Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:23][N:24]([CH2:32][C:33]#[CH:34])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[CH3:23][N:24]([CH2:32][C:33]#[C:34][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28]
Reactant: O=C(c1ccc(I)cc1)c1ccc(OC2CCCCO2)cc1
Reactant: C#CCN(C)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CN(CC#Cc1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
A 25 mL Schlenk flask was charged with (4-iodophenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (408 mg, 1 mmol), Pd(PPh3)2Cl2 (18 mg, 0.025 mmol), CuI (10 mg, 0.05 mmol), Et3N (10 mL), and tert-butyl methyl(prop-2-ynyl)carbamate (255 mg, 1.5 mmol). The flask was flushed with argon three times and the mixture was stirred at 90° C. for 3 h. The solvent was evaporated under vacuum and the residue was purified by columnchromatography to give the desired product (270 mg, 60% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:14][C:6]2[C:7]([CH3:13])=[N:8][CH:9]=[C:10]([CH:11]=O)[C:5]=2[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:36]([F:41])([F:40])C([O-])=O.[Na+]>COCCOCCOC>[F:40][C:36]([F:41])=[CH:11][C:10]1[CH:9]=[N:8][C:7]([CH3:13])=[C:6]2[O:14][C:2]([CH3:15])([CH3:1])[O:3][CH2:4][C:5]=12
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Cc1ncc(C=O)c2c1OC(C)(C)OC2
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOCCOC
Product: Cc1ncc(C=C(F)F)c2c1OC(C)(C)OC2

Procedure:
A mixture of 0.1 mole of 2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine-5-carboxaldehyde, 0.11 mole of triphenylphosphine and 0.11 mole of sodium chlorodifluoroacetate in 100 ml. of diglyme is heated under nitrogen at 90° for 24 hours. The reaction mixture is then filtered and concentrated in vacuo. Chromatography of the residue on silica gel and elution with ether-petroleum ether (10-50%) gives 5-(2,2-difluorovinyl)2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine.
Reaction SMILES: [Br:1][C:2]1[C:15]2[CH:14]=[C:13]([C:16](O)=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.S(Cl)(Cl)=O.[NH:23]1[CH2:28][CH2:27][NH:26][C@H:25]([C:29]([OH:31])=[O:30])[C@@H:24]1[C:32]([OH:34])=[O:33].[OH-].[Na+]>O1CCOCC1.C1C=CC=CC=1>[Br:1][C:2]1[C:15]2[CH:14]=[C:13]([C:16]([N:23]3[CH2:28][CH2:27][NH:26][C@H:25]([C:29]([OH:31])=[O:30])[C@@H:24]3[C:32]([OH:34])=[O:33])=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C(O)c1ccc2c(c1)c(Br)cc1ccccc12
Reactant: O=C(O)[C@H]1NCCN[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: O=C(O)[C@H]1NCCN(C(=O)c2ccc3c(c2)c(Br)cc2ccccc23)[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
10-Bromophenanthrene-2-carboxylic acid (2, 0.663 g, 2.2 mmol) was added to benzene (50 ml) containing excess thionyl chloride and the mixture heated under reflux overnight. The following day, the mixture was evaporated under reduced pressure and the resulting acid chloride (3) used without further purification. (_)-Cis-piperazine-2,3-dicarboxylic acid (4, 0.46 g, 2.6 mmol) was added to 0.991 M aqueous sodium hydroxide (8 ml, 8 mmol) and dioxan (10 ml) and the mixture was cooled to 0° C. A solution of the crude acid chloride (3) in dry dioxan was then added and the mixture was stirred at 0° C. for 5 min and then at room temperature overnight. The following day, the reaction mixture was reduced to˜ half the volume by evaporation under reduced pressure and was then acidified with 6 M aqueous hydrochloric acid. The resulting precipitate was collected by filtration, heated in dioxan (50-100 ml) and filtered. This procedure was then repeated twice. The resulting solid was added to water just below the boiling point and stirred in order to dissolve water soluble by-products. The insoluble material was collected by filtration, washed with dioxan and dried to give (±)-cis-1-(10-bromophenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (5) as a white solid. 1H NMR (270 MHz, D2O/NaOD):—2.5-3.4 (m, 4H), 4.3 (d, 0.5 H), 5.5 (d, 0.5 H), 7.2-7.6 (m), 7.65-7.8 (m), 7.75 (s) 7.95-8.2 (m), 8.1 (s) and 8.25-8.5 (m).
Reaction SMILES: C(O[C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12]Br)C.[CH2:15]([O:17][C:18](=[O:29])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:16].NC1C=CC=CC=1>>[CH2:15]([O:17][C:18](=[O:29])[CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:12][C:6]3[C:5](=[CH:10][C:9]([F:11])=[CH:8][CH:7]=3)[C:4]2=[O:14])=[CH:26][CH:27]=1)[CH3:16]
Reactant: CCOC(=O)c1cc(F)ccc1CBr
Reactant: CCOC(=O)CCCc1ccc(N)cc1
Solvent: Nc1ccccc1
Product: CCOC(=O)CCCc1ccc(N2Cc3ccc(F)cc3C2=O)cc1

