Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:43][CH:44]([CH3:53])[C@@H:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)O>ClCCl>[CH3:43][CH:44]([CH3:53])[C@@H:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[O:2][C:1](=[O:3])[CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8]
Reactant: CC(C)[C@H](O)c1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O[C@H](c1ccccc1)C(C)C
Yield: 32 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (298 mg, 0.73 mmol), 4-N,N-dimethylaminopyridine (95 mg, 0.77 mmol, 1.2 eq), 1,3-dicyclohexylcarbodiimide (243 mg, 1.18 mmol, 1.8 eq) in dichloromethane (10 mL) was treated with (S)-2-methyl-1-phenyl-1-propanol (100 mg, 0.64 mmol, 1.3 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 104 mg (32%) of L-isoleucine, N-[1-(2-(2-methyl-1-(S)-phenyl-1-propoxy)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:4]2([CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([O:22][CH3:23])[CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.[H-].[Na+].IC.[C:37](OCC)(=O)C>CN(C=O)C.O>[CH:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([N:7]2[CH2:8][CH2:9][C:4]3([O:24][C@H:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:26][C@H:2]([O:1][CH3:37])[CH2:3]3)[CH2:5][CH2:6]2)=[O:11])=[CH:13][C:14]=1[O:22][CH3:23])([CH3:20])[CH3:21]
Reactant: COc1cc(C(=O)N2CCC3(CC2)C[C@@H](O)C[C@@H](c2ccccc2)O3)ccc1OC(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)C[C@@H](OC)C[C@@H](c2ccccc2)O3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [cis-8-hydroxy-10-phenyl-11-oxa-3-azaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methoxy-phenyl)methanone (139 mg, 0.3 mmol) in DMF (4 mL) was added sodium hydride (34 mg, 1.5 mmol). The mixture was stirred at room temperature for 30 minutes. Iodomethane (187 μL, 3.00 mmol) was added. The mixture was stirred at room temperature overnight, then repartitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with water (3×), brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (50-60% ethyl acetate-Hex) to provide (4-isopropoxy-3-methoxy-phenyl)-[cis-8-methoxy-10-phenyl-11-oxa-3-azaspiro[5.5]undecan-3-yl]methanone (102 mg). 1H NMR (400 MHz, CDCl3) δ 7.48-7.33 (m, 4H), 7.33-7.28 (m, 1H), 7.01-6.90 (m, 2H), 6.86 (d, J=8.2 Hz, 1H), 4.66-4.46 (m, 2H), 4.12-3.90 (m, 2H), 3.86 (s, 3H), 3.76-3.61 (m, 1H), 3.48 (s, 1H), 3.37 (d, J=4.5 Hz, 3H), 3.21 (t, J=11.8 Hz, 1H), 2.28 (dd, J=39.8, 13.2 Hz, 2H), 2.00 (dd, J=12.6, 2.7 Hz, 1H), 1.85-1.62 (m, 3H), 1.59-1.44 (m, 1H), 1.42-1.33 (m, 7H). ESI-MS m/z calc. 453.25, found 454.5 (M+1)+; Retention time: 1.65 minutes (3 minute run).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]([CH3:12])[N:8]=[C:9]([CH3:11])[CH:10]=1)C.O.[NH2:15][NH2:16]>C(O)C>[CH3:12][N:7]1[C:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])=[CH:10][C:9]([CH3:11])=[N:8]1
Reactant: NN
Reactant: CCOC(=O)Cc1cc(C)nn1C
Solvent: O
Solvent: CCO
Product: Cc1cc(CC(=O)NN)n(C)n1
Yield: 78 %

Procedure:
As described for example 112a, (2,5-dimethyl-2H-pyrazol-3-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) at reflux for 16 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 78%). MS: m/e=169.3 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][NH2:20].O>CN(C)C=O>[C:1]1([CH:7]2[CH2:8][C:9](=[O:18])[CH2:10][CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:20]2[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Reactant: CN
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(c2ccccc2)CC(=O)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 60.4 %

