Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[O:7]([CH2:26][CH2:27][NH:28][C:29]([C:31]1[S:32][C:33]2[C:39](=[O:40])[CH:38]=[C:37](OC)[C:36](=[O:43])[C:34]=2[N:35]=1)=[O:30])[CH2:8][CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]2[C:21](=[O:22])[CH:20]=[C:19](OC)[C:18](=[O:25])[C:16]=2[N:17]=1)=[O:12].CO>C(O)C.ClCCl>[O:7]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]2[C:21](=[O:22])[CH:20]=[C:19]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:18](=[O:25])[C:16]=2[N:17]=1)=[O:12])[CH2:26][CH2:27][NH:28][C:29]([C:31]1[S:32][C:33]2[C:39](=[O:40])[CH:38]=[C:37]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:36](=[O:43])[C:34]=2[N:35]=1)=[O:30]
Reactant: COC1=CC(=O)c2sc(C(=O)NCCOCCNC(=O)c3nc4c(s3)C(=O)C=C(OC)C4=O)nc2C1=O
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CN(C)CCNC1=CC(=O)c2sc(C(=O)NCCOCCNC(=O)c3nc4c(s3)C(=O)C=C(NCCN(C)C)C4=O)nc2C1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
81 μl (0.73 mmol; 2 eq.) of N,N-dimethylethylenediamine is added to 200 mg of N,N′-(oxydiethane-2,1-diyl)bis(5-methoxy-4,7-dioxo-4,7-dihydro-1,3-benzothiazole-2-carboxamide) in solution in 300 ml of anhydrous ethanol. The reaction mixture is stirred at 60° C. for 4 hours then the solvent is evaporated off under reduced pressure. The residue is purified on a silica column (eluent: methanol in dichloromethane: gradient of 0 to 20% over 30 minutes then for 15 minutes with 20% of methanol in dichloromethane) and 12 mg (yield=5%) of expected compound is obtained in the form of a red powder.
Reaction SMILES: [C:1]1([CH:7]([NH:31]C(OCC2C=CC=CC=2)=O)[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:19]([O:21]CC4C=CC=CC=4)=[O:20])=[C:15]([Cl:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.[N+](C)([O-])=O.C(OCC)(=O)C>[C:1]1([CH:7]([C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:19]([OH:21])=[O:20])=[C:15]([Cl:18])[CH2:16][S:17][C@H:12]23)=[O:9])[NH2:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CS[C@H]12)c1ccccc1)OCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: NC(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of benzyl 7β-(α-phenyl-α-carbobenzoxyaminoacetamido)-3-chloro-3-cephem-4-carboxylate (295 mg) in methylene chloride (6 ml) is added a solution of aluminum chloride (267 mg) in nitromethane (3 ml) under ice cooling. After stirring for 2 hours at room temperature, the mixture is diluted with ethyl acetate, washed with dilute hydrochloric acid, and extracted with an aqueous solution of 5% sodium hydrogen carbonate. The extract is acidified with hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, and evaporated. The residue is recrystallized from a mixture of ethyl acetate and ether to give 7β-(α-phenyl-glycinamido)-3-chloro-3-cephem-4-carboxylic acid (167 mg). Yield: 91.4%.
Reaction SMILES: C(OC([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)([CH3:13])[CH2:11][O:10][S:9]1(=[O:22])=[O:21])=O)(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O>[Br:20][C:16]1[CH:15]=[C:14]([C:12]2([CH3:13])[CH2:11][O:10][S:9](=[O:22])(=[O:21])[NH:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C(C)(c2cccc(Br)c2)COS1(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(c2cccc(Br)c2)COS(=O)(=O)N1
Reaction time: 3 h
Yield: 91 %

Procedure:
3-(tert-Butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (DC4; R6=Me) (10.8 g, 28 mmol) was dissolved in 25% TFA in DCM (40 mL, 5 eq) and the mixture was left standing at RT for 3 h. The mixture was concentrated in vacuo to give 7.3 g (91%) of 4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide as a yellow oil. 1H NMR (CDCl3) δ 7.59 (t, J=1.8 Hz, 1H), 7.48-7.52 (m, 1H), 7.39-7.42 (m, 1H), 7.30 (t, J=8.1 Hz, 1H), 4.59 (m, 2H), 1.82 (s, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([CH3:26])([CH3:25])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:21]([O:20][C:18]([NH:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1([CH3:26])[CH3:25])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCNCC1(C)C
Reaction time: 3.5 h
Yield: 99.4 %

