Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:13][CH2:14][CH3:15].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[C:16]1([N:22]2[C:8](=[O:10])[C:7]3=[CH:6][NH:5][CH:4]=[C:3]([CH2:13][CH2:14][CH3:15])[C:2]3=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1cncc(C(=O)OCC)c1Cl
Reactant: NNc1ccccc1
Solvent: CCCCO
Product: CCCc1c[nH]cc2c(=O)n(-c3ccccc3)nc1-2
Yield: 83.6 %

Procedure:
A mixture of ethyl 4-chloro-3-propyl-5-pyridinecarboxylate (0.5123 g, 2.25 mmol) and phenylhydrazine (0.32 ml, 3.25 mmol) in anhydrous 1-butanol (18 ml) was stirred at reflux under nitrogen for 50 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2Cl2) to give 0.4767 g (84%) of the title compound as a yellow solid; mp 221-224° C. (CH2Cl2-EtOAc-hexane); 1H NMR (360 MHz, DMSO-d6) δ0.95 (3H, t, J 7.3 Hz), 1.77 (2H, m), 2.63 (2H, t, J 7.3 Hz), 7.15 (1H, t, J 7.4 Hz), 7.36 (1H, s), 7.42 (2H, t, J 7.4 Hz), 8.19 (2H, d, J 7.5 Hz), 8.47 (1H, s), 12.14 (1H, br s); MS (ES+) m/z 254 [MH]+. Anal. found: C, 71.22; H, 5.59; N, 16.45. C15H15N3O requires: C, 71.13; H, 5.97; N, 16.59%.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH:6]2[N:8](C(OCC3C=CC=CC=3)=O)[CH:3]1[CH2:4][C@H:5]2[C:19]([O:21][CH2:22]C)=[O:20]>CO.[Pd]>[F:24][C:2]1([F:1])[CH2:7][CH:6]2[NH:8][CH:3]1[CH2:4][CH:5]2[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)[C@@H]1CC2N(C(=O)OCc3ccccc3)C1CC2(F)F
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CC2NC1CC2(F)F
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of O7-benzyl O5-ethyl (5R)-2,2-difluoro-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate (0.33 g, 1.0 mmol), 10% Pd/C (0.4 g) in methanol (20 mL) was stirred for 24 hours at 1 atm of H2. Removal of catalyst and solvent afforded crude methyl 2,2-difluoro-7-azabicyclo[2.2.1]heptane-5-carboxylate 151a, which was used in next step without purification. Yield: 100%. MS: calc'd (MH +) 192, measured (MH +) 192.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1>CCOCC>[CH3:7][C:6]1([CH3:8])[CH2:5][C@@H:4]([CH3:10])[CH2:3][C:2](=[O:1])[CH2:9]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Solvent: CCOCC
Product: C[C@H]1CC(=O)CC(C)(C)C1
Yield: 65.4 %

