Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26])(OC(C)(C)C)=O.ClC1N=C2C(N=CN2[C@@H]2C[C@H](N3[N:53]=[C:52]([CH2:54][CH3:55])[CH:51]=[N:50]3)C=C2)=C(Cl)N=1>>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]3[N:53]=[C:52]([CH2:54][CH3:55])[CH:51]=[N:50]3)[C@@H:10]([OH:26])[C@H:11]2[OH:25])=[C:19]([Cl:23])[N:18]=1
Reactant: CCc1cnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)n1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
The titled compound is prepared analogously to (1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (AA4) by replacing di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine with 2,6-dichloro-9-[(1R,4S)-4-(4-ethyl-[1,2,3]triazol-2-yl)-cyclopent-2-enyl]-9H-purine (Step 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.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.Cl.[CH3:67][N:68]([CH:76]1[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]1)[CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:31])[F:32])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:79]3[CH2:78][CH2:77][CH:76]([N:68]([CH3:67])[CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH2:81][CH2:80]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)CCN(C)C1CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)CCN(C)C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg, 0.22 mmol) in DMF (10 mL) was added HATU (123 mg, 0.32 mmol), DIEA (83 mg, 0.64 mmol), and ethyl 3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride (200 mg). The resulting solution was stirred at room temperature overnight. Water (50 mL) was added. The resulting mixture was extracted with DCM (×3) and the organic layers combined. The combined organic layers were washed brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (82 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (18.0% MeCN up to 36.0% in 8 min); Detector, 254/220. 20.3 mg product was obtained. This resulted in 20.3 mg (13%) of the formic acid salt of ethyl 3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]methyl)amino]propanoate as an off-white solid. LCMS (Method 28) [M+H]+=659.2, RT=0.90 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.5, 7.2 Hz), 8.68-8.66 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.03 (t, 1H, J=73.2 Hz), 5.36-5.15 (m, 2H), 4.48-4.33 (m, 1H), 4.02 (q, 2H, J=7.2 Hz), 4.00-3.96 (m, 1H), 3.18-3.00 (m, 1H), 2.89-2.80 (m, 3H), 2.68-2.54 (m, 3H), 2.31 (s, 3H), 1.85-1.76 (m, 2H), 1.61-1.25 (m, 2H), 1.19 (t, 3H, J=6.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([N:1]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[CH:3][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C1CCC(=O)O1
Product: COc1ccc(N2C(=O)CCC2=O)cn1
Temperature: 25 °C

Procedure:
A mixture of 5-amino-2-methoxypyridine (1.24 g, 10.0 mmol) and succinic anhydride (1.00 g, 10.0 mmol) was heated with a heat gun for 10 minutes. After cooling to room temperature the product was purified by flash column chromatography (SiO2, ethyl acetate:acetone 25:75). Evaporation of the solvent yielded the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[Cl:16][C:17]1[CH:18]=[C:19]([C@H:24]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S@:43]([CH3:45])=[O:44])[CH2:33][CH2:32]2)[CH2:25][NH:26][CH2:27][CH3:28])[CH:20]=[CH:21][C:22]=1[Cl:23].ClC1C=C([C@H](CCN2CCC(C3C=CC=CC=3[S@](C)=O)CC2)CNC)C=CC=1Cl.ClC(OCC)=O>>[Cl:16][C:17]1[CH:18]=[C:19]([C@H:24]([CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S@:43]([CH3:45])=[O:44])[CH2:35][CH2:36]2)[CH2:25][N:26]([CH2:27][CH3:28])[C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:15])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: N#Cc1cc(C(=O)O)c2ccccc2c1
Reactant: CCNC[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)Cl
Agent: CNC[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1
Product: CCN(C[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12

