Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][N:36]1[CH2:41][CH2:40]C(O)[CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH:24]2[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CN1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC4CCN(C)CC4)cc3)c2cc1OC
Yield: 55.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-methyl-4-piperidinol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (41 mg, yield 47%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[N:36]1([S:33]([C:30]2[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:28][CH:29]=2)(=[O:34])=[O:35])[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1)N1CCOCC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-(4-bromo-benzenesulfonyl)-morpholine (example B.26) (276 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (450 mg, 77%). MS (ISP) 581.2 [(M+H)+]; mp 229–231° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].C=O.[C:32]1(C)C=CC=CC=1>C(O)CCC>[OH:1][C:2]1[C:7]([CH2:32][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:6][C:5]([C:8]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:9])[CH3:10])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1
Reactant: CCNCC
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: Cc1ccccc1
Agent: C=O
Solvent: CCCCO
Product: CCN(CC)Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O

Procedure:
2-(2-Hydroxy-5-tert-octylphenyl)-2H-benzotriazole (70.0 g, 0.22 mol), diethylamine (24.3 g, 0.33 tool) and paraformaldehyde (11.2 g) are dissolved in 55 mL of n-butanol. The mixture is heated with agitation at reflux (95° to 100° C.) for 50 hours. The solvent is then removed by vacuum distillation to give an off-white solid as product in high yield (>99%). This Mannich base is identified as the above-named compound by thin layer chromatography using toluene as the mobile phase.
Reaction SMILES: P(Br)(Br)[Br:2].[I:5][C:6]1[C:13]([I:14])=[CH:12][C:11]([I:15])=[CH:10][C:7]=1[CH2:8]O.O.C(Cl)Cl>O1CCCC1>[I:5][C:6]1[C:13]([I:14])=[CH:12][C:11]([I:15])=[CH:10][C:7]=1[CH2:8][Br:2]
Reactant: BrP(Br)Br
Reactant: OCc1cc(I)cc(I)c1I
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: BrCc1cc(I)cc(I)c1I
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
A solution of phosphorous tribromide (3.8 ml, 40 mmol) was added dropwise to a solution of 2,3,5-triiodobenzyl alcohol 1 (9.72 g, 20 mmol) in dry tetrahydrofuran (50 ml) at 0° C. under dry nitrogen gas flow. The reaction mixture was stirred 5 minutes at 0° C., then 20 minutes at room temperature (18° C.), then cold H2O/DCM (60/60 ml) was added. The resulting aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic extracts were washed with NaHCO3aq (20 ml) and H2O (20 ml) then dried (Na2SO4), filtered and concentrated. The white solid was also washed with cold methanol (45 ml). 9.35 g of 2,3,5-triiodobenzyl bromide in the form of a white clean solid was obtained in 85% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:23](=[O:24])[CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-phenylacetamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and phenyl acetyl chloride in a similar manner as described above to give a white solid (86% yield). 1H-NMR (CDCl3): δ 8.88 (s, 1H), 7.57 (m, 1H), 7.37-7.27 (m, 3H), 7.27-7.20 (m, 3H), 7.15 (d, 1H), 5.74 (d, 1H), 5.08 (m, 1H), 3.61 (s, 2H), 2.62 (m, 2H), 2.13 (m, 1H), 1.81 (m, 2H), 1.67 (m, 1H); MS m/z 383 (M−1).
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[CH3:14][N:15]1[CH2:20][CH2:19]C(=O)[CH2:17][CH2:16]1.O.[CH2:23]1COCC1>[Cl-].[Na+].O>[CH3:23][O:8][C:6](=[O:7])[CH:4]=[C:5]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: CN1CCC(=O)CC1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C=C1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaH (7.08 g, 177 mmol) (60% in oil) was washed with hexanes (3× under N2), suspended in 250 mL of THF and cooled to 0° C. To this mixture was added 20.1 g (115 mmol) of trimethylphosphonoacetate in 20 mL of THF and the resulting mixture was stirred at 20° C. for 30 min. 1-Methylpiperid-4-one (10 g, 88.5 mmol) in 25 mL of THF was added and stirring was continued for 4 h. Water (5 mL) was carefully added and the mixture was poured into brine, extracted with 800 mL EtOAc. Drying and evaporation gave crude (1-methyl-piperidin-4-ylidene)-acetic acid methyl ester as a 1:1 mixture of isomers.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].C([O-])=O.[NH4+].[CH:8](O)=O.C(O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Pd].O>[CH3:8][O:3][CH:1]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCO
Reactant: OCc1ccccc1
Reactant: O=CO
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: COC(C)c1ccccc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
Pd/C (5 mol %) is weighed into a reaction flask. A solvent mixture consisting of ethanol and water (4:1) and ammonium formate (30 mol %) is added, the reaction flask is capped with a rubber septa and the mixture is heated (80° C.) for 2 minutes. Formic acid (3 equivalents) and then benzyl alcohol are added by syringe. The reaction is run for 20 minutes and the reaction is quenched with brine. The product is extracted by DCM and the organic phase is dried by Na2SO4. The product ethylbenzene was analyzed by 1H NMR and produced in 60% yield.
Reaction SMILES: Cl.[C:2]([C:5]1[O:6]C(=O)[C:8](=[O:10])[N:9]=1)([CH3:4])=[CH2:3].[Cl:12]C(Cl)C>O>[C:5]([N:9]=[C:8]=[O:10])(=[O:6])[C:2]([CH3:4])=[CH2:3].[CH3:3][CH:2]([CH2:4][Cl:12])[C:5]([N:9]=[C:8]=[O:10])=[O:6]
Reactant: CC(Cl)Cl
Reactant: C=C(C)C1=NC(=O)C(=O)O1
Agent: Cl
Solvent: O
Product: C=C(C)C(=O)N=C=O
Product: CC(CCl)C(=O)N=C=O
Reaction time: 5.5 h

