Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]#[N:12])[O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.NC1C2C(=CC=C(CN)C=2)C=CN=1>>[NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][NH2:12])[O:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cc2c(N)nccc2o1
Agent: NCc1ccc2ccnc(N)c2c1
Product: NCc1cc2c(N)nccc2o1

Procedure:
This compound was prepared from 4-amino-furo[3,2-c]pyridine-2-carbonitrile (5.7 g), using the procedure described for 1-amino-7-(aminomethyl)isoquinoline. Yield: 3.5 g (60%); yellow crystals; m.p. 142-144° C., EI-MS: 163 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=1[F:12].[CH2:14]([NH2:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[F:12][C:5]1[CH:6]=[CH:7][C:8]([CH2:10][NH:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:13]
Reactant: CCCCCCN
Reactant: COC(=O)c1cc(C=O)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCCCCNCc1ccc(F)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.7 %

Procedure:
To solution of 2-fluoro-5-formylbenzoic acid methyl ester (1.0 g; 5.49 mmol) in anhydrous DCE (50 mL) were added hexylamine (Aldrich, 0.87 mL; 6.59 mmol), triacetoxyborohydride (1.74 g; 8.24 mmol) and acetic acid (0.47 mL; 8.24 mmol). The resulting mixture was stirred at room temperature under N2 atmosphere for 5 hours. The mixture was poured into a saturated solution of NaHCO3 and extracted with DCM (2×200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (DCM/MeOH/NH4OH, 98:2:0.1) gave 920 mg (63%) of the title compound as a yellow cream. HPLC, Rt: 2.34 min (purity=94.9%), LC/MS: M+(ESI): 268.1, 1H NMR (CDCl3) δ: 7.8 (dd, J=2.2, 8.2 Hz, 1H), 7.42 (m, 1H), 7.00 (dd, J=8.2, 2.2 Hz, 1H), 3.91 (s, 3H), 3.76 (s, 2H), 2.58 (t, J=7.1 Hz, 2H), 1.46 (qt, J=6.7 Hz, 2H), 1.22 (m, 6H), 0.86 (t, J=6.7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH3:16])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1Br.C([Li])CCC.CCCCCC.CN(C)[CH:30]=[O:31]>O1CCCC1.[Cl-].[Na+].O>[Br:1][C:2]1[N:3]=[C:4]([CH3:16])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: Cc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(Br)c(C=O)n1COCC[Si](C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
4,5-Dibromo-2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)imidazol (29.2 g) was dissolved in tetrahydrofurane (250 ml) and a 1.63N n-butyl lithium/hexane solution (58.1 ml) was dropwise added over 20 min at −55° C. to −60° C. The mixture was stirred at −60° C. for 30 min and N,N-dimethylformamide (58 g) was dropwise added at −55° C. to −60° C., and the mixture was stirred at room temperature for 1 hr. Saturated brine was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give the objective compound (18.5 g) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[NH:33][C@@H:32]([CH3:34])[CH2:31][N:30]([C:35]2[S:36][C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[C@H:32]([CH3:34])[CH2:31][N:30]([C:35]3[S:36][C:37]4[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=4[N:39]=3)[CH2:29][C@@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2nc3ccccc3s2)C[C@H](C)N1
Product: C[C@@H]1CN(c2nc3ccccc3s2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-benzothiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:23])[C:10]2[N:11]=[CH:12][C:13]3[N:18]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[S:16][C:14]=3[N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:24][C:25]1[C:33]([C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:20]([NH:19][C:17]1[S:16][C:14]2[N:15]=[C:10]([N:9]([CH3:23])[C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:33]([C:34]5([C:37]#[N:38])[CH2:35][CH2:36]5)[C:25]=4[Cl:24])[CH:3]=3)[N:11]=[CH:12][C:13]=2[N:18]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1nc2cnc(N(C)c3ccc(F)c(N)c3)nc2s1
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(N(C)c3ccc(F)c(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)c3)nc2s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
A solution of N-{5-[(3-amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (100 mg, 301 μmol) produced in Example D17(iv), 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (167 mg, 753 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (286 mg, 753 μmol) in pyridine (4 mL) was stirred at 90° C. for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=20/80→0/100) and silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (79 mg, 49%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22]CN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCC1CCC[N:67]([C:71]([O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:72])[CH2:66]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:67]([C:71]([O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:72])[CH2:66]1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCBr)C1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 3-(3-bromopropyl)-1-piperidinecarboxylate. LCMS (System D): tRET=3.39 min; MH+ 497
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)(=[O:3])[CH3:2]>ClCCl.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(NC(C)=O)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-6-chloro-2-(3-chlorobenzoyl)-1-(ethoxycarbonyl)indole (step 1). m.p.: 152-154° C. (dichloromethane/hexane)
Reaction SMILES: [Na].[C:2]([O:6][CH3:7])(=[O:5])[CH2:3][SH:4].[Cl:8][C:9](Cl)=[CH:10][C:11]#[N:12]>CO>[NH2:12][C:11]1[CH:10]=[C:9]([Cl:8])[S:4][C:3]=1[C:2]([O:6][CH3:7])=[O:5]
Reactant: N#CC=C(Cl)Cl
Reactant: COC(=O)CS
Agent: [Na]
Solvent: CO
Product: COC(=O)c1sc(Cl)cc1N

