Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])/[CH:5]=[CH:6]/[C:7](O)=[O:8])[CH3:2].[C:11]([OH:15])([CH3:14])([CH3:13])[CH3:12].C1CCC(N=C=NC2CCCCC2)CC1.CC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([O:15][C:7](=[O:8])/[CH:6]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)/C=C/C(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution of fumaric acid mono-ethyl ester (721 mg, 5 mmol) and tert-butanol (0.938 mL, 10 mmol) in 10 mL of DCM was added DMAP (122 mg, 1 mmol) followed by DCC (2.06 g, 10 mmol). The resulting mixture was stirred at rt for 16 h, taken to dryness under reduced pressure, stirred overnight with 50 mL acetone and filtered to remove DCU. The resulting filtrate was concentrated under reduced pressure, and the residue taken up in EtOAc. The EtOAc was washed twice with 30 mL 0.1 M KHSO4, and once with 30 mL saturated NaHCO3 and once with 30 mL of brine. The resulting EtOAc solution was treated with charcoal and dried over magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel flash chromatography using a gradient of 0–15% EtOAc in hexanes as eluent to give essentially pure (one peak on HPLC) 4-1 (350 mg, 35% yield).
Reaction SMILES: [NH3:1].C(Cl)Cl.C1COCC1.Cl.[CH2:11]([NH2:14])[CH2:12][CH3:13].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:14][C:11]1[C:12]2[C:20](=[CH:19][CH:18]=[CH:17][CH:13]=2)[N:15]=[CH:16][N:1]=1.[NH3:14]
Reactant: c1ccncc1
Reactant: CCCN
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1ncnc2ccccc12

Procedure:
To prepare the compound I-1, a 4-hydroxy-[1,5]-naphthyridine, a 4-hydroxyquinazoline, a 5-hydroxyquinoxaline or a 4-hydroxyquinoline derivative can be converted into the corresponding chloro derivative by heating in phosphorous oxychloride between 40° C. and 100° C. neat or in an inert solvent like 1,2-DCE, or to the corresponding trifluoromethanesulphonyloxy derivative by reaction with trifluoromethanesulphonic anhydride, in the presence of an organic base between −40° C. and 80° C. in an aprotic solvent like DCM or THF (K. Ritter, Synthesis (1993), 735). The corresponding 4-amino-[1,5]-naphthyridine, 4-aminoquinazoline, 5-aminoquinoxaline or 4-aminoquinoline derivatives can then be obtained by reaction of the corresponding trifluoromethanesulphonyloxy derivatives with ammonia in a solvent like DCM or THF, or with n-propylamine hydrochloride in pyridine between −20° C. and 100° C. (R. Radinov, Synthesis (1986), 886). The corresponding 4-aminoquinazoline can also be obtained from its 4-chloro analogue by reaction with ammonia under the same conditions.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10]O.[Br:12][C:13]1[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:10][CH2:9][C:8]#[C:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:18]=1
Reactant: OCCC#Cc1ccccn1
Reactant: O=c1ccc(Br)c[nH]1
Product: O=c1ccc(Br)cn1CCC#Cc1ccccn1
Yield: 23.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 109(D), from 4-(pyridin-2-yl)but-3-yn-1-ol (700 mg, 4.76 mmol, Example 3(A)) and 5-bromo-1H-pyridin-2-one (870 mg, 5.00 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 334 mg (1.10 mmol, 23%) of 5-bromo-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one.
Reaction SMILES: C1COCC1.[CH2:6]([Mg]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][C:16]1[C:21](Br)=[N:20][C:19]([Br:23])=[C:18]([Cl:24])[N:17]=1>[Cl-].[Zn+2].[Cl-].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.O>[NH2:15][C:16]1[C:21]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:20][C:19]([Br:23])=[C:18]([Cl:24])[N:17]=1
Reactant: Nc1nc(Cl)c(Br)nc1Br
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(Cl)c(Br)nc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
Under an argon atmosphere, to anhydrous THF (40 mL) was added zinc chloride (1.0 M in diethyl ether) (23.7 mL, 23.7 mmol), and to the mixture was added benzyl magnesium chloride (2.0 M in THF) (10.4 mL, 20.8 mmol). After stirring at room temperature for 30 minutes, to the mixture were successively added dichlorobis(triphenylphosphine)palladium(II) (488 mg, 695 μmol) and 2-amino-3,5-dibromo-6-chloropyrazine (4) (4.00 g, 13.9 mmol) at room temperature. The mixture was stirred overnight (15 hours and a half) at room temperature as it was. After to the mixture was added water, the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=5/1) to give 2-amino-3-benzyl-5-bromo-6-chloropyrazine (5) (3.64 g, 12.2 mmol, 87.6%) as a yellow solid. TLC Rf=0.25 (n-hexane/ethyl acetate=4/1); 1H NMR (500 MHz, CDCl3) δ 4.08 (s, 2H), 4.50 (s, 2H), 7.19-7.24 (m, 2H), 7.27-7.37 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 40.1, 123.8, 127.5, 128.4, 129.3, 135.3, 139.5, 144.9, 151.3.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:66][CH2:65][CH2:64][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([NH:36][C@H:37]([C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][CH2:46][C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[Cl:49])=[O:44])=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3].C(Cl)(Cl)[Cl:75].CO>Cl.C(OCC)(=O)C>[NH:1]([Cl:75])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:66][CH2:65][CH2:64][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([NH:36][C@H:37]([C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][CH2:46][C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[Cl:49])=[O:44])=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3]
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NCl)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1

