Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21].[CH3:22][N:23]([CH3:28])[CH2:24][C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH3:22][N:23]([CH3:28])[CH2:24][C:25]([O:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21])=[O:26]
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Reactant: CN(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CN(C)CC(=O)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a suitable reaction vessel containing 5 ml of pyridine, there is added one g (0.035 mols) of 3-hydroxymethyl-diphenylhydantoin, 0.36 g (0.0035 mols) of N,N-dimethylglycine and 0.79 g (0.0035 mols) of dicyclohexylcarbodiimide (DCCI). The reaction mixture is stirred at room temperature for a period of approximately 24 hours, after which the final product, mp 128°-130°, yield 0.86 g (66.7%) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[C:24]([C:26]([CH3:38])([O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])[CH3:27])#[N:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>C(OCC)(=O)C.CN(C)C(=O)C>[C:14]([NH:13][C:11]1[S:12][C:8]2[C:7]([C:19]#[N:20])=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([O:28][C:26]([C:24]#[N:25])([CH3:27])[CH3:38])[CH:30]=4)[CH:23]=[CH:22][CH:21]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(OC(C)(C)C#N)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.5 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii), 3-(1-cyano-1-methylethoxy)benzoic acid (114 mg, 0.555 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (211 mg, 0.554 mmol), and pyridine (2 mL)/N,N-dimethylacetamide (1.2 mL) was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate (10 ml), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound (162 mg, 69%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12](S(C3C=CC(C)=CC=3)(=O)=O)[C@@H:11]([CH2:42][C@H:43](OS(C)(=O)=O)[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.[NH:50]1[CH:54]=[CH:53][N:52]=[CH:51]1>>[N:50]1([C@@H:43]([CH3:44])[CH2:42][C@@H:11]2[NH:12][CH2:13][C@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[C@@H:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)[CH:54]=[CH:53][N:52]=[CH:51]1
Reactant: c1c[nH]cn1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@@H](C)OS(C)(=O)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN[C@@H](C[C@H](C)n4ccnc4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 42a, methanesulfonic acid (R)-2-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-1-methyl-ethyl ester (from example 38b) are reacted with imidazol to afford the title compound as a colourless oil. Rf=0.22 (dichlormethane-methanol 10:1); Rt=4.60.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[CH3:13][CH:14]([CH3:18])[CH2:15][CH2:16]Br>>[CH3:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: OCCCCCCCCCCBr
Reactant: CC(C)CCBr
Product: CC(C)CCCCCCCCCCCCO
Yield: 62 %

Procedure:
13-methyltetradecan-1-ol was prepared from 10-bromodecanol and 3-methylbutylbromide in 62% yield. The 1H NMR and MS-ESI data matched those reported by Yuasa et al. (Yuasa and Tsuruta (2004) Flavour and Fragrance Journal 19:199-204).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9](O)=[O:10])([O-:5])=[O:4].B(F)(F)F.CCOCC>C1COCC1>[N+:3]([C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)([O-:5])=[O:4]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a suspension of NaBH4 (2.85 g, 75.4 mmol) in dry THF (40 mL) at 0° C. was added a solution of 3,5-dinitrobenzoic acid (8.0 g, 37.7 mmol) in THF (20 mL), followed by the addition of BF3.OEt2 (12.5 mL, 98.0 mmol). The resulting mixture was warmed to 25° C. and stirred for 1 hour after which the reaction was quenched with 1 M HCl. The aqueous phase was extracted with DCM and the organic phase was then washed with saturated Na2CO3. The organic phase was dried over MgSO4 and evaporated under reduced pressure to give the title compound 6 as an orange solid (5.01 g, 25.3 mmol, 67%). 1H NMR (400 MHz, ((CD3)2C)) δ 8.91 (t, J=0.4 Hz, 1H), 8.57 (dd, J=1.2, 2.0 Hz, 2H), 4.93 (d, J=5.2 Hz, 2H), 3.57 (bs, 1H); 13C NMR (75 MHz, (CD3)2CO) δ 149.4, 148.4 (2C), 127.0 (2C), 117.6, 62.8; HRMS (ESI) Calculated for C7H5N2O5 [M−H]−: 197.0204. Found: 197.0200. m.p.: 89° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:30]([C:25]3[N:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:31])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: O=C(O)c1ncccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), pyrimidine-2-carboxylic acid (12 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL DMF. A few drops of DMSO were added to obtain a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for one hour, then at 80° C. for 16 hours. Reaction did not reach completion before workup. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the final product as a light yellowish solid (3 mg, 9% yield). MS (apci) m/z=422.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:13][N:14]=[C:15]=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O1CCOCC1.O>[CH3:12][O:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:13]([NH:14][CH3:15])=[N:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CN=C=O
Reactant: COc1cccc(N)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CNc1nc2cccc(OC)c2c(=O)o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A mixture of 2-amino-6-methoxybenzoic acid (2.00 g, 12.0 mmol) and methylisocyanate (1.00 g, 17.5 mmol) in dioxane (50 ml) was stirred at 80° C. for 2 h. After cooling to room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.88 g, 36.0 mmol) and triethylamine (5.00 ml, 36.0 mmol) were added. The mixture was stirred at room temperature for 16 h, diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 20% ethyl acetate/n-hexane to afford 1.06 g (43%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].CO>O>[CH2:32]([N:34]([CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1)[CH2:35][CH3:36])[CH3:33]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CCNCC
Solvent: CO
Solvent: O
Product: CCOC(=O)c1c(CN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 11.8 %