Procedure:
Prepared according to the general procedure from isophorone (138 mg, 1.09 mmol) in 0.2 M Et2O for 48 h at room temperature to provide the title compound as a colorless oil (100 mg, 65% yield, 97% ee) after purification by flash chromatography on silica gel (5% Et2O/pentane). The physical data were identical in all respects to those previously reported (Allinger et al. (1975), J. Org. Chem. 40:1316 (reported a rotation of +20.3° for the (S)-enantiomer that is 75% ee)). The enantiomeric ratio was determined by GLC using a Hydrodex-B-TBDAc (50 m×0.25 mm) column (110° C. isotherm, 1 mL/min.); (S) isomer tr=11.8 min. and (R) isomer tr=12.4 min. [α]D22=−18.7°(c=1.03, CHCl3).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:11][C:12](=[O:41])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=3Br)[CH:23]=2)=[CH:17][C:16]=1[CH3:40]>>[CH3:40][C:16]1[CH:17]=[C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:30]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:23]=2)[CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][C:12]([OH:11])=[O:41]
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1ccccc1
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using phenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 74 mg (49%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H23O4F3 492, found 493 (M+1, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.O[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:18]3)=[N:7][CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(OCCCO)nc1
Reactant: COC(=O)C(C)n1ccc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(C)n1ccc2cc(OCCCOc3ccc(C#N)cn3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of 6-(3-hydroxypropoxy)nicotinonitrile (Example 66, 0.55 g, 3.09 mmol) and methyl 2-(5-hydroxy-1H-indol-1-yl)propanoate (Example 7, 0.34 g, 1.55 mmol) in CH2Cl2 (7.73 mL) were added triphenylphosphine (0.61 g, 2.32 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.59 g, 2.32 mmol). The yellow reaction mixture was stirred at rt for 18 h and then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (eluting with 67% hexanes/EtOAc) to give the title compound (0.5 g, 85%). 1H NMR (400 MHz, CD2Cl2) δ 8.49 (dd, 1H), 7.79 (dd, 1H), 7.25-7.09 (m, 3H), 6.85-6.83 (m, 2H), 6.47 (d, 1H), 5.11 (qt, 1H), 4.60 (t, 2H), 4.17 (t, 2H), 3.71 (s, 3H), 2.35-2.25 (m, 2H), 1.82 (d, 3H).
Reaction SMILES: N[CH:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17].[BrH:18].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N(OCCC(C)C)=O>C(Cl)Cl>[Br:18][CH:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17]
Reactant: C=CC[C@@H]1C(N)C(=O)N1C(C(=O)OC)=C(C)C
Reactant: Br
Agent: CC(C)CCON=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CC[C@@H]1C(Br)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
A mixture of methyl 2-[(4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (815 mg), triethylamine hydrobromide (2.50 g) and p-toluenesulfonic acid hydrate (1.17 g) in methylene chloride (30 ml) was cooled to 0° C. and isopentyl nitrite (0.54 ml) was added. After stirring for 20 minutes at the same temperature, the mixture was concentrated and the residue was dissolved in ethyl acetate (50 ml). The solution was washed successively with 10% aqueous sodium bisulfite, water and brine, dried over magnesium sulfate and evaporated to give methyl 2-[(4R)-3-bromo-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (840 mg) as a crude oil.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])=[CH:9][CH:8]=1)[CH2:5][CH3:6].[Li+].[OH-]>C1COCC1.CO.O.C(OCC)(=O)C>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17][C@H:16]2[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([CH:4]([CH2:5][CH3:6])[C:3]([OH:44])=[O:2])=[CH:12][CH:11]=2)=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CCC(C(=O)OC)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(C(=O)O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
A mixture of 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-butyric acid methyl ester (23 mg, 0.036 mmol) was dissolved in THF (0.9 mL) and methanol (0.3 mL), then 2N LiOH (1 mL) was added and stirred at room temperature for 2 hours. The mixture was diluted with water and ethyl acetate. The organic phase was separated then concentrated to yield 2-(4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-butyric acid (16.4 mg, 72.9%) as an off-white powder. HRMS (ES+) m/z Calcd for C33H33Cl2F2N3O3+H [(M+H)+]: 628.1940. found: 628.1939.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]([CH3:40])[S:31]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)(=[O:33])=[O:32])[CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:12][CH:11]=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl.[Cl-].[Na+].O>[CH3:40][N:30]([S:31]([C:34]1[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=1)(=[O:33])=[O:32])[CH2:29][CH2:28][N:25]1[CH2:24][CH2:23][N:22]([C:17]2[C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][O:8][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:11][CH:12]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:27][CH2:26]1
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCN1CCN(c2nccnc2-c2ccc(CO)cc2)CC1)S(=O)(=O)c1cnn(C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCN(c2nccnc2-c2ccc(COS(C)(=O)=O)cc2)CC1)S(=O)(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add triethylamine (0.653 mmol, 0.091 mL) to a stirred solution of 1-methyl-1H-pyrazole-4-sulfonic acid {2-[3′-(4-hydroxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethyl}-methyl-amide (0.594 mmol, 0.280 g) in dry dichloromethane (5 mL) at room temperature under nitrogen. Add methanesulfonyl chloride (0.653 mmol, 0.051 mL). Allow the mixture to warm to room temperature and stir 1 hr. Dilute with dichloromethane and brine. Separate and extract the aqueous phase with dichloromethane. Combine organics, dry over Na2SO4, and concentrate to dryness to afford the title preparation (0.330 g, crude). The material is used without further purification. MS ES: m/z=550 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[Cl:1][C:2]1[NH:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:29]([NH:28][C:19]3[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=3[F:17])=[O:30])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1[nH]c(Cl)cc1-c1ccc(N)cc1
Solvent: C1CCOC1
Product: NC(=O)c1[nH]c(Cl)cc1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To 0.055 g (0.233 mmol) of 5-chloro-3-(4-aminophenyl)-1H-pyrrole-2-carboxamide dissolved in 5 cm3 of tetrahydrofuran is added, at a temperature in the region of 20° C. under an argon atmosphere, 0.035 cm3 (0.245 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate. After stirring for 2 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is recrystallized from 4 cm3 of acetonitrile. After filtering through a No. 3 sinter funnel, the solid is washed with 2 cm3 of acetonitrile and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. for 4 hours to give 0.076 g of 5-chloro-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrole-2-carboxamide in the form of a yellow solid; 1H NMR (400 MHz, DMSO d6, δ in ppm): 6.16 (s, 1H); 6.45 (broad m, 1H); 7.12 (broad m, 1H); 7.38 (partially masked m, 1H); 7.40 (d, J=9.0 Hz, 2H); 7.45 (d, J=9.0 Hz, 2H); 7.49 (dd, J=9.0 and 11.0 Hz, 1H); 8.63 (dd, J=2.0 and 7.5 Hz, 1H); 8.90 (d, J=2.5 Hz, 1H); 9.22 (s, 1H); 12.1 (broad m, 1H); ES+: m/z=291: [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](=O)[CH2:25][CH2:26][CH2:27][Cl:28]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:24]([CH2:25][CH2:26][CH2:27][Cl:28])[CH2:23][Cl:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: O=C(CCl)CCCCl
Solvent: C1CCOC1
Product: ClCCCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1,5-dichloro-2-pentanone under nitrogen to give 7-chloro-2-[[2-chloro-1-(3-chloropropyl)ethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[C:26]([C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[C:17]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([N:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)=[N:3][C:4]([C:28]([F:31])([F:30])[F:29])=[CH:5][CH:6]=1)#[CH:27]
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Reactant: CN1CCNCC1
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2N2CCN(C)CC2)cc(F)c1NS(C)(=O)=O
Yield: 15 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (70 mg, 0.057 mmol) was reacted with N-methylpiperazine (30 μl) as in example 46 to give the title compound (13 mg, 15%) after recrystallization with Hex/EtOAc.
Reaction SMILES: [I:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[H-].[Na+].Cl[CH2:14][C:15]([CH3:17])=[CH2:16].O>CN(C=O)C>[I:1][C:2]1[C:3]([O:10][CH2:16][C:15]([CH3:17])=[CH2:14])=[CH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cccc(O)c1I
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)COc1cccc(OC)c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 2-iodo-3-(methyloxy)phenol (Intermediate 47, 10.3 g) in DMF (100 ml, SCRC) was added NaH (60%, wt., 1.977 g, 49.4 mmol) portionwise. The reaction mixture was stirred at room temperature for 1 hour and 3-chloro-2-methyl-1-propene (3.73 g, 41.2 mmol, Aldrich) was added. The resulting mixture was stirred at room temperature for 2 hours and water (50 ml) was added. The reaction mixture was extracted with ethyl acetate (3 times 200 ml, SCRC) and the combined organic layer were dried, evaporated and purified by silica gel chromatography with as eluents EtOAc/PE (1/30) to afford the title compound as a yellow liquid (11.6 g)
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:9].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:2]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([O:7][CH3:6])=[O:9])=[CH:15][CH:14]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCOc1ccc(C(=O)OC)cc1