Procedure:
The solution of 100 mg (0.080 mmol) of Boc-Ala-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 13) in 3 ml of hydrogen chloride in ethyl acetate (4 mol/L) was stirred at room temperature for 2 h and TLC (chloroform/methanol, 10:1) indicated complete disappearance of Boc-Ala-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 13). The reaction mixture was evaporated under reduced pressure with ethyl acetate, repeatedly, to remove hydrogen chloride. The residue was triturated with ether to provide the title compound as a colorless powder, which was used for the next reaction directly.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH3:12]>C(O)C>[NH2:1][C:2]1[C:7]([N:11]([CH3:12])[CH3:10])=[N:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: CNC
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCO
Product: CN(C)c1nc(Br)cnc1N

Procedure:
2-Amino-3,5-dibromopyrazine (1.0 g) was dissolved in a solution of dimethylamine in ethanol (33% w/v; 20 ml) and the solution was heated under reflux for 18 hours. Volatile material was removed by evaporation and the residue was purified by elution with dichloromethane through a silica gel Mega Bond Elut column to give 2-amino-5-bromo-3-dimethylaminopyrazine (0.67 g); 1H NMR (d6 -DMSO): 2.75 (s, 6H), 6.1-6.2 (br s, 2H), 7.6 (s, 1H); mass spectrum (+ve CI): 217 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([C:7]1[CH2:11][CH2:10][O:9][CH:8]=1)=[O:6])[CH3:2].[CH2:13]([OH:15])[CH3:14]>ClCCl>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH:7]1[CH2:11][CH2:10][O:9][CH:8]1[O:15][CH2:13][CH3:14])=[O:6])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)C(=O)C1=COCC1
Solvent: ClCCl
Product: CCOC(=O)C(=O)C1CCOC1OCC
Temperature: 45 °C
Reaction time: 12 h

Procedure:
Ethyl-2-(4,5-dihydrofuran-3-yl)-2-oxoacetate (10 g) was dissolved in Ethanol (50 ml) and Dichloromethane (50 ml). The reaction mass was stirred at 40-50° C. for 12 hrs. Reaction mass was concentrated to residue under vacuum at 40° C. Residue was dissolved in dichloromethane (50 ml) and washed with water (50 ml). Reaction mass was concentrated to residue to get ethyl-2-(2-ethoxytetrahydrofuran-3-yl)-2-oxoacetate (Yield 9.9 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][OH:22].C(N(CC)CC)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:19][CH2:20][CH2:21][OH:22])=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NCCO)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (590 mg, 2.12 mmol) in 2-propanol (20 mL) was added 2-aminoethanol (142 mg, 2.33 mmol) followed by triethylamine (235 mg, 2.33 mmol). The reaction mixture was stirred at reflux for 16 hours and the solvent was then removed under reduced pressure. The residue was washed with 2-propanol (1 mL) and dried by evaporation to afford 2-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethanol. (Yield 0.7 g, crude). LC-MS: [M+H]+ 304.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][NH:9][CH:10]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:4]([CH:10]=[N:9][CH:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CNCc1ncccc1Br
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Brc1cccn2cncc12
Temperature: 0 °C
Yield: 63.1 %

Procedure:
A suspension of N-[(3-bromopyridin-2-yl)methyl]formamide (312.0 mg, 1.451 mmol) in toluene (7.0 mL) was charged with phosphorus oxychloride (0.50 mL, 5.4 mmol) and then refluxed for 1 h. The mixture was concentrated. The residue was cooled to 0° C. and water was added slowly. To the cooled aqueous suspension, aqueous ammonium hydroxide was added until the pH was basic, and the mixture was then extracted with ethyl acetate. The organic fraction was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the residue by ISCO chromatography (100% ethyl acetate) afforded 180.5 mg (63%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J=0.51 Hz, 1H), 8.39 (td, J=0.88, 7.07 Hz, 1H), 7.38 (t, J=0.88 Hz, 1H), 7.12 (d, J=7.07 Hz, 1H), 6.60 (dd, J=6.90, 6.90 Hz, 1H); MS (ESI): 197.05, 198.99 [M+H]+; HPLC tR=2.86 min (ZQ3: polar—5 min).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([CH3:29])([O:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2].[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([CH3:21])([O:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:29])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc3c(c2n1CC(C)(C)OCCS(C)(=O)=O)CCCC3
Yield: 75.8 %