Procedure:
In a flame dried flask under a nitrogen atmosphere, and with mechanical stirring, a solution of about 1.2 g (0.05 mole) of sodium metal dissolved in 30 ml of dry methanol was treated dropwise with 2.35 g (1.98 ml, 0.022 mole) of methyl thioglycolate while maintaining the temperature below 25° C. A solution of 2.70 g (0.022 mole) of 3,3-dichloroacrylonitrile [R. L. Soulen, D. B. Clifford, F. F. Crim and J. A. Johnston, J. Org. Chem. 36 (22), 3386-3391 (1971)] and 10 ml of methanol was then added dropwise at a rate such as to keep the reaction temperature <28° C. The reaction mixture became cloudy and orange. Stirring was continued for an hour. The mixture was concentrated under reduced pressure, was diluted with water, and was extracted five times with 60 ml portions of chloroform. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to furnish an oil which was chromatographed under moderate pressure ("flash" chromatography) on a column of silica gel (Woelm 32-63 micrometers, i.d. 5 cm×height 18 cm); the eluant was isopropyl ether; 15 ml fractions were taken. Fractions 15-20 were combined and evaporated to give methyl 3-amino-5-chloro-2-thiophenecarboxylate as a colorless solid: m.p. 99°-101° C.; yield 0.60 g (14%); ir (KBr) 3448 cm-1, 3343, 1674, 1615, 1546, 1455, 1425 along others; 1H-nmr (CDCl3) delta 3.8 ppm (s, 3H), 5.3 (broad s, 2H), 6.4 (s, 1H); mass spectrum 191 (molecular ion), 159 (-32, CH3OH, parent peak) and others.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:15][C:16]1[C:17](=O)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1>CO>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:22]3[C:16](=[O:15])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccccc1=O
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CO
Product: O=c1cccccc1N1CCN(Cc2ccccc2)CC1
Yield: 81.9 %

Procedure:
A mixture of 1-(phenylmethyl)-piperazine (3.2 g) and 2-methoxy-2,4,6-cycloheptatrien-1-one (1.6 g) in methanol (6 ml) was refluxed for 10 hr and evaporated. The residue was dissolved in a mixture of chloroform and water. The organic phase was separated, dried and evaporated. The residue was chromatographed on silica gel (200 g) using methanol-chloroform (5:95). The eluates were evaporated to give the title compound (2.7 g): mp 78°-80° C.; ir(CHCl3) 2400, 1705, 1620, 1350 and 1570 cm-1 ; uv max(MeOH) 343 (ε=9440) and 250 nm (ε=14975); nmr(CDCl3) δ2.9 (s, 3H), 3.5 (m, 8H), 6.27 (s, 2H), 7.0 (m, 5H) and 14.5 (broad, 2H); and Anal. Calcd for C18H20N2O2 : C, 77.11% H, 7.19% N, 9.99% and Found: C, 77.08% H, 7.17% N, 9.74%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH3:18]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([N:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:17][CH3:18])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCNc1ccncc1
Solvent: CCN(CC)CC
Product: CCN(c1ccncc1)c1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(4-pyridyl)-2-ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-(ethylamino)pyridine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:31][OH:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=O)C1C=CC=CC=1.C(O)(=O)[CH:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.ClCCl.[C].[Pd].CO.C1COCC1>[C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:31][OH:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:8])[CH:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Reactant: CCCC(CCC)C(=O)O
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCC(CCC)C(=O)N[C@H](C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12)[C@@H](C)CC
Temperature: 0 °C
Reaction time: 15 h
Yield: 84.7 %

