Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15]C(C)(C)C)=O)=O)C.[NH2:21]/[C:22](/[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[CH:23]\[C:24]([O:26][CH2:27][CH3:28])=[O:25].[C:37]([C:40]1[CH:47]=[CH:46][C:43](C=O)=[CH:42][CH:41]=1)([OH:39])=[O:38].N1CCCCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C1(C)C=CC=CC=1.O>[CH2:27]([O:26][C:24]([C:23]1[C:22]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[N:21][C:6]2[C@H:8]3[N:9]([C:13](=[O:15])[C:5]=2[C:4]=1[C:43]1[CH:46]=[CH:47][C:40]([C:37]([OH:39])=[O:38])=[CH:41][CH:42]=1)[CH2:10][CH2:11][CH2:12]3)=[O:25])[CH3:28]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CCOC(=O)/C=C(\N)Cc1ccc(F)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Cc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 2 h

Procedure:
tert-Butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (14.0 g, 49.1 mmol, 1 equiv), ethyl (2Z)-3-amino-4-(4-fluorophenyl)-2-butenoate (11.0 g, 49.1 mmol, 1 equiv), 4-carboxybenzaldehyde (7.37 g, 49.1 mmol, 1 equiv), and piperidine (2.43 mL, 24.5 mmol, 0.5 equiv) were combined in toluene (50 mL). After 2 h at 90° C., the reaction was cooled to ambient tempand concentrated. The residue was redissolved in 70 mL of CH3CN and 70 mL of H2O and then CAN (63.8 g, 98.3 mmol, 2 equiv) was added. After 0.5 h the reaction mixture was extracted with EtOAc (2×100 mL) and the combined organic portions were concentrated to a brown oil. The crude oil was then treated with TFA (50 mL). After 1 h, the mixture was concentrated to a brown oil. A CH2Cl2 solution (100 mL) of this crude oil was treated with Et3N (10 mL). After 8 h, the mixture was concentrated to a brown foam. The residue was redissolved in EtOAc and washed 1× NaHCO3, 1× H2O. The organics were then dried (Na2SO4), filtered and concentrated. Chromatography on silica gel using 90% EtOAc/ 10% MeOH eluted the product. Upon concentration the material was isolated as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.07 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.24 (dd, J=8.4, 2.9 Hz, 2H), 6.94 (t, J=8.6 Hz, 2H), 4.75 (dd, J=10.5, 6.5 Hz, 1H), 4.31 (dd, J=28.7, 14.4 Hz, 2H), 3.84 (dd, J=14.3, 7.2 Hz, 2H), 3.76–3.69 (m, 1H), 3.40–3.35 (m, 1H), 2.53–2.48 (m, 1H), 2.34–2.26 (m, 2H), 1.44–1.39 (m, 1H), 0.74 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH:34]1[CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH:34]1([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:37][CH2:36][CH2:35]1
Reactant: O=S(=O)(c1ccccc1Br)C1CCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)C3CCC3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(cyclobutylsulfonyl)benzene. MS (ESI): mass calcd. for C20H18FN3O2S, 383.11; m/z found, 384.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.44 (s, 1H), 8.17 (dd, J=7.9, 1.1, 1H), 8.13 (d, J=1.4, 1H), 7.96 (m, 1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.46 (dd, J=7.6, 1.1, 1H), 7.34 (s, 1H), 7.31 (dd, J=6.4, 1.5, 1H), 3.65-3.53 (m, 1H), 2.39-2.26 (m, 2H), 2.08-1.98 (m, 2H), 1.98-1.87 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1>C(O)C.COCCOC.C(OCC)(=O)C.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>[O:1]1[CH:5]=[CH:4][C:3]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:21]=3)=[CH:12][CH:11]=2)=[CH:2]1
Reactant: Brc1ccc(-c2ncccn2)cc1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCO
Product: c1cnc(-c2ccc(-c3ccoc3)cc2)nc1
Temperature: 25 °C
Yield: 65 %

Procedure:
A suspension of 3-furanboronic acid (672 mg, 6 mmol) in 2M aq. Na3CO3 (10 mL, 20 mmol) and ethanol (8 mL) was added to a solution of 2-(4-bromo-phenyl)pyrimidine (1.30 g, 5.55 mmol, prepared as described in U.S. Pat. No. 5,780,473) and tetrakis(triphenylphosphine)palladium (693 mg, 0.60 mmol) in DME (30 mL). The reaction mixture was refluxed for 18 h, cooled to rt, diluted with ethyl acetate, washed with sat. aq. NaHCO3 and brine, dried with Na2SO4, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 3:1 hexanes/ethyl acetate) gave 793 mg (65%) of the title compound. MS 223 (M+H)+.
