Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.S(Cl)(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])O.[N:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1.ClC1C2C(=CC=CC=2)NC1=O>ClCCl.CN(C)C=O.O>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[N:42]1[CH2:43][CH2:44][N:39]([C:36]2[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=2)[CH2:40][CH2:41]1
Reactant: COc1ccc(C2(O)C(=O)Nc3ccc(Cl)cc32)c(OC)c1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C1Nc2ccccc2C1Cl
Solvent: c1ccncc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1ccc(C2(N3CCN(c4ccncc4)CC3)C(=O)Nc3ccc(Cl)cc32)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
Pyridine (1.51 mL, 18.76 mmol) and thionyl chloride (1.03 mL, 14.07 mmol) were added to a solution of 5-chloro-3-(2,4-dimethoxyphenyl)-3-hydroxy-1,3-dihydroindol-2-one (prepared as described in WO 2005/030755, 3.00 g, 9.38 mmol) in dichloromethane (70 mL) while cooling in ice. The reaction mixture was then stirred at 0° C. for 1 hour. While stirring, water was added to the reaction mixture, and it was then extracted with dichloromethane. The organic phase was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. 1-Pyridin-4-yl-piperazine (2.17 g, 13.31 mmol) was added to a solution of the 3-chloro-oxindole intermediate obtained in this way in dimethylformamide (25 mL), and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted again with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure, resulting in 1.00 g of the title compound which was employed without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(Cl)c(C)sc3n2)cc1
Reactant: NCc1ccc(F)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3c(Cl)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)[CH:8]=[N:7][CH:6]=1)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([C:9]3[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=3)[C:4]([OH:36])=[O:3])[CH:12]=2)[NH:17][N:18]=1
Reactant: CCOC(=O)c1cncc(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cncc(C(=O)O)c3)cc12
Temperature: 70 °C
Reaction time: 7 h
Yield: 192.7 %

Procedure:
To a solution of 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-nicotinic acid ethyl ester (494 mg, 0.98 mmol) in THF (20 mL) was added tetra-n-butylammonium fluoride in THF (1M, 10 ml, 10 mmol) and activated 4 Å molecular sieves. The resulting mixture was stirred at 70° C. for 7 h. The sieves were filtered off, washing with ethyl acetate and the resulting filtrate concentrated. The residue was distributed between dichloromethane and water. The aqueous phase was extracted three times with dichloromethane and the organic phases combined, dried over sodium sulfate, filtered and concentrated to afford of 5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-nicotinic acid (654 mg, 62% purity, 405 mg, 119% yield) as a brown solid. 1H-NMR (500 MHz, d6-DMSO) δ 13.98 (s, 1H), 8.99 (d, 1H), 8.95 (s, 1H), 8.88 (d, 1H), 8.43 (t, 1H), 8.40 (d, 1H), 7.67 (dd, 1H), 7.47 (ddd, 1H), 7.23 (d, 1H), 7.10 (dt, 1H), 3.86 (s, 3H). MS: m/z 345 (96%) [M−H−].
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.Cl.[NH:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[O:29]=[S:26]1(=[O:30])[CH2:27][CH2:28][N:23]([C:13]([C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:24][CH2:25]1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: O=S1(=O)CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)N1CCS(=O)(=O)CC1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 47 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), thiomorpholine 1,1-dioxide hydrochloride (8.84 mg, 0.51 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (9.8 mg, 46.6%). 1H NMR (400 MHz, CD3OD) δ 0.92 (d, J=6.82 Hz, 3 H) 1.02 (d, J=6.32 Hz, 3 H) 2.60 (dt, J=10.61, 6.57 Hz, 1 H) 2.90-3.03 (m, 1 H) 3.03-3.25 (m, 3 H) 3.86-4.01 (m, 1 H) 4.13 (ddd, J=14.78, 8.59, 2.40 Hz, 1 H) 4.21-4.41 (m, 2 H) 4.92-5.06 (m, 1 H) 5.06-5.18 (m, 1 H) 5.57 (d, J=10.61 Hz, 1 H) 7.89 (s, 1 H) 8.18 (d, J=3.28 Hz, 1 H). [M+H] calc'd for C18H21FN4O4S, 409; found, 409.3.
Reaction SMILES: [CH:1]1([N:6]([C:11](=[O:16])[CH:12]([CH3:15])[CH2:13][SH:14])[CH2:7][C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(SSC2N=CC=CC=2)N=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]1([N:6]2[C:11](=[O:16])[CH:12]([CH3:15])[CH2:13][S:14][C:8](=[O:9])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CS)C(=O)N(CC(=O)O)C1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: Cc1ccccc1
Product: CC1CSC(=O)CN(C2CCCC2)C1=O
Temperature: 25 °C

