Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]=2[N:14]=[CH:13][C:12]2=[CH:21][CH:22]=[CH:23][N:11]12>CCOCC.O1CCCC1>[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]=2[NH:14][CH:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]2=[CH:21][CH:22]=[CH:23][N:11]12
Reactant: Br[Mg]c1ccccc1
Reactant: CN1c2ccncc2N=Cc2cccn21
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1c2ccncc2NC(c2ccccc2)c2cccn21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64 %

Procedure:
To 15 ml of a 3M solution of phenyl magnesium bromide in ether diluted with 15 ml of tetrahydrofuran was added a solution of 4.45 g of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 75 ml of tetrahydrofuran. After stirring at ambient temperature for 45 minutes, the reaction mixture was quenched into an iced ammonium chloride solution. The aqueous layer was extracted with ethyl acetate (2×), and the combined organics were washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The resultant solid was purified via flash chromatography (compound preadsorbed on silica; elution with diethyl ether) and recrystallized from toluene to yield 4.0 g (64%) of 10,11-dihydro-5-methyl-10-phenyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, mp 200°-203° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O.[OH-].[Na+]>C(O)(=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]([Br:15])=[CH:13][N:14]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N1CCN(c2nccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ncc(Br)s2)CC1
Yield: 68.1 %

Procedure:
A solution of 4-acetyl-1-(thiazol-2-yl)piperazine (3.1 g) and N-bromosuccinimide (2.9 g) in acetic acid (14 ml) was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown solid (2.9 g). The obtained pale-brown solid was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give the title compound (2.1 g) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][NH:23][C:24](=[O:27])[CH2:25]Cl.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][NH:23][C:24](=[O:27])[CH2:25][N:29]=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nnc(CNC(=O)CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)CN=[N+]=[N-])n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 2',5-dichloro-2-[3-(2-chloroacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (1.533 g) in dimethylformamide (15 ml), sodium azide (0.228 g) is added portionwise, and the resultant mixture is stirred at room temperature for 2.25 hours and allowed to stand overnight. The reaction mixture is evaporated under reduced pressure to remove the solvent, and the residue is shaken with chloroform. The organic layer is washed with water, dried and evaporated to remove the chloroform. The residue is washed with ether to give 2',5-dichloro-2-[3-(2-azidoacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (1.45 g). The yield is 93.2%.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[C:8]3[CH2:31][S:30][CH2:29][CH2:28][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:16]([O:26][CH3:27])[CH:15]=3)[N:12]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.C([O-])(O)=O.[Na+].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8]3[CH2:31][S:30](=[O:42])[CH2:29][CH2:28][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:16]([O:26][CH3:27])[CH:15]=3)[N:12]=2)=[CH:32][CH:33]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CSCC3)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CS(=O)CC3)ccc1-n1cnc(C)c1
Yield: 18.7 %

Procedure:
4-(4-Fluorobenzyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (254 mg, 0.55 mmol) and meta-chloroperbenzoic acid (95 mg, 0.55 mmol) was slurrified in DCM (4 mL). Saturated NaHCO3 and water were added to the reaction mixture, the organic phase was separated and the solvent was evaporated. The crude product was purified on preparative HPLC yielding 4-(4-fluorobenzyl)-N-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine 6-oxide (49.0 mg, 18%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:14]([CH3:15])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
4-Aminobiphenyl (15 g, 88.76 mmol)in toluene (250 ml) was added acetic anhydride (8.5 ml, 90 mmol). The mixture was stirred at ambient temperature for 1 hour. Following the reaction the mixture was poured into petroleum ether (500 ml), the product was filtered off, washed with petroleum ether and dried to yield 4-acetaminobiphenyl (18.7 g).
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=2)[CH:15]=1)=[O:13].[C:25]([O:29][C:30]([N:32]1[C@@H:36]([CH3:37])[CH2:35][CH2:34][C@H:33]1[C:38]([OH:40])=[O:39])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[CH3:37][C@@H:36]1[N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])[C@H:33]([C:38]([O:40][CH2:11][C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[CH:15]=2)=[O:13])=[O:39])[CH2:34][CH2:35]1
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3cc(Br)ccc3c2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
DIPEA (0.823 mL, 4.71 mmol) was added to a stirred slurry of 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (Intermediate 118) (1.03 g, 3.14 mmol) and (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (0.720 g, 3.14 mmol) in acetonitrile (50 mL) and the reaction was stirred at rt overnight. The reaction was concentrated to dryness and purified by BIOTAGE® Horizon (40 g SiO2, 10-20% EtOAc/hexanes) to yield (2S,5S)-2-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (1.09 g) as a yellow solidified foam. LC-MS retention time 4.413 min; m/z 476, 478.20 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 8.57 (br. s., 1 H), 8.14 (d, J=1.5 Hz, 1 H), 8.01 (d, J=8.5 Hz, 1 H), 7.96 (d, J=8.8 Hz, 1 H), 7.91 (d, J=8.8 Hz, 1 H), 7.68 (dd, J=8.8, 1.8 Hz, 1 H), 5.62-5.70 (m, 1 H), 5.47-5.60 (m, 1 H), 4.46 (t, J=7.3 Hz, 1 H), 3.92-4.06 (m, 1 H), 2.26-2.37 (m, 2 H), 2.05-2.19 (m, 1 H), 1.67-1.82 (m, 1 H), 1.46 (d, J=6.8 Hz, 9 H), 1.30 (d, J=6.5 Hz, 3 H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][CH:21]([F:30])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:30][CH:21]([F:20])[C:22]1[CH:23]=[C:24]([NH:25][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1ccc(F)c(C(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2ccc(F)c(C(F)F)c2)nc(N2CCOCC2)cc1=O
Yield: 24.7 %