Procedure:
A mixture of ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (4.0 g), diethylamine (1.28 g) and methanol (45 ml) was stirred at room temperature for 4 days. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate gave ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (0.51 g, 18%). This compound was recrystallized from ethyl acetate-hexane. Colorless prisms, mp. 130°-131° C.
Reaction SMILES: N1(C2C3C=NC(NC(=O)N)=CC=3NN=2)CCOCC1.[CH3:20][N:21]1[CH2:25][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:23]([NH:32][C:33]([NH:35][C:36]2[N:41]=[CH:40][C:39]3[C:42]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[N:43][NH:44][C:38]=3[CH:37]=2)=[O:34])[CH2:22]1>CO>[CH3:20][N:21]1[CH2:25][C@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:23]([NH:32][C:33]([NH:35][C:36]2[N:41]=[CH:40][C:39]3[C:42]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[N:43][NH:44][C:38]=3[CH:37]=2)=[O:34])[CH2:22]1
Reactant: CN1C[C@@H](NC(=O)Nc2cc3[nH]nc(N4CCOCC4)c3cn2)[C@H](c2ccccc2)C1
Agent: NC(=O)Nc1cc2[nH]nc(N3CCOCC3)c2cn1
Solvent: CO
Product: CN1C[C@H](NC(=O)Nc2cc3[nH]nc(N4CCOCC4)c3cn2)[C@@H](c2ccccc2)C1
Yield: 50 %

Procedure:
The enatiomers of 1-[(3R and S, 4S and R)-1-Methyl-4-phenylpyrrolidin-3-yl]-3-(3-morpholin-4-yl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (63.5 mg, 0.098 mmol) were separated by SFC (Berger Multigram II SFC, column: Chiral Technology IC 2.1×25 cm, 5 uM, mobile phase: 40% to 60% MeOH+0.25% dimethyl ethylamine in CO2(1), flow rate: 70 mL/min, 12 min run time). The fractions were collected and the solvent evaporated in vacuo, dissolved in ACN/water, and lyophilized to afford 1-[(3R,4S)-1-methyl-4-phenylpyrrolidin-3-yl]-3-(3-morpholin-4-yl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (15.6 mg, 0.037 mmol, 50%) and 1-[(3S,4R)-1-methyl-4-phenylpyrrolidin-3-yl]-3-(3-morpholin-4-yl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (Example 42 was obtained as the trifluoroacetic acid salt of the compound). MS ESI calc'd. For C22H27N7O2 [M+1]+ 422. found 422. 1H NMR (500 MHz, DMSO-d6) δ 12.0 (s, 1H), 8.90 (s, 1H), 8.79 (s, 1H), 7.88-7.80 (m, 1H), 7.35 (s, 1H), 7.35-7.23 (m, 4H), 7.23-7.14 (m, 1H), 4.21-4.18 (m, 1H), 3.82-3.69 (m, 4H), 3.36-3.30 (m, 4H), 3.13-3.01 (m, 2H), 2.82 (dd, J=4.5, 9.4 Hz, 1H), 2.54 (dd, J=4.5, 9.4 Hz, 1H), 2.43-2.33 (m, 1H), 2.28 (s, 3H) (Example 41). MS ESI calc'd. For C22H27N7O2 [M+1]+ 422. found 422. 1H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.97 (s, 1H), 8.79 (s, 1H), 7.88-7.80 (m, 1H), 7.32 (s, 1H), 7.35-7.23 (m, 4H), 7.23-7.14 (m, 1H), 4.21-4.18 (m, 1H), 3.81-3.70 (m, 4H), 3.36-3.30 (m, 4H), 3.13-3.01 (m, 2H), 2.82 (dd, J=4.5, 9.4 Hz, 1H), 2.54 (dd, J=4.5, 9.4 Hz, 1H), 2.43-2.33 (m, 1H), 2.28 (s, 3H). (Example 42).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:37]4[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:45])=[CH:39][CH:38]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-(trifluoromethyl)-benzenesulfonyl chloride. Purity (ELSD, based on MW=629.6)=94%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C:60](=[O:71])[C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH2:68][CH2:69][NH2:70])=[N:63][CH:62]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C:60](=[O:71])[C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH2:68][CH2:69][NH:70][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:21])=[N:63][CH:62]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Reactant: NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.1 %