Procedure:
A mixture of 2-(ethoxymethyl)-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 9, 1.70 g, 4.04 mmol) and platinum(IV) oxide (1.0 g) in trifluoroacetic acid (20 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) hydrogen pressure for 40 hours. The mixture was filtered through CELITE filter agent, which was washed afterwards with dichloromethane. The filtrate was concentrated under reduced pressure to afford an oil that was suspended in water (20 mL) and adjusted to pH 13 with 50% aqueous sodium hydroxide. The mixture was extracted with dichloromethane (3×50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a white solid. The solid was recrystallized from toluene to afford 1.3 g of 2-(ethoxymethyl)-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a white, fluffy powder, mp 150-153° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([OH:20])[CH2:9]2)=[CH:3][CH:2]=1.[CH3:27][CH2:28][OH:29]>Cl.Cl.CCO>[CH2:28]([O:29][C:11](=[O:19])[C@H:10]([OH:20])[CH2:9][C@H:8]([NH2:12])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:6][CH:5]=1)[CH3:27]
Reactant: CC(C)(C)C(=O)N1C(=O)[C@H](O)C[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Temperature: 92.5 °C

Procedure:
(3R,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-hydroxypyrrolidin-2-one (56 g, 0.156 mol) was dissolved in EtOH (700 mL) and 12N HCl (700 mL). The mixture was heated to 90-95° C. for 20 hours. The mixture was concentrated on an 80° C. water bath under reduced pressure. EtOH (100 mL) was added to the residue, and the resulting mixture was filtered to yield a yellow solid. This solid was suspended in 3N HCl/EtOH (800 mL). The mixture was refluxed for 3 hours. The solution was concentrated to a reduced volume (˜200 mL volume), and ether (200 mL) was added. The resulting slightly yellow solid was filtered and dried under reduced pressure to yield (2R,4R)-4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (43 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([N:9]=[C:10]=S)[CH:3]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH:9][C:10]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)[CH:3]=1
Reactant: S=C=Nc1cc(Cl)c(Cl)cn1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1cnc(NC2=NC[C@@]3(CN4CCC3CC4)O2)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
To 4,5-dichloro-2-isothiocyanatopyridine (0.25 g, 1.22 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.43 mL, 3.05 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.29 g, 1.24 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.57 mL, 3.66 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(4,5-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.09 g, 0.27 mmol, 22% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.81 (s, 1 H), 8.32 (d, J=6.10 Hz, 1 H), 7.03 (s, 1 H), 3.83 (d, J=9.46 Hz, 1 H), 3.57 (d, J=9.77 Hz, 1 H), 2.98 (s, 2 H), 2.71-2.79 (m, 2 H), 2.65 (t, J=7.78 Hz, 2 H), 1.99 (s, 1 H), 1.86 (s, 1 H), 1.53-1.61 (m, 2 H), 1.41-1.49 (m, 1 H). MS (LC/MS) R.T.=0.78; [M+H]+=327.0.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[CH:29]=[N:28][NH:27][C:14]3=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1>C1COCC1>[CH:30]1([CH2:33][NH:34][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]4[CH:29]=[N:28][NH:27][C:14]4=[N:15][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)[CH:8]=[CH:7][N:6]=2)[CH2:32][CH2:31]1
Reactant: CS(=O)(=O)c1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Reactant: NCC1CC1
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(-c2nc3[nH]ncc3cc2-c2ccnc(NCC3CC3)n2)c1
Yield: 69.4 %

