Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH2:23])[CH2:18]2)[N:3]=1.C([O-])(O)=O.[Na+].[CH2:29]([O:32][C:33](Cl)=[O:34])[CH2:30]Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O.C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([N:23]3[CH2:30][CH2:29][O:32][C:33]3=[O:34])[CH2:18]2)[N:3]=1
Reactant: O=C(Cl)OCCCl
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@@H](N)C3)nc(N)n2)cc1F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCC[C@@H](N4CCOC4=O)C3)nc(N)n2)cc1F
Reaction time: 0.08 h
Yield: 83.5 %

Procedure:
Into a 40 mL vial was added 4-{2-amino-6-[(3R)-3-amino-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (100 mg, 0.260 mmol) followed by THF (3 mL) and saturated NaHCO3 (1.5 mL), and the resulting mixture was stirred for 5 minutes. Then 2-chloroethyl chloridocarbonate (0.032 mL, 0.311 mmol) was added, and the reaction mixture was capped and stirred at room temperature overnight. The reaction was then diluted with 5 mL of water and extracted with EtOAc (3×10 mL). The organic was combined and washed with saturated NaCl, dried over MgSO4, filtered and concentrated. The resulting light yellow solid (114 mg) was dissolved in DMF (3.00 mL), and then Cs2CO3 (127 mg, 0.389 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction was incomplete. Additional 0.5 equiv of Cs2CO3 was added, and the reaction mixture was continue to stir at room temperature. After 5 hours, the reaction was completed, and then it was diluted with 10 mL water, and extracted with EtOAc (3×10 mL). The organics were combined, washed with saturated NaCl, dried over MgSO4, filtered and concentrated to afford the crude title compound (83 mg). LC-MS (ES) m/z=383 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[Cl:7][CH2:8][C:9](Cl)=[O:10]>C1(C)C=CC=CC=1>[Cl:7][CH2:8][C:9]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])=[O:10]
Reactant: O=C(Cl)CCl
Reactant: O=C1CCCN1
Solvent: Cc1ccccc1
Product: O=C(CCl)N1CCCC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.2 %

Procedure:
To an initial charge of 81.0 g of 2-pyrrolidone in 200 ml of toluene there are added, dropwise and with ice cooling, 54.7 g of chloroacetyl chloride such that the temperature of the reaction mixture remains at 5° C. Following the addition the reaction mixture is stirred at room temperature for 6 hours. The resulting precipitate is filtered off with suction and the solvent is removed in vacuo to give 74.5 g of N-(chloroacetyl)pyrrolidone, corresponding to a yield of 97%.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][CH:32]([CH3:34])[CH3:33]>>[CH3:31][CH:32]([CH3:34])[CH2:33][O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)C
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)COCCCc1c[nH]cn1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 2-methylpropane chloride are treated as described in Example 5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:19])=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][Br:19])=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)nc1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: BrCc1ccc(OCc2ccccc2)nc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
(6-(Benzyloxy)pyridin-3-yl)methanol (3 g, 14 mmol) was added to a solution of phosphorus oxybromide (4.8 g, 16.8 mmol) in DCM (40 mL) under N2 at 0° C. The mixture was stirred at 20° C. for 1 hour. The mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc) to afford 2-(benzyloxy)-5-(bromomethyl)pyridine. MS ESI calc'd. for C13H13BrNO [M+H]+ 278 and 280. found 278 and 280. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J=2.4 Hz, 1H), 7.81-7.79 (m, 1H), 7.45-7.31 (m, 5H), 6.90 (d, J=8.4 Hz, 1H), 5.35 (s, 2H), 4.72 (s, 2H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C@@H:12]2[CH2:15][C@H:14]([OH:16])[CH2:13]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[CH3:24][S:25]([O:16][CH:14]1[CH2:15][CH:12]([CH2:11][N:8]2[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:10][CH2:9]2)[CH2:13]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)N1CCN(C[C@H]2C[C@@H](O)C2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OC1CC(CN2CCN(S(C)(=O)=O)CC2)C1
Reaction time: 1 h