Procedure:
A solution of N-cyclopentyl-N-(3-mercapto-2-methylpropanoyl)glycine (2.0 g., 8.1 mmol) in 125 ml of toluene was freed of air by bubbling nitrogen through it. To this solution was then added 2,2'-dipyridyldisulfide (2.7 g., 12.2 mmol) and triphenylphosphine (3.2 g., 12.2 mmol) and the resulting solution was stirred under nitrogen for 5 hours. This solution was then diluted to 250 ml with toluene and added at a rate of 20-25 ml/hr to 2 l of reluxing toluene under nitrogen. The resulting mixture was stirred at reflux for 48 hours and then cooled to room temperature. The solution was washed successively with 0.1N hydrochloric acid saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, and then filtered and concentrated under vacuum. The resulting solid material was dissolved in 25% ethyl acetate/hexane, filtered to remove the triphenyl phosphine oxide which crystallized, and purified by medium pressure liquid chromatography, eluting with 25% ethyl acetate/hexane, to give 0.8 g. of a pale yellow solid. This solid was recrystallized from 10% ethyl acetate/hexane to give 0.5 g (27%) of 4-cyclopentyl-6,7-dihydro-6-methyl-1,4-thiazapen-2,5-(3H,4H)-dione as a white crystalline solid, mp. 77°-79°.
Reaction SMILES: C([O:8][C:9](=[O:21])[CH2:10][NH:11][C:12](=[O:20])[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[O:19]=[C:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH2:13][C:12]([NH:11][CH2:10][C:9]([OH:21])=[O:8])=[O:20]
Reactant: O=C(CN1CCCC1=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)CNC(=O)CN1CCCC1=O
Yield: 99.9 %

Procedure:
2.9 g (0.01 mole) of N-(2-oxo-1-pyrrolidineacetyl)-glycine benzyl ester (compound 1.b) above) are dissolved in 50 ml of acetic acid and hydrogenated in the presence of palladium supported on carbon (Pd/C) at ambient temperature, under a hydrogen pressure of 4 kg. The catalyst is filtered off, the filtrate is evaporated to dryness and the syrup obtained is triturated with anhydrous diethyl ether, a white powder being obtained: 2 g of N-(2-oxo-1-pyrrolidineacetyl)-glycine are thus isolated; M.P. 149°-150° C. Yield: 100% of theory.
Reaction SMILES: C[O:2][CH:3](OC)[CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>O>[CH:3]([CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1)=[O:2]
Reactant: COC(OC)C1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(C=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 103.8 %

Procedure:
A mixture of N-{2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (1.18 g), trifluoroacetic acid (3 mL), concentrated sulfuric acid (3 mL) and water (10 mL) was stirred at 50° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (1.1 g, yield 99%) as a brown amorphous solid from a fraction eluted with ethyl acetate:hexane=50:50. MS: 406 (MH+).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([CH:7]2[CH:12]=[CH:11][N:10](C(=O)C(C)(C)C)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br-].[Na+].[C:22](=[O:25])(O)[O-:23].[Na+]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C(O)(=O)C>[C:22]([C:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)=[CH:5][CH:6]=1)([OH:23])=[O:25]
Reactant: O=C([O-])O
Reactant: Cc1ccc(C2C=CN(C(=O)C(C)(C)C)CC2)cc1
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Temperature: 162.5 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
177.2 g (0.75 mol) of 4-p-tolyl-N-pivaloyldihydropyridine, 1511.2 g of acetic acid, 3.74 g (15.0 mmol) of cobalt(II) acetate tetrahydrate, 3.68 g (15.0 mmol) of manganese(II) acetate tetrahydrate and 3.09 g (30.0 mmol) of sodium bromide are placed in a 3.5 l autoclave. The autoclave is made inert using nitrogen and is heated to 160-165° C. When this temperature has been reached, about 450 l/h of air are introduced and an internal pressure of 16-18 bar is maintained by means of a pressure maintenance device. Air is introduced for about 30-40 minutes, the autoclave is then once again made inert by injection of nitrogen and the mixture is cooled. The greenish solution (becomes orange-red on cooling) is taken from the autoclave and evaporated to a weight of 370 g on a rotary evaporator. The thick suspension is filtered on a suction filter and the crystals are washed 3 times with 50 g each time of 75% strength by weight acetic acid. The crude product obtained in this way is taken up in 75 ml of 0.4% strength by weight sodium bicarbonate solution, stirred for 30 minutes at about 50° C. and filtered off. Drying leaves 4-(4′-carboxyphenyl)pyridine in a yield of 90%. HPLC purity: >98% (a/a).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:11]/1)=[O:5].[CH3:31][O:32][CH2:33]/[CH:34]=[CH:35]/B1OC(C)(C)C(C)(C)O1.[F-].[Cs+].C(OCC)(=O)C>C(COC)OC.CO>[C:12]([C:10]1[N:9]([CH3:16])[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)/[C:7](=[N:6]/[C:4](=[O:5])[C:3]2[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:2]=2/[CH:35]=[CH:34]/[CH2:33][O:32][CH3:31])/[CH:11]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2Br)n1C[C@H]1CCCO1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC/C=C/c1ccc(C(F)(F)F)cc1C(=O)/N=c1\cc(C(C)(C)C)n(C)n1C[C@H]1CCCO1
Yield: 51.6 %