Procedure:
(+)-1-Benzyloxycarbonyl-4-t-butyloxycarbonylamino-3,3-dimethylpiperidine (75 g, 0.207 mol) was dissolved in 500 ml methanol and the solution was transferred to a Parr reactor. Wet 10% palladium on carbon (7.5 g) was added to the solution and was stirred at 200 psi hydrogen pressure. Reaction progress was monitored on TLC and reaction was completed in 3-4 hrs. The reaction mixture was filtered as soon as it was completed. The residue was washed with 100 ml methanol. Filtrate was evaporated to dryness to afford the required product (47 g) in quantitative yield.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[S:41](Cl)(=[O:43])=[O:42])=[O:35].N1C=CC=CC=1>ClCCl>[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[S:41](=[O:43])(=[O:42])[NH:8][C:7]1[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)[C:2]=1[F:1])=[O:35]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. methyl-3-(chlorosulfonyl)thiophene-2-carboxylate (17 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 25 mg of the target compound, methyl-3-(N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)sulfamoyl)thiophene-2-carboxylate (percentage yield: 86%), was obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][CH2:14][C:15]1[N:16]=[CH:17][N:18]2[CH:22]=[CH:21][S:20][C:19]=12>ClCCl>[CH3:8][S:9]([NH:13][CH2:14][C:15]1[N:16]=[CH:17][N:18]2[CH:22]=[CH:21][S:20][C:19]=12)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ncn2ccsc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1ncn2ccsc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.18 ml) and 0.075 ml of methanesulfonyl chloride were added in that order under ice cooling to a solution of 134 mg of 7-aminomethylimidazo[5,1-b]thiazole in 2.5 ml of dry dichloromethane. In this state, the system was stirred for 2 hr while gradually raising the temperature to room temperature. The reaction solution was diluted with 20 ml of dichloromethane, followed by washing with saturated brine. The aqueous layer was extracted with 10 ml of dichloromethane. The organic layers were combined together, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation. The oil thus obtained was purified using Sephadex LH-20 (dichloromethane:methanol=1:1) to give 30 mg of 7-(methanesulfonylaminomethyl)imidazo[5,1-b]thiazole as a light yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)[N:4]=[CH:3]1.[CH3:21][C:22]1[S:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1>[OH-].[K+].CCO>[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[C:15](=[CH:27][C:25]2[S:26][C:22]([CH3:21])=[CH:23][CH:24]=2)[CH2:14][CH2:13]3)[N:4]=[CH:3]1
Reactant: O=C1CCCc2cc(OCCc3c[nH]cn3)ccc21
Reactant: Cc1ccc(C=O)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C=C2CCc3cc(OCCc4c[nH]cn4)ccc3C2=O)s1
Yield: 53.1 %

Procedure:
According to the method of Example 34, 6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one, monohydrochloride (0.313 g, 1.07 mmol) was reacted with 5-methyl-2-thiophene carboxaldehyde (0.142 g, 1.13 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.207 g (44%) of the title compound as a bright orange solid, mp 69-70° C.: CI-MS m/e 364 (M+), 365 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:26])[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.CC(=O)OCC.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]>[CH:16]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]2[CH2:29][CH2:30][N:31]([C:12]3[CH:11]=[N:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)[CH2:32][CH2:33]2)=[O:26])[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCN(C(=O)OC2CCNCC2)CC1
Reactant: Brc1ccc(OCc2ccccc2)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)OC2CCN(c3ccc(OCc4ccccc4)nc3)CC2)CC1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 20.4 %