Procedure:
A mixture of N-benzyloxycarbonyl-(L)-isoleucyl-(L)-tryptophanol(2.14 g), palladium-carbon (5%, 50% wet, 1.0 g) and methanol-THF (5:1, 30 ml) was subjected to catalytic hydrogenation at room temperature and atomospheric pressure. After the catalyst was filtered off, the filterate was concentrated under reduced pressure to yield an oily substance. The oil and valproic acid (0.71 g) were dissolved in N,N-dimethylformamide (20 ml), and 1-hydroxybenzotriazole (HOBt) (0.82 g) and a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD·HCl)(1.13 g) in dichloromethane (20 ml) were added thereto at 0° C. After stirring at 0° C. for 1 hour and at room temperature for 15 hours, the reaction mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate (120 ml). The mixture was successively washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and brine, and dried (MgSO4). The organic solvent was evaporated off to yield N-valproyl-(L)-isoleucyl-(L)-tryptophanol (1.78 g, 84.8%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless needles.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][CH:25]=2)=[O:34])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c[nH]c3ccccc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1H-Indole-3-carboxylic acid. LC-MS (basic): tR=0.86 min; [M+H]+=491.2.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29]([CH2:32][CH2:33]Br)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:30])=[O:31])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=S(=O)(CCBr)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCS(=O)(=O)c2ccccc2)CC1
Yield: 57.8 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (7 g) and 2-(phenylsulfonyl)ethyl bromide (5.6 g) were reacted and treated in the same manner as in Example 199 to give 2.74 g of 4-amino-5-chloro-2-methoxy-N-((1-(2-(phenylsulfonyl)ethyl)-piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: [C-]#N.[Na+].Br[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.[CH3:14][NH:15]CCNC.[OH-].[NH4+]>[Cu]I.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[NH:10]1[C:11]2[C:7](=[CH:6][C:5]([C:14]#[N:15])=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc2[nH]ccc2c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
An oven dried screw cap test tube was charged with NaCN (98 mg, 2.00 mmol) dried KI (55 mg, 0.331 mmol, 20 mol %) and CuI (32 mg, 0.168 mmol, 10 mol %), 5-Bromoindole (327 mg, 1.667 mmol), evacuated and backfilled with argon three times. Anhydrous toluene (1.1 mL) and N,N′-dimethylethylenediamine (180 μL, 1.691 mmol) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting yellow color suspension was cooled to room temperature, 2 mL of ethyl acetate, 1 mL of ammonium hydroxide 30% and 1 mL of water were added. The mixture was stirred at 25° C. for 10 min then the organic layer was separated and the aqueous layer was extracted three times with ethyl acetate (3×2 mL). The organic layers combined were washed with 5 mL of water and dried over MgSO4. The GC analysis showed complete conversion of starting material with a desired product area of 99%. The solvent was removed at reduced pressure. Purification of the residue by flash chromatography on silica gel (2×15 cm; hexane/ethyl acetate 10:1) provided 225 mg (95% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:4]=2[N:3]=1.[Br-].[CH:19]1([CH2:22][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][CH2:16][C:14]2[CH:13]=[CH:12][C:5]3=[C:6]4[C:11](=[C:2]([NH2:1])[N:3]=[C:4]3[CH:15]=2)[N:10]=[CH:9][CH:8]=[CH:7]4)[CH2:21][CH2:20]1
Reactant: c1ccc([P+](CC2CC2)(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1nc2cc(C=O)ccc2c2cccnc12
Agent: [Br-]
Product: Nc1nc2cc(CCC3CC3)ccc2c2cccnc12

