Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[SH:32][C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=O.[CH3:42][C:43]([CH3:48])([CH3:47])[CH2:44][CH2:45][NH2:46]>CN(C=O)C.CCCCCC.CC(C)=O>[CH3:42][C:43]([CH3:48])([CH3:47])[CH2:44][CH2:45][NH:46][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][CH:40]=[N:41][C:33]=1[SH:32]
Reactant: CC(C)(C)CCN
Reactant: O=C(O)c1cccnc1S
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CCNC(=O)c1cccnc1S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
5.84 ml (33.8 mmol) of DIPEA and 4.66 g (14.5 mmol) of TBTU were added at 0° C. to a solution of 1.50 g (9.7 mmol) of 2-mercapto-nicotinic acid in DMF (30 ml). After stirring for 30 min at 0° C., 1.6 ml (11.6 mmol) of 3,3-dimethylbutan-1-amine were added and then the mixture was stirred for 16 h at RT. Dilution with water (100 ml) and extraction with EA (2×100 ml) were then carried out. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/acetone 1:1) of the residue yielded 1.4 g (5.9 mmol, 61%) of N-(3,3-dimethylbutyl)-2-mercapto-nicotinamide.
Reaction SMILES: I[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:12]([C:14]1[N:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][CH:15]=1)#[N:13].C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:9][O:8][C:5]1[N:4]=[C:3]([O:10][CH3:11])[C:2]([C:18]2[N:19]=[C:14]([C:12]#[N:13])[CH:15]=[CH:16][CH:17]=2)=[CH:7][N:6]=1
Reactant: COc1ncc(I)c(OC)n1
Reactant: CC1(C)OB(c2cccc(C#N)n2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2cccc(C#N)n2)c(OC)n1
Yield: 43.9 %

Procedure:
5-Iodo-2,4-dimethoxy-pyrimidine (500 mg, 1.88 mmol) was dissolved in degassed n-PrOH (40 ml) and then 6-cyano-pyridine-2-boronic acid pinacol ester (650 mg, 2.82 mmol), Na2CO3 (598 mg, 5.64 mmol), PPh3 (164 mg, 0.62 mmol) and Pd(OAc)2 (42 mg, 0.19 mmol) were added. The suspension was stirred at reflux for 3 hours. The solvent was evaporated and the crude was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The crude was triturated with iPrOH to give 200 mg of the title compound (44% yield).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[CH3:12][Si:13]([CH3:30])([CH3:29])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH:27]=[O:28].Cl>O1CCCC1>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][C:3]([CH:27]([C:19]3[N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:29])([CH3:30])[CH3:12])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=3)[OH:28])=[CH:11][C:7]1=2
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Reactant: Brc1ccc2ccsc2c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C(O)c2ccc3ccsc3c2)nc2ccccc21
Reaction time: 12 h

Procedure:
To a suspension of magnesium (86 mg) in tetrahydrofuran is added a solution of 6-bromobenzo[b]thiophene (which can be prepared according to WO2006/107784) (500 mg) in tetrahydrofuran. After reflux for 3 h, a solution of 1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole-2-carbaldehyde (which can be prepared according to US2003/220341 or U.S. Pat. No. 6,476,041 for example) (635 mg) in tetrahydrofuran is added to the Grignard reagent at room temperature. After stirring for 12 h, the reaction mixture is treated with diluted hydrochloric acid and the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 90/10) to afford benzo[b]thiophen-6-yl[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH:18]([OH:19])[C:17]([CH3:21])([CH3:20])[CH2:16][C:15](=[O:22])[C:14]([CH3:23])=[CH:13]2)[CH2:8][CH2:7]1)=[O:5])C.[ClH:24]>C(O)(=O)C>[ClH:24].[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH:18]([OH:19])[C:17]([CH3:20])([CH3:21])[CH2:16][C:15](=[O:22])[C:14]([CH3:23])=[CH:13]2)[CH2:8][CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1CCN(C2C=C(C)C(=O)CC(C)(C)C2O)CC1
Agent: Cl
Solvent: CC(=O)O
Product: CC1=CC(N2CCC(C(=O)O)CC2)C(O)C(C)(C)CC1=O
Temperature: 80 °C
Yield: 80.2 %