Procedure:
Intermediate 37, cis-3-{[4-(methylsulfonyl)piperazin-1-yl]methyl}cyclobutanol and triethylamine were dissolved in CH2Cl2 (50 mL). MsCl was added dropwise at −20° C. under stirring in argon. The temperature was brought to ambient within 1 h. Water (100 mL) was added, and the layers were separated. The organic one was washed with water, brine, dried with Na2SO4, and evaporated, to give the title compound. This crude product was used for the next stage without additional purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[CH2:14][CH2:13][C:12]2=O)=O)=[CH:4][CH:3]=1.[CH3:22][C:23]1[N:24]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[NH:36])=[CH:30][CH:29]=2)[CH:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+].CCO>O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:11]3[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[CH2:14][CH2:13][C:12]=3[N:36]=[C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([N:24]4[CH:25]=[CH:26][N:27]=[C:23]4[CH3:22])=[CH:29][CH:30]=3)[N:37]=2)=[CH:4][CH:3]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: O=C1CCC(C(F)(F)F)CC1C(=O)Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CC(C(F)(F)F)CC3)cc1
Temperature: 130 °C
Yield: 24.9 %

Procedure:
2-(2-(4-Fluorophenyl)acetyl)-4-(trifluoromethyl)cyclohexanone (75 mg, 0.25 mmol), 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (53.4 mg, 0.25 mmol) and potassium carbonate (68.6 mg, 0.50 mmol) were added to a microwave vial. EtOH (3 mL) was added and the reaction was heated to 130° C. for 2 h. DCM (3 mL) and water (3 mL) were added. The organic phase was separated and the solvent was evaporated. The product was purified by preparative HPLC yielding 4-(4-fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroquinazolin-2-amine (30.0 mg, 25.1%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10](OC1C=CC(Br)=CC=1)(C)[C:11]([O-])=[O:12].S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:8][CH2:9][CH2:10][C:11]2=[O:12]
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)[O-]
Reactant: Oc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: O=C1CCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
4-Bromophenol (105 g, 0.61 mole) was converted into methyl(4-bromophenoxy)propanoate by the method referred to in Description 11A. This ester (125 g, 0.48 mole) was then added slowly to concentrated sulphuric acid (500 ml) and the resulting yellow solution stirred at room temperature for 30 minutes. This solution was poured slowly into ice/water (5 liters) and the mixture extracted using ethyl acetate (2×700 ml). The organic solution was washed with 10% sodium carbonate solution (2×300 ml) and brine (1×300 ml), dried (Na2SO4) and evaporated to dryness to give a pale yellow solid. This was recrystallised from ethyl acetate/petroleum ether (60°-80° C.) to give the title compound as a white crystalline solid (43.4 g, 31%). M.p. 79°-80°.
Reaction SMILES: ClC1N=C(O[C@@H]([C@H]2CNC(=O)C2)C)C2N(C(C)C)C=NC=2C=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33]2[N:38]=[C:37]([O:39][C@@H:40]([CH:42]3[CH2:46][NH:45][C:44](=[O:47])[CH2:43]3)[CH3:41])[C:36]3[N:48]([CH:51]([CH3:53])[CH3:52])[CH:49]=[N:50][C:35]=3[CH:34]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33]2[N:38]=[C:37]([O:39][C@@H:40]([C@H:42]3[CH2:46][NH:45][C:44](=[O:47])[CH2:43]3)[CH3:41])[C:36]3[N:48]([CH:51]([CH3:53])[CH3:52])[CH:49]=[N:50][C:35]=3[CH:34]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(-c2cc3ncn(C(C)C)c3c(O[C@H](C)C3CNC(=O)C3)n2)cc1OC
Agent: CC(C)n1cnc2cc(Cl)nc(O[C@H](C)[C@H]3CNC(=O)C3)c21
Product: COc1ccc(-c2cc3ncn(C(C)C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC

Procedure:
Following the procedure of Example 3.08, beginning with (R)-4-((R)-1-(6-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.23 (52 mg crude), R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.07 was synthesized.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[CH2:4][NH2:1])=[CH:15][CH:14]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Azidomethyl-5-(4-bromo-phenyl)-3-methyl-isoxazole (3.18 g, 10.85 mmol) in THF (30 mL) and H2O (10 mL) was treated with triphenylphosphine (2.85 g, 10.86 mmol) and the reaction stirred overnight at room temperature. After aqueous workup, the crude material was purified by silica gel chromatography to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9](OCC)=[O:10])[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][CH2:9][OH:10])[CH:2]=1
Reactant: CCOC(=O)C=Cc1cccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC=Cc1cccnc1

Procedure:
Ethyl 3-(3-pyridyl)acrylate was reduced using lithium aluminum hydride to give 3-(3-pyridyl)-2-propen-1-ol. In 30 ml of acetone 710 mg of 3-(3-pyridyl)-2-propen-1-ol and 980 mg of methyl p-toluenesulfonate were heated under reflux for 22 hours. The reaction mixture was subjected by decantation to remove the solvent and then washed with acetone and ether. The residue was dried under reduced pressure to give 1.3 g of the desired compound as an orange-colored oil.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[CH2:35][O:36][Si](C(C)(C)C)(C)C)[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17](/[C:20](/[CH2:30][CH3:31])=[CH:21]/[CH2:22][CH2:23][C:24]([CH2:28][CH3:29])([OH:27])[CH2:25][CH3:26])[CH:16]=1)(C(C)(C)C)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[CH2:35][OH:36])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17](/[C:20](/[CH2:30][CH3:31])=[CH:21]/[CH2:22][CH2:23][C:24]([CH2:28][CH3:29])([OH:27])[CH2:25][CH3:26])[CH:16]=1
Reactant: CC/C(=C\CCC(O)(CC)CC)c1csc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CC/C(=C\CCC(O)(CC)CC)c1csc(COc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to that of Example 6(l), by reaction of 1 g (1.5 mmol) of (E)-7-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-thienyl}-3-ethylnon-6-en-3-ol with 3.7 mL (3.7 mmol) of 1.0 M tetrabutylammonium bromide, the desired product is obtained in the form of white crystals (m.p.=73-74° C.; m=480 mg; Y=74%).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:37]2[CH:42]=[CH:41][C:40]([O:43]COC)=[CH:39][CH:38]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[S:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:7][CH:6]=1.CCCCCC>O1CCCC1.C(O)C.Cl>[OH:43][C:40]1[CH:39]=[CH:38][C:37]([CH:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[S:21]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH2:28][CH2:29]2)(=[O:22])=[O:23])=[CH:42][CH:41]=1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCCCCC
Product: O=S(=O)(c1[nH]c2ccccc2c1C(c1ccc(O)cc1)c1ccc(O)cc1)N1CCN(c2ccccc2Cl)CC1
Yield: 88.8 %

Procedure:
Compound 241 (1.0 g, 1.51 mmol) obtained in Example 242 was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and ethanol (30 ml), and 20 ml of 2N hydrochloric acid was added thereto, followed by heating under reflux for 2 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was added thereto for neutralization. The mixture was stirred and the precipitated crystals were collected to give a crude product. The obtained crude product was washed with ethanol and a little amount of hexane to give 0.77 g (yield: 89%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[S:30](=O)(=[O:33])([OH:32])[OH:31]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc(S(=O)(=O)O)sc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (5 g), acetic anhydride (4.3 ml) and sulfuric acid (0.97 ml) in dichloromethane (47 ml) was stirred at ambient temperature overnight. The mixture was concentrated to give a crude blue oil of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-sulfonic acid (10.5 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][CH2:25][CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:21]([Cl:32])=[CH:20][N:19]=1>>[Cl:32][C:21]1[C:22]([NH:24][CH2:25][CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)NCCNc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(NCCNS(C)(=O)=O)n3)cc2CC1