Procedure:
1,5-Diphenyl-1,4-pentadien-3-one (20b, 4.00 g, 17.1 mmol) was dissolved in dimethyl formamide (60 ml). Methylamine (51, 6.0 ml, 70.0 mmol, 40% in water) was added and the mixture stirred for 96 hr at room temperature. The mixture was poured into water (250 ml) and stirred for 1 hr at room temperature. The resulting mixture was extracted into ethyl ether, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethanol to give 2.74 g (60%) of a white solid: mp 147-149° C. [expected mp 148-150° C.]; 1H NMR δ 1.82 (s, 3H), 2.50, (dd, 2H, J=12.3, 2.5 Hz), 2.82 (t, 2H, J=13.3 Hz), 3.45 (dd, 2H, J=12.9, 2.4 Hz), 7.34, (m, 10H); 13C NMR: δ 40.8, 50.8, 70.2, 127.0, 127.6, 128.8, 143.1, 206.8.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([C:9]2[N:13]([CH2:14][CH2:15][CH:16]3[C:21](=[O:22])[O:20][C:19](C)(C)[O:18][C:17]3=[O:25])[C:12]([Cl:26])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:29]O>Cl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([C:9]2[N:13]([CH2:14][CH2:15][CH:16]([C:21]([O:20][CH3:19])=[O:22])[C:17]([O:18][CH3:29])=[O:25])[C:12]([Cl:26])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: CC1(C)OC(=O)C(CCn2c(Cl)ccc2C(=O)c2ccc(Cl)cc2)C(=O)O1
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COC(=O)C(CCn1c(Cl)ccc1C(=O)c1ccc(Cl)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The 5-(4-chlorobenzoyl)-2-chloro-1-[2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)ethyl]pyrrole sodium salt from Example 3A was dissolved in methanol saturated with hydrogen chloride (30 mL) and stirred at 0° C. for three hours. The solution was diluted with methanol (30 mL) and allowed to warm to room temperature, and was then stirred for another four hours. The solvent was then evaporated under reduced pressure at 10°-20° C. The residue was partitioned between ether and water (150 mL+50 mL), and the water was extracted with ether (2×150 mL). The combined ether extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed on Florisil® (50 g/g mixture), eluting the product with hexane/ethyl acetate, 7:3. The product so obtained (1.912 g, 68%) was a colorless crystalline solid, which was recrystallized from dichloromethane/hexane to afford 5-(4-chlorobenzoyl)-2-chloro-1-[3,3-di(methoxycarbonyl)propyl]pyrrole, having the following properties:
Reaction SMILES: F[C:2]1[C:7]([C:8]2([F:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:14][C:8]1([C:7]2[C:2]([O:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:16]4[S:15][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[N:17]=4)=[CH:30][CH:29]=3)=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: Fc1nccnc1C1(F)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: FC1(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCOCC1
Temperature: 80 °C

Procedure:
To a solution of 2-fluoro-3-(4-fluorotetrahydro-2H-pyran-4-yl)pyrazine (0.055 g, 0.275 mmol) and 4-(benzo[d]thiazol-2-ylamino)phenol (0.100 g, 0.412 mmol) in DMSO (0.9 mL) was added cesium carbonate (0.179 g, 0.549 mmol). The resulting mixture was heated to 80° C. overnight. The reaction mixture was partitioned between water, brine and DCM. The aqueous layer was back extracted with DCM and the combined organic layer was dried (Na2SO4) and concentrated. Purification by prep-plate TLC (5% MeOH/DCM) produced product. MS (ESI, pos. ion) m/z: 423.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.IC.[C:21](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:21][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:17])([F:1])[F:18])[CH:11]=2)[CH:7]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2n1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 90.1 %

