Cl.Br[C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.C1(N(C)C2CCCCC2)CCCCC1.[O:37]1[CH2:41][CH:40]=[CH:39][CH2:38]1>[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[O:37]1[CH:38]=[CH:39][CH:40]([C:3]2[C:4]([O:9][C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:12][CH:11]=3)=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:41]1
Reactant: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: C1=CCOC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C1=CC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CO1
Temperature: 80 °C

Procedure:
To a 25 mL microwave vial was added Bis(tri-tert-butylphosphine) palladium (0) (121 mg, 0.238 mmol) and N-(4-(3-bromopyridin-2-yloxy)phenyl)pyridin-2-amine hydrochloride (900 mg, 2.377 mmol) before sealing and evacuating and backfilling with nitrogen. After addition of dioxane (11.900 ml), N-cyclohexyl-N-methylcyclohexanamine (1.008 ml, 4.75 mmol), and 2,5-dihydrofuran (0.701 ml, 9.51 mmol), the black suspension was heated to 80° C. for 5 h. The reaction mixture was cooled to room temperature, transferred to a 100 mL round bottom flask, and concentrated under reduced pressure. The material was taken up in DCM and adsorbed onto silica before purifying by flash chromatography (0 to 75% ethyl acetate/hexanes), affording a mixture of 2- and 3-dihydrofuranyl products that was used without separation.
Reaction SMILES: Br[CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[N+:11]([C:10]1[C:3]([CH2:2][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])([O-:13])=[O:12]
Reactant: N#Cc1cccc([N+](=O)[O-])c1CBr
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc([N+](=O)[O-])c1CN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of 2-(bromomethyl)-3-nitrobenzonitrile (1.10 g, 4.56 mmol) and pyrrolidine (0.65 g, 9.13 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.85 g, 18.25 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 2 h and evaporated to dryness under reduced pressure. The residue was diluted with water (10 mL) and extracted with CH2Cl2 (3×50 mL). The CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-nitro-2-(pyrrolidin-1-ylmethyl)benzonitrile (0.96 g, 91%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.90 (d, 1 H, J=7.6 Hz), 7.83 (dd, 1H, J=7.6, 0.8 Hz), 7.52 (t, 1H, J=7.6 Hz), 4.14 (s, 2H), 2.52 (br s, 4H), 1.72 (br s, 4H).
Reaction SMILES: [NH2:1]/[C:2](/[C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:3]\[C:4](=[S:6])[NH2:5].C(=O)([O-])[O-].[K+].[K+].II.O>C(OCC)C>[C:7]([C:2]1[CH:3]=[C:4]([NH2:5])[S:6][N:1]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)/C(N)=C/C(N)=S
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1cc(N)sn1
Yield: 53 %

Procedure:
To a stirred solution of (Z)-3-amino-4,4-dimethyl-pent-2-enethioic acid amide (8.3 g, 525 mmol) and potassium carbonate (14.4 g, 105 mmol) in 140 mL of diethyl ether is added a solution of iodine (13.2 g, 52.5 mmol) in 20 mL of diethyl ether at reflux. The mixture is refluxed for 2 h and cooled. Water is added and the layers separated. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture is purified by flash chromatography to afford title compound in 53% yield. ESI m/z 157=MH+
Reaction SMILES: [N:1]1([C:10]2[CH:51]=[CH:50][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]3[S:22][C:21]([C:23]4[CH:32]=[C:31]5[C:26]([CH2:27][CH2:28][CH2:29][N:30]5[C:33](=[O:44])[NH:34][C:35]5[S:36][C:37]6[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=6[N:39]=5)=[CH:25][CH:24]=4)=[N:20][C:19]=3[C:45]([O:47]CC)=[O:46])=[CH:12][CH:11]=2)[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:4]2[CH:3]=[N:2]1.CO.C1COCC1.[Li+].[OH-]>O>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]3[S:22][C:21]([C:23]4[CH:32]=[C:31]5[C:26]([CH2:27][CH2:28][CH2:29][N:30]5[C:33](=[O:44])[NH:34][C:35]5[S:36][C:37]6[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=6[N:39]=5)=[CH:25][CH:24]=4)=[N:20][C:19]=3[C:45]([OH:47])=[O:46])=[CH:50][CH:51]=2)[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)sc1CCCOc1ccc(-n2ncc3cncnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)sc1CCCOc1ccc(-n2ncc3cncnc32)cc1
Temperature: 60 °C