Reaction SMILES: C([Li])[CH2:2][CH2:3][CH3:4].Br[C:7]1[CH:20]=[CH:19][C:10]2[O:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[O:14][C:9]=2[C:8]=1[CH3:21].[CH2:22]([O:24]CC)C.Cl>O>[F:17][C:12]1([F:18])[O:11][C:10]2[CH:19]=[CH:20][C:7]([CH:22]([OH:24])[CH:3]([CH3:2])[CH3:4])=[C:8]([CH3:21])[C:9]=2[O:14][C:13]1([F:16])[F:15]
Reactant: Cc1c(Br)ccc2c1OC(F)(F)C(F)(F)O2
Reactant: [Li]CCCC
Reactant: CCOCC
Agent: Cl
Solvent: O
Product: Cc1c(C(O)C(C)C)ccc2c1OC(F)(F)C(F)(F)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 7.8 ml of n-butyllithium (1.57 M-n-hexane solution) was dropwise added at −50° C. to a mixture comprising 3.36 g of 6-bromo-2,2,3,3,-tetrafluoro-5-methyl-1,4-benzodioxane and 40.6 ml of ethyl ether, and then the mixture was stirred at the same temperature for 30 minutes. 0.89 g of isobutylaldehyde was dropwise added thereto at a temperature of at most −70° C., and the temperature was raised to room temperature followed by a reaction for 15 hours. After completion of the reaction, the reaction mixture was put into water, and then weakly acidified by an addition of hydrochloric acid. Then the mixture was extracted with ether, and the extract was washed with water and dried over magnesium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to obtain 1.90 g of oily 1-(2,2,3,3,-tetrafluoro-5-methyl-1,4-benzodioxan-6-yl)-2-methylpropanol. The NMR spectrum data of this product were as follows.
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39].CN(C)CCCNC1N=C2C(C3C=CC=C(C(F)(F)F)C=3)=C(C)C(C3N(C4C=CC(C#N)=CC=4)N=CC=3)=CN2N=1>>[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH:39][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCN
Agent: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19, 92 mg, 0.19 mmol) and N,N-dimethyl-ethane-1,2-diamine (1.5 mL) using a similar method to that used in Example 28 (61 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([Cl:28])=[CH:22][C:21]=3[Cl:29])=[C:12]([C:17]#[N:18])[CH:13]=[N:14]2)=[CH:9][C:8]=1[O:30][CH3:31])(=O)=O.[CH:34]([C:36]1[O:37][CH:38]=[C:39](B(O)O)[CH:40]=1)=[O:35]>COCCOC.C(=O)(O)[O-].[Na+]>[Cl:29][C:21]1[CH:22]=[C:23]([Cl:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:39]3[CH:40]=[C:36]([CH:34]=[O:35])[O:37][CH:38]=3)=[C:8]([O:30][CH3:31])[CH:9]=2)[N:14]=[CH:13][C:12]=1[C:17]#[N:18]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(OS(=O)(=O)C(F)(F)F)c(OC)cc23)c(Cl)cc1Cl
Reactant: O=Cc1cc(B(O)O)co1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4coc(C=O)c4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl trifluoromethanesulfonate (835 mg, 1.60 mmol), 2-formyl-4-furan boronic acid (446 mg, 3.21 mmol), and tetrakis(triphenylphosphine)pallidium (0) (20 mg) in 40 mL of ethylene glycol dimethyl ether and 25 mL of saturated aqueous sodium bicarbonate is heated at reflux for 3 hours and then cooled to room temperature. The reaction mixture is partitioned between dichloromethane and water. The aqueous layer is extracted with 10% methanol in ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the solid is collected by filtration to provide 723 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(5-formyl-3-furyl)-6-methoxy-3-quinolinecarbonitrile as a light yellow solid, mp 238-241° C.; 1H NMR (DMSO-d6) δ 3.88 (s, 3H), 4.09 (s, 3H), 7.38 (s, 1H), 7.76 (s, 1H), 8.01 (s, 1H), 8.29 (broad s, 2H), 8.48 (s, 1H), 8.77 (s, 1H), 9.71 (s, 1H), 9.87 (s, 1H); MS 468.0, 470.0 (M+H)+; HRMS calcd: 468.05124, found: 468.0511 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:19][CH2:20][OH:21]>CN(C=O)C>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:19][CH2:20][OH:21])[CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: OCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCCN(CCO)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
1-Methylhomopiperazine (2.00 g, 17.5 mmol) and DIPEA (3.0 mL, 18.4 mmol) were dissolved in DMF (25 mL). 2-bromethanol (1.3 mL, 18.4 mmol) was added slowly over 5 minutes. The reaction mixture was stirred at 100° C. for 2 hours and then at room temperature for 48 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (−300 mL) and then washed sequentially with 1M aq Na2CO3 solution (5×200 mL), dried (MgSO4) and concentrated in vacuo to give 2-(4-methylhomopiperazin-1-yl)ethanol (2.77 g, 100%) as a brown oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][C:13](=[O:15])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:16][Mg]Cl>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:12][C:13]([CH3:16])([OH:15])[CH2:14]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CC(c2ncc3c(Cl)nccn23)C1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)CC(c2ncc3c(Cl)nccn23)C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (1.95 g, 8.80 mmol) in anhydrous THF (77.78 mL) at −78° C. under an atmosphere of nitrogen was treated slowly with a 3.0 M solution of methylmagnesium chloride in THF (5.9 mL). The solution stirred for 3 hr at −78° C. then quenched with 40 mL of semi-saturated aqueous NH4Cl (NH4Cl dilution in 1:1 mixture with water) at −78° C. and allowed to warm up to rt. The mixture was then extracted with EtOAc (3×40 mL) and the combined extracts washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was purified by chromatography over silica gel eluting with 1:1 EtOAc/DCM to 4% MeOH in (1:1) EtOAc/DCM to afford desired product. 1H-NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 3 H), 2.74-2.60 (m, 4 H), 3.75-3.39 (m, 1 H), 7.35 (d, J=5.04 Hz, 1 H), 7.71 (d, J=5.00 Hz, 1 H) and 7.86 (s, 1 H). MS (ES+): m/z 238.15 and 240.17 [MH+].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.[Cl:16][C:17]1[C:22]([CH3:23])=[C:21]([C:24]([F:27])([F:26])[F:25])[N:20]=[CH:19][N:18]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[ClH:16].[CH3:23][C:22]1[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)=[N:18][CH:19]=[N:20][C:21]=1[C:24]([F:27])([F:25])[F:26]
Reactant: Cc1c(Cl)ncnc1C(F)(F)F
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncnc1C(F)(F)F
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 100 mg, 0.465 mmol), 4-chloro-5-methyl-6-(trifluoromethyl)pyrimidine (ANICHEM CAS425394-59-8, 83 mg, 0.465 mmol) and triethylamine (0.130 mL, 0.929 mmol) were added together in N,N-dimethylformamide (5 mL) and the resulting mixture was stirred at room temperature for overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by trituration in diethyl ether. The resulting solid was dissolved in 1:1 ethyl acetate:methanol and 4M HCl in 1,4-dioxane was added. The mixture was then evaporated under reduced pressure, the resulting residue was triturated again in diethyl ether the mixture was allowed to cool to room temperature and the white solid was collected to give the titled compound as a white solid (175 mgs);
