Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[C:24]([CH3:27])[N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[C:24]([CH3:27])[N:19]3[C:20](=[O:23])[C:21]=2[C:34]2[CH:33]=[CH:32][C:31]([O:30][C:29]([F:28])([F:40])[F:41])=[CH:36][CH:35]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(/C=C/c2nc3scc(C)n3c(=O)c2I)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1cccc(/C=C/c2nc3scc(C)n3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CC1
Yield: 46.8 %

Procedure:
The title compound was prepared from Intermediate 17 (100 mg, 0.202 mmol) and 4-trifluoromethoxyphenylboronic acid (58 mg, 0.283 mmol) using Pd[(C6H5)3P]4 (90 mg, 0.008 mmol) and sodium carbonate (128 mg, 1.213 mmol) in toluene (10 ml) and ethanol (5 ml) and water (4 ml) according to the procedure outlined in Example 1 to afford crude residue which was purified by column chromatography using 10% ethyl acetate in petroleum ether to afford 50 mg of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 0.24-0.26 (m, 2H), 0.48-0.50 (m, 2H), 0.90-1.10 (m, 1H), 2.65 (s, 3H), 3.67 (d, J=6.9 Hz, 2H), 3.76 (s, 3H), 6.83 (d, J=15.6 Hz, 2H), 6.90-6.91 (m, 2H), 6.98-7.01 (m, 4H), 7.43 (s, 4H), 8.10 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 529.19 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[CH:33][CH:32]=1.[CH2:41](O)[CH3:42]>>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:30][C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[CH:33][CH:32]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:41][CH3:42])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: CCO
Reactant: COc1cccc(COc2ccc(Sc3ccc(NC(C)=O)cc3)c(N)c2)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(OCc4cccc(OC)c4)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 153a (33 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (14 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.69-1.93 (m, 2H) 2.02 (s, 3H) 2.99 (t, J=6.99 Hz, 2H) 3.75 (s, 3H) 5.13 (s, 2H) 6.29 (d, J=7.35 Hz, 1H) 6.91 (dd, J=8.09, 2.57 Hz, 1H) 6.95-7.05 (m, 2H) 7.13 (d, J=8.82 Hz, 2H) 7.16-7.24 (m, 2H) 7.31 (t, J=8.09 Hz, 1H) 7.38 (d, J=8.46 Hz, 1H) 7.42 (d, J=8.82 Hz, 2H) 7.80 (d, J=8.82 Hz, 1H) 8.35 (d, J=6.99 Hz, 1H) 8.97 (d, J=8.82 Hz, 1H) 9.97 (s, 1H) 11.00 (s, 1H) 14.36 (s, 1H); MS (ESI+) m/z 565 (M+H)+.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:18]>CN(C)C=O>[CH3:17][O:16][C:12]1[CH:13]=[CH:14][C:15]2[N:7]3[C:8]([O:18][CH2:4][CH2:5][CH2:6]3)=[CH:9][C:10]=2[N:11]=1
Reactant: COc1ccc2c(n1)CC(=O)N2CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(cc3n2CCCO3)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under an inert atmosphere, 160 mg (4 mmol) of sodium hydride (60% in oil) are added slowly at 0° C. to a solution of 380 mg (1.34 mmol) of the compound obtained in Step E in 10 ml of N,N-dimethylformamide. The reaction mixture is stirred at 0° C. for 30 minutes before being hydrolysed with ice and then extracted with ethyl acetate. The organic phase is washed several times with water, dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant: ethyl acetate/petroleum ether, 95:5) to yield the title compound in the form of a brown solid.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([CH2:18][N:19]5[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]5)=[CH:16][CH:17]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=S1(=O)CCN(Cc2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(CN5CCS(=O)(=O)CC5)cc4)nn23)c1