Procedure:
A mixture of ethyl 6-(trifluoromethyl)-1H-indole-2-carboxylate (100 mg, 0.39 mmol), iodomethane (36 microL, 0.58 mmol), and potassium carbonate (134 mg, 0.97 mmol) in DMF was stirred at room temperature for 7 hours. Then, the mixture was poured into water, and the aqueous layer was extracted with dichloromethane (three times). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (20:1-10:1) to give 95.3 mg (90% yield) of the title compound as a white solid:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:5]2.[Li]CCCC.CON(C)[C:29](=[O:32])[CH2:30][CH3:31]>C1COCC1>[Si:14]([O:13][CH2:12][C:6]1[N:7]([CH3:11])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:29](=[O:32])[CH2:30][CH3:31])=[CH:10][CH:9]=2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Cn1c(CO[Si](C)(C)C(C)(C)C)cc2cc(Br)ccc21
Reactant: CCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)c1ccc2c(c1)cc(CO[Si](C)(C)C(C)(C)C)n2C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
To a stirred solution of 5-bromo-2-((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-indole (3.76 g, 10.6 mmol), prepared according to procedure described in Example 39 Step 3, in THF (15 mL) was added n-BuLi (2.5 M solution in hexanes, 5.1 mL, 12.7 mmol, 1.2 eq) at −78° C. dropwise. The mixture was stirred for 30 min at −78° C. before a solution of N-methoxy-N-methylpropionamide (1.49 g, 12.7 mmol, 1.2 eq) in THF (5 mL) was added. After stirred at −78° C. for 10 min, the reaction was quenched with saturated aqueous NH4Cl solution. The resulting mixture was extracted by ether (3×30 mL) and combined organic layers were dried over Na2SO4. The crude product was purified by flash chromatography (0-10% EtOAc in hexanes) to give the title compound (2.70 g, 77%).
Reaction SMILES: [F:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([O:12]C([Sn](C)(C)C)=C)[CH3:11].Cl>CN(C)C=O.O.[Cl-].[Na+].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>[Cl:8][C:5]1[N:4]=[C:3]([C:10](=[O:12])[CH3:11])[C:2]([F:1])=[CH:7][N:6]=1
Reactant: C=C(OCC)[Sn](C)(C)C
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1nc(Cl)ncc1F
Temperature: 70 °C
Yield: 91.8 %

Procedure:
A solution of 5-fluoro-2,4-dichloro-pyrimidine (20 g, 119.8 mmol) and (1-ethoxyethenyl)trimethylstannane (43.26 g, 119.8 mmol) in dimethylformamide (200 mL) is purged at room temperature with nitrogen and bis(triphenylphosphine)palladium(II) chloride (1.70 g, 2.40 mmol) is then added. The resulting mixture is heated at 70° C. for 2 hours under nitrogen. The reaction is cooled to 50° C. and aqueous 5 N hydrogen chloride (100 mL) is added. The reaction is stirred at 50° C. for two more hours. The reaction is cooled, diluted with water (200 mL) and brine. This solution is extracted five times with diethyl ether. The combined organic layers are dried over sodium sulfate and concentrated under vacuum. The crude product is purified over silica gel with a 30 minute, 5% to 50% ethyl acetate in hexanes gradient, to give the title compound (19.2 g, 92%). GC/MS (m/e): (35Cl/37Cl) 174/176.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:8]([F:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CCCCCCCCCCCCN>>[F:17][C:8]1[C:9]([O:11][CH2:12][C:13]([F:15])([F:16])[F:14])=[N:10][CH:2]=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(OCC(F)(F)F)nc1Cl
Agent: CCCCCCCCCCCCN
Product: O=C(O)c1cnc(OCC(F)(F)F)c(F)c1
Yield: 75 %

Procedure:
The title compound is prepared in 75% yield (21.0 g, a white solid) from 2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (32.2 g, 118 mmol, Step-1 of Amine-12) by the similar manner in Step-4 of Amine-12.
Reaction SMILES: O.[OH:2][CH2:3][C:4]12[O:11][CH:7]([CH2:8][CH:9]1[CH3:10])[CH2:6][C:5]2([CH3:13])[CH3:12]>C(O)C>[CH:3]([C:4]12[O:11][C@H:7]([CH2:8][C@H:9]1[CH3:10])[CH2:6][C:5]2([CH3:12])[CH3:13])=[O:2]
Reactant: CC1CC2CC(C)(C)C1(CO)O2
Solvent: O
Solvent: CCO
Product: C[C@@H]1C[C@@H]2CC(C)(C)C1(C=O)O2
Yield: 85 %