Procedure:
To a solution of 2-(benzyloxy)-5-bromopyridine (1.5 g, 5.6 mmol), piperidin-4-yl 4-isopropylpiperazine-1-carboxylate (2.15 g, 8.4 mmol) in toluene (30 mL) was added Pd2(dba)3 (1.57 g, 2.2 mmol), BINAP (2.79 g, 4.4 mmol) and t-BuOK (3.78 g, 33.8 mmol). The reaction was stirred under the microwave irradiation at 120° C. for 20 min. The mixture was diluted with EA (100 mL) and washed with water (3×50 mL). The organic phase was separated, dried and concentrated to dryness. The residue was taken into dilute HCl (pH=1, 100 mL) and the mixture was extracted with DCM (3×100 mL) to remove impurities. The aqueous phase was made basic (pH=9-10) with solid Na2CO3 and extracted with DCM (3×100 mL). The combined organic layers were dried, concentrated and purified by silica gel chromatography (EA/MeOH=50/1) to give the title compound as a white solid (500 mg, 20%). [LCMS: Rt=2.09 mim, m/z 439.3 (M+H)+].
Reaction SMILES: B.CSC.[CH:5]1([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([C:29]4[CH:30]=[C:31]5[C:36](=[CH:37][CH:38]=4)[O:35][CH:34]([C:39]([NH2:41])=O)[CH2:33][CH2:32]5)(=[O:28])=[O:27])=[CH:21][CH:20]=3)[N:15]=[N:14]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.Cl.[OH-].[Na+]>O1CCCC1.CO>[CH:5]1([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[N:16]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][S:26]([C:29]4[CH:30]=[C:31]5[C:36](=[CH:37][CH:38]=4)[O:35][CH:34]([CH2:39][NH2:41])[CH2:33][CH2:32]5)(=[O:27])=[O:28])=[CH:23][CH:24]=3)[N:15]=[N:14]2)[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NC(=O)C1CCc2cc(S(=O)(=O)Nc3ccc(-n4nnn(CCCC5CCCC5)c4=O)cc3)ccc2O1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: NCC1CCc2cc(S(=O)(=O)Nc3ccc(-n4nnn(CCCC5CCCC5)c4=O)cc3)ccc2O1
Temperature: 0 °C
Yield: 79.4 %

Procedure:
Borane-methyl sulfide complex (2.0 M solution in tetrahydrofuran, 17.1 mL, 34.2 mmol) was added to a cooled (0° C.) solution of the compound from Example 23 (3.0 g, 5.70 mmol) in tetrahydrofuran (75 mL). The mixture was heated to reflux for 90 minutes then cooled to 0° C. Methanol was added until gas evolution ceased, then 6N HCl (15 mL) was added. The mixture was heated to reflux for 60 minutes then cooled to 0° C. The mixture was brought to pH=12 with 10% aqueous sodium hydroxide and extracted with ethyl acetate (2×). the combined organic layers were dried (Na2SO4) and concentrated to a solid. Silica gel chromatography (gradient elution from 50:50 hexane/ethyl acetate to 45:45:10 hexane/ethyl acetate/methanol to 90:10 ethyl acetate/methanol) afforded a colorless solid (2.32 g, 80%). Mp 125-130° C. (dec); 1H NMR (DMSO- d6, 300 MHz) δ 7.64 (d, J=8.8 Hz, 2 H), 7.54 (d, J=2.2 Hz, 1 H), 7.47 (dd, J=8.5 Hz, 2.2 Hz, 1 H), 7.22 (d, J=8.8 Hz, 2 H), 6.84 (d, J=8.8 Hz, 1 H), 5.6 (br s, 3 H), 4.04 (m, 1 H), 3.92 (t, J=7.0 Hz, 2 H), 2.83 (d, J=5.5 Hz, 2 H), 2.76 (m, 2 H), 2.0 (m, 1 H), 1.8-1.4 (m, 10 H), 1.30 (m, 2 H), 1.03 (m, 2 H); MS (FAB) m/z 513 (MH+).
Reaction SMILES: B.[CH3:2][O:3][P:4]([CH2:8][P:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])([O:11][CH2:12][CH3:13])=[O:10])(=[O:7])[O:5][CH3:6].[OH-].[Na+].OO.S(=O)(O)[O-:30].[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:6][O:5][P:4]([CH2:8][P:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:30])([O:11][CH2:12][CH3:13])=[O:10])(=[O:7])[O:3][CH3:2]
Reactant: O=S([O-])O
Reactant: C=CCCCCCCCCCP(=O)(CP(=O)(OC)OC)OCC
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOP(=O)(CCCCCCCCCCCO)CP(=O)(OC)OC
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
A 1.0 M tetrahydrofuran solution of borane (81.5 mL, 81.5 mmol) was added to a flask containing anhydrous tetrahydrofuran (450 mL) under a nitrogen atmosphere. The solution was cooled to −10° C. using an ice/salt water bath. ((10-undecenyl)-ethoxyphosphinyl)methylphosphonic acid dimethyl ester (30 g, 81.4 mmol) was added slowly to the borane solution. The reaction mixture was stirred at −10° C. for 15 minutes and then warmed to ambient temperature and stirred for 2 hours. The solution was again cooled to −10° C. and 1N NaOH (81.4 mL, 81.4 mmol) was added dropwise in a manner that controlled the frothing. This addition was followed by the addition of a 30 wt % hydrogen peroxide solution (28.6 g). This mixture was then heated to 50° C. for 2 hours and then allowed to cool to ambient temperature. The excess peroxide was then reduced by the addition of aqueous sodium bisulfite (22 g in 120 mL water). The volatiles were removed by rotary evaporation to give a viscous liquid. The liquid was dissolved in ethyl acetate (800 mL) and then extracted twice with water (500 mL). The water layer was collected and extracted with ethyl acetate (600 mL). The organic extracts were combined and dried over sodium sulfate. The solvent was then removed by rotary evaporation revealing a viscous liquid. The liquid was placed under high vacuum to remove remaining volatiles providing the desired product (28.5 g, 90% yield). 1H NMR (400 MHz CDCl3): δ 4.0 (m, 2H), 3.7 (m, 6H), 3.5 (t, 2H), 2.3 (m, 2H), 1.8 (m, 2H), 1.5 (m, 4H), 1.2 (m, 18H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10](Cl)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[NH:12]1[CH2:15][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][NH:2][C:3]([C:5]1[C:10]([N:12]2[CH2:15][CH:14]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=4[N:17]=3)[CH2:13]2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1nccnc1Cl
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1nccnc1N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Temperature: 100 °C
Yield: 49.8 %