Procedure:
N-tert-Butyl-3-{2-[4-(1,1-dioxo-1 $1(6)-thiomorpholin-4-ylmethyl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzenesulfonamide was prepared from (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenyl]-amine and 3-t-Butylsulfamoylphenylboronic acid in an analogous manner to Example 1031b. Product isolated as a yellow foam (90 mg, 71%). LCMS (m/e) 569 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.79 (s, 1H), 8.72 (s, 1H), 8.17 (d, 1H, J=7.9 Hz), 7.87 (d, 1H, J=7.9 Hz), 7.63-7.53 (m, 3H), 7.33 (d, 2H, J=8.3 Hz), 7.13 (s, 1H), 7.03 (d, 1H, J=4.8 Hz), 6.84 (d, 1H, J=4.8 Hz), 4.92 (s, 1H), 3.63 (s, 2H), 3.14-3.04 (m, 4H), 3.04-2.96 (m, 4H), 1.22 (s, 9H).
Reaction SMILES: [CH3:1][S:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13]([OH:15])=O.[CH3:20][CH2:21]OCC.C([Li])C.Cl>C1C=CC=CC=1>[CH3:1][S:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[CH2:20][CH3:21]
Reactant: CCOCC
Reactant: CSC(C)(C)CCCC(C)CC=CC(C)=CC(=O)O
Agent: Cl
Agent: [Li]CC
Solvent: c1ccccc1
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)(C)SC
Reaction time: 3 h

Procedure:
To a stirred solution of 2.5 g. of 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoic acid in 20 ml. of dry ether is added slowly at 0°, 23 ml. of a one molar solution of ethyl lithium in benzene. After about 3 hours at 20°, the mixture is poured into iced 1N hydrochloric acid (100 ml.) with vigorous stirring. The ether layer is separated, combined with ethereal washings of the aqueous phase, washed with water, saturated potassium bicarbonate and then saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to yield 13-methylthio-5,9,13-trimethyltetradeca-4,6-dien-3-one, which can be purified by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-])=[CH:5][CH:4]=1.COS(OC)(=O)=O.[C-:25]#[N:26].[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[N:12]=[C:13]([C:25]#[N:26])[CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(C=Cc2cccc[n+]2[O-])cc1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)O
Product: COc1ccc(C=Cc2cccc(C#N)n2)cc1

Procedure:
Following the general method described in example 2b, 2-[2-(4-methoxy-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a yellow crystalline material. Mp. 121–122° C. (isopropanol), MS: m/e=236 (M+)
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[F:17])=[N+]=[N-].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][C@H:5]1[F:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](F)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](F)C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 79.5 %

Procedure:
To a solution of 0.59 g (2.42 mmol) of trans-4-azido-1-Boc-3-fluoropiperidine 4 in 10 mL of MeOH was added 0.61 g (9.67 mmol) of ammonium formate and 0.25 g (0.24 mmol Pd) of 10% Pd on carbon. The reaction mixture was stirred under N2-atmosphere at 50° C. for 5 h. After cooling, the mixture was filtered over diatomaceous earth and evaporated under reduced pressure. The crude mixture was then subjected to flash silicagel chromatography (5% Et3N in EtOAc, short path column) to give 0.42 g (80%) of trans-4-amino-1-Boc-3-fluoropiperidine 5 as an oil. 1H NMR (CDCl3): δ 1.39 (9H, s); 1.60 (2H, s(br)); 1.76-1.86 (1H, m); 2.65-2.76 (2H, m); 2.78-2.90 (2H, m); 3.89-3.97 (1H, m); 4.01 (1H, dm, J=48.5 Hz); 4.15-4.30 (1H, m). 19F NMR (CDCl3): δ −191.0 to −190.3 (1F, m). 13C NMR (CDCl3): δ 28.4 (3×), 31.8, 41.9 (br), 46.2 (br), 53.5 (d, J=18.5 Hz), 80.3, 93.0 (d, J=177.7 Hz), 154.6. IR (ATR, cm−1): ν=1685, 1415, 1244, 1152, 1028. MS (ES+) m/z (%): 204 (M−CH3+H+), 163 (M−3CH3+2H+, 100).
Reaction SMILES: CC1NC(C)=C([CH:7]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)C)N=1.[As](=O)(O)(O)[OH:21].OCC([CH2:29][OH:30])O>S(=O)(=O)(O)O.O>[CH3:7][C:9]1[C:10]([C:29]([OH:30])=[O:21])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2
Reactant: O=[As](O)(O)O
Reactant: Cc1nc(C(C)c2cccc3cccnc23)c(C)[nH]1
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(=O)O)ccc2cccnc12
Temperature: 160 °C
Yield: 51.9 %