Procedure:
Using standard acylation conditions, 3-cyano-1-naphthoic acid (0.118 g) was converted to the acid chloride and reacted with N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-ethylamine (0.336 g) (prepared according to methods described for N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine, except ethyl chloroformate was used in place of acetyl chloride for the amine acylation prior to amide reduction). mp 115-118° C. (dec); 1H NMR (300 MHz, DMSO-d6) δ 8.65 (d), 8.10 (m), 7.95-7.15 (m), 6.50 (m), 3.60 (s), 3.25-2.95 (m), 2.95-2.40 (m), 2.40-1.70 (m), 1.35 (m), 0.9 (m); MS APCI, m/z=646 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cu][C:14]#[N:15].CN1CCCC1=O.C(N)CN>S([O-])([O-])(=O)=O.[Cu+2].O>[C:14]([C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:15]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: NCCN
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cc(C#N)ccc1O
Temperature: 25 °C
Yield: 14.7 %

Procedure:
Methyl 5-bromo-2-hydroxybenzoate (25.6 g, 129 mmol), copper(I) cyanide (20.8 g, 257 mmol) and copper sulfate (200 mg) were added to N-methyl-2-pyrrolidone (250 ml) and the mixture was refluxed under heating for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into a mixture of water (500 ml) and ethylenediamine (10 ml). After filtration, the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=5/1) to give 3.35 g of methyl 5-cyano-2-hydroxybenzoate as a colorless solid (15%). This solid (3.35 g, 18.9 mmol) and potassium carbonate (5.23 g, 37.0 mmol) were added to N,N-dimethylformamide (45 ml), and ethyl bromoacetate (2.21 ml, 19.9 mmol) was gradually added, which was followed by stirring at room temperature for 18 hours. Water was added to the reaction mixture and the mixture was extracted with an equivalent mixture of ethyl acetate and n-hexane. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give a crude product of ethyl 4-cyano-2-methoxycarbonylphenoxyacetate. This product (3.39 g, 19.3 mol) was dissolved in ethanol (20 ml) and the obtained solution was gradually added to a solution of metallic sodium (622 mg, 27.1 mmol) dissolved in ethanol (50 ml). The mixture was stirred at room temperature for 45 minutes. Low boiling matters were distilled away from the reaction mixture under reduced pressure and water (200 ml) was added to the residue. Dilute hydrochloric acid was added to adjust the pH to 2-3. The resulting precipitate was collected by filtration to quantitatively give 2.98 g of ethyl 5-cyano-3-hydroxy-2-benzofurancarboxylate as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[Br:43])[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1.[C:44](Cl)(=[O:48])[CH:45]([CH3:47])[CH3:46]>>[Br:43][C:42]1[CH:41]=[CH:40][C:4]([CH2:5][O:6][CH:7]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:8]2)=[CH:3][C:2]=1[NH:1][C:44](=[O:48])[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Br)c(N)c2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Br)c(NC(=O)C(C)C)c2)cc1

Procedure:
Analogously to Example 18e, 4.30 g of tert-butyl 3-(3-amino-4-bromobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate are reacted with 0.78 ml of isobutyryl chloride. The title compound is obtained as a colourless oil. Rt=6.12.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:15])[CH2:7][CH2:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1)C>C1COCC1.CO>[C:9]1([CH2:8][CH2:7][C:6]([OH:15])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: CCOC(=O)CCC1=CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC1=CCCCC1
Reaction time: 2 h