Procedure:
A slurry of 4-bromo-1-butene (1.4 g), methyl p-hydroxybenzoate (1.5 g) and K2CO3 (1.8 g) in acetone was heated to reflux for 18 hours. The reaction was cooled, filtered, and concentrated to a yellow oil. The oil was chromatographed with 20% ethyl acetate/hexanes to give the titled compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1>ClC1C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:15][CH3:16])[N:3]=[C:2]([N:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)[N:11]=[C:10]2[NH2:12]
Reactant: C1CSCCN1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: Clc1ccccc1
Product: COc1cc2nc(N3CCSCC3)nc(N)c2cc1OC
Temperature: 25 °C

Procedure:
A mixture of 8.00 g of 2-chloro-6,7-dimethoxy-4-quinazolinamine and 6.90 g. of thiomorpholine in 80 ml of chlorobenzene was refluxed for 18 hrs. The reaction mixture was cooled to room temperature, and the precipitate was collected. There was deposited 8.00 g (70.2%) of white powder, mp 267°-269°, dec. The product was recrystallized from methanol to give an analytical sample, mp 270°-271°, dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.C1COCC1.C1(C)C=CC=CC=1.CON(C)[C:25]([C:27]1[C:32]([NH2:33])=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26].Cl>C1COCC1>[NH2:33][C:32]1[C:27]([C:25]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:26])=[N:28][CH:29]=[CH:30][N:31]=1
Reactant: CON(C)C(=O)c1nccnc1N
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1nccnc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.9 M 4-chlorophenyl magnesium bromide in THF/toluene (9.15 ml, 8.24 mmol) is added dropwise to a solution of 3-amino-pyrazine-2-carboxylic acid methoxy-methylamide (0.5 g, 2.74 mmol) in THF (15 ml) at 0° C. The reaction is allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture is cooled to 0° C. and 2 M HCl (20 ml) is added. The product is extracted into EtOAc (3×40 ml), dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, 0-5% MeOH in DCM) yields (3-Amino-pyrazin-2-yl)-(4-chloro-phenyl)-methanone as a yellow solid.
Reaction SMILES: C([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7]1)(=O)C.[OH-].[Na+]>Cl>[NH2:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7]1
Reactant: CC(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCC1CN(Cc2ccc(F)cc2)CCO1
Reaction time: 4 h