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:26])[N:10]3[CH2:17][C@H:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:15][C@H:11]3[C:12](=[O:14])[NH:13][C:7]=2[CH:6]=[CH:5][C:4]=1[O:27][CH3:28].[H-].[Na+].[CH3:31][Si:32]([CH2:35][CH2:36][O:37][CH2:38]Cl)([CH3:34])[CH3:33].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:26])[N:10]3[CH2:17][C@H:16]([O:18][Si:19]([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:20])[CH3:21])[CH2:15][C@H:11]3[C:12](=[O:14])[N:13]([CH2:38][O:37][CH2:36][CH2:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:27][CH3:28]
Reactant: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A solution of 171 (6.50 g, 15.99 mmol) in anhydrous DMF (27.5 mL) was added dropwise to a stirred suspension of NaH (0.422 g, 0.704 g of a 60% dispersion in mineral oil, 18.34 mmol) at 0° C. and the reaction mixture was allowed to stir for 30 minutes. A solution of SEM chloride (3.11 mL, 2.93 g, 17.59 mmol) in anhydrous DMF (5 mL) was added dropwise to the stirred reaction mixture at 0° C. and allowed to stir at room temperature for 16 h. The reaction mixture was poured into water (200 mL) to afford a white precipitate, which was extracted with diethyl ether (4×300 mL). The organic layer was washed with water (2×50 mL), brine (2×50 mL) and dried over anhydrous MgSO4. Filtration and evaporation of the solvent in vacuo afforded the crude product, which was purified by flash column chromatography using an 80:20 mixture of petroleum ether:EtOAc as eluent. Pure fractions were combined and evaporated in vacuo to afford the product (172) as a yellow oil (7.01 g, 13.1 mmol, 82%). 1H NMR (270 MHz, CDCl3) δ7.35 (s, 1H, ArH), 7.24 (s, 1H, ArH), 5.52 (d, 2H, J=9.89 Hz, SEM amino acetal CH2), 4.65 (d, 2H, J=9.90 Hz, SEM amino acetal CH2), 4.61-4.56 (m, 1H, 2), 4.23 (dd, 1H, J=4.40 Hz, 8.24 Hz, 11a), 3.94 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.68 (m, 4H, SEM 1′ CH2+3), 2.86 (m, 1H, 1), 2.02 (m, 1H, 1), 0.98 (t, 2H, J=8.25 Hz, SEM 2′ CH2), 0.88 (s, 9H, TBDMS t-Bu CH3), 0.10 (s, 6H, 2×TBDMS SiCH3), 0.03 (s, 9H, 3× SEM SiCH3); 13C NMR (67.8 MHz, CDCl3) δ170.0, 165.6, 151.8, 147.1, 133.9, 121.5, 111.2, 105.5, 78.1, 69.6, 67.0, 56.5, 56.2, 56.1, 53.6, 35.5, 25.7, 18.4, −1.3, −4.8.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:11]([O:15][C:16](=[O:19])[CH2:17]Br)(C)(C)C.[H-].[Na+].[C:22]([OH:28])([C:24](F)(F)F)=[O:23]>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:24][C:22]([OH:28])=[O:23])[C:5]2[C:4]([C:10]=1[CH:9]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)=[CH:9][CH:8]=[C:17]([C:16]([O:15][CH3:11])=[O:19])[CH:6]=2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(O)C(F)(F)F
Reactant: Brc1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)O)c2c1

Procedure:
The 2-bromoindole from example 2 was N-alkylated with tert-butylbromoacetate using NaH in DMF and the tert-butyl ester cleaved with TFA as described in example 6 to give the title compound of example 8 as a white solid.