Procedure:
2N LiOH (3.5 mL) was added to a solution of 3-Cyclohex-1-enyl-propionic acid ethyl ester (0.6 g, 3.4 mmol, from Step 1 dissolved in THF (12 mL) and MeOH (3 mL). The mixture was stirred for 2 h under N2 and then partitioned between 1N HCl and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to a clear oil. 1H NMR (CDCl3): δ 1.54 (m, 2H), 1.62 (m, 2H), 1.92 (m, 2H), 1.97 (m, 2H), 2.26 (m, 2H), 2.46 (t, 2H, J=8.3 Hz), 5.44 (s, 1H).
Reaction SMILES: O.C(O)C.[CH3:5][C@@H:6]1[C@H:40]([OH:41])[C@@H:39]([CH3:42])[C@@H:38]([OH:43])[C@@H:37]([CH3:44])[C@H:36]([O:45][C:46]([CH3:48])=[O:47])[C@H:35]([CH3:49])[C@@H:34]([O:50][CH3:51])[CH:33]=[CH:32][O:31][C@:28]2([CH3:52])[C:29](=[O:30])[C:18]3[C:19]([O:27]2)=[C:20]([CH3:26])[C:21]([OH:25])=[C:22]2[C:23](=[O:24])[C:14](=[CH:15][C:16]4(OC(=O)CO4)[C:17]=32)[NH:13][C:11](=[O:12])[C:10]([CH3:58])=[CH:9][CH:8]=[CH:7]1.[NH2:59][C:60]1[CH:65]=[C:64]([CH3:66])[CH:63]=[CH:62][N:61]=1>CC(C)=O>[CH3:66][C:64]1[CH:63]=[CH:62][N:61]2[C:15]3[C:14]4[NH:13][C:11](=[O:12])[C:10]([CH3:58])=[CH:9][CH:8]=[CH:7][C@H:6]([CH3:5])[C@H:40]([OH:41])[C@@H:39]([CH3:42])[C@@H:38]([OH:43])[C@@H:37]([CH3:44])[C@H:36]([O:45][C:46]([CH3:48])=[O:47])[C@H:35]([CH3:49])[C@@H:34]([O:50][CH3:51])[CH:33]=[CH:32][O:31][C@:28]5([CH3:52])[C:29](=[O:30])[C:18]6=[C:19]([O:27]5)[C:20]([CH3:26])=[C:21]([OH:25])[C:22](=[C:17]6[C:16]=3[N:59]=[C:60]2[CH:65]=1)[C:23]=4[OH:24]
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C2(C=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O)OCC(=O)O2
Reactant: Cc1ccnc(N)c1
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c5c(nc6cc(C)ccn65)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C2(C=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O)OCC(=O)O2
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c5c(nc6cc(C)ccn65)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In flask equipped with a mechanic stirrer, 200 ml of demineralized water, 150 ml of ethyl alcohol, 50 ml of acetone, 100 g of Rifamycin O and 43.3 g of 2-amino-4-methylpyridine are loaded in succession at room temperature. After loading, the mixture is kept under stirring at room temperature for 24 hours, then is cooled to 10° C. for 60 minutes. Then the precipitate is filtered and washed by means of a mixture of 100 ml of demineralized water and 100 ml of ethyl alcohol and at least with two washing of 100 ml of demineralized water. The product is dried under vacuum at 70° C. until the water content is between 2.0 and 4.5%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1)#[CH:2].[Li]CCCC.[C:15]([C:19](OCC)=O)([F:18])([F:17])[F:16].B(F)(F)F.O(CC)CC.[NH2:33][NH2:34]>C1COCC1.C1C=CC=CC=1>[F:9][C:5]1[CH:4]=[C:3]([C:1]2[NH:34][N:33]=[C:19]([C:15]([F:18])([F:17])[F:16])[CH:2]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: C#Cc1cccc(F)c1
Reactant: NN
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccccc1
Product: Fc1cccc(-c2cc(C(F)(F)F)n[nH]2)c1

Procedure:
Following protocol H, 1-Ethynyl-3-fluoro-benzene was treated with n-BuLi, CF3CO2Et and BF3-OEt2 in THF. Reaction with hydrazine in benzene under similar reaction conditions yielded title compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][OH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:16]1[CH2:30][CH:17]1[CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>>[OH:16][CH:17]([CH2:30][O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)[CH2:18][N:19]1[C:20](=[O:29])[C:21]2[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:24]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: OCc1cccc(CN2CCCCC2)c1
Product: O=C1c2ccccc2C(=O)N1CC(O)COCc1cccc(CN2CCCCC2)c1
Temperature: 130 °C
Reaction time: 1.33 h
Yield: 42.1 %