Procedure:
The title compound 5-(3-(4-(H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy)propyl)-2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiazole-4-carboxylic acid (23) was prepared by the following procedure: To ethyl 5-(3-(4-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy)propyl)-2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiazole-4-carboxylate (231) (120 mg, 0.17 mmol) was added MeOH and THF. LiOH (20 mg, 0.85 mmol) was dissolved in water and added to the reaction mixture. The reaction mixture was stirred and heated at 60° C. for two hours. The reaction was cooled and put in refrigerator overnight. The precipitate was transferred to a centrifuge tube and centrifuged down at 17,000 RPM. The precipitate was washed water. Then the precipitate was added to acetonitrile and water and lyophilized to give 69 mg (59° %) of the desired product 5-(3-(4-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy)propyl)-2-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)thiazole-4-carboxylic acid (23): 1H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 9.10 (s, 1H), 8.61 (s, 1H), 8.04 (d. J=8.7, 2H), 7.66 (s, 1H), 7.45 (d. J=34.2, 2H), 7.20 (t, J=18.3, 5H), 4.12 (s, 3H), 3.95 (s, 3H), 2.79 (s, 2H), 2.16 (s, 3H), 1.89 (s, 2H), −0.00 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:17])[C:6]3[CH:7]=[CH:8][C:9]([C:12]4[O:16][CH:15]=[N:14][CH:13]=4)=[CH:10][CH:11]=3)[CH2:19][CH2:20]2)=[N:30][CH:29]=1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Clc1cnc(Cl)nc1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(Cl)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2,5-dichloro-pyrimidine following a procedure analogous to that described in Example 19. LC (method 5): tR=2.27 min; Mass spectrum (ESI+): m/z=424/426 (Cl) [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:18]1([C:21]([CH3:29])([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[NH2:22])[CH2:20][CH2:19]1>>[CH:18]1([C:21]([NH:22][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH3:29])[CH2:20][CH2:19]1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: Cc1nc(C(C)(NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.42 mmol) and α-cyclopropyl-α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1155536-64-3, 106.88 mg, 0.64 mmol) as starting materials, and isolated (12 mg, 7.3%) as white solid; LC-MS (UV peak area, ESI) 83.46%, 384.0 (M+H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O1CCOCC1>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of tert-butyl 1-piperazine-carboxylate (932 mg, 5 mmol) and triethyl amine (836 μL, 6 mmol) in dioxane (10 mL) was added 4-bromo-benzenesulfonyl chloride (1.28 g, 5 mmol). A white precipitate begins to form almost immediately. The reaction mixture was stirred for 1 hour at room temperature and the filtered. The filtrate was concentrated in vacuo to yield the product as a shiny white solid (1.85 g, 91%). 1H NMR (CDCl3) δ 1.44 (s, 9H), 3.01 (t, 4H, J=5.1 Hz), 3.53 (t, 4H, J=5.1 Hz), 7.64 (dt, 2H, J=2.1, 8.7 Hz), 7.70 (dt, 2H, J=2.1, 8.7).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][CH:6]=[O:7].[CH:12]1(/[CH:18]=[CH:19]/[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[CH2:4]([C@@H:5]1[C:6](=[O:7])[O:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][C@@H:18]1[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: CCOC(=O)C(=O)/C=C/C1CCCCC1
Reactant: O=CCCc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C[C@H](C2CCCCC2)[C@H](Cc2ccccc2)C(=O)O1
Yield: 85 %

Procedure:
Prepared according to the general procedure from 2-chloro-hydrocinnamaldehyde and (E)-ethyl 4-cyclohexyl-2-oxobut-3-enoate using 2 mol % 1 as the catalyst in 85% yield as a single diastereomer (colorless oil). [α]D20 (c 1.20, CHCl3)=+83.5; 1H NMR (400 MHz, CDCl3) δ 7.33-7.21 (m, 5H), 6.48 (d, 1H, J=6.5 Hz), 4.30 (dq, 1H, J=7.2, 1.8 Hz), 3.38 (dd, 1H, J=14.3, 5.7 Hz), 2.97-2.91 (m, 1H), 2.77 (dd, 1H, J=14.3, 9.1 Hz), 2.45-2.41 (m, 1H), 1.76-1.62 (m, 5H), 1.47-1.44 (m, 1H), 1.34 (t, 3H, J=7.2 Hz), 1.27-1.06 (m, 4H), 0.93-0.89 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 170.4, 160.7, 142.8, 138.6, 128.9, 126.9, 117.6, 62.0, 43.0, 39.4, 37.7, 31.7, 31.4, 27.2, 26.8, 26.1, 14.3; IR (thin film) ν 3520, 3086, 3028, 2981, 2928, 2853, 1770, 1731, 1660, 1453, 1369, 1309, 1262, 1120, 1094, 1013 cm−1; HRMS (ESI) calcd for C21H26O4 [M+Na]+ 365.1723, found 365.1721; 95% ee (4S,5S)-isomer as determined by HPLC (AS-H, 20:1 hexanes/i-PrOH), tr (4S,5S)=19.1 min, tr (4R,5R)=15.7 min.