Procedure:
To a solution of Example 88 (146 mg, 0.299 mmol) and (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (148 mg, 0.747 mmol) in dimethoxyethane (1 mL) and methanol (0.5 mL) was added palladium tetrakistriphenyl phosphine (86 mg, 0.075 mmol) and cesium fluoride (159 mg, 1.05 mmol). This mixture was microwaved at 100° C. for 10 minutes. To the reaction was added ethyl acetate and the mixture was filtered through celite and purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% solvent A in hexanes, solvent A: 10% MeOH in ethyl acetate) to afford the title compound (74 mg, 52%). 1H NMR (300 MHz, CDCl3) δ ppm 1.44 (s, 9H) 1.71-1.85 (m, 3 H) 1.98-2.07 (m, 1H) 3.37 (s, 3H) 3.69-3.82 (m, 2H) 3.88 (s, 3H) 4.11-4.13 (m, 2H) 4.18-4.32 (m, 2H) 4.48-4.58 (m, 1H) 6.22 (dt, J=15.96, 6.30 Hz, 1H) 7.03 (s, 1H) 7.46-7.53 (m, 1H) 7.57-7.65 (m, 2H) 8.20 (s, 1H); MS (DCI/NH3) m/z 480 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.N[C:12]1[C:13](C)=[CH:14]C=[CH:16][CH:17]=1.Cl.C[N:21](C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:13]1([CH3:14])[C:3]([C:8]([NH2:21])=[O:10])=[CH:2][CH:16]=[CH:17][CH:12]=1.[NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Cc1ccccc1N
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: Nc1nccnc1C(=O)O
Solvent: ClCCl
Product: Cc1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-aminopyrazine carboxylic acid (5.0 g, 35.94 mmol), methylene chloride (110 mL), 4-dimethylaminopyridine (10.98 g, 89.85 mmol), o-toluidine (4.22 mL, 39.53 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.27 g, 43.13 mmol) was stirred overnight at ambient temperature. The solvent was removed and the residue was diluted with ethyl acetate. This organic phase was extracted with 1N lithium chloride (LiCl), water, and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (2.75×4 inches) with elution proceeding as follows: hexane (300 mL), nil; 20% ethyl acetate/hexane (500 mL), unweighed recovered o-toluidine; 20% ethyl acetate/hexane (1000 mL) and 30% ethyl acetate/hexane (2000 mL), 4.79 g (58%) of 3-aminopyrazine-2-carboxylic acid o-toluamide as a yellow crystalline solid.
Reaction SMILES: C1(COC(=O)[NH:10][CH2:11][C@@H:12]2[C@H:16]([OH:17])[CH2:15][N:14]([CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=4)[N:23]=[CH:22][CH:21]=3)[CH2:13]2)C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:10][CH2:11][C@H:12]1[CH2:13][N:14]([CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[N:23]=[CH:22][CH:21]=2)[CH2:15][C@H:16]1[OH:17]
Reactant: COc1ccc2nccc(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nccc(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of phenylmethyl[((3S,4S)-4-hydroxy-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (1.46 g, 3.34 mmole) in MeOH (100 mL) in a round bottom flask was added Pd(OH)2 (˜100 mg). The reaction contents were stirred under a balloon of H2 overnight at RT. The reaction contents were filtered through Celite® (MeOH) and concentrated to give the title compound (x g, quant.) as a light yellow foam: LC-MS (ES) m/e 303 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1)([CH3:3])[CH3:2].CO.O>O1CCCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CC#N)c([N+](=O)[O-])c1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(CCN)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.8 %