Procedure:
By using 2-bromomethyl-5-fluorobenzoic acid ethyl ester and 4-(4-amino-phenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(6-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester as an orange oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[N:22]([C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2)=[C:23]=S.CCN=C=NCCCN(C)C>CN(C=O)C.O>[C:25]12([NH:22][C:23]3[O:19][C:18]([C:16]4[CH:15]=[CH:14][C:12]5[N:13]=[C:9]([C:3]6[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=6[Cl:1])[NH:10][C:11]=5[CH:17]=4)=[N:20][N:21]=3)[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cccc(Cl)c1-c1nc2ccc(-c3nnc(NC45CC6CC(CC(C6)C4)C5)o3)cc2[nH]1
Temperature: 25 °C

Procedure:
Combine 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (100 mg, 0.310 mmol) and 1-isothiocyanato-adamantane (78 mg, 0.403 mmol) in DMF (2 mL) and heat to 70° C. for 1 hr. Add EDCI (119 mg, 0.620 mmol) and heat the reaction for 1 hr. Allow the reaction to cool to room temp and dilute with water (10 mL). Collect the resulting precipitate by filtration and purify the solid by reverse-phase HPLC (35-65% ACN/H2O+5 mM NH4OH) to afford the title compound as a white solid: 1H NMR (400 MHz, MeOD) δ ppm 1.74-1.82 (m, 6H) 2.12 (s, 6H) 2.15 (br. s., 3H) 7.55-7.63 (m, 3H) 7.76 (br. s., 1H) 7.93 (br. s., 1H) 8.18 (br. s., 1H); MS (m/z) 480.1 (M+1).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH3:6])=O.[CH3:7][CH2:8][CH2:9][CH2:10]CC>>[O:3]1[C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH:1]=[CH:2]1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Product: c1ccc2occc2c1
Yield: 62.9 %

Procedure:
A solution of 30 (10.3 g; 39.3 mmol), EtOH (250 mL) and saturated NaHCO3 (100 mL) were heated to reflux for 1 h. The reaction mixture was cooled to room temperature and the EtOH removed in vacuo. Ice was added to the residue aqueous solution and the reaction carefully acidified to about pH 2 with 2 N HCl. The resulting mixture was extracted with EtOAc (2×300 mL) and the combined organic phase washed with brine, dried (NaSO4), filtered and evaporated to yield a brown oil (8.8 g). The crude product was run through a silica gel column with 15% EtOAc:hexane to yield 31 (5.44 g; 62.9%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:2].[CH2:16]=O.[CH:18]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])(=[O:22])=[O:21])=[CH2:19]>>[CH2:1]([O:3][C:4]([CH:5]1[CH2:16][CH:18]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:30])([F:32])[F:31])(=[O:21])=[O:22])[CH2:19][N:6]1[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([Cl:14])[CH:8]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)CNc1ccc(F)c(Cl)c1
Reactant: C=CS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: C=O
Product: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ccc(F)c(Cl)c1

Procedure:
In analogy to the procedure described in example 343d, (3-chloro-4-fluoro-phenylamino)-acetic acid ethyl ester (CAS Reg. No. 2344-98-1) was reacted with paraformaldehyde and 1-ethenesulfonyl-2-trifluoromethyl-benzene (example 243c) to give the title compound as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[S:28])[CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[CH:21]=4)=[S:28])=[CH:7][CH:6]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Cc1cccc(N=C=S)c1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=S)Nc2ccc(-c3c(C)sc4ncnc(N)c34)cc2)c1
Yield: 80 %