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[CH2:11]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[N:26][C:27]([C@H:30]3[CH2:35][CH2:34][C@H:33]([C:36]([NH2:38])=O)[CH2:32][CH2:31]3)=[N:28][CH:29]=2)=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:11]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[N:28][C:27]([C@H:30]3[CH2:31][CH2:32][C@H:33]([C:36]#[N:38])[CH2:34][CH2:35]3)=[N:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCc1ccc(-c2cnc([C@H]3CC[C@H](C(N)=O)CC3)nc2)cc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCc1ccc(-c2cnc([C@H]3CC[C@H](C#N)CC3)nc2)cc1
Temperature: 55 °C

Procedure:
6.0 Ml. of benzenesulfonyl chloride are added dropwise while stirring to a suspension of 10.8 g. of trans-4-[5-(p-n-heptylphenyl)-2-pyrimidinyl]cyclohexane carboxamide in 150 ml. of pyridine. The mixture is then warmed to 55° C. for 2 hours in an oilbath. The mixture is poured into ice-water and the product is taken up in methylene chloride. The extract is washed successively with dilute hydrochloric acid, saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The crude product is chromatographed on a column of 300 g. of silica gel with toluene/5% acetone (v/v). The fractions which are pure according to thin-layer chromatography are combined and evaporated. The residue is dissolved in hexane, filtered hot with active carbon and recrystallized. The crystallizate is dried in vacuo overnight. There is obtained trans-4-[5-(p-n-heptylphenyl)-2-pyrimidinyl]cyclohexane carbonitrile; melting point 83.5° C., clearing point 160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19])=[CH:15][CH:14]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][C:22](=[O:23])[C:21]([S:18]([NH:17][C:16]1[CH:25]=[CH:26][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)(=[O:20])=[O:19])=[CH:7]2
Reactant: COc1ccc(NS(=O)(=O)CC(=O)O)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CC(=O)O
Product: COc1ccc(NS(=O)(=O)c2cc3cc(Cl)ccc3oc2=O)cc1

Procedure:
A solution of 5-chlorosalicylaldehyde (1 mmol) and 4-methoxyanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 175-177° C.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:17]=[C:16]([Cl:18])[C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:8]([Cl:19])[CH:7]=1)(=[O:5])[CH3:4]>C(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([Cl:19])[C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:16]([Cl:18])[CH:17]=1)=[O:5]
Reactant: COC(=O)COc1c(Cl)cc(C(C)=O)cc1Cl
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)COc1c(Cl)cc(C(=O)CBr)cc1Cl
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A solution of bromine (0.77 ml) in chloroform (10 ml) was added dropwise over 15 minutes to a stirred solution of the product from step (i) (4.16 g) in chloroform (40 ml) at 25° C. The temperature was raised to 40° C. for 1 hour and then stirring continued for a further 18 hours at ambient temperature. The solvent was removed in vacuo and the residual oil purified by flash chromatography on silica, eluting with dichloromethane, to give a crystalline solid. Recrystallisation from methanol gave methyl 4-bromoacetyl-2,6-dichlorophenoxyacetate, 1.88 g, as white crystals: m.p. 89°-90° C.; NMR (d6DMSO) δ8.06 (2H, s), 4.93 (2H, s) 4.82 (2H, s) 3.72 (3H, s); m/e 355/357 (M+H)+, 1 Br pattern; calculated for C11H9BrCl2O4 : C, 37.1; H, 2.3. found: C, 36.8; H, 2.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=O)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:11]1[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(=O)[nH]1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(3,4-dichloro-phenyl)-6-methyl-1H-pyrimidin-2-one (2.51 g, 9.84 mmol) and phosphoroxychloride (35 mL) according to the general procedure I. Obtained as a brown solid (1.55 g, 58%). MS (EI) 272.1 [(M)+]; mp 123° C. (dec.).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.C1COCC1>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([N:25]3[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][C@@H:20]3[CH3:19])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 92.8 %

Procedure:
To a mixed solution of a commercially available product of 1-(diphenylmethyl)azetidin-3-one (300 mg, 1.26 mmol), THF (6.0 mL) and acetic acid (500 μL) was added a commercially available product of tert-butyl(3S)-3-methylpiperazine-1-carboxylate (304 mg, 1.51 mmol) at room temperature. The resultant mixture was stirred at room temperature for 1 hour and 40 minutes. Sodium triacetoxyborohydride (536 mg, 2.52 mmol) was added to the reaction mixture at room temperature, and the resultant mixture was stirred at room temperature for 13 hours and 45 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture, and the resultant solution was extracted with ethyl acetate. An organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate and then filtrated. A filtrate was concentrated under a reduced pressure and the resultant residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=5:1) to give the title compound (493 mg, yield: 93%).