Procedure:
To 2-isopropenyloxazoline-4,5-dione hydrochloride (200 g; 1.14 mol), dichloroethane (800 g) was added, and the resultant mixture was heated to 60°-65° C. while stirring for about 5.5 hours. After cooling with water, the reaction mixture was distilled under reduced pressure to give methacryloyl isocyanate (25.3 g) and alpha-methyl-beta-chloropropionyl isocyanate (80.7 g).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[Cl:24][CH2:25][C:26]#[C:27][CH2:28][OH:29]>C(Cl)Cl.C(Cl)Cl.O>[C:6]([Si:10]([O:29][CH2:28][C:27]#[C:26][CH2:25][Cl:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC#CCCl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC#CCCl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of imidazole (691 mg, 10.2 mmol) and tert-butylchlorodiphenylsilane (2.65 ml, 10.1 mmol) in DCM (15.3 mL) at 0° C. was added 4-chlorobut-2-yn-1-ol (824 μL, 9.18 mmol). After 2 h of stirring at rt it was diluted with DCM/water and the layers were separated. The aqueous layer was extracted with DCM (2×) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue dissolved in dioxane and reconcentrated (2×) then used directly without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:47])[NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]5[N:29]=[C:30]([C@@H:33]6[CH2:37][CH2:36][CH2:35][N:34]6[C:38](=[O:46])[CH2:39][C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=6)[NH:31][CH:32]=5)=[CH:24][CH:23]=4)[CH:17]=[CH:16][C:15]=3[S:48][C:49]3[CH:54]=[CH:53][C:52]([NH:55]C(=O)OC(C)(C)C)=[CH:51][CH:50]=3)=[N:11][CH:10]=[N:9][C:8]=2[N:63]=1)([CH3:3])[CH3:2].Cl.O1CCOCC1>O1CCCC1>[NH2:55][C:52]1[CH:51]=[CH:50][C:49]([S:48][C:15]2[CH:16]=[CH:17][C:18]([C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([C@@H:33]5[CH2:37][CH2:36][CH2:35][N:34]5[C:38](=[O:46])[CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[O:47])=[CH:19][C:14]=2[NH:13][C:12]2[C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:63][C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:54][CH:53]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)Cc6ccccc6)n5)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)Cc6ccccc6)n5)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Reaction time: 4 h
Yield: 41.9 %