Procedure:
A mixture of 3-amino-2-methylbenzoic acid (18) (6.1 g, 39.7 mmol), arsenic acid (7.4 g, 52.3 mmol), and glycerol (5.8 mL, 79.4 mmol) in sulfuric acid (9 mL) was heated at 160° C. for 5 hours. The reaction mixture was cooled to room temperature and diluted with water. The mixture was filtered through a bed of celite and the filtrate was adjusted with 2 M NaOH to pH˜6. The aqueous layer was extracted numerous times with chloroform/isopropanol. The pooled organic layers were removed under vacuum. The solid residue was triturated with chloroform. The mixture was to filtered, and the solid was washed with hexane and dried under high vacuum to give 8-methylquinoline-7-carboxylic acid (19) 3.86 g (20.6 mmol, 52% yield).
Reaction SMILES: C(C1C=C([N:9]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:10]([NH:12]C2CCNCC2)=[O:11])C=CC=1)#N.C(N(CC)CC)C.C1(CS(Cl)(=O)=O)C=CC=CC=1>O1CCCC1>[CH:19]1([NH:9][C:10]([NH2:12])=[O:11])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: N#Cc1cccc(N(C(=O)NC2CCNCC2)C2CCCCCC2)c1
Agent: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
N-(3-Cyanophenyl)-N'-(piperidin-4-yl)cycloheptylurea (2.07 g, 6.95 mmol) in tetrahydrofuran (100 ml) with triethylamine (7.64 mmol, 0.77 g, 1.1 ml) was cooled to 0° C. and a-toluenesulfonyl chloride (1.46 g, 7.64 mmol) in tetrahydrofuran (60 ml) was added dropwise. The reaction was allowed to cool to ambient temperature and was stirred for 18 h. The solvent was removed in vacuo and the residue patitioned between water and 5:1 ethyl acetate:acetone. The organic layer was washed with 1N HCl and 1N NaOH, then brine. It was dried (Na2SO4) and evaporated to give 2.63 g of crude product. Purification by medium pressure liquid chromatography on a silica gel column (350 g) gave N-(3-cyanophenyl)-N'-(1-((phenyl)methane)sulfonyl)piperidin-4-yl)cycloheptylurea (1.81 g, 4.0 mmol, 58%, mp 203-204° C.); HRMS (M+H)+ calc. 453.196038, found 453.198085.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C1N=CN([C:14](N2C=NC=C2)=[O:15])C=1>CN(C)C=O>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:14]1=[O:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1N
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2[nH]1
Reaction time: 22 h
Yield: 98 %

Procedure:
To a stirred solution of 1,2-phenylenediamine (10.00 g, 0.092 mol) in dimethylformamide (150 cm3) was added 1,1′-carbonyldiimidiazole (CDI, 14.99 g, 0.092 mol). After 22 hours, the reaction mixture was evaporated and then slurried in ethyl acetate. The resulting mixture was filtered, washed with ethyl acetate, and the residue dried in vacuo to give 1,3-dihydrobenzoimidazol-2-one (12.10 g, 98%) as a white solid:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37]1.CCOCC>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:36](=[O:42])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(-c2nn3c(NCCCCNC(=O)CCC(=O)O)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 108.5 %

Procedure:
To a solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (25 mg, 0.05 mmol) in dichloromethane (4 mL) was added succinic anhydride (6 mg, 0.6 mmol). The resultant solution was stirred overnight and then ether was added. The precipitated solids were recovered by filtration to give 4-[(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]-4-oxobutanoic acid (31 mg, 99%) as a white solid. 1H NMR (CDCl3/CD3OD): δ 7.71 (m, 2 H), 7.47 (d, 2 H), 7.32 (m, 1 H), 6.97 (d, 2 H), 6.15 (d, 1 H), 6.04 (d, 1 H), 4.30 (m, 1 H), 3.88 (s, 3 H), 3.38–3.27 (m, 4 H), 2.62 (m, 2 H), 2.45 (m, 2 H), 2.10–2.00 (m, 2 H), 1.84–1.55 (m, 10 H); MS m/z 572 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>C(Cl)Cl.C(OCC)C>[C:23]([O:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:15][CH:14]=1)(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)Cl
Reactant: OCc1ccc(OC2CCCCO2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: C=C(C)C(=O)OCc1ccc(OC2CCCCO2)cc1
Reaction time: 3.5 h
Yield: 8.8 %