Procedure:
N-(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-ethyl)-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-ethyl]-methanesulfonamide in an analogous manner to Example 298. Product isolated as a white solid (34 mg, 21%). m.p.=92-95° C.; LCMS (m/e) 469 (M+1); 1H-NMR (d6-DMSO, 400 MHz) δ 9.06 (s, 1H), 7.93 (s, 1H), 7.45-7.39 (m, 2H), 7.17-7.07 (m, 2H), 6.97 (d, 1H, J=8.6 Hz), 3.58-3.49 (m, 2H), 3.47-3.40 (m, 2H), 3.23 (s, 3H), 3.24-3.17 (m, 2H), 2.89 (s, 3H) 2.79-2.71 (m, 4H), 2.65-2.54 (m, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(C(C(C(O)=O)O)O)(O)=O.[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.CC1C=CC(S(O[CH2:34][CH2:35][C:36]2[O:37][C:38]3[CH:44]=[CH:43][C:42]([C:45]4[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][CH:46]=4)=[CH:41][C:39]=3[CH:40]=2)(=O)=O)=CC=1>C(#N)C>[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:34][CH2:35][C:36]1[O:37][C:38]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][CH:46]=3)=[CH:41][C:39]=2[CH:40]=1
Reactant: C[C@@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3cc(-c4ccc(C#N)cc4)ccc3o2)cc1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Temperature: 55 °C