Procedure:
To a stirred solution of 0.154 g of (4-isopropyl-2-nitrophenyl)acetonitrile in 2 mL of tetrahydrofuran was added 1.62 mL of 0.93 mol/L borane-tetrahydrofuran complex under ice-cooling, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was cooled under ice-cooling, and to the mixture were added 2 mL of methanol and 20 mL of water. After the mixture was extracted with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate) to give 64 mg of 2-(4-isopropyl-2-nitrophenyl)ethylamine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[CH3:52][C:53]1[CH:54]=[C:55](B(O)O)[CH:56]=[CH:57][C:58]=1[CH3:59].C([O-])([O-])=O.[Cs+].[Cs+]>C(O)C.O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:55]3[CH:56]=[CH:57][C:58]([CH3:59])=[C:53]([CH3:52])[CH:54]=3)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(C)c5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (Step 2, Example 1u) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added (3,4-dimethylphenyl)boronic acid (120 mg, 0.8 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), and Cs2CO3 (390 mg, 1.2 mmol). The reaction was heated to 60° C. for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9](NC(C)C)(C)C.[Li].IC.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)NC(C)C
Reactant: Nc1cccnc1Cl
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CNc1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 2-chloro-3-pyridinamine (0.0465 mol) in THF (45ml) at −78° C. under N2 flow, lithium diisopropylamine (0.0513 mol, 2 M) was added dropwise. The mixture was allowed to warm to 0° C. and was stirred for 1 hour and then cooled to −78° C. Then iodomethane (0.0582 mol) was added and the reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. A saturated NH4Cl-solution was added and the mixture was extracted with ethyl acetate. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: hexane/ethyl acetate 80/20). The product fractions were collected and the solvent was evaporated, yielding 5.91 g of 2-chloro-N-methyl-3-pyridinamine (intermediate 28).
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([B:15]3[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C>[CH:1]1([C@H:6]([N:10]2[CH:14]=[C:13]([B:15]3[O:19][C:18]([CH3:21])([CH3:20])[C:17]([CH3:23])([CH3:22])[O:16]3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Solvent: CCO
Product: CC1(C)OB(c2cnn([C@H](CC#N)C3CCCC3)c2)OC1(C)C
Reaction time: 0.12 h
Yield: 94.5 %

Procedure:
A solution of racemic 3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (23, 13.1 g, 41.56 mmol) in a mixture of ethanol and hexanes (8:2 by volume) was injected into preparative HPLC system equipped with a chiral column (20×250 mm) packed with amylose tri(3,5-dimethylphenyl)carbamate immobilized on silicagel (Chiralpak® IA) from Chiral Technologies Inc. The chiral column was eluted with mobile phase made by a mixture of ethanol (EtOH) and hexanes in a 1 to 9 volume ratio at a flow rate of 18 mL/min at room temperature. The column elution was monitored by UV at wavelength 220 nm. Under these conditions, a baseline separation of the two enantiomers was achieved and the retention times were 7.0 minutes (Peak 1, the undesired (S)-enantiomer (S)-24) and 8.3 minutes (Peak 2, the desired (R)-enantiomer (R)-24), respectively. Each injection was 0.8 mL of feed solution at a concentration of 100 mg/mL and each run cycle was 14 minutes by using stack injections. Total 164 injections were taken for this separation process. Fractions for Peak 1 (the undesired (S)-enantiomer, (S)-24) and Peak 2 (the desired (R)-enantiomer, (R)-24) were collected separately from each injection, and fractions collected for each peak were concentrated under reduced pressure. The residue from each evaporator was further dried under high vacuum to constant weight to afford (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile ((R)-24, 6.19 g, 6.55 g theoretical, 94.5% yield) from Peak 2 as off-white solids and (S)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile ((S)-24, 6.08 g, 6.55 g theoretical, 92.8% yield) from Peak 1 as off-white solids.