Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O>[CH3:1][C:2]1([CH3:20])[O:7][C:6](=[S:30])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(C#N)cs3)cc21
Solvent: O
Product: CC1(C)OC(=S)Nc2ccc(-c3cc(C#N)cs3)cc21

Procedure:
The title compound was prepared in a manner similar to Example 16 using 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)thiophene-3-carbonitrile and Lawesson's reagent. The product was obtained in the form of yellow crystals: m.p. 258-259° C. 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 8.54 (d, 1H, J=0.9 Hz), 7.96 (s, 1H), 7.69-7.62 (m, 2H), 7.11-7.08 (d, 1H, J=8.3 Hz), 1.69 (s, 6H); MS (ESI) m/z 299 [M−H]−; Anal. Calcd. For C15H12N2OS2.½ H2O: C, 58.0; H, 4.24; N, 9.05. Found: C, 58.33; H, 3.85; N, 8.39.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].[Cl:19][C:20]1[CH:25]=[C:24]([N+]([O-])=O)[CH:23]=[C:22]([Cl:29])[N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([O:18][C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]=2[Cl:7])[CH:23]=[C:22]([Cl:29])[N:21]=1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc(Oc2cc(Cl)nc(Cl)c2)c(Cl)c1
Temperature: 0 °C

Procedure:
16.5 gm (0.12 mol) of potassium carbonate were added in portions to an ice-cooled and stirred suspension of 19.65 gm (0.1 mol) of 2-chloro-4-trifluoromethyl-phenol and 19.29 gm (0.1 mol) of 2,6-dichloro-4-nitro-pyridine. The resulting mixture was stirred for 2 hours at room temperature, and was then stirred into 250 ml of ice water. An oil separated out, which crystallized after some time. The crystalline product was collected by suction filtration, washed with water and dissolved in chloroform. The resulting solution was shaken with water, and the organic phase was separated, dried with sodium sulfate and evaporated to dryness. 25.3 gm (75% of theory) of the title compound were obtained as a colorless substance having a melting point of 66° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[C:14]2[N:16]([C:20]3[C:32]([Cl:33])=[CH:31][C:23]([O:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[C:22]([O:34][CH2:35][C:36]4[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][C:37]=4[F:44])[CH:21]=3)[C:17](=[O:19])[NH:18][C:13]2=[C:12]([CH3:45])[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[Cl:33][C:32]1[C:20]([N:16]2[C:14]3=[N:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]([CH3:45])=[C:13]3[NH:18][C:17]2=[O:19])=[CH:21][C:22]([O:34][CH2:35][C:36]2[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][C:37]=2[F:44])=[C:23]([CH:31]=1)[O:24][CH2:25][C:26]([N:28]([CH3:29])[CH3:30])=[O:27]
Reactant: COc1cccc(F)c1COc1cc(-n2c(=O)[nH]c3c(C)cc(CO[Si](C)(C)C(C)(C)C)nc32)c(Cl)cc1OCC(=O)N(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(F)c1COc1cc(-n2c(=O)[nH]c3c(C)cc(CO)nc32)c(Cl)cc1OCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a solution of 2-{4-[5-(tert-butyldimethylsilyloxy)methyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one-3-yl]-5-chloro-2-(2-fluoro-6-methoxybenzyloxy)phenoxy}-N,N-dimethylacetamide (40 mg) in tetrahydrofuran (0.6 mL) was added tetra(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 1.2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=2/1), and collected by filtration. The collected solids were dried under reduced pressure to give the title compound (16 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:29][CH2:30][CH2:31][N:32]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[CH2:33][C:34](OCC)=[O:35].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:29]2[CH2:30][CH2:31][N:32]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[CH2:33][C:34]2=[O:35])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: CCOC(=O)CN(CCN)C(=O)OCC[Si](C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1CN1CCN(C(=O)OCC[Si](C)(C)C)CC1=O)CCCN2
Reaction time: 12 h

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 2.50 g, 10.58 mmol), ethyl 2-((2-aminoethyl)((2-(trimethylsilyl)ethoxy)carbonyl)amino)acetate para-toluene sulphonate (intermediate 124, 8.37 g, 18.09 mmol) and triethylamine (3.23 ml, 23.28 mmol) in 1,2-dichloroethane (10 ml) at room temperature was stirred for 12 h and sodium triacetoxyborohydride (4.72 g, 21.16 mmol) added. The reaction mixture was stirred for 18 h at room temperature, partitioned between saturated aqueous NaHCO3 solution and EtOAc, the EtOAc phase washed with brine, dried over MgSO4 and evaporated. The residue was applied to a RediSep® silica column and purified by normal phase chromatography, eluting with a gradient from heptane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a yellow oil. (UPLC-MS 6) tR 0.42; ESI-MS 322.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[Cl:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:27]1[C:32]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN(Cc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 42.2 %