Procedure:
Workup: The reaction mixture obtained as in Example 1a was mixed with 200 ml of water at RT, the upper phase was separated off, and the aqueous phase was extracted three times with 150 ml of hexane each time. The organic phases were combined, washed twice with 150 ml of water and evaporated (rotary evaporator). The residue of 25.5 g was distilled to result in 22.1 g of 1-formyl-2,2,6-trimethyl-7-oxabicyclo[2.2.1]heptane with a boiling point of 54-61° C. under 1.5 mbar, which is 90% pure according to gas chromatography (GC), (equivalent to a yield of 85% of theory). A byproduct was ascertained to be 1-hydroxymethyl-2,2,6-trimethyl-7-oxabicyclo[2.2.1]heptane (about 4% of theory). The structure of the product was evident for example from the 1H-NMR spectrum: 250 MHz, (C6D6), δ=1.09 (d, J=8 Hz, 3 H), 4.16 (t, J=6 Hz, 1 H), 9.94 (s, 1 H); [α]D25 =-20.7 (c=1, ethanol).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[CH:10]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:50]1[O:53][CH:51]1[CH3:52]>CO.Cl>[OH:53][CH:51]([CH3:52])[CH2:50][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH2:27][O:26][C:25]4=[O:34])[CH2:20][CH2:19]3)=[O:17])=[C:11]([O:35][CH2:36][C:37]([F:40])([F:38])[F:39])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CC1CO1
Reactant: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(O)CN1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride (0.30 g, 0.5 mmol) from Example 2 in MeOH (10 mL) was added DIEA (0.17 mL, 1.0 mmol) and propylene oxide (1 mL, 13 mmol). The solution was stirred for 18 h at ambient temperature and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3:0.3 CH2Cl2 :MeOH:NH4OH as eluant. The free base was dissolved in MeOH containing 1.5 equivalents of 3 N aqueous HCl. The resulting solution was evaporated under reduced pressure and the residue was lyophilized from CH3CN:H2O to give the hydrochloride salt of the title compound as an amorphous solid.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH:21]([CH3:23])[CH3:22])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:27])(=O)=O>ClCCl>[Cl:27][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:21]([CH3:23])[CH3:22])[S:10]1(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)c1cccc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Solvent: ClCCl
Product: CC(C)c1cccc2c1C(=O)N(CCl)S2(=O)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-Phenylthiomethyl-4-isopropylsaccharin (53.5 g), sulfuryl chloride (40 mL, 67.2 g) and dichloromethane (250 mL) were mixed with stirring at room temperature. The mixture underwent a slightly exothermic reaction and was allowed to stand for 17 hours at room temperature, then stripped of volatiles. The residue crystallized with hexane in three crops 33.65 g, m.r. 101°-102° C.; 3.45 g, m.r. 100°-101° C.; 0.45 g, m.r. 99°-100° C.; total, 38.55 g, 91% yield). The three crops were combined and recrystallized from isopropyl alcohol (30 mL)-cyclohexane (270 mL) affording 2-chloromethyl-4-isopropylsaccharin in two crops (33.5 g, m.r. 101°-102.5° C.; 2.65 g, m.r. 100°-101° C.).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[NH:29]C(=O)OC(C)(C)C)=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:11]=1)#[N:2]>C(O)(C(F)(F)F)=O>[NH2:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[NH:22][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:11]=2)[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2cccc(-c3ncccn3)c2)n1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude tert-butyl (1S,2R)-2-(5-cyano-6-(3-(pyrimidin-2-yl)phenylamino)pyrazin-2-ylamino)cyclohexylcarbamate was dissolved in TFA (3 mL). After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2S)-2-aminocyclohexylamino)-3-(3-(pyrimidin-2-yl)phenylamino)pyrazine-2-carbonitrile (60 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][CH:8]=[CH:9][C:2]=12.[C:10]([O:14][C:15](=[O:34])[N:16]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][N:27]=1)[CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH3:13])([CH3:12])[CH3:11].[OH-].[K+]>CO>[C:10]([O:14][C:15](=[O:34])[N:16]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:33])[C:9]2[C:2]3[C:3](=[N:4][CH:5]=[CH:6][N:1]=3)[NH:7][CH:8]=2)=[CH:28][N:27]=1)[CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)cn1
Reactant: c1cnc2[nH]ccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3c[nH]c4nccnc34)cn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
To 5H-Pyrrolo[2,3-b]pyrazine (3, 0.150 g, 1.26 mmol) in 2.2 mL of methanol, (5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (6, 0.52 g, 1.5 mmol) and potassium hydroxide (0.230 g, 4.10 mmol) were added. The reaction was allowed to stir at room temperature overnight, then concentrated and poured into saturated sodium bicarbonate, and extracted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and purified by silica gel chromatography to provide the desired compound (7, 0.22 g, 38%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([O:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:26](=[O:35])[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(C(C)C)CC)(C)C.[N:45]1([CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[O:35]=[C:26]1[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C@H:12]([CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[C:13](=[O:14])[N:54]3[CH2:55][CH2:56][CH:51]([N:45]4[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:52][CH2:53]3)=[O:18])[CH2:20][CH2:21]2)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (500 mg, 1.05 mmol), diisopropylethylamine (0.37 mL, 2.11 mmol), and 4-piperidinopiperidine (355 mg, 2.0 equiv) in dimethylformamide (4 mL) and dichloromethane (4 mL) at 0° C. was added PyBOP® (576 mg, 1.11 mmol). The reaction was stirred at 0° C. for 4 h, was concentrated, and purified by column chromatography (95:5:1 to 93:7:1 dichloromethane/methanol/triethylamine). The resulting residue was dissolved in 5% methanol/dichloromethane and passed through a basic alumina column to give 600 mg (88%) as a white powder. Mass spec.: 625.56 (MH)+.
Reaction SMILES: [OH:1][C:2]1([CH2:15][SH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[C:23](=[O:29])[CH:22]=[CH:21]2>C(#N)C>[F:17][C:18]1[CH:19]=[C:20]2[C:25]([C:24](=[O:28])[C:23](=[O:29])[CH:22]=[C:21]2[S:16][CH2:15][C:2]2([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]2)=[CH:26][CH:27]=1
Reactant: O=C1C=Cc2cc(F)ccc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CS)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(O)(CSC2=CC(=O)C(=O)c3ccc(F)cc32)CC1