Procedure:
A solution of Example 1E (60 mg, 0.23 mmol) and 3-methylphenyl isothiocyanate in DMF (2 mL) was stirred at room temperature, for 48 hours, quenched with water, and filtered. The filter cake was dried to provide the desired product (75 mg, 80%). MS(ESI(+)) m/e 406 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H); 9.84 (s, 1H); 8.27 (s, 1H); 7.65 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.30-7.18 (m, 3H); 6.97 (d, J=6.9 Hz, 1H); 2.30 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[CH2:29]([N:32]=[C:33]=[O:34])[CH2:30][CH3:31]>>[CH2:29]([NH:32][C:33]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])=[O:34])[CH2:30][CH3:31]
Reactant: CCCN=C=O
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Product: CCCNC(=O)NCC(C)(C)c1nc(-c2ccc3cc(OC)ccc3c2)c(-c2ccncc2)[nH]1
Yield: 49 %

Procedure:
The title compound (12 mg, 49%) was prepared starting from the product of Example 2 and n-propyl isocyanate using the method described in Example 10; MS(ES) m/e 458 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19](C=O)[CH2:18][C:17]4[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]C(O)=O.[C:35]([O:39][C:40](=[O:54])[NH:41][S:42]([CH2:45][CH2:46][CH2:47][N:48]([CH3:53])[CH2:49][CH2:50][NH:51][CH3:52])(=[O:44])=[O:43])([CH3:38])([CH3:37])[CH3:36].CCN(CC)CC.[BH3-]C#N.[Na+]>CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([CH2:52][N:51]([CH3:31])[CH2:50][CH2:49][N:48]([CH3:53])[CH2:47][CH2:46][CH2:45][S:42](=[O:43])(=[O:44])[NH:41][C:40](=[O:54])[O:39][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:18][C:17]4[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C=O)Cc1ccccc1-3
Reactant: CNCCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C)Cc1ccccc1-3
Reaction time: 0.08 h

Procedure:
Methyl 13-cyclohexyl-6-formyl-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate was dissolved in MeOH (0.04 M), HOAc (5 eq.) and tert-butyl[(3-{methyl[2-(methylamino)ethyl]amino}propyl)sulfonyl]carbamate (2 eq. Example 15, steps 1-3) were added followed by Et3N (3 eq.) and the mixture was stirred for 5 min. NaCNBH3 (2 eq.) was added and the mixture was stirred for 18 h. All volatiles were evaporated and the residual material was dissolved in EtOAc. The solution was extracted with sat. aq. NaHCO3, water and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo and the compound was used without purification in the next reaction. (ES) m/z 697 (M+H)+.
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:7]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)=[CH:6][C:5]=1[O:4][CH2:3][CH:2]([OH:1])[CH2:19][N:29]1[CH2:30][CH2:31][N:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OCC1CO1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CO
Product: COc1ccc(C2CNC(=O)C2)cc1OCC(O)CN1CCN(c2ccccc2)CC1
Yield: 61 %

Procedure:
15.5 millimoles of 4-[3-(2,3-epoxypropoxy)-4-methoxyphenyl]-2-pyrrolidone is dissolved in 50 ml. of methanol. After the addition of 15.5 mmol of 1-phenylpiperazine (95% strength), the reaction mixture is heated for 3 hours under reflux. After cooling of the reaction solution, the solvent is removed under vacuum at 40°. The residue is taken up in 50 ml. of 1N hydrochloric acid and extracted twice with 100 ml. of chloroform. The aqueous phase is adjusted to be alkaline with 2N sodium hydroxide solution and thereafter extracted three times with ethyl acetate. The combined ethyl acetate phase are washed with saturated sodium chloride solution, and the solvent, after drying over sodium sulfate, is distilled off under vacuum. The residue is recrystallized from ethanol, thus obtaining in a 61% yield 4-{4-methoxy-3-[3-(4-phenylpiperazin-1-yl)-2-hydroxypropoxy ]phenyl}-2-pyrrolidone, m.p. 143°-144°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH:5][CH:6]=[C:7]1[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]1=[O:16].[N:22]1([CH2:27][CH2:28][CH2:29]Cl)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[N:22]1([CH2:27][CH2:28][CH2:29][O:1][C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[NH:5][CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:14])([CH3:15])[O:9][C:8]2=[O:16])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1O
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OCCCN1CCCC1
Temperature: 80 °C
Yield: 37 %

