Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[C:10]2[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]([CH3:22])=[CH:21][C:9]1=2.[H-].[K+].Br[CH2:45][C:46]([OH:48])=[O:47].Cl>O1CCCC1.O.C(OCC)(=O)C>[F:37][C:36]([F:39])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:40])([F:1])[F:41])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][CH2:45][C:46]([OH:48])=[O:47])[C:10]2[CH:18]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:20]([CH3:22])=[CH:21][C:9]1=2
Reactant: O=C(O)CBr
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CCO)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2c(cc1C(F)(F)F)N(CCOCC(=O)O)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-ethanol (0.17 mmol) in tetrahydrofuran (5 mL), add potassium hydride (0.67 mmol) at room temperature. After stirring for 30 minutes add bromoacetic acid (0.25 mmol) as a solution in tetrahydrofuran (1 mL). After stirring an additional 0.5 h, quench the reaction with wet tetrahydrofuran (2 mL), dilute with water (1 mL), and ethyl acetate (5 mL). Neutralize the reaction with 5M HCl, separate the organic phase, and wash the aqueous with ethyl acetate (2×5 mL). Dry the combined organic phases over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with methanol/dichloromethane (0.5-4%) to afford the title compound as a colorless foam. MS (ES+): 655 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1(O)[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2.[C:28]1([CH2:34][O:35][NH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:8][C:9]1([NH:36][O:35][CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: NOCc1ccccc1
Reactant: CC1(O)CCCc2nc(OCc3ccccc3)ccc21
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(NOCc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
Trifluoroacetic acid (17.4 g) was added in one portion to a solution of 5,6,7,8-tetrahydro-5-methyl-2-(phenylmethoxy)-quinolin-5-ol (41 g), phenylmethoxyamine (47 g), and toluene (770 ml) at room temperature. The solution was stirred at room temperature for 24 hrs, and then quenched with concentrated ammonium hydroxide solution. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over potassium carbonate, filtered, and the filtrate was concentrated. Purification by high performance liquid chromatography (silica gel, elution with ethyl acetate-hexanes) gave 44.2 g (77%) of 5,6,7,8-tetrahydro-5-methyl-N,2-bis(phenylmethoxy)-5-quinolinamine.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH3:24][C:25]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:27][C:26]4[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:25]=4[CH3:24])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1ccc(N)c(C)c1
Product: Cc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)c(C)c1

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2,4-dimethylaniline (42.3 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2,4-dimethylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (22.4 mg).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)C(=O)[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][C:32]([F:35])([F:34])[F:33].O.[NH2:38][NH2:39].[C:40](=[O:43])([O-])O.[Na+]>CN(C=O)C>[F:33][C:32]([F:34])([F:35])[O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:23]1[C:3]2[C:40](=[O:43])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:39][N:38]=1
Reactant: O=C([O-])O
Reactant: NN
Reactant: O=C(Cc1ccccc1OC(F)(F)F)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3OC(F)(F)F)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a suspension of 4-hydroxy-3-(2-trifluoromethoxyphenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (1.01 g, 2.0 mmol) produced in Synthesis Example 17 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 388 μL), and the mixture was stirred at 100 to 110° C. for 1 hour. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(2-trifluoromethoxybenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (516 mg, yield 51%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C@H:13]([NH:18]C(=O)OC(C)(C)C)[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][C:10]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C@H:13]([NH2:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][C:10]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](N)c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1

Procedure:
(R)-tert-Butyl 1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylcarbamate (3.25 g, 7.13 mmol) was treated with TFA (10 mL) in CH2Cl2 (30 ml). Once the reaction was complete, the reaction was concentrated in vacuo and then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organics were separated, then washed with H2O, brine, then dried over Na2SO4, filtered, and evaporated under reduced pressure to give (R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropan-1-amine which was directly used for the next step without further purification (2.32 g, 91%). LC/MS (uplc): MH+ 357.1, 0.82 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]([NH2:18])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].CO[CH:21](OC)[CH2:22]Br>COCCOCCOC>[CH2:14]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([C:16]2[O:17][CH:21]=[CH:22][N:18]=2)=[CH:10]1)[CH3:15]
Reactant: CCn1cc(C(N)=O)c2ccc(C(=O)OC)cc21
Reactant: COC(CBr)OC
Solvent: COCCOCCOC
Product: CCn1cc(-c2ncco2)c2ccc(C(=O)OC)cc21
Temperature: 125 °C
Yield: 45.5 %