Procedure:
A solution of 5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (90 mg, 0.2 mmol, obtained in example 127) and (cyclopropylmethyl)amine (75 mg, 1.0 mmol) in THF (2 mL) was heated in a closed vessel at 60° C. overnight. It was allowed to cool and concentrated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 57 mg of the desired compound (yield: 67%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)=[O:14]>C1COCC1>[CH2:3]([O:10][CH2:12][C:13]([N:15]1[CH2:16][CH2:17][N:18]([S:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)(=[O:22])=[O:23])[CH2:19][CH2:20]1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCc1ccccc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
To a suspension of sodium hydride (35.88 mg, 60 percent in oil) in dry THF (20 mL) cooled to 0° C. under nitrogen atmosphere, a solution of benzylalcohol (0.09 g, 0.717 mmol) in THF (1 mL) was added drop wise to the mixture over 25 minutes, and the mixture was brought to room temperature and stirred for 2 h. The reaction was again cooled to 0° C., to which a solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5) in THF (20 mL) was added drop wise over 30 minutes. After being stirred for over night at room temperature, the reaction mixture was poured into ice cold water and extracted with ethyl acetate (2×10 mL). The organic layer was washed with brine solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant crude product was purified by column chromatography on silica gel (hexane:ethyl acetate:1:1) to obtain the title product (60 mg, 24%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:6][C:7](Cl)=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:18]=2)=[CH:13][C:12]=1[O:32][CH3:33]>N1C=CC=CC=1.ClCCl>[NH2:26][C:24]1[C:25]2[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:7](=[O:8])[O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[C:12]([O:32][CH3:33])[CH:13]=3)=[CH:18][N:19]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Reactant: CC(C)(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)OCC(C)(C)C
Reaction time: 0.17 h

Procedure:
Neopentylchloroformate (28 uL, 0.186 mmol) was added dropwise to a stirring solution of 5-(4-amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.155 mmol) in pyridine (1 mL) and dichloromethane (1 mL) under nitrogen at 0° C. After 10 minutes, the ice water bath was removed and the resulting mixture was stirred for 4 hours. The solvent was evaporated and the residue was taken into ethyl acetate. The organic layer was washed, dried and evaporated. The solid was purified by preparative TLC using dichloromethane/methanol (95:5) as the mobile phase to give neopentyl N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate. 1H NMR (CDCl3) δ 1.00 (s 9H), 1.78 (m, 2H), 1.90 (m, 4H), 2.26 (m, 2H), 3.91 (s, 2H), 3.94 (s, 3H), 5.22 (m, 3H), 6.22 (s, 1H), 7.01 (s, 1H), 7.08 (d, J=8 Hz, 1H), 7.25 (s, 1H), 8.17 (br. d, 1H), 8.32 (s, 1H); LC/MS (MH+=438).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([Cl:20])=[N:9][S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1)(=O)=O.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([CH3:35])[C:23]=1[CH3:36]>>[Cl:20][C:8]1[C:7]([CH2:6][O:5][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([CH3:35])[C:23]=2[CH3:36])=[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[S:10][N:9]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CCc1ccc(-c2snc(Cl)c2COS(C)(=O)=O)cc1
Product: CCOC(=O)CCc1ccc(OCc2c(Cl)nsc2-c2ccc(CC)cc2)c(C)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 127 following Step 6 by coupling [3-chloro-5-(4-ethylphenyl)-1,2-thiazol-4-yl]methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate to afford the desired product as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:29][N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=O.[CH:38]1[C:46]2[C:45]3[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:44]=3[O:43][C:42]=2[CH:41]=[CH:40][C:39]=1[NH2:52]>>[CH3:29][N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH:52][C:39]1[CH:40]=[CH:41][C:42]2[O:43][C:44]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C:45]=3[C:46]=2[CH:38]=1)=[O:34]
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CN1CCC[C@H]1C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 69.4 %

Procedure:
Following the procedure of Example 30, triethylamine (0.21 mL, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.24 g, 1.3 mmol), N-hydroxybenzotriazole (0.17 g, 1.3 mmol), N-methyl-L-proline (0.077 g, 0.60 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.12 g, 0.60 mmol) provided 1-methyl-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl-L-prolinamide (0.13 g). MS (ES) m/z 313.2 ([M+H]+); HRMS: calcd for C19H24N2O2+H+, 313.19105; found (ESI, [M+H]+), 313.1918.
Reaction SMILES: C([N:3]1[C:10]2[N:6]([N:7]=[CH:8][C:9]=2[CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH2:5][CH2:4]1)=O.[NH3:18]>CO>[NH:3]1[C:10]2[N:6]([N:7]=[CH:8][C:9]=2[CH2:11][CH2:12][C:13]([NH2:18])=[O:15])[CH2:5][CH2:4]1
Reactant: N
Reactant: CCOC(=O)CCc1cnn2c1N(C=O)CC2
Solvent: CO
Product: NC(=O)CCc1cnn2c1NCC2

Procedure:
A solution of ethyl 3-(1-formyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)propanoate (10 g) in a mixture of methanol (50 ml) and an aqueous solution of 28% ammonia (104 ml) was stirred at room temperature for 41 hours. After evaporation of the solvent in vacuo, the residue was triturated with diisopropyl alcohol, dried in vacuo to give 3-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)propanamide (6.44 g).