Procedure:
A mixture of 5-((3-hydroxy-4-methoxyanilino)methylene)-2,2-dimethyl-1,3dioxane-4,6-dione (10 g, 34.1 mmol), (prepared as described for the starting material in Example 3), 3-(pyrrolidin-1-yl)propyl chloride (7.55 g, 51.1 mmol), (J. Am. Chem. Soc. 1955, 77, 2272), potassium carbonate (7.06 g, 51.1 mmol) and potassium iodide (600 mg, 3.41 mmol) in DMF (100 ml) was heated at 80° C. for 2 hours. The mixture was poured into water (800 ml) and the precipitate was collected by filtration. The solid was dissolved in methylene chloride and the organic solution was washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was dissolved in ether and the insoluble materials were removed by filtration. The volatiles were removed by evaporation and the residue was precipitated by trituration with petroleum ether, collected by filtration and dried under vacuum to give 5-((3-(3-pyrrolidin-1-ylpropoxy)-4-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (5.1 g, 37%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][CH:20]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][CH:24]=1)[CH2:21][NH2:22]>>[CH3:18][O:19][CH:20]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][CH:24]=1)[CH2:21][NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1cccc(C(CN)OC)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cccc(C(CNc2cc(C(F)(F)F)nc(-c3cccnc3)n2)OC)c1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 2,5-dimethoxyphenylethylamine (28 mg, 0.232 mmol) similar to Example 186 and was isolated as an off white solid (35 mg, 54% yield). 1H NMR (CDCl3): 9.59 (brs, 1H), 8.69 (d, J 4.8 Hz, 1H), 7.37 (dd, J 4.8, 8.4 Hz, 1H), 6.76 (m, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 3.00 (t, 2H), 1.67 (s, 2H).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:44]=[CH:43][N:14]3[C:15](=[O:42])[C:16]([C:25](=[O:41])[CH2:26][C:27]4[N:28]=[N:29][N:30](CC5C=CC(OC)=CC=5)[N:31]=4)=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]>FC(F)(F)C(O)=O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:44]=[CH:43][N:14]3[C:15](=[O:42])[C:16]([C:25](=[O:41])[CH2:26][C:27]4[N:28]=[N:29][NH:30][N:31]=4)=[C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2nnc(CC(=O)c3c(N4CCOCC4)nc4cc(CCc5nc(C(C)C)cs5)ccn4c3=O)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1csc(CCc2ccn3c(=O)c(C(=O)Cc4nn[nH]n4)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
The 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-3-{2-[2-(4-methoxybenzyl)-2H -1,2,3,4-tetrazol-5-yl]acetyl}-2-morpholino-4 H-pyrido[1,2-a]pyrimidin-4-one (8.9 mg, 0.014 mmol) obtained in (D) was dissolved in trifluoroacetic acid (5 ml)and stirred at room temperature for 18 hours. The solvent was evaporated, and the residue was purified by preparative TLC (chloroform:methanol=10:1, v/v) and lyophilized from dioxane to obtain the title compound (4.8 mg, 67.0%) as pale yellow powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1([F:15])[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]1.[NH:16]([CH3:18])[CH3:17]>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:7][C:8]1([F:15])[CH2:11][CH:10]([C:12]([N:16]([CH3:18])[CH3:17])=[O:13])[CH2:9]1
Reactant: CNC
Reactant: O=C(O)C1CC(F)(F)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Oxalyl chloride (21.74 mL, 248 mmol) was added dropwise to a stirred solution of 3,3-difluorocyclobutanecarboxylic acid (26 g, 191 mmol; prepared as described in ref: Elend, D. et al., Syn. Comm., 35:657 (2005)) in CH2Cl2 (500 mL) and DMF (0.5 mL) at 0° C. The reaction mixture was allowed to come to RT and stirred at RT for 1 h prior to being concentrated at RT using a rotary evaporator at ca. 50 mm Hg vacuum. After adding THF (300 mL) to the resulting residue, the stirred solution was cooled 0° C. prior to addition of a 2M solution of Me2NH (478 mL, 955 mmol) in THF. After stirring the reaction mixture at RT for 0.5 h, the mixture was partitioned between ether and 5% aq. Na2CO3. The organic layer was dried over MgSO4 and concentrated in vacuo at RT. After portioning the residue between CH2Cl2 and water, the organic layer was dried over MgSO4 and concentrated in vacuo at RT to give 3,3-difluoro-N,N-dimethylcyclobutanecarboxamide (24 g, 147 mmol, 77% yield) as a brown semi solid, used as such in the next step. 1H NMR (400 MHz, CDCl3) δ ppm 2.82-3.13 (9H, m), 2.62-2.79 (2H, m).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Br:12])[N:3]=1.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:12][C:4]1[N:3]=[C:2]([N:18]2[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CCN1CCNCC1
Reactant: Brc1cc2ccccc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Yield: 73.3 %