Procedure:
A mixture of 150 mg (0.61 mmol) of 6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide in diglyme (3.6 mL), and bromoacetaldehyde dimethyl acetal (430 μL, 3.7 mmol) is heated at 125° C. for 2 h. The reaction mixture is cooled and partitioned in H2O and EtOAc. The organic phase is dried and concentrated and the product is purified by silica gel chromatography (EtOAc/CH2Cl2 5-10%). The product containing fractions are combined and concentrated and the solid is triturated with hexanes to yield methyl 1-ethyl-3-oxazol-2-yl-1H-indole-6-carboxylate (75 mg, 46%) as a yellow solid.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@H:8]([O:12][C:13]1[CH:36]=[CH:35][C:16]2[C:17]3[N:21]([CH2:22][CH2:23][O:24][C:15]=2[CH:14]=1)[CH:20]=[C:19]([C:25]1[N:26]([CH2:30][C:31]([F:34])([F:33])[F:32])[N:27]=[CH:28][N:29]=1)[N:18]=3)[C:9]([NH2:11])=[O:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C.O>[OH:6][CH2:7][C@H:8]([O:12][C:13]1[CH:36]=[CH:35][C:16]2[C:17]3[N:21]([CH:20]=[C:19]([C:25]4[N:26]([CH2:30][C:31]([F:32])([F:33])[F:34])[N:27]=[CH:28][N:29]=4)[N:18]=3)[CH2:22][CH2:23][O:24][C:15]=2[CH:14]=1)[C:9]([NH2:11])=[O:10]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)[C@H](CO)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of (S)-3-(tert-butyl-dimethyl-silanyloxy)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionamide (101 mg, 0.18 mmol) in THF (5 mL) was added TBAF (0.22 mL, 1M solution in THF, 0.22 mmol) and the reaction mixture was stirred at RT for 2 hr. The reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL) added. A white precipitate formed which was collected by filtration and dried in vacuo to yield 513 as a white solid (45 mg, 56%). LCMS: RT=2.98 min, [M+H]+=439; 1H NMR (400 MHz, d6-DMSO) 8.23 (1H, d, J=8.7 Hz), 8.03 (1H, s), 7.96 (1H, s), 7.50 (1H, br s), 7.30 (1H, br s), 6.77 (1H, dd, J=8.9, 2.7 Hz), 6.54 (1H, d, J=2.6 Hz), 5.86 (2H, q, J=8.9 Hz), 5.09 (1H, t, J=5.8 Hz), 4.54 (1H, t, J=4.9 Hz), 4.50-4.41 (4H, m), 3.74-3.67 (2H, m)
Reaction SMILES: S1[C:5]2=CC=[CH:8][CH:9]=[N:10][C:4]2=[CH:3]C1.CN(C)C=O.[C:16](#N)[CH3:17].[C:19](=O)([O-])[O-].[K+].[K+]>CS(C)=O.CC(C)=O>[CH:16]([N:10]([CH:4]([CH3:3])[CH3:5])[CH2:9][CH3:8])([CH3:17])[CH3:19]
Reactant: C1=CC=C2SCC=C2N=C1
Reactant: O=C([O-])[O-]
Reactant: CC#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCN(C(C)C)C(C)C