Procedure:
A mixture of 10.25 g (0.05 mol) of 3-(1-piperidylmethyl)-benzyl alcohol and 10.15 g (0.05 mol) of N-(2,3-epoxypropyl)-phthalimide is stirred under nitrogen for 80 minutes at 130° C. The viscous resin obtained is chromatographed on silica gel, using methylene chloride/methanol 9:1. The main fraction yields 8.60 g (42%) of the title compound in the form of a light brown oil after concentration by evaporation.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][NH:9][CH3:10])([CH3:5])([CH3:4])[CH3:3].[CH2:12](N(CC)CC)C.BrC[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].O>C(#N)C>[C:24]([C:23]1[CH:22]=[C:21]([CH:28]=[CH:27][CH:26]=1)[CH2:10][N:9]([CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])[CH3:12])#[N:25]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CNCC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CN(CC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a stirred solution of sarcosine tert-butyl ester hydrochloride (8.1 g, 44.9 mmol) and triethylamine (17 mL, 122.4 mmol) in acetonitrile (100 mL) under N2, was added 3-(bromomethyl)benzonitrile (8 g, 40.8 mmol) portionwise over a period of 10 min at 0° C. After being stirred at RT for 3 h, the reaction mixture was poured into water and extracted with DCM. Then the organic layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a pale green liquid (9 g, 85%). 1H NMR (DMSO-d6, 400 MHz) δ 7.71-7.72 (2H, m), 7.63-7.65 (1H, m), 7.53-7.55 (1H, m), 3.66 (2H, s), 3.18 (2H, s), 2.22 (3H, s), 1.41 (9H, s).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH:19]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[C:18]3[C:29]([CH3:36])=[C:30]([OH:35])[C:31]([CH3:34])=[C:32]([CH3:33])[C:17]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1.O>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH:19]([C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[C:18]3[C:29]([CH3:36])=[C:30]([O:35][CH2:43][C:42]4[CH:45]=[CH:46][C:39]([O:38][CH3:37])=[CH:40][CH:41]=4)[C:31]([CH3:34])=[C:32]([CH3:33])[C:17]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCN(Cc3ccccc3)CC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C2(CCN(Cc4ccccc4)CC2)O3)cc1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 81.4 mg, 1.81 mmol) was added to a solution of 1′-benzyl-3-(4-isopropylphenyl)-4,6,7-trimethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol (824.0 mg. 1.81 mmol) in N,N-dimethylformamide (15 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-methoxybenzyl chloride (319.9 mg, 2.04 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain the title compound (539 mg, yield 52%). This was amorphous.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[C:10]3[CH2:11][CH2:12][C:13](=[O:18])[C:14]=3[CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[C:10]4[CH2:11][CH2:12][C:13](=[O:18])[C:14]=4[CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: O=C1CCc2c(Oc3cncc(Cl)n3)cccc21
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3cccc4c3CCC4=O)n2)cc(OC)c1OC
Yield: 23 %

Procedure:
Using Method EE with 2-chloro-6-(indanone-4-oxy)-pyrazine (200 mg, 0.77 mmol) and 3,4,5-trimethoxyaniline (169 mg, 0.92 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (71 mg). Yield: 23%. 1H NMR (250 MHz, DMSO-d6) δ 2.69 (t, 2H, H3, J=3.7 Hz), 2.98 (t, 2H, H2, J=5.2 Hz), 3.43 (s, 6H, [CH3O]3+5), 3.59 (s, 3H, [CH3O]4), 6.75 (s, 2H, Harom2′+6′), 7.56-7.62 (m, 3H, Harom), 7.90 (s, 1H, HPz 5), 8.04 (s, 1H, HPz 3), 9.62 (s, 1H, NH). m/z: 408.1 [(M+H)+, calcd for C22H21N3O5 407.1].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[C:9](=[CH:14]\[C:15]([CH3:18])([CH3:17])[CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.[H][H]>C(O)C>[CH3:13][O:12][C:10](=[O:11])[C@@H:9]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)/C(=C/C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: [H][H]
Solvent: CCO
Solvent: C1COCCO1
Product: COC(=O)[C@@H](CC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
Methyl (2Z)-2-[(tert-butoxycarbonyl)amino]-4,4-dimethylpent-2-enoate (Example 4A, 60 g, 233.2 mmol) is dissolved in ethanol p.a./dioxane 3:1 (1000 ml). Argon is passed through for about 10 min using a cannula. The solution is placed into an ultrasound bath (about 5 min), and (+)-1,2-bis[(2R,5R)diethylphospholano]benzene(cyclooctadiene)rhodium(I) triflate (600 mg, 1% by weight) is added. The mixture is hydrogenated under 3.5 bar hydrogen pressure and at RT for 3 days. The reaction mixture is filtered through kieselguhr and the eluate is concentrated. The crude product is chromatographed (silica gel, eluent: cyclohexane/ethyl acetate 4:1). 60 g (99% of theory) of the title compound are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11]([Cl:18])[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.[NH2:23][C@H:24]([C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]>C(#N)C>[ClH:18].[NH2:23][C@H:24]([C@@H:28]1[CH2:32][CH2:31][N:30]([C:11]2[C:12]([F:17])=[CH:13][N:14]3[C:9]([C:10]=2[CH3:19])=[C:8]([CH:20]2[CH2:21][CH2:22]2)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]3=[O:16])[CH2:29]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCC[C@H](N)[C@@H]1CCNC1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Solvent: CC#N
Product: CCC[C@H](N)[C@@H]1CCN(c2c(F)cn3c(=O)c(C(=O)O)cc(C4CC4)c3c2C)C1
Product: Cl