Procedure:
To a stirred solution of 62.4 g (0.3 mol) of 4-tetrahydropyranyloxy benzyl alcohol and 58.5 mL of triethylamine in 225 mL of methylene chloride and 225 mL of diethyl ether cooled in an ice bath was added dropwise 31.9 mL (0.33 mol) of methacrylyl chloride at a rate such that the temperature did not exceed 30° C. After 3.5 hr, the mixture was filtered, and the filtrate was evaporated. The residual oil was treated with ether and triethylamine and washed with water. The organic layer was dried (sodium sulfate) and evaporated to a yellow oil, which, on standing, gradually crystallized. The crystals were rinsed with a small amount of methanol to give 7.3 g of colorless crystals, m.p. 36-36.7° C. The product can be recrystallized from hexane at low temperature. 1H NMR (360 MHz, THF-d8): 1.5-1.82 (m's, 6H, CH2), 1.90 (m, 3H, CH3C=), 3.5 (m, 1H, OCH 2), 3.8 (m, 1H, OCH2), 5.07 (s, 2H, ArCH2OOC), 5.40 (t, J=3, 1H, OCHO), 5.52 (m, 1H, =CH), 6.05 (m, 1H, =CH), 7.0 (m, 2H, ArH), 7.27 (m, 2H, ArH).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:21]([O:23][CH2:24][CH2:25]Br)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[ClH:28].[C:29]1([C:35]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:28].[CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:21]([O:23][CH2:24][CH2:25][N:38]2[CH2:39][CH2:40][C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:36][CH2:37]2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCBr)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 41.5 %

Procedure:
2.35 g of 3-methyl 5-(2-bromoethyl) (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate, 1.46 g of 4,4-diphenylpiperidine hydrochloride and 1.55 g of finely powdered potassium carbonate in 15 ml of anhydrous dimethylformamide are stirred for 6 h at 80° C. After the mixture has cooled, 100 ml of water are added and the mixture is then extracted with ether. The ether phase is washed twice with water, dried over sodium sulphate and then evaporated in vacuo. The residue is chromatographed over a silica gel column using a 95:5 chloroform/ethanol as the mobile phase. The chromatographically pure fractions are collected and evaporated. The residue is dissolved in ether and 2 ml of a saturated solution of hydrogen chloride in ether are added to the solution, crystallisation occurring. The product is filtered off under suction, washed with ether and dried. 1.4 g of the title compound of m.p. 155°-158° C. (decomp.) and [α]22D =+68.4° (c=1, methanol) are obtained.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24]>>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([F:16])[CH:3]=2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Product: O=C1NCCn2c1cc1cc(F)cc(-c3ccc(F)c(F)c3)c12

Procedure:
The title compound, light grey solid (72 mg, 91%), MS (ISP) m/z=317.1 [(M+H)+], mp 289.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [N:1]#[C:2][Br:3].[F:4][C:5]([F:12])([F:11])[C@@:6]([CH3:10])([NH2:9])[CH2:7][NH2:8].C(O)C>ClCCl.C(#N)C>[BrH:3].[CH3:10][C@@:6]1([C:5]([F:12])([F:11])[F:4])[CH2:7][NH:8][C:2]([NH2:1])=[N:9]1
Reactant: N#CBr
Reactant: C[C@](N)(CN)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCO
Product: Br
Product: C[C@@]1(C(F)(F)F)CNC(N)=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
11.60 mL (34.90 mmol) of cyanogen bromide dissolved in dichloromethane are added portionwise to a solution, cooled to 4° C., of 4.50 g (31.70 mmol) of (S)-3,3,3-trifluoro-2-methylpropane-1,2-diamine in 20 mL of acetonitrile, while maintaining the temperature between 5 and 10° C. At the end of the addition, the reaction mixture is left at 5° C. for 30 minutes. The mixture obtained is then stirred at room temperature overnight. The resulting mixture is then concentrated under vacuum. The residue obtained is taken up twice with ethanol and then twice with toluene, and evaporated to dryness each time. The solid obtained is triturated with ethyl ether and then filtered off to give 4.50 g of (S)-4-methyl-4-trifluoromethyl-4,5-dihydro-1H-imidazol-2-ylamine hydrobromide in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[O:26][CH3:27]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2[O:26][CH3:27])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: COc1ccc(OC)c(Br)c1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2cc(OC)ccc2OC)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, (Example 1), and 2-bromo-4-methoxyanisole (Aldrich), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,5-dimethoxy-phenyl)-methanone as a white solid. MS (M+H)+, 320.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]2[N:4]([N:5]=[C:6]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[C:7]3[CH:15]=[C:14]4[O:16][CH2:17][O:18][C:13]4=[CH:12][C:8]=3[CH2:9]2)[C:3]1=[O:28].O.NN.C(O)C>CO.[Ni]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:6]2[C:7]3[CH:15]=[C:14]4[O:16][CH2:17][O:18][C:13]4=[CH:12][C:8]=3[CH2:9][CH:10]3[CH2:11][N:2]([CH3:1])[C:3](=[O:28])[N:4]3[N:5]=2)=[CH:24][CH:23]=1
Reactant: CN1CC2Cc3cc4c(cc3C(c3ccc([N+](=O)[O-])cc3)=NN2C1=O)OCO4
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CO
Product: CN1CC2Cc3cc4c(cc3C(c3ccc(N)cc3)=NN2C1=O)OCO4
Yield: 71.4 %