Procedure:
A solution of 2-acetylaminomethyl-4-(4-fluorobenzyl)morpholine (3.0 g) in 10% hydrochloric acid (50 ml) is refluxed with stirring for 4 hours. The reaction mixture is adjusted to pH 11 with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. Removal of the solvent under reduced pressure gives the title compound as an oil.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=O.C(O)C.[NH2:20][C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>C1C=CC=CC=1>[N:20]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)=[CH:2][N:22]2[CH:23]=[CH:24][CH:25]=[N:26][C:21]=12
Reactant: Nc1ncccn1
Reactant: CCOC(=O)Cc1ccc(C(=O)CCl)cc1
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc(-c2cn3cccnc3n2)cc1
Yield: 46.3 %

Procedure:
A mixture of 48 g of ethyl 4-(chloroacetyl)phenylacetate, 100 ml of ethanol and 38 g of 2-aminopyrimidine is heated under reflux for 3 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried and concentrated to give a brown oil. To the oil is added benzene, and the crystalline precipitate is filtered off and recrystallized from ethyl acetate to give 26 g of ethyl 4-(imidazo[1,2-a]-pyrimidine-2-yl)phenylacetate as pale brown crystals melting at 155°-158°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH:13]1[CH:18]2[CH:14]1[CH2:15][N:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17]2)[CH2:8][CH2:9][CH2:10][CH2:11]Br)(C)(C)[CH3:2].BrCCCCl.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[CH:41]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:42][C:43]([OH:45])=[O:44].N12CCCN=C1CCCCC2>C1(C)C(C)=CC=CC=1>[CH2:19]([N:16]1[CH2:15][CH:14]2[CH:18]([CH:13]2[N:7]([C:6]([O:5][CH2:1][CH3:2])=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11][O:44][C:43](=[O:45])[CH2:42][CH:41]([C:35]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=2[O:33][CH3:32])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:17]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(C)cc1C(CC(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(CCCCBr)C1C2CN(Cc3ccccc3)CC21
Agent: ClCCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)N(CCCCOC(=O)CC(c1ccccc1)c1cc(C)ccc1OC)C1C2CN(Cc3ccccc3)CC21

Procedure:
The compound, 3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-(4-bromobutyl)-carbamic acid t-butyl ester, 211.5 mg, 0.5 mmole, 1 eq (prepared by reacting boc-protected 3-benzyl-3-azabicylo[3.1.0]hex-6-yl amine, which in turn, was prepared following the procedure of T. F. Braish et al., Synlett, 1996, 1100, with 1-bromo-3-chloropropane) was dissolved in xylene (15 ml). To the reaction mixture, 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid (203 mg, 0.75 mmole, 1.5 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.75 mmole, 1.5 eq) were added. The resulting reaction mixture was refluxed for 2 hrs. Xylene was removed under reduced pressure and the residue was purified by column chromatography by using ethyl acetate in hexane solvent system to yield the compound, 3-(2-methoxy-5-methylphenyl)-3-phenyl propionic acid 4-[(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)-ethoxy carbonylamino]butyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[N:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:20]1[N:24]2[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:23]2=[N:22][CH:21]=1)CCC>>[F:14][C:5]1[CH:4]=[CH:3][C:2]([C:20]2[N:24]3[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[N:28][C:23]3=[N:22][CH:21]=2)=[CH:7][C:6]=1[C:8]1[N:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Fc1ccc(Br)cc1-c1cccnn1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1cccnn1

Procedure:
3-(5-Bromo-2-fluorophenyl)pyridazine (80.6 mg, 0.3 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.45 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then crystallisation from methanol, gave 3-[4-fluoro-3-(pyridazin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 9.24 (1H, dd, J 5 and 1), 8.92 (1H, d, J 7), 8.48 (1H, dd, J 7 and 2), 8.16 (1H, s), 8.07-8.11 (1H, m), 7.66-7.71 (1H, m), 7.63 (1H, dd, J 9 and 5), 7.45 (1H, dd, J 11 and 9), 7.30 (1H, d, J 7); m/z (ES+) 359 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:28][OH:29].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:30]([CH:27]([N:26]([CH2:20][C:18]1[S:19][C:12]2[C:11](=[O:22])[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=2[CH:17]=1)[CH3:25])[CH2:28][OH:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: CNC(CO)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)C(CO)Cc1ccccc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 73.9 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (50 mg, 0.13 mmol), racemic 2-(methylamino)-3-phenylpropan-1-ol (Tetrahedron 2001, 57, 3425)(33 mg, 0.20 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 10 hours at that temperature. After cooling to room temperature, the solution was diluted with water (7 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (49 mg) as a white solid.