Procedure:
The 4-(4 -ethoxycarbonylpiperidino)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 24 (0.68 g, 2.1 millimoles) was dissolved in acetic acid (5 ml), 6N hydrochloric acid (2 ml) was added and the mixture was heated at 80° C. for 90 minutes. Concentration to dryness followed by washing with ethyl acetate gave 0.56 g (80.2%) of 4-(4 -carboxypiperidino)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one hydrochloride.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=2)[CH:13]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]([O:22][C:23](=[O:33])[N:24]([CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:33])[N:24]([CH:26]1[CH2:27][CH2:28][CH:29]([NH:32][CH2:13][C:12]2[CH:15]=[C:8]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:9]=[CH:10][C:11]=2[O:16][CH3:17])[CH2:30][CH2:31]1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(N)CC1
Reactant: COc1ccc(-c2cccnc2F)cc1C=O
Product: COc1ccc(-c2cccnc2F)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Following the synthetic protocol described in Method C′; {4-[5-(2-Fluoro-pyridin-3-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester is prepared starting from 5-(2-Fluoro-pyridin-3-yl)-2-methoxy-benzaldehyde and (4-Amino-cyclohexyl)-methyl-carbamic acid tert-butyl ester. The desired product is isolated in 70%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9](O)=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:18][O:17][N:16]([CH3:15])[C:9]([C:6]1[CH:7]=[N:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)=[O:10]
Reactant: CNOC
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Reaction time: 60 h
Yield: 93.2 %

Procedure:
Dissolve 6-(trifluoromethyl)pyridine-3-carboxylic acid (0.949 g, 4.767 mmol) in DMF (10 mL) and add N,O-dimethylhydroxylamine hydrochloride (0.590 g, 5.959 mmol), and DIPEA (1.67 mL, 9.534 mmol), followed by BOP (2.259 g, 5.005 mmol). Stir the resulting mixture for about 60 hours. Pour reaction mixture into water (200 mL). Extract with EtOAc (4×75 mL). Wash the combined organic extracts with a saturated sodium chloride aqueous solution (5×75 mL). Dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Dissolve the residue in EtOAc (100 mL). Sequentially wash the residue in EtOAc with a saturated NaHCO3 aqueous solution (50 mL) to remove any residual acid starting material, followed by water (2×50 mL), and then a saturated sodium chloride aqueous solution (2×50 mL). Dry the organic layer over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound as a clear liquid (1.04 g, 93% yield). 1H NMR (400.43 MHz, d6-DMSO) δ 8.90 (d, J=2.0 Hz, 1H), 8.25-8.23 (m, 1H), 7.96 (dd, J=0.7, 8.1 Hz, 1H), 3.52 (s, 3H), 3.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH2:12]([O:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[O:18][S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])[C:13]#[CH:14]>ClCCl>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:23](=[O:24])[NH:22][S:19]([O:18][C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[O:15][CH2:12][C:13]#[CH:14])(=[O:21])=[O:20])[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: C#CCOc1ccccc1OS(=O)(=O)N=C=O
Solvent: ClCCl
Product: C#CCOc1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
3.1 g (0.02 mol) of 2-amino-4,6-dimethoxypyrimidine are dissolved in 30 ml of dichloromethane, and 5.1 g (0.02 mol) of 2-propargyloxyphenoxysulfonyl isocyanate--dissolved in 20 ml of dichloromethane--are added at 0° C. After the reaction mixture has been stirred for 24 hours at room temperature, it is diluted with 50 ml of dichloromethane, washed with 50 ml of 1N hydrochloric acid and 50 ml of water, dried and evaporated. The oily residue crystallizes on trituration with diethyl ether. 7.4 g (91% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-1-(2-propargyloxyphenoxysulfonyl)urea of melting point 125°-126° C. are obtained.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=C>>[C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH3:8]
Reactant: C=CC(=O)OCC
Solvent: C=COC(C)=O
Product: CCOC(C)=O
Reaction time: 3 h