Procedure:
tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (2-chloropyridin-3-yl)boronic acid (189 mg), sodium carbonate (254 mg), and tetrakis(triphenylphosphine)palladium (116 mg) were suspended in 1,2-dimethoxyethane (10 mL) and water (4 mL), and the mixture was stirred at 105° C. for 2 hr. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1→1:4) to give the title compound as a pale-yellow oil (yield 195 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([NH2:15])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[S:27])[NH2:15])[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(Cn2cc(C(N)=O)cn2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc(C(N)=S)cn2)cc1
Yield: 51.2 %

Procedure:
According to Scheme 1 Step 4: A solution of 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (109 mmol, 25.1 g) and Lawesson's reagent (109 mmol, 43.9 g) in CHCl3/toluene (1:1, 136 mL) was stirred at 85° C. for 12 hours. The reaction mixture was evaporated and the residue was recrystallized in EtOAc/pentane to yield 13.8 g of 1-(4-methoxybenzyl)-1H-pyrazole-4-carbothioamide. The mother liquors were evaporated and the crude residue was purified by flash chromatography over silica gel using DCM/EtOAc (100:0 to 70:30) to yield 1-(4-methoxybenzyl)-1H-pyrazole-4-carbothioamide (94.6 mmol, 23.4 g, 87%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12](Cl)[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[N:3]=1.ClC1C=C(Cl)N=C(N)N=1.[Br:27]C1C=CC(OC)=C(B(O)O)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Br:27])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[N:3]=1
Reactant: COc1ccc(Br)cc1B(O)O
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Agent: Nc1nc(Cl)cc(Cl)n1
Product: COc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Yield: 53 %

Procedure:
Following the method described in Example 4 for the synthesis of 4-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-2-yl-amine, 4,6-dichloro-pyrimidin-2-yl-amine and 5-bromo-2-methoxy-phenyl boronic acid provided 4-chloro-6-(5-bromo-2-methoxy-phenyl)-pyrimidin-2-yl-amine (53% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH2:9][CH2:10][CH3:11])[C:6]([OH:8])=[O:7].[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33](O)[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:39]2)=[CH:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33]([O:7][C:6](=[O:8])[C:5]([O:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[CH3:1])([CH3:12])[CH2:9][CH2:10][CH3:11])[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH2:39]2)=[CH:26]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CCCC(C)(Oc1ccccc1C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCCC(C)(Oc1ccccc1C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 57.1 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 0.35 g of (2RS)-2-(2-methylphenoxy)-2-methylvaleric acid and 0.46 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 0.36 g of the title compound as a colorless foam.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:22][CH:21]4[CH2:23][C:24]([O:26]CC)=[O:25])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:2]1=2.FC(F)(F)C(O)=O>CO.[OH-].[Na+]>[O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:22][CH:21]4[CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:2]1=2
Reactant: CCOC(=O)CC1CC1c1ccc(OCCc2ccc3c(n2)NCCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CC1c1ccc(OCCc2ccc3c(n2)NCCO3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
The product of step 7 (380 mg, 1 mmol) was dissolved in 5 ml methanol and 2.5 ml 1N sodium hydroxide solution. The reaction was stirred at room temperature for 18 h, acidified with 1 ml trifluoroacetic acid, and concentrated. The residue was purified on HPLC using acetonitrile gradient 15-50% in 30 min to yield 210 mg desired product as an yellow oil. FAB-MS:(MH+)=355.H MNR(CDCl3) δ 0.78 (m, 1H), 0.86 (m, 1H), 1.21 (m, 1H), 1.70 (m, 1H), 2.35 (m, 2H), 3.12 (t, 2H), 3.63 (t, 2H), 4.22 (t, 2H), 4.26 (t, 2H), 6.65 (d, 1H), 6.79 (d, 2H), 7.0 (d, 2H), 7.6 (d, 1H). Anal Calcd. for C20H22N2O4 plus 1 CF3COOH and 0.2H2O: C, 55.98; H, 5.00; N, 5.93. Found: 55.90; H, 5.28; N, 5.24.
Reaction SMILES: [O:1]=[P:2]12[O:13][P:11]3([O:14]P(OP([O:10]3)([O:9]1)=O)(=O)[O:3]2)=[O:12].[CH2:15]([O:19][CH2:20][CH2:21]O)[CH2:16][CH2:17][CH3:18]>C(Cl)Cl>[CH2:15]([O:19][CH2:20][CH2:21][O:10][P:11]([O:13][P:2]([OH:9])([OH:3])=[O:1])([O:14][CH2:21][CH2:20][O:19][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])[CH2:16][CH2:17][CH3:18]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: CCCCOCCO
Solvent: ClCCl
Product: CCCCOCCOP(=O)(OCCOCCCC)OP(=O)(O)O