Procedure:
Bromo-pyrazines II-4 react with tetrahydro-benzo or thieno-azepine compounds III or their hydrochlorides in solvents like N,N-dimethylformamide, acetonitrile, acetone or dimethylsulfoxide in the presence of a base like potassium carbonate or a tertiary amine like diisopropyl-ethylamine at temperatures between room temperature and 80° C. to form the desired 3-(tetrahydro-benzo- or thieno-azepine-3-yl)-pyrazine-2-carbonitriles I-6. 3-(Tetrahydro-benzo- or thieno-azepine-3-yl)-pyrazine-2-carbonitriles of formula I-7 can be prepared according to scheme 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1Cl.[I-:13].[Na+]>CC(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1[I:13]
Reactant: Nc1nc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(I)c(Cl)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 5,6-dichloro-3-nitropyridin-2-amine (15 g, 72.1 mmol) in AcOH (70 mL) was added sodium iodide (43.2 g 149.9 mmol). The mixture was stirred at 90° C. for 2 h, cooled to rt, diluted with water (70 mL) and filtered. The solid residue was washed with water, and then dried under vacuum to afford the desired product as a pale yellow solid, which was used in the next step without further purification. LC-MS: calculated for C5H3ClIN3O2 299.45, observed m/e: 299.94 (M+H)+ (Rt 2.18/5 min).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:32]1([CH2:38]/[CH:39]=[CH:40]/[CH2:41]I)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[Cl-].[Na+]>CCCCCC.O1CCCC1>[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:31])[C@H:27]([CH:28]([CH3:29])[CH3:30])[CH2:41]/[CH:40]=[CH:39]/[CH2:38][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: IC/C=C/CC1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[C@H](C/C=C/CC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
The chloride (B) (38.6 g) was added to a solution of sodium iodide (55.7 g) in acetone (1 litre) and the solution was allowed to stand overnight. Hexane (500 ml) was added and the precipitated solid was removed by filtration. The filtrate was concentrated and the residue partitioned between water (500 ml) and hexane (500 ml). The organic phase was separated, washed with saturated sodium thiosulphate solution (500 ml) and saturated sodium chloride solution (2×500 ml), and dried (MgSO4). The solvent was removed by evaporation and the residual liquid distilled under vacuum to give (2E)-4-cyclohexyl-1-iodobut-2-ene (C) as a dark liquid (44.9 g), b.p. 80°-85° C. at 0.15 mm Hg; NMR: 0.8-1.8(complex m, 11H), 1.9(t, 2H), 3.9(m, 2H), 5.7(m, 2H). (iii) A 1.6M solution of butyllithium in hexane (93.9 ml) was added dropwise over 30 minutes to a stirred solution of diisopropylamine (21.9 ml) in dry tetrahydrofuran (THF) (200 ml) at 0° C. under an atmosphere of argon. The temperature was maintained at 0° C. for 30 minutes and then the solution was cooled to -40° C. A solution of (4S)-4-benzyl-3-(3-methylbutyryl)oxazolidin-2-one (31.3 g) (obtained as described in Tetrahedron. 1987, 44, 5525) in dry THF (70 ml) was added dropwise over 30 minutes. The solution was kept at -40° C. for 30 minutes and then the temperature was allowed to rise to 0° C. A solution of iodide (C) (39.0 g) in dry THF (75 ml) was added dropwise over 30 minutes, and then the solution was stirred at 0° C. for 1 hour. Saturated sodium chloride solution (250 ml) was added and the mixture was extracted with ether (3×250 ml). The extracts were washed with saturated sodium chloride solution (2×250 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (8:92 v/v), to give (4s)-4-benzyl-3-[(2S,4E)-6-cyclohexyl-2-isopropylhex-4-enoyl]oxazolidin-2-one (A) (34.5 g) as a clear oil; NMR: 0.8 -1.2(complex m, 12H), 1.6(m, 6H), 1.85(t, 1H), 2.0(m, 2H), 2.35(m, 2H), 2.6(m, 1H), 3.3(dt, 1H), 3.8(m, 1H), 4.1(d, 1H), 4.7(m, 1H), 5.4(m, 2H), 7.3(m, 5H); mass spectrum (+ve FAB), 398 (M+H+); 22 [α]436 +45.8 (c, 1.04, CHCl3). ##STR1##
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].Br[C:23]1[CH:24]=[CH:25][C:26]([CH:29]=[O:30])=[N:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH:29]([C:26]1[N:27]=[CH:28][C:23]([C:16]2[CH:17]=[CH:18][C:12]3[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:14][C:13]=3[CH:15]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: O=Cc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C=O)nc3)cc2C1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
A mixture of (4-{[(1,1-dimethylethyl)oxycarbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (500 mg, 1.7 mmol), 5-bromopicolinaldehyde (380 mg, 2.0 mmol), cesium carbonate (1.66 g, 5.0 mmol), and dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (125 mg, 0.17 mmol) in dioxane (5.0 mL) and water (1.0 mL) was degassed with nitrogen, and then stirred at 90° C. with microwave irradiation for 30 min. The reaction mixture was cooled to room temperature, and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×), the combined organic layers were washed with brine (1×), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (hexanes/ethyl acetate 4:1) provided 1,1-dimethylethyl 7-(6-formylpyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxylate (580 mg, 96% yield) as a colorless solid. MS (EI) for C20H22N2O4: 355 (MH+).
Reaction SMILES: C(C1C=CC(C=O)=CC=1)CCCCCC.C(O)(=O)CC(O)=O.[CH2:23]([C:30]1[CH:40]=[CH:39][C:33]([CH:34]=[CH:35][C:36](O)=[O:37])=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].S(Cl)([Cl:43])=O>N1CCCCC1.CCOCC.N1C=CC=CC=1>[CH2:23]([C:30]1[CH:40]=[CH:39][C:33]([CH:34]=[CH:35][C:36]([Cl:43])=[O:37])=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCc1ccc(C=CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: CCCCCCCc1ccc(C=O)cc1
Agent: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CCCCCCCc1ccc(C=CC(=O)Cl)cc1