Procedure:
Finely divided vinyl acetate-ethyl acetate copolymer is prepared exactly as described in Example 1 except that in place of the 59.3 parts vinyl acetate there is used a 70:30 mixture of vinyl acetate and ethyl acrylate and the post-heating time at 85° C. is three hours. The resulting dispersion contains 50.8% solids and has a particle size of 0.44 micron. The polymer has a reduced specific viscosity of 1.24 which corresponds to a molecular weight above 100,000 and has a second order transition temperature of 6° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C@H:28]2[CH2:30][C@H:29]2[CH2:31]I)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([C@H:28]2[CH2:30][C@H:29]2[CH2:31][O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CI)CC1
Reactant: CS(=O)(=O)c1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(Methylsulfonyl)benzyl alcohol (1.0 g, 5.4 mmol) was dissolved in DMF (12 mL), and sodium hydride (60 wt % dispersion in oil, 320 mg, 8 mmol) was added. The iodide from step A (2.35 g, 6.4 mmol) in DMF (12 mL) was added and the resulting solution was stirred at RT for 15 h. The solution was quenched with sat. NH4Cl, and EtOAc. The organic layer was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel column chromatography (2/1 hexanes/EtOAc) which provided the title compound.
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([N:13]1[CH2:16][CH:15]([C:17]2[C:22]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:14]1)=[O:12].CCN(CC)CC.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([N:13]1[CH2:14][CH:15]([C:17]2[C:22]([C:23]3[CH2:24][CH2:25][N:26]([C:36](=[O:38])[CH3:37])[CH2:27][CH:28]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:16]1)=[O:12]
Reactant: O=C(c1nc2ccccc2[nH]1)N1CC(c2nccnc2C2=CCNCC2)C1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC=C(c2nccnc2C2CN(C(=O)c3nc4ccccc4[nH]3)C2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of (1H-benzoimidazol-2-yl)-{3-[3-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone hydrochloride (187 mg, 0.47 mmol) in dry CH2Cl2 (10 mL) was added Et3N (1 mL). The reaction mixture was cooled to 0° C. with an ice bath, and acetyl chloride (39 mg, 0.50 mmol) was added dropwise. After 1 h, the reaction mixture was warmed to RT, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product (170 mg, 0.42 mmol, 90% yield). ESI-MS (M+1): 403 calc. for C22H22N6O2 402.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[CH:3][CH:2]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Co]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:3][CH:2]=1
Reactant: N#CCCCc1ccncc1
Reactant: [H][H]
Agent: [Co]
Solvent: CCN(CC)CC
Solvent: CCO
Product: NCCCCc1ccncc1
Yield: 31.5 %