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (300 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(2-aminoethylamino)nicotinamide (284 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (493 mg, 89%) as a yellow solid. 1H NMR (DMSO-d6)δ2.41 (s, 3H, pyrrole-CH3), 2.43 (s, 3H, pyrrole-CH3), 3.43 (m, 2H, CH2), 3.48 (m, 2H, CH2), 4.86 (s, 2H, benzene-NH2), 6.56 (m, 2H), 6.76 (d, J=8.0 Hz, 1H), 6.84 (m, 1H), 6.92 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 7.26 (s 1H), 7.71˜7.77 (m, 3H), 7.94 (d,J=8.0 Hz, 1H), 8.65 (s, 1H), 9.38 (s, 1H, benzene-NH), 10.90 (s, 1H, indolinone-NH), 13.69 (s, 1H, pyrrole-NH). LC-MS (m/z) 554 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1)[C:3]([NH2:5])=[O:4].[ClH:12]>O>[ClH:12].[ClH:12].[NH2:1][CH:2]([CH:6]1[CH2:11][NH:10][CH:9]=[N:8][CH2:7]1)[C:3]([NH2:5])=[O:4]
Reactant: NC(=O)C(N)c1cncnc1
Agent: Cl
Solvent: O
Product: NC(=O)C(N)C1CN=CNC1
Yield: 92.5 %

Procedure:
Amino(pyrimidin-5-yl)acetamide (950 mg, 6.7 mmol) is suspended in a mixture of 50 ml water and concentrated hydrochloric acid (13.3 mmol). The mixture is hydrogenated at 26 psig over 300 mg Pd-on-carbon 10% in a Parr hydrogenator for 3h. Then the suspension is filtered and the filter rinsed twice with hot water (20 ml). The filtrate can be evaporated in vacuo to give 1.41 g yellow oil (92%). The oil is crystallized from anhydrous methanol/THF to give 1.33 g (87%) white crystals, identified by 300 MHz nmr.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([C:11]1[CH:16]=[C:15]([S:17][CH3:18])[CH:14]=[CH:13][C:12]=1[O:19][CH3:20])=[N:6]2.[OH-:21].[K+]>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][C:15]([S:17][CH3:18])=[CH:16][C:11]=1[C:5]1[N:4]=[C:3]2[C:7](=[N:8][CH:9]=[N:10][C:2]2=[O:21])[N:6]=1
Reactant: [OH-]
Reactant: COc1ccc(SC)cc1-c1nc2ncnc(Cl)c2[nH]1
Agent: [K+]
Product: COc1ccc(SC)cc1C1=NC2=NC=NC(=O)C2=N1