Procedure:
8.8 G. of p-n-heptylbenzaldehyde and 8.74 g. of malonic acid are dissolved in 7 ml. of absolute pyridine, treated with 8 drops of piperidine and heated at 90°-100° C. for 68 hours. The mixture is then taken up in ether and washed with dilute hydrochloric acid. After recrystallization from ether/hexane, there are obtained 7.5 g. of p-n-heptylcinnamic acid having a melting point of 121°-122° C. and a clearing point of 150°-153° C. 8.2 G. of this acid are boiled at reflux in 120 ml. of thionyl chloride for 30 minutes. The excess thionyl chloride is removed by distillation, the residue taken up three times in absolute toluene, concentrated and dried. The p-n-heptylcinnamic acid chloride obtained can be used in the process directly.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[C:6]([CH3:15])([CH3:14])[C:5]1=[O:16])(=O)C.Cl>C(O)(C)C.O>[F:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][C:5](=[O:16])[C:6]2([CH3:15])[CH3:14]
Reactant: CC(=O)N1C(=O)C(C)(C)c2cc(F)ccc21
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC1(C)C(=O)Nc2ccc(F)cc21

Procedure:
2.10 g (9.49 mmol) 1-acetyl-5-fluoro-3,3-dimethyl-1,3-dihydro-indol-2-one in 20 mL isopropanol were refluxed with 50 mL of an aqueous 6N hydrochloric acid solution for 1 h. After cooling the isopropanol was eliminated i. vac. The residue was diluted with 100 mL water and cooled with ice. The precipitated substance was suction filtered and washed with 30 mL water. The solid was dried in the CAD.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[CH:33][C:7]=2[N+:6]=1[O-])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>[Ni].C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([S:34]([N:37]([CH3:39])[CH3:38])(=[O:35])=[O:36])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(S(=O)(=O)N(C)C)cc2[n+]1[O-]
Agent: [Ni]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(S(=O)(=O)N(C)C)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-dimethylaminosulphonyl-3-N-oxido-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate by catalytic hydrogenation in the presence of Raney nickel and subsequent reaction with trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:33][CH2:34][CH3:35])=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:36]1([C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:50])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[C:24]([O:33][CH2:34][CH3:35])=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1nc(C(F)(F)F)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(F)(F)F)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 5) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C33H35N7O4F3Cl2 [(M+H)+] 720.2074, observed 720.2075.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:17][C:18]1[C:27]2[CH:26]=[N:25][C:24](S(C)=O)=[N:23][C:22]=2[N:21]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=2)[C:20](=[O:42])[CH:19]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:24]1[N:25]=[CH:26][C:27]2[C:18]([CH3:17])=[CH:19][C:20](=[O:42])[N:21]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[C:22]=2[N:23]=1
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C)CC5)cc4OC)nc32)c1
Temperature: 100 °C
Yield: 31 %

Procedure:
To a suspension of 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (Green Chempharm; 3.45 g, 15.57 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b) (4.59 g, 12.46 mmol) in anhydrous tert-butanol (40 mL) and dioxane (5 mL) at RT was added DIEA (4.33 mL, 24.92 mmol). The mixture was heated at 100° C. for 40 h. The reaction mixture was concentrated under reduced pressure (rotary evaporator) to remove the volatiles and the resulting crude residue was suspended in Et2O and filtered. The greenish-brown amorphous solid was washed with Et2O (3×50 mL) and this removed most of the remaining aniline starting material. The crude material was dry-packed on silica gel and purified on a silica gel column (1-20% MeOH in DCM) affording N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5) (2.03 g, 3.86 mmol, 31% yield) as a yellow amorphous solid. m/z (ESI, +ve ion) 526.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (1H, s), 8.80 (1H, s), 8.09 (1H, s), 7.88 (1H, d, J=8.2 Hz), 7.56 (1H, J=1.9 Hz), 7.50 (1H, t, 1=8.1 Hz), 7.27 (1H, d, J=8.8 Hz), 6.97 (1H, dt, J=6.9, 1.0 Hz), 6.52 (1H, d, J=2.5 Hz), 6.37-6.48 (1H, m), 6.29-6.35 (1H, m), 6.19-6.29 (1H, m), 6.01 (1H, br. s.), 5.71-5.80 (1H, m), 3.78 (3H, s), 3.02 (4H, br. s.), 2.46 (3H, s), 2.43 (4H, t, J=4.9 Hz), 2.22 (3H, s).