Procedure:
A mixture of 3-chloro-pyrazine-2-carboxylic acid methylamide (100 mg, 0.41 mmol) and 2-azetidin-3-yl-5-chloro-1H-benzoimidazole (as prepared by Preparation 5) (71 mg, 0.41 mmol) and K2CO3 (113 mg, 0.82 mmol) was dissolved in DMF (20 mL) and heated for 2 h at 100° C. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give the pure product (70 mg, yield 44%). [M+1] 343. IC50 (uM) 3.882.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccc(-c2ncc(Br)cn2)cc1)C(=O)O)OCc1ccccc1
Yield: 99.9 %

Procedure:
Prepared using General Procedure 8: To a stirred solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoate (1.08 g, 2.11 mmol) INT-7 in DCM (10 mL) was added TFA (5 mL). After 16 h the mixture was diluted with toluene (10 mL) and evaporated. Further toluene (2×10 mL) was evaporated from the residue to afford 962 mg (100%) of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoic acid as an off-white solid. LCMS-ESI (m/z) calculated for C21H18BrN3O4: 455.1. found 456.0 [M+H]+, tR=5.81 min (Method 10).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:21])=[CH:8][CH:9]=2)[N:4]=1.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:21])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:2][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2
Reactant: O=c1c2ccc(F)cc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccc(F)cc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 52.6 %

Procedure:
Prepared according to Procedure C using Intermediate 2c (200 mg, 0.619 mmol), 6-mercaptopurine monohydrate (116 mg, 0.681 mmol), K2CO3 (95 mg, 0.687 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 143 mg of a white crystalline solid (53%), mp 151.4-154.2° C. (discolors). 1H NMR (DMSO-d6) δ: 13.55 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 8.23 (dd, J=6.3, 8.7 Hz, 1H); 7.77 (dd, J=1.7, 7.4 Hz, 1H); 7.64 (d, J=7.4 Hz, 1H); 7.57 (d, J=9.8 Hz, 1H); 7.45-7.52 (m, 3H); 4.48 (s, 2H). 13C NMR (DMSO-d6) ppm: 169.0 (d, J=253 Hz), 162.6, 159.3, 157.0, 154.0, 152.2, 151.7 (d, J=13 Hz), 146.1, 136.5, 134.7, 134.2, 134.0, 133.0, 132.6 (d, J=11 Hz), 131.3, 120.2, 118.9 (d, J=24 Hz), 115.3 (d, J=22 Hz), 34.6. MS (ES): m/z 439.0 (M+). Anal. calcd. for C20H12ClFN6OS.0.4C2H6O.0.4H2O (0.15KCl: C, 52.52; H, 3.22; Cl, 8.57; N, 17.67. Found: C, 52.25; H, 3.11; Cl, 8.20; N, 17.69.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:28]([CH3:39])=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[C:28]([CH3:39])=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1c(NC(=O)C(C)C)cccc1C1CCN(CCCN)CC1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: Cc1c(NC(=O)C(C)C)cccc1C1CCN(CCCNC(=O)C(c2ccccc2)c2ccccc2)CC1