Procedure:
To a reaction flask containing 500 ml of methylene chloride under a nitrogen atmosphere is added with stirring phosphorus pentoxide (270 g, 1.9 moles). 2-Butoxyethanol (425 g, 3.6 moles) is added from a dropping funnel over about 2 hr, during which a gentle reflux occurs. At the end of the addition, only a small amount of unreacted P2O5 remains. The contents of the flask are a clear yellow solution. At the end of 24 h additional reaction, the contents of the flask are darker in color and no P2O5 is observed.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])O)=[C:16]([F:30])[CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)=[C:16]([F:30])[CH:15]=1
Reactant: Cc1cc(F)ccc1C(O)c1ccc(Cl)cc1F
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3C)c3ccc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.14 g (4.23 mmol) of the compound from Example 180A in analogy to the synthesis of the compound from Example 278. 554 mg (31% of theory) of the target compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([Br:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:22][C:23]([F:36])([F:35])[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br:13][C:12]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([O:24][C:23]([F:35])([F:22])[F:36])=[CH:26][CH:27]=3)[CH:7]=[CH:6][CH:5]=2)=[N:9][N:10]([CH3:14])[CH:11]=1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(Br)c(-c2cccc(NC(=O)Cc3ccc(OC(F)(F)F)cc3)c2)n1
Temperature: 70 °C
Yield: 67.6 %

Procedure:
A solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (35 mg, 0.14 mmol) and triethylamine (23 μL, 0.17 mmol) in DMF (0.5 mL) was added in one portion to a stirred solution of 4-trifluoromethoxyphenylacetic acid (31 mg, 0.14 mmol), HBTU (53 mg, 0.14 mmol) and HOBT (19 mg, 0.14 mmol) in DMF (1 mL). The mixture was heated at 70° C. for 24 h and then quenched with aqueous sodium bicarbonate solution. Ethyl acetate was added and the organic phase separated, washed with water (.times.3), brine, dried (MgSO4) and evaporated. Chromatography on flash silica (50% EtOAc/hexane) gave the title compound as a colourless solid (43 mg, 68%). m.p. 141.2-142.5° C. (EtOAc/hexane).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([C:10]2[C:11]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH:29]=3)=[N:12][C:13]([C:16]([NH:18][C:19]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])=[CH:14][CH:15]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.S(Cl)(Cl)=O.[CH3:46]O>CCOCC>[ClH:2].[Cl:2][C:3]1[C:4]([C:10]2[C:11]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:40])[CH3:41])[CH:29]=3)=[N:12][C:13]([C:16]([NH:18][C:19]3([C:25]([O:27][CH3:46])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:17])=[CH:14][CH:15]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CO
Reactant: CN(C)CCCOc1cc(-c2nc(C(=O)NC3(C(=O)O)CCCCC3)ccc2-c2ncc(Cl)cc2Cl)ccc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(NC(=O)c2ccc(-c3ncc(Cl)cc3Cl)c(-c3ccc(Cl)c(OCCCN(C)C)c3)n2)CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 300 mg (0.47 mmol) of 1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclo-hexanecarboxylic acid hydrochloride in 10 mL of methanol and cooled to 0° C. is added 0.07 mL (0.93 mmol) of thionyl chloride. The reaction mixture is warmed to room temperature and stirred for 20 hours, and then concentrated under reduced pressure. The residue obtained is taken up in 20 mL of ether and solidified. After drying under reduced pressure, 268 mg of methyl 1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylate hydro-chloride are obtained in the form of a white powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([O:12][CH3:13])([CH3:11])[CH3:10])[CH3:2].[S:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[CH:23]1.[BH4-].[Na+].C(Cl)Cl.CO>CO>[CH2:1]([N:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)[CH:28]=2)[CH:16]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([O:12][CH3:13])([CH3:11])[CH3:10])[CH3:2]
Reactant: CCN(C/C=C/C#CC(C)(C)OC)Cc1cccc(N)c1
Reactant: O=Cc1cccc(-c2ccsc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCN(C/C=C/C#CC(C)(C)OC)Cc1cccc(NCc2cccc(-c3ccsc3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
65 mg of (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-aminobenzylamine and 43 mg of 3-(3thienyl)benzaldehyde were dissolved in 2 ml of methanol, and the solution was stirred overnight at room temperature. With stirring under ice cooling, 12.9 mg of sodium borohydride was added, and stirred for 1 hour at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and water. The organic layer was separated, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated. The residue was purified by silica gel column chromatography Wakogel C-200, 5 g; eluting solvent: methylene chloride/ methanol=60/1] to give 87 mg (yield 84%) of the captioned compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:13]=[O:14].[CH3:15][Mg]Br>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:13]([OH:14])[CH3:15]
Reactant: C[Mg]Br
Reactant: O=Cc1nc2ccccn2c(=O)c1Br
Solvent: C1CCOC1
Product: CC(O)c1nc2ccccn2c(=O)c1Br
Temperature: 9 °C