Procedure:
Potassium carbonate powder (2.28 kg, 16.5 mol, 325 mesh) and milled (2R)-2-methylpyrrolidine tartrate (1.78 kg, 7.48 mol) were combined in acetonitrile (37.4 kg) and heated at 55° C. with agitation for 36 hours. The mixture was chilled to about 25° C., and the product from Example 1C (2.07 kg, 4.98 mol) was added to the mixture in portions. The reaction mixture was heated at 65° C. with -agitation for about 48 hours. The mixture was cooled to about 25° C., filtered, and the filtrate was concentrated to a volume of about 10 L. The mixture was partitioned between toluene (32.3 kg) and 5% NaHCO3 solution (23.7 kg). The organic phase was separated and washed with 5% NaHCO3 solution (23.7 kg). The organic phase was then extracted with a mixture of CH3SO3H:N-methylpyrrolidinone:H2O (10:20:70 v/v/v) (32 kg, 8.0 kg respectively). The extract was treated with isopropyl acetate (32.5 kg) and the pH adjusted to about 12 with 50% NaOH solution (about. 4.9 kg) at about 30° C. After stirring, the organic phase was separated and the aqueous phase was extracted with isopropyl acetate (IPAC) (6.0 kg). The organic phases were combined, washed with 5% NaHCO3 (33 kg×3), distilled water (33 kg×2), distilled to a volume of about 10 L, and chased with IPAC (15.6 kg) to about 10 L. The mixture was diluted with isopropyl alcohol (14.5 kg) and concentrated to 10 L. Additional 14.5 kg of isopropyl alcohol was added and the solution concentrated to a volume of 10 L. The solution was treated with active carbon (Darco KB-B, 0.125 kg) and heated at 30° C. with stirring for 1 hour. The mixture was filtered through a pad of Celite® and the Celite® washed with isopropyl alcohol (6.3 kg). The filtrate (about 13 kg) was used directly in the next step (1.17 kg).
Reaction SMILES: [K:1].Br[CH2:3][B-:4]([F:7])([F:6])[F:5].[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>O1CCCC1>[K:1].[C:17]([O:16][C:14]([N:8]1[CH2:13][CH2:12][N:11]([CH2:3][B-:4]([F:7])([F:6])[F:5])[CH2:10][CH2:9]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: F[B-](F)(F)CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [K]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C[B-](F)(F)F)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
5.00 g potassium-bromomethyl-trifluoroborate are added to a solution of 4.87 g tert-butyl piperazine-1-carboxylate in 25 ml of tetrahydrofuran. The mixture is stirred for 3 h at 80° C. and then cooled to ambient temperature. The solvent is removed, and the residue is suspended in 50 ml acetone and combined with 3.44 g potassium carbonate. The mixture is stirred overnight at ambient temperature. Then the mixture is filtered and the filtrate is evaporated down. The oil remaining is combined with diisopropylether and the colourless precipitate formed after a while is separated off and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=S)[C:10]2([F:24])[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([C@@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[CH2:11][C:10]2([F:24])[F:23])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)C2(F)F)CC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1([C@@H]2CN([C@@H](C)c3ccccc3)CC2(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3,3-difluoro-1-[1-(S)-phenylethyl]-2-pyrrolidinethione (2.883 g, 8.157 mmol) was dissolved in anhydrous ethanol (80 ml), and the solution was mixed with Raney nickel (8 ml) and stirred at room temperature for 30 minutes. After removing the catalyst by celite filtration (ethanol washing), the resulting filtrate was concentrated under reduced-pressure. The thus obtained residue was dissolved in diethyl ether (150 ml), washed with 10% ammonia water (100 ml×4) and saturated brine (100 ml) in that order and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=4:1, to thereby obtain 2.540 g (96.3%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[N:9][C:8]([C@@H:19]([NH:21][C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][N:26]3[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[CH3:20])=[CH:7]2.[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C(=O)C.O.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.Cl[Pd]Cl.[Fe+2]>[CH3:37][N:38]1[CH:42]=[C:41]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)=[N:9][C:8]([C@@H:19]([NH:21][C:22]2[N:30]=[CH:29][N:28]=[C:27]4[C:23]=2[N:24]=[CH:25][N:26]4[CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH3:20])=[CH:7]3)[CH:40]=[N:39]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1cc2cccc(Cl)c2c(N2CCN(C)CC2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1cc2cccc(-c3cnn(C)c3)c2c(N2CCN(C)CC2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
N—((S)-1-(8-chloro-1-(4-methylpiperazin-1-yl)isoquinolin-3-yl)ethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine 140 (80 mg, 0.16 mmol, 1.0 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (66 mg, 0.32 mmol, 2.0 eq), PdCl2(dppf) (13 mg, 0.016 mmol, 0.1 eq) and Na2CO3 (84 mg, 0.79 mmol, 5.0 eq) were suspended in a mixture of N,N-dimethylacetamide (5 mL) and water (2 mL). The resulting mixture was degassed and back-filled with argon three times and then stirred at 80° C. under argon overnight. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product, N—((S)-1-(8-(1-methyl-1H-pyrazol-4-yl)-1-(4-methylpiperazin-1-yl)isoquinolin-3-yl)ethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine 141.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:20][O:21]CC2C=CC(OC)=CC=2)[CH:9]([CH3:10])[C:8](=[O:11])[N:7]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])[CH2:6]1)=[O:4].C(Cl)Cl.O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:20][OH:21])[CH:9]([CH3:10])[C:8](=[O:11])[N:7]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(COCc2ccc(OC)cc2)CN(c2c(C)cccc2C)C(=O)C1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1(CO)CN(c2c(C)cccc2C)C(=O)C1C
Yield: 71.5 %

Procedure:
To a vigorously stirring mixture of 1-(2,6-dimethylphenyl)-3-(4-methoxy-benzyloxymethyl)-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step b, 736 mg, 1.79 mmol) in 5:1 CH2Cl2/H2O (12 mL) was added 2,3-dichloro-5,6-dicyanobenzoquinone (609.5 mg, 2.68 mmol) at room temperature and stirred for 2 h at the same temperature. The reaction mixture was diluted with CH2Cl2 (25 mL) and filtered through celite, washed with CH2Cl2 (3×25 mL). The filtrate was then washed with saturated NaHCO3 solution (3×30 mL), water (30 mL), brine (30 mL), dried and evaporated. The obtained residue was purified by flash chromatography (SiO2, 20→70% EtOAc/hexanes) to give 1-(2,6-dimethylphenyl)-3-hydroxymethyl-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (373 mg, 72% yield). LC-MS: R, (retention time): 1.2 min, MS: (ES) m/z 292.2 (M+H+).