Procedure:
A 171 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 4 mL of anhydrous acetonitrile, reacted with (3R,1S)-3-(1-amino-3-methylpropyl)pyrrolidine (400 mg, 1.32 mmol, prepared as described by Plummet et al., Tetr. Lett. 34:7529-32 (1993), and carried forward as described in Example 253j-l, omitting the deprotection reaction, to give the title product. MS (high resolution) found: 402.2174; calc: 402.2193 (M+H)+ ; 1H NMR (D6 -DMSO) δ: 0.60 (m, 2H), 0.95 (d, 3H), 1.06 (d, 3H), 1.75 (m, 1H), 2.13 (m, 1H), 2.29 (m, 2H), 2.50 (s, 3H), 3.66 (m, 3H), 3.78 (m, 1H), 3.97 (m, 1H), 7.88 (s, 1H), 9.08 (d, 1H), 13.82 (bs, 1H). Anal. Calcd for C22H29N3O3FCl.0.75H2O: C, 58.53; H, 6.81; N, 9.31; Found: C, 58.88; H, 6.70; N, 9.26.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH2:16])=[O:15].[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(#N)C.ClCCl>[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[C:14]([NH2:16])=[O:15])=[O:23])=[CH:20][CH:19]=1
Reactant: NC(=O)c1cccn1N
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nn2cccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (277 μl, 2.00 mmol) is added to a suspension of 1-amino-1H-pyrrole-2-carboxylic acid amide (250 mg, 2.00 mmol) in acetonitrile (4.0 ml). Under external cooling with ice, a solution of 4-methylbenzoyl chloride (264 μl, 2.00 mmol) in dichloromethane (0.6 ml) is added dropwise. The reaction mixture is stirred at room temperature for 18 hours. The solvents are evaporated and the residue is taken up in dichloromethane and saturated NaHCO3 solution. A precipitate forms which is filtered off, washed with water and dried under vacuum to give 1-(4-methyl-benzoylamino)-1H-pyrrole-2-carboxylic acid amide as white crystals; HPLC/MS 1.57 min (A), [M+H] 244;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.O>ClCCl>[F:19][C:20]([F:28])([F:29])[C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:10](=[O:12])[CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:26][CH:27]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1ccccc1CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1CC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
5.0 g of 2-methoxyphenylacetic acid was dissolved in 20 ml dichloromethane, and 4.6 g of oxalyl dichloride was added, and the mixture was stirred at room temperature for 3 hours. The solvent and an excessive oxalyl dichloride were evapoarated, and the residue was dissolved in 20 ml dichloromethane. Under ice-cooling, 14 g of 4-trifluoromethyl aniline was added thereto, followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and then the solvent was evpoarated. The resulting solid was collected by filtration and washed with diethyl ether, to give 8.0 g of N-[4-(trifluoromethyl)phenyl]-2-(2-methoxyphenyl)acetamide as a colorless solid.