Procedure:
A solution of 30.0 g of 4-pyridinebutanenitrile in 200 ml of ethanol containing 7.5 ml of triethylamine was hydrogenated over 7.5 g of Raney cobalt at 100° C. and 1200 lbs. hydrogen pressure. The crude product obtained after filtration and concentration, was distilled to give 9.7 g (31%) of 4-pyridinebutanamine, bp 105°-112° C./0.8 mm. A second fraction (15.3 g, bp 112°-122° C.) consisted of a mixture by thin layer chromatography and was redistilled to give 4.74 g (15%) of 4-pyridinebutanamine, bp 95°-98° C./0.15 mm. The product was further characterized as the hydrochloride salt, mp 124°-125° C. (ethanolether).
Reaction SMILES: [C:1]([O:5][C:6]([C@:8]1([C:19](=[O:24])[N:20]([O:22][CH3:23])[CH3:21])[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:9]1[CH2:17][OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]I>[Ag]=O>[C:1]([O:5][C:6]([C@:8]1([C:19](=[O:24])[N:20]([O:22][CH3:23])[CH3:21])[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:9]1[CH2:17][O:18][CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CON(C)C(=O)[C@]1(C(=O)OC(C)(C)C)[C@H](CO)[C@@H]1c1ccccc1
Agent: O=[Ag]
Product: COC[C@@H]1[C@H](c2ccccc2)[C@]1(C(=O)OC(C)(C)C)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
The above (1R*,2R*,3R*)-2-hydroxymethyl-1-(methoxy-methyl-carbamoyl)-3-phenyl-cyclopropanecarboxylic acid t-butyl ester (0.050 g, 0.15 mmol) was dissolved in 1 mL of methyl iodide. To this solution was added silver oxide (0.69 g, 3.0 mmol) and the mixture was stirred overnight at room temperature under N2 (in the dark). This reaction was incomplete and additional methyl iodide and silver oxide were added. After stirring overnight, the reaction appeared stalled. The catalyst was filtered off through celite and the residue was rinsed with ether. The filtrate was concentrated to a clear oil and purified by prep-TLC using 1:1 hexanes/EtOAc to afford 30 mg of the desired product (58%). This reaction was repeated numerous times to bring up more material. Note: If a huge excess of silver oxide was not used, the reaction often led to a reversion to the lactone product.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([C:20]#[N:21])[C:15](=[O:19])[NH:16][C:17]=3[CH3:18])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N.S(=O)(=O)(O)[OH:24]>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([C:20]([NH2:21])=[O:24])[C:15](=[O:19])[NH:16][C:17]=3[CH3:18])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(-n2ccnc2)cc1
Reactant: O=S(=O)(O)O
Agent: N
Product: Cc1[nH]c(=O)c(C(N)=O)cc1-c1ccc(-n2ccnc2)cc1
Temperature: 25 °C

Procedure:
A solution of 1,2-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3-pyridinecarbonitrile (5.0 g) in 25 ml of concentrated sulfuric acid is heated on a steam bath for 40 minutes, cooled to room temperature and poured into 150 ml of ice. The mixture is adjusted to pH 8 with concentrated ammonia. The solid is collected and recrystallized successively from 10:1 water/acetic acid, dimethylformamide, and 2-methoxyethanol to give 2.06 g of 1,2-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3-pyridinecarboxamide, mp 311°-315° C. (dec).
Reaction SMILES: [Br-].[C:2]([C:7]([CH2:9][N+:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:20](=[O:22])[NH2:21])[C:11]=1[NH2:23])=O)([O:4][CH2:5][CH3:6])=[O:3]>C(O)C>[C:20]([C:12]1[C:11]2[N:10]([CH:9]=[C:7]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:23]=2)[C:19]2[C:14]([N:13]=1)=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:22])[NH2:21]
Reactant: CCOC(=O)C(=O)C[n+]1c(N)c(C(N)=O)nc2ccccc21
Agent: [Br-]
Solvent: CCO
Product: CCOC(=O)c1cn2c(n1)c(C(N)=O)nc1ccccc12
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
A suspension of 1 g of the product of Step A in 100 ml of ethanol was refluxed with stirring for 90 minutes and the resulting yellow solution was concentrated and cooled. The mixture was filtered to obtain 0.55 g of ethyl 4-carbamoyl-imidazo-[1,2-a]-quinoxaline-2-carboxylate as a pale yellow crystalline solid. Recrystallization from ethanol yielded soft white needles melting at 280°-284° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:14]([CH2:22][CH:23]=[CH:24][Cl:25])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Cl:25][CH2:24][CH:23]1[C:2]2[C:11]3[CH:10]=[CH:9][C:8]([C:12]#[N:13])=[CH:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:14]([C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2cc(C#N)ccc2c1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1ccc1cc(C#N)ccc21