Procedure:
tert-butyl 4-{[(7-fluoro-3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}-4-hydroxypiperidine-1-carboxylate was synthesized using tert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate, 6-fluoronaphthalene-1,2-dione, acetonitrile as the solvent and conditions outlined in procedure F [step (i)]. The intermediate was purified by flash column chromatography (SiO2, 30% EtOAc in hexanes to 50% EtOAc in hexanes).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:6]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:7]=2[S:8][CH:9]=1.[F:16][C:17]([F:35])([F:34])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(C#N)(C)=O.CCOCC>[F:16][C:17]([F:34])([F:35])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][O:14][C:11]3[CH:12]=[CH:13][C:6]4[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[CH:9][S:8][C:7]=4[CH:10]=3)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccc(COc2ccc(CCl)cc2)cc1
Reactant: COC(=O)Cc1csc2cc(O)ccc12
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: O=C(O)Cc1csc2cc(OCc3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)ccc12
Yield: 62 %

Procedure:
Compounds 5C, 5E and cesium carbonate in 10 mL AcCN stirred at 60° C. for 18 hours. The reaction was then cooled, diluted with Et2O and filtered through Celite®. The filtrate was collected and concentrated in vacuo. Recrystalisation from CHCl3/Hexanes gave 340 mg (62%) of the title compound. MS m/z 487 (M+1).