Procedure:
1,3-Dibromoisoquinoline (2.70 g), N-ethylpiperazine (1.16 g) and potassium carbonate (3.50 g) were reacted in DMF (30 ml) at 80° C. for 5 hr. The reaction solution was evaporated, and then partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried and evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give the title compound (2.21 g) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.CN([CH:19]=[O:20])C.[NH4+].[Cl-]>C1COCC1>[F:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C=O)c(F)c1
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of 4-bromo-3-fluoro anisole (34.4 g, 168 mmol) in anhydrous THF (300 mL) was added dropwise, at −78° C. under argon, n-BuLi (2.5 M in THF, 101 mL, 252 mol). After 5 min DMF (40 mL, 503 mmol) was added and the reaction micture was kept at −78° C. for 2 hrs. Aqueous NH4Cl (250 mL) was carefully added and the layers separated. The aqueous phase was further extracted with ethyl acetate. The organic phases were combined and washed successively with water, brine and dried (MgSO4). The residue was purified on silica gel (eluent: 10% ethyl acetate in hexane) to give 13.99 g of 2-fluoro-4-methoxy-benzaldehyde (54%). 1H NMR (300 MHz; CDCl3): 3.88 (s, 3 H), 6.65 (d, J=12.3 Hz, 1 H), 6.80 (d, J=8.7 Hz, 1 H), 7.82 (t, J=8.7 Hz, 1 H), 10.21 (s, 1 H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.N1[CH2:13][CH2:12][O:11]CC1.O.[C:15]1(C)[CH:20]=CC=C[CH:16]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:15]([C:20]1[O:7][C:4]2[CH2:3][CH2:2][S:1][CH2:6][C:5]=2[C:12](=[O:11])[CH:13]=1)[CH3:16]
Reactant: C1COCCN1
Reactant: O=C1CCSCC1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCc1cc(=O)c2c(o1)CCSC2
Temperature: 120 °C

Procedure:
A solution of tetrahydrothiopyran-4-one (20.0 g), morpholine (15.0 g) and p-toluenesulphonic acid (200 mg) in toluene (100 ml) was heated under reflux for 24 hours with azeotropic removal of water. Volatile material was removed by evaporation and the residue was heated with 5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (68 g) at 120° C. for 3 hours. The mixture was dissolved in dichloromethane (300 ml) and the solution was washed with 2M sodium hydroxide solution (2×100 ml), water (2×100 ml) and saturated sodium chloride solution (100 ml). The organic phase was then dried (MgSO4) and volatile material was removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give 7,8-dihydro-2-ethyl-thiopyrano[4,3-b]pyran-4(5H)-one (B) (9.2 g), as an oil; NMR (CDCl3) 1.2(t, 3H). 2.55(q, 2H), 2.8-2.9(m, 4H), 3.55(s, 2H), 6.1(s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:22]1([CH2:28][CH2:29]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][O:20][C:19](=[O:21])[CH2:18][NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)OCCc1ccccc1

Procedure:
Following General Procedure X and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester (from Example 73 below) using General Procedure O) and 2-phenylethanol (Aldrich), the title compound was prepared as a solid (mp=154.0-155.2° C.). The reaction was monitored by tlc (Rf=0.15 in 15% EtOAc/hexanes) and the product was purified by flash chromatography using 15% EtOAc/hexanes as the eluent.