Procedure:
Example 33 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-2-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.49 (d, 1H, J=8.0 Hz), 7.35–7.19 (m, 11H), 7.09–7.02 (m, 3H), 4.90 (s, 1H), 3.41 (dd, 2H, J=5.6, 11.6 Hz), 2.99 (d, 2H, J=12.8 Hz), 2.72 (m, 1H), 2.59 (m, 1H), 2.43 (t, 2H, J=6.4 Hz), 2.19 (s, 3H), 2.06–2.00 (m, 2H), 1.75–1.60 (m, 6H), 1.30 (d, 6H, J=6.8 Hz); ESMS m/e: 512.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[NH:19]1[C:23]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)=[N:22][N:21]=[N:20]1.[BH3-]C#N.[Na+].Cl>CN1C(=O)N(C)CC1.CO.C(O)(=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:28][C:27]4[CH:26]=[CH:25][C:24]([C:23]5[NH:19][N:20]=[N:21][N:22]=5)=[CH:31][CH:30]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(-c2nnn[nH]2)cc1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CN1CCN(C)C1=O
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(NCc4ccc(-c5nnn[nH]5)cc4)c23)c1

Procedure:
Under a nitrogen atmosphere, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1 H-pyrazolo[3,4-d]pyrimidine (see Step 1.6), 261 mg (1.5 mmol) of 4-(tetrazol-5-yl)-benzaldehyde and 180 mg of acetic acid are stirred in 39 ml of DMEU/methanol (1:2) at RT for 1 hour. Then 440 mg (7 mmol) of NaCNBH3 are added and the reaction mixture is heated to boiling. After 15 hours a further 440 mg of NaCNBH3 are added and the reaction mixture is again stirred at boiling temperature for 15 hours, then poured into 0.6 liter of a 1 aqueous K2B4O7.4H2O solution and stirred overnight to complete the reaction. The mixture is acidified to pH 3.9 with 2N HCl and the product that precipitates is filtered off and washed with water. Heating in 20 ml of ethanol and filtration yield 4-(3chloro-phenylamino)-3-[4-(tetrazol-5-yl)-benzylamino]-1H-pyrazolo-[3,4-d]pyrimidine; HPLC:tRet(grad20-100/20)=9.8; MS: (M)+=418.
Reaction SMILES: [F:1][C:2]12[CH2:12][C:6]3([F:13])[CH2:7][C:8]([F:11])([CH2:10][C:4]([CH2:14][OH:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.CC(C)([O-])C.[K+].[Cl:22][C:23]1[C:24](F)=[CH:25][C:26]([F:32])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29]>CS(C)=O.C(OCC)(=O)C.O.Cl>[Cl:22][C:23]1[C:24]([O:15][CH2:14][C:4]23[CH2:10][C:8]4([F:11])[CH2:9][C:2]([F:1])([CH2:12][C:6]([F:13])([CH2:7]4)[CH2:5]2)[CH2:3]3)=[CH:25][C:26]([F:32])=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29]
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3(F)CC(F)(CC(F)(C3)C1)C2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Reaction time: 0.33 h
Yield: 40.1 %

Procedure:
A mixture of (3,5,7-trifluoroadamantan-1-yl)methanol (1.37 g, 6.22 mmol) and potassium tert-butoxide (0.91 g, 8.09 mmol) in anhydrous dimethylsulfoxide (20 mL) was stirred under nitrogen for 20 minutes. The reaction mixture was treated with a mixture of 5-chloro-2,4-difluorobenzoic acid (1.20 g, 6.22 mmol) and potassium tert-butoxide (0.70 g, 6.22 mmol) in anhydrous dimethylsulfoxide (10 mL) that had been stirred for 10 min. The resulting mixture was stirred under nitrogen at ambient temperature for 20 hours, diluted with ethyl acetate (120 mL), water (20 mL) and 1 M aqueous hydrochloric acid solution (50 mL). The separated organic layer was washed with 1 M aqueous hydrochloric acid solution (50 mL) and brine; dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the title compound (0.98 g, 40%): 1H NMR (300 MHz, DMSO-d6) δ 13.13 (br s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.18 (d, J=12.6 Hz, 1H), 4.00 (s, 2H), 2.25-2.14 (m, 3H), 2.06-1.96 (m, 3H), 1.81-1.73 (m, 6H); MS (ES−) m/z 391.2, 393.2 (M−1).