Procedure:
0.38 g (1.0 mmol) of the nitro compound of Example 3 is reduced in 20 ml of methanol with RaNi and hydrazine hydrate analogously to Example 2. After boiling with ethanol, 0.25 g (71%) of the title compound of ethanol with a melting point of 280-289° C. (decomposition) is obtained.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH3:17])[N:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([CH3:35])[C:29]=1[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:23]([NH:25]O)=[NH:24])[CH3:19]>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:10]3[O:12][N:25]=[C:23]([C:22]4[CH:27]=[C:28]([CH3:35])[C:29]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:20]([CH2:18][CH3:19])[CH:21]=4)[N:24]=3)[CH:13]=[C:14]([O:16][CH3:17])[N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)cc(C2CCCCC2)n1
Reactant: CCc1cc(C(=N)NO)cc(C)c1NS(C)(=O)=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCCC4)c3)n2)cc(C)c1NS(C)(=O)=O
Yield: 10.1 %

Procedure:
The title compound (7 mg) is prepared in analogy to Example 11 starting from 2-cyclohexyl-6-methoxy-isonicotinic acid (40 mg, 147 μmol) and 3-ethyl-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine (42 mg, 155 mmol); LC-MS**: tR=0.94 min, [M+H]+=471.02; 1H NMR (CDCl3): δ1.35 (t, J=7.8 Hz, 3H), 1.40-1.70 (m, 5H), 1.77-1.84 (m, 1H), 1.88-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.56 (s, 3H), 2.71-2.81 (m, 1H), 2.93 (q, J=7.0 Hz, 2H), 3.18 (s, 3H), 4.03 (s, 3H), 5.87 (s, 1H), 7.32 (s, 1H), 7.49 (s, 1H), 7.97 (s, 1H), 7.99 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([NH:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18](O)=[O:19])(=O)[CH3:10].P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:10][C:9]1[N:4]([C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[Br:1])[C:18](=[O:19])[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[N:12]=1
Reactant: Nc1ccccc1Br
Reactant: CC(=O)Nc1ccsc1C(=O)O
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: Cc1nc2ccsc2c(=O)n1-c1ccccc1Br
Temperature: 105 °C
Yield: 42.7 %

Procedure:
To a mixture of pyridine (6 mL), 2-bromoaniline (1.03 g, 6 mmol), and 3-acetamidothiophene-2-carboxylic acid (0.555 g, 3 mmol) was added phosphorus trichloride (0.03 mL, 3.45 mmol). The reaction was heated to 105° C. for 4 hours, cooled to ambient temperature and partitioned between chloroform and water (an insoluble precipitate was removed by filtration). Phases were separated and the aqueous layer was extracted with chloroform. The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated to a dull yellow film. This residue was flash chromatographed on silica gel (30×125 mm) eluting with 15-25% ethyl acetate/hexane to afford 0.411 g (47%) of 2-methyl-3-(2-bromophenyl)-3H-thieno[3,2-d]pyrimidin-4-one as a yellow foam,