Procedure:
Prepared analogously to Example 16 from 6-chloro-8-(2-methoxy-5-methylmercapto-phenyl)-purine by reaction with 20% potassium hydroxide solution.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.[CH3:28][N:29]([C@@H:46]([C:54](=[O:57])[NH:55][CH3:56])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:30](=[O:45])[CH:31]([NH:43][CH3:44])[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:43]([CH3:44])[C@@H:31]([C:30](=[O:45])[N:29]([CH3:28])[C@@H:46]([C:54](=[O:57])[NH:55][CH3:56])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (200 mg, 0.82 mmol), 1-hydroxy-7-azabenzotriazole (112 mg, 0.82 mmol) and 1-ethyl-3-(3-s dimethylaminopropyl)-carbodiimide hydrochloride (173 mg, 0.90 mmol) were dissolved in a mixture of methylene chloride (10 mL) and N,N-dimethylformamide (1 mL) and strirred for 15 min. N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (332 mg, 0.82 mol) dissolved in methylene chloride (5 mL) and diisopropylethylamine (0.14 mL) were added and the mixture was stirred overnight under nitrogen atmosphere. The mixture was diluted with methylene chloride (50 mL), washed with water (50 mL), sodium hydrogen carbonate (30 mL, saturated), and sodium hydrogensulfate (30 mL, 5%). The phases were separated and the organic phase was dried with magnesium sulfate and evaporated in vacuo. The residue was chromatographed (silica, 2×40 cm) to afford 450 mg of ((3E)-1,1dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=O)[CH:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[C:11](=[O:17])[O:10]1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:9](=[O:10])[C@@H:13]2[CH2:14][CH2:15][CH2:16][C@@H:12]2[C:11]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C1OC(=O)C2CCCC12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1[C@H]2CCC[C@H]2C(=O)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of benzylamine (6.4 mL) and tetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione (8 gm) in tetrahydrofuran (28 mL) was heated under reflux for 18 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and filtered through a pad of celite. Evaporation under reduced pressure gave crude (3aR,6aS)-2-benzyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3 aH)-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-:15][Si](C)(C)C)(C)C.[Na+].O>C1COCC1>[NH2:15][CH2:10][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:9]
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-(3-chlorophenyl)oxirane (13 g, 84 mmol) in THF (84 mL) was added NaHMDS (1 M in THF) (252 mL, 252 mmol) slowly at 0° C. The reaction mixture was warmed up to room temperature and stirred for overnight. To the reaction mixture, water (33 mL, 2.5 mL/g) added. After stirring for 5 h at room temperature, solvent was removed in vacuo to about ¼ and partitioned by DCM. The bottom layer is a little cloudy and the top layer was a brown solution. Both layers were concentrated, which contained the desired (R)-2-amino-1-(3-chlorophenyl)ethanol (14 g, 97%). The combined products were used in next step without further purification. LCMS (m/z): 172.1 (MH+), 0.37 min.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH2:12])=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.[OH-].[Na+]>C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH2:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(C(N)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCC(CN)CC1
Yield: 23.3 %

Procedure:
To a suspension of 10.0 g of LAN in 500 mL of dry THF, at room temperature, was added portionwise 39.7 g of 1-isopropylpiperidine-4-carboxamide and the mixture was refluxed 18 h. The cooled reaction mixture was diluted with 150 mL THF and treated dropwise with 10 mL H2O and 10 mL 5 N NaOH, respectively. The resulting gray mixture was refluxed 18 h, filtered and evaporated. The residue partially dissolved in hexane to give 25.5 g of crude yellow liquid and 6.9 g hexane insoluble starting carboxamide. HPLC purification on silica gel of the 25.5 g liquid, eluting with 20% MeOH-EtOAc gave 1-isopropylpiperidine-4-methylamine (8.5 g, 28%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCOCC1.O>[CH2:18]([O:25][C:26]([NH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@H](CO)Cc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a mixture of L-phenylalaninol (20.2 g, 0.134 mol), sodium carbonate (21.1 g, 0.200 mol) and 1,4-dioxane (150 mL) was added a solution of benzyloxycarbonyl chloride (19.1 mL, 0.134 mol) in 1,4-dioxane (50 mL) and the mixture was stirred at room temperature for 3 hours. Water (300 mL) was added to the reaction mixture and the obtained mixture was added to ice-cooled 0.5 N hydrochloric acid (500 mL). The precipitated crystals were collected by filtration and washed with hexane and dried to give N-benzyloxycarbonyl-L-phenylalaninol as white crystals (28.8 g, 76%).