Procedure:
8-(2-Cyclopropylethyl)benzo[f][1,7]naphthyridin-5-amine was prepared from 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 87) with (cyclopropylmethyl)triphenylphosphonium bromide following the procedures described for Example 91 (wittig reaction) and Example 92 (reduction). 1H NMR (acetone-d6): δ 8.99 (dd, 1H), 8.88 (dd, 1H), 8.35 (d, 1H), 7.83 (dd, 1H), 7.47 (d, 1H), 7.23 (dd, 1H), 6.64 (br s, 2H), 1.60 (q, 2H), 1.34-1.25 (m, 1H), 0.91-0.72 (m, 2H), 0.45-0.41 (m, 2H), 0.11-0.07 (m, 2H). LRMS [M+H]=264.1.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[OH:9].S([O-])(O)=O.[Na+]>>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: COC1CCCC[C@@H]1O
Agent: O=S([O-])O
Agent: [Na+]
Product: CO[C@H]1CCCCC1=O

Procedure:
Reaction was carried out in the same manner as in Example 16. After the peak due to (S)-2-methoxycyclohexanol had disappeared, the reaction solution was given 2 g of sodium hydrogensulfite with stirring so that the reaction solution did not change potassium iodide starch paper into purple any longer. The reaction solution was extracted twice with 100 g of dichloroethane. The dichloroethane layers were combined together and washed with a saturated aqueous solution of sodium chloride. After concentration and distillation in the same manner as in Example 1, there was obtained 10.9 g (85 mmol) of (S)-2-methoxycyclohexanone having a chemical purity of 99.4% and an optical purity of 99.5% ee (measured immediately after distillation). As in Example 3, this product was sealed in a glass ample, with the atmosphere therein replaced with argon. The glass ample was heated at a prescribed temperature for 20 hours. After cooling to room temperature, the ample was opened and the content was tested for optical purity. The results are shown in Table 3.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:18][OH:19])[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=1)[CH2:18][OH:19]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cc(F)cc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CO)Cc1cc(F)cc(F)c1

Procedure:
Dissolve [2-(3,5-difluorophenyl)-1-(S)-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester (4.57 g, 15.9 mmol) in dichloromethane (20 mL). Add trifluoroacetic acid (20 mL) and stir 45 min and concentrate to give the title compound as a thick residue.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@:25]([CH:44]2[CH2:46][CH:45]2[C:47]([O:49]C)=[O:48])([CH3:43])[C:24]1=[O:51])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@:25]([CH:44]2[CH2:46][CH:45]2[C:47]([OH:49])=[O:48])([CH3:43])[C:24]1=[O:51])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(C2CC2C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(C2CC2C(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of the ester from Example 248, Step E (10 mg, 0.013 mmol) in THF (1.0 mL) was added sodium hydroxide (404 μL, 0.404 mmol, 1M aqueous solution). The reaction was stirred at rt for 24 hours. After this time the reaction was partitioned between EtOAc (30 mL) and 1.0 M HCl (5 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo to give the title compound as a single diastereomer. Mass Spectrum (ESI) m/z=728.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=2)[CH:7]=1
Reactant: Cc1ccnc(Br)c1
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccnc(-c2ccc(C)c([N+](=O)[O-])c2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 66.3 %

Procedure:
To a suspension of 2-bromo-4-methylpyridine (5.16 g), 4-methyl-3-nitrophenylboronic acid (7.06 g) and tetrakis(triphenylphosphine)-palladium (1.73 g) in 1,2-dimethoxyethane (100 ml) was added 2M aqueous solution of sodium carbonate (39 ml). The mixture was stirred at 80° C. for 12 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. 2-Propanol was added to the residue. The precipitate was collected by filtration and dried under reduced pressure to give 4-(4-methylpyridin-2-yl)-2-nitrotoluene (4.54 g).