Procedure:
To a solution of the Product of Example 1K (0.092 g, 0.11 mmol) in tetrahydrofuran (1 mL) was added 4 M HCl in dioxane (1 mL, 4.2 mol) at ambient temperature. After stirred for four hours, the solid HCl salt of the product was filtered off and taken up in a small amount of methanol and added to a NaHCO3 solution. The free amine was extracted into ethyl acetate, concentrated and purified by combi-flash 12 g column, eluting with 0-10% Methanol in dichloromethane to give a yellow solid (0.035 g, 43%). 1H NMR (400 MHz, Solvent) d ppm 1.36 (d, J=7.02 Hz, 6H) 1.89-2.36 (m, 4H) 3.24 (dd, J=13.89, 6.87 Hz, 1H) 3.50-3.81 (m, 4H) 5.09-5.20 (m, 1H) 6.66 (d, J=8.54 Hz, 2H) 6.98-7.10 (m, 2H) 7.12-7.35 (m, 7H) 7.55 (d, J=8.54 Hz, 1H) 7.66-7.79 (m, 5H) 7.96 (s, 1H) 8.49 (s, 1H) 8.76 (d, J=8.24 Hz, 1H)
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:9]2[C@@:5]([C:12]([O:14][CH3:15])=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@@H:3]1[CH2:16][OH:17].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[OH:1][C@@H:2]1[C@@H:9]2[C@@:5]([C:12]([O:14][CH3:15])=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@@H:3]1[CH2:16][O:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: COC(=O)[C@]12O[C@H](CO)[C@H](O)[C@H]1OC(C)(C)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)[C@]12O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@H](O)[C@H]1OC(C)(C)O2
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of 11 (1.0 g, 4.0 mmol) in pyridine (13 mL, Aldrich) at 0° C. (ice water bath) was added TsCl (0.76 g, 4.0 mmol, Aldrich) in portions. The resulting mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc/H2O. The EtOAc layer was washed with H2O (2×40 mL), brine (1×40 mL) and dried over MgSO4. EtOAc was evaporated and the crude material was purified by silica gel chromatography using EtOAc/Hexane. Product 17 was obtained as a white solid (1.0 g; yield 63%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[N:12]=[C:11]([NH2:25])[N:10]=2)[CH2:5][CH2:4]1.Br[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>>[NH2:25][C:11]1[N:12]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:27]4[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=4)[CH2:22]3)=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)[N:10]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(C#N)cn3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt and 6-bromonicotinonitrile using procedures analogous to those for Example 14. Analytic LCMS (M+H)+: m/z=427.4.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[NH:21])[O:19]C)[N:8]=1.C[NH:26][CH2:27][CH:28]([O:32]CC)[O:29]CC.[CH3:35][OH:36]>>[C:18]([OH:19])(=[O:36])/[CH:17]=[CH:27]\[C:28]([OH:29])=[O:32].[CH3:35][N:21]1[CH:28]=[CH:27][N:26]=[C:18]1[CH2:17][CH2:16][CH2:15][CH2:14][S:13][C:9]1[N:8]=[C:7]([NH:6][C:5]([NH2:22])=[N:4][CH2:3][C:2]([F:24])([F:23])[F:1])[CH:12]=[CH:11][CH:10]=1
Reactant: CO
Reactant: COC(=N)CCCCSc1cccc(NC(N)=NCC(F)(F)F)n1
Reactant: CCOC(CNC)OCC
Product: Cn1ccnc1CCCCSc1cccc(NC(N)=NCC(F)(F)F)n1
Product: O=C(O)/C=C\C(=O)O

Procedure:
A solution of methyl 5-[2-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-6-ylthio]valerimidate (0.3 g.) and N-methyl-2,2-diethoxyethylamine (0.44 g.) in MeOH (3 ml.) was kept at room temperature for 48 hours and then evaporated to dryness. The residue was dissolved in concentrated aqueous HCl and the solution heated at 90° for 30 minutes and then evaporated to dryness. The residue was partitioned between H2O and EtOAc and the aqueous phase basified with 10N NaOH and then extracted with EtOAc. The EtOAc extract was dried and evaporated to dryness and the residue dissolved in acetone. This solution was added to a solution of maleic acid in acetone, and the precipitate (0.12 g.) was collected and crystallised from EtOH to give 1-methyl-2-[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]pyrid-6-ylthio)butyl]imidazole hydrogen maleate, m.p. 107°-110°.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]([CH:17]=[CH:18][C:19](=[O:21])[CH3:20])=[C:11]([CH3:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:23](I)[CH2:24][CH2:25][CH3:26]>>[Si:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[C:12]([CH:17]=[CH:18][C:19](=[O:21])[CH2:20][CH2:23][CH2:24][CH2:25][CH3:26])=[C:11]([CH3:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCI
Reactant: CC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Product: CCCCCC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C

Procedure:
The entitled compound was prepared from 4-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1enyl]but-3-en-2-one and n-butyl iodide in the same manner as described in Example 2-(1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[O:12].[NH2:22][C:23]1[S:27][C:26]([SH:28])=[N:25][N:24]=1.[C:29]1(N)C=CC=C[C:30]=1N>>[S:28]=[C:26]1[S:27][C:23]([NH:22][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]([C:2]2[CH:1]=[CH:10][C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:30][CH:29]=3)=[CH:4][CH:3]=2)=[O:12])=[N:24][NH:25]1
Reactant: O=C(O)CCCCCCC(=O)c1ccc2ccccc2c1
Reactant: Nc1ccccc1N
Reactant: Nc1nnc(S)s1
Product: O=C(CCCCCCC(=O)c1ccc(-c2ccccc2)cc1)Nc1n[nH]c(=S)s1
Yield: 34 %