Procedure:
To a stirred solution of 3-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde (2.14 g, 8.46 mmol) in THF (85 mL) was added methylmagnesium bromide (3M in Et2O, 5.64 mL, 16.92 mmol) drop wise at 0° C. The mixture was allowed to warm to 9° C. over 4.5 h, when the reaction was quenched with sat. aq NH4Cl (50 mL), water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extract were washed with water(50 mL), brine(50 mL), dried over Na2SO4, filtered and cond under reduced pressure to give a dark brown solid, which was purified by silica gel column chromatography using 0-60% EtOAc in Hexane to give the desired product 3-bromo-2-(1-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid: 1HNMR (400 MHz, DMSO-d6): δ 8.94-8.99 (dd,1H), 8.00-8.06 (m,1H), 7.76-7.78 (dd,1H), 7.40-7.47 (m,1H), 5.3(s,1H), 5.0 (m,1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:10])=O)=[O:5])[CH3:2].Cl.[CH3:18][O:19][C:20](=[O:26])[C@@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>>[CH3:18][O:19][C:20]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:8](=[O:10])[C@H:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:26]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CCOC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Product: CCOC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OC)c1ccccc1
Yield: 56.7 %

Procedure:
Reaction of 2.0 g of (R)-ethoxycarbonylamino-phenyl-acetic acid and 1.50 g of (L)-proline methyl ester hydrochloride according to the procedure described for example 91b gave 1.70 g (57%) of the title compound as a colorless oil. (+)-APCI-MS: 335 (MH+).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[C:11](=[O:26])[NH:12][CH:13]=[C:14]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)[N:15]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>O1CCOCC1>[C:1]1([CH:7]([N:9]2[C:10]3=[N:15][C:14]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)=[CH:13][N:12]=[C:11]3[O:26][C:27]2=[O:28])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Nc1nc(-c2cccc3ncccc23)c[nH]c1=O)c1ccccc1
Solvent: C1COCCO1
Product: CC(c1ccccc1)n1c(=O)oc2ncc(-c3cccc4ncccc34)nc21
Yield: 52 %

Procedure:
3-(1-Phenyl-ethyl)-5-quinolin-5-yl-3H-oxazole[4,5-b]pyrazin-2-one. 3-(1-Phenyl-ethylamino)-5-quinolin-5-yl-1H-pyrazin-2-one (50 mg, 0.15 mmol), 1,1′-carbonyldiimidazole (470 mg, 1.5 mmol), and dioxane (5 mL) were heated together in a pressure tube to 150° C. for 20 hours. The reaction was filtered through celite, rinsed with EtOAc, and then concentrated. The residue was purified via Biotage silica gel chromatography (0-100% ethyl acetate in hexanes). The product factions were concentrated and then triturated with ether to give a white solid, (28 mg, 52% yield). 1H NMR (400 MHz, CD3OD) δ 9.73 (dd, J=4.1, 1.8, 1 H), 9.11 (s, 1 H), 9.09 (d, J=8.2, 1 H), 8.93 (d, J=8.6, 1 H), 8.66 (m, 1 H), 8.58 (dd, J=7.2, 1.4, 1 H), 8.31 (m, 2 H), 8.26 (dd, J=8.6, 4.3, 1 H), 8.17 (m, 2 H), 6.43 (q, J=7.0, 1 H), 2.71 (d, J=7.0, 3 H); MS (ESI) m/z 369.4 [M+1]+.