Procedure:
A solution of 142 (6.78 g, 16.1 mmol) in dry benzene (80 mL) was treated with Bu3SnH (4.33 mL, 16.1 mmol), followed by AIBN (0.3 g, 1.8 mmol). The mixture was stirred at reflux under N2 for 2 h, then concentrated under reduced pressure, and the residue was chromatographed on silica gel. Elution with CH2Cl2 gave an oil that was triturated with iPr2O, to provide 143 contaminated with tert-butyl 7-cyano-1-methyl-1,2-dihydro-3H-benzo[e]indole-3-carboxylate. Two recrystallizations from CH2ClrPr2O gave pure tert-butyl 1-(chloromethyl)-7-cyano-1,2-dihydro-3H-benzo[e]indole-3-carboxylate (143) (4.49 g, 81%): mp 171-172° C.; 1H MR [(CD3)2SO] δ 8.55 (d, J=1.4 Hz, 1H), 8.18 (v br, 1H), 8.07 (d, J=8.7 Hz, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.75 (dd, J=8.7, 1.7 Hz, 1 H), 4.34-4.25 (m, 1H), 4.21 (t, J=10.5 Hz, 1H), 4.09 (dd, J=11.3, 2.8 Hz, 1H), 4.03 (dd, J=11.1, 3.1 Hz, 1H), 3.93 (dd, J=11.1, 6.7 Hz, 1H), 1.55 (s, 9H). Anal. (C19H19ClN2O2.¼H2O) C, H, N.
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][N:8]=1>CN(C=O)C>[Br:3][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][N:8]=1
Reactant: Cc1cnc(O)c([N+](=O)[O-])c1
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: Cc1cnc(Br)c([N+](=O)[O-])c1
Temperature: 5 °C
Yield: 85.8 %

Procedure:
POBr3 (222.8 g, 0.78 mol) was added in portions to 2-hydroxy-5-methyl-3-nitropyridine (100 g, 0.65 mol) in DMF (500 mL) with stirring at 0-10° C. then the reaction mixture was stirred at 80° C. under nitrogen for 12 hours. Reaction mixture was cooled and poured into crushed ice (1 Kg), obtained solid was filtered, washed thoroughly with ice-cold water (2×500 mL), dried in a desiccator under high vacuum for one day to obtain 2-bromo-5-methyl-3-nitropyridine as yellow solid (121 g) in 86% yield. (M+H) Expected: 217; found 216.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:19][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[O:17][CH3:18])[CH:7]([CH2:6][C:5]1[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:3]([O:2][CH3:1])[CH:4]=1)[N:8]([CH2:20][C:21](=[O:22])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH2:10]2)[CH3:42]
Reactant: COc1cc2c(cc1O)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl bromoacetate
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][O:17][CH3:18])[C:11](=[O:19])[CH:10]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][O:17][CH3:18])[C:11](=[O:19])[CH:10]=1
Reactant: COCCn1ccc(OCc2ccccc2)cc1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCn1ccc(O)cc1=O

Procedure:
A mixture of 4-benzyloxy-1-(2-methoxy-ethyl)-1H-pyridin-2-one (1.4 g) and 10% palladium on carbon (100 mg) was stirred in ethyl acetate (50 mL) under a hydrogen atmosphere for 17 h. Then, the mixture was filtered through celite and concentrated to afford 4-hydroxy-1-(2-methoxy-ethyl)-1H-pyridin-2-one as a colourless solid. δH (300 MHz, CH3OD) 3.67 (2H, t), 4.10 (2H, t), 4.86 (3H, s), 5.85 (1H, d), 6.04 (1H, dd) and 7.48 (1H, d).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[NH:26][C:27](=[O:31])[O:28][CH2:29][CH3:30])[C:8]1[N:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[NH:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[NH:26][C:27](=[O:31])[O:28][CH2:29][CH3:30])[C:8]1[N:13]=[CH:12][C:11]([N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)Nc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-carbamate (614 mg) is dissolved in toluene (6.5 ml), and thereto are added tris(dibenzylideneacetone)dipalladium(0) (87 mg), 2-(di-tert-butylphosphino)biphenyl (114 mg), morpholine (166 μl) and sodium tert-butoxide (183 mg) and the mixture is stirred under nitrogen flow at 60° C. for 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-carbamate (476 mg). MS (m/z): 652 [M+H]+