Procedure:
Following the procedure described in Example 22, but substituting carboxylic acid 50h for carboxylic acid 50g and 5-amino-1,3,4thiadiazole-2-thiol for 1,2-phenylenediamine respectively, the title compound 79 was obtained in 34% yield. 1H NMR (300 MHz, 20% CD3OD in CDCl3): δ 7.91 (d, J=8.4 Hz, 2H), 7.58(d, J=8.4 Hz, 2H), 7.52 (m, 2H), 7.38-7.26 (m, 3H), 2.90 (t, J=7.2 Hz, 2H), 2.30 (t, J=7.2 Hz, 2H), 1.62 (m, 4H), 1.30 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:31][C:32]([C@H:34](OS(C(F)(F)F)(=O)=O)[CH3:35])=[O:33]>>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[C@H:34]([C:32]([OH:33])=[O:31])[CH3:35])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCCN(C)C
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(CCN(C)C)[C@@H](C)C(=O)O

Procedure:
N′-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N,N-dimethylethane-1,2-diamine was coupled with ethyl O-trifluoromethanesulfonyl-D-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-[2-(dimethylamino)ethyl]-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.24 (d, 3H); 2.36 (s, 6H); 2.63 (m, 2H); 2.77 (m, 1H); 2.86 (m, 1H); 3.41 (q, 1H); 3.80 (d, 1H); 3.89 (d, 1H); 3.96 (s, 3H); 7.21 (s, 1H); 7.29 (t, 1H); 7.49 (t, 1H); 7.60 (t, 1H); 8.36 (s, 1H); 8.44 (s, 1H); 9.71 (brs, 1H); Mass Spectrum: (M+H)+ 476.
Reaction SMILES: [CH3:1]C1C=CC(S(O)(=O)=O)=CC=1.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]=[O:20].[CH2:21]([O:23]C(=O)C)C>CO.CCCCCC>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]([O:23][CH3:21])[O:20][CH3:1]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccncc1Br
Solvent: CCCCCC
Solvent: CO
Product: COC(OC)c1ccncc1Br
Yield: 93.5 %

Procedure:
PTSA (834 mg, 4.384 mmol) was added to a solution of 3-bromo-pyridine-4-carbaldehyde (600 mg, 3.2256 mmol) in methanol (20 mL). The resulting mixture was heated to reflux for 4 hours. The reaction was monitored by TLC (20% ethylacetate in hexane). The reaction mixture was concentrated and basified with NaHCO3 solution. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine solution, dried over Na7SO4, filtered and the filtrate was concentrated to afford 700 mg of 3-Bromo-4-dimethoxymethyl-pyridine (93.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.Br[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=1.[Sn].CO>O1CCOCC1.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>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=3)[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: O=Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Sn]
Solvent: CO
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Yield: 52.1 %

Procedure:
A solution of 408 (1 g, 2.40 mmol) and 6-bromonicotinaldehyde (450 mg, 2.40 mmol) in dioxane (10 mL) was treated sequentially with bistirmethyl tin (500 μL, 787 mg, 2.40 mmol) and Pd(PPh3)4 (270 mg, 0.24 mmol). The reaction mixture was heated to reflux under nitrogen overnight and concentrated. The residue was purified by flash chromatography using the gradient 5%-10% MeOH in DCM as an eluent and subsequent trituration with MeOH, yielding pure 438 (494 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.11 (s, 1H), 9.10 (m, 1H), 8.65 (d, 1H, J=5.2 Hz), 8.62 (s, 1H), 8.51 (d, 1H, J=8.8 Hz), 8.48 (dd, 1H, J=2.8 Hz, J=10.4 Hz), 8.38 (dd, 1H, J=2.1 Hz, J=8.2 Hz), 8.20 (m, 1H), 7.73 (t, 1H, J=9.0 Hz), 7.01 (d, 1H, J=5.5 Hz). LCMS: (M+H) 395.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.F[C:39](F)(F)C([O-])=O.CCN(C(C)C)C(C)C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][N:33]2[CH3:39])=[O:31])[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)C2CCCCN2)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCCCC1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1

Procedure:
To a round-bottomed flask equipped with magnetic stirring was added N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]-2-piperidylcarboxamide, trifluoroacetate (Step 2) (0.16 mmol), ClCH2CH2Cl (1 mL) and DIEA (Aldrich) (0.06 mL, 0.32 mmol). Formaldehyde (Aldrich, 37% aqueous soln) (0.03 mL, 0.33 mmol) was added to the reaction mixture, followed by NaBH(OAc)3 (Aldrich Chemical Company) (52 mg, 0.25 mmol), and the reaction mixture was stirred at RT 18 h. The mixture was diluted with CH2Cl2, and the organic solution was washed with satd NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 5:95 MeOH—CH2Cl2) to give N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]-(1-methyl(2-piperidyl))carboxamide as a white solid, (71 mg) (two diastereomers). MS (ESI, pos. ion) m/z: 562 (M+H); (ESI, neg. ion) m/z: 560 (M−H). Calc'd for C27H36ClN5O4S: 561.22.