Procedure:
The product is prepared according to the procedure described in example 5, but using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 322 mg of 3-(difluoromethyl)-4-fluoroaniline (example 76, stage 2), and 250 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 98 mg of N-[3-(difluoromethyl)-4-fluorophenyl]-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:26]([OH:27])=[CH:25][C:20]4[N:21]=[C:22]([CH3:24])[O:23][C:19]=4[CH:18]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4=[CH:18][C:19]5[O:23][C:22]([CH3:24])=[N:21][C:20]=5[CH:25]=[C:26]4[O:27][CH2:35]3)[C:9]2=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1nc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc2o1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: Cc1nc2cc3c(cc2o1)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one was obtained (68%) as a colorless solid: mp 240-242° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ7.66 (d, J=7.2 Hz, 2H), 7.45-7.29 (m, 9H), 7.11-6.97 (m, 4H), 6.89 (t, J=7.2 Hz, 1H), 6.46 (d, J=7.8 Hz, 1H), 6.01 (d, J=5.7 Hz, 1H), 5.41 (d, J=5.7 Hz, 1H), 2.47 (s, 3H); 13C NMR (75 MHz, CDCl3) δ175.1, 164.5, 151.3, 146.2, 143.7, 138.6, 138.0, 137.3, 129.9, 129.8, 129.0, 128.9, 128.8, 128.3, 128.0, 127.7, 124.6, 122.8, 114.0, 112.7, 111.8, 110.7, 88.7, 75.8, 58.6, 14.8; MS (ES+) m/z 497.1 (M+39).
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].[C:52]([O:56][C:57]([N:59]1[CH2:63][CH2:62][C@H:61]([O:64][C:65]2[C:66]3[CH2:74][NH:73][CH2:72][CH2:71][C:67]=3[N:68]=[CH:69][N:70]=2)[CH2:60]1)=[O:58])([CH3:55])([CH3:54])[CH3:53]>O1CCOCC1>[C:52]([O:56][C:57]([N:59]1[CH2:63][CH2:62][C@H:61]([O:64][C:65]2[C:66]3[CH2:74][N:73]([C:2]4[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=4)[CH2:72][CH2:71][C:67]=3[N:68]=[CH:69][N:70]=2)[CH2:60]1)=[O:58])([CH3:55])([CH3:53])[CH3:54]
Reactant: COc1ncc(Br)c(OC)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)c(OC)n1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
5-Bromo-2,4-dimethoxy-pyrimidine (89 mg, 0.41 mmol), X-Phos (46 mg, 0.09 mmol) bis(dibenzylideneacetone)palladium(0) (29 mg, 0.03 mmol), cesium carbonate (203 mg, 0.62 mmol) were combined and flushed 10 min with Argon. To this mixture was added (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 7) (100 mg, 0.31 mmol) in dioxane (4 mL), the vial was capped and the reaction mixture was stirred at 120° C. for 4.5 h. The mixture was allowed to cool to rt and filtered through a celite pad. The filtrate was diluted with EtOAc (20 mL) and washed with sat. NaHCO3(aq) (10 mL), brine (10 mL), dried (Na2SO4) and concentrated in vacuo. Dissolved in dioxane (4 mL) and added to a glass vial containing 5-bromo-2,4-dimethoxy-pyrimidine (89 mg, 0.41 mmol), X-Phos (46 mg, 0.09 mmol) tris(dibenzylideneacetone)dipalladium(0) (29 mg, 0.03 mmol), cesium carbonate (203 mg, 0.62 mmol). The vial was capped and the reaction mixture was stirred at 120° C. for 4.5 h. The mixture was allowed to cool to rt and filtered through a celite pad. The filtrate was diluted with EtOAc (20 mL) and washed with sat. NaHCO3(aq) (10 mL) then brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give (S)-3-(6-(2,4-dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester which was used without further purification. (S)-3-(6-(2,4-dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in CH2Cl2 (2.0 mL) and TFA added (1 mL). The resulting mixture was stirred for 30 min. at room temperature. The reaction mixture was concentrated in vacuo. Purification by preparative reverse phase Gilson HPLC and subsequent neutralization of the combined fractions by PL-HCO3 cartridge & lyophilisation gave 6-(2,4-dimethoxy-pyrimidin-5-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a yellow powder (11 mg, 10% yield over 2 steps). LCMS: [M+H]+=359.1, Rt(2)=0.79 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[CH3:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21]>>[OH:21][C:14]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([CH3:10])[CH:12]=2)[NH:16][C:15]1=[O:20]
Reactant: COc1cccc(Br)c1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Product: COc1cccc(C2(O)C(=O)Nc3ccc(C)cc32)c1
Yield: 94.3 %

Procedure:
With 5.61 g of 3-methoxy bromobenzene and 3.23 g of 5-methyl isatin as starting materials, 5.09 g of the title compound was obtained by a similar method to Step 21-1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[N:44]([CH:47]1[CH2:51][CH2:50][S:49](=[O:53])(=[O:52])[CH2:48]1)=[C:45]=[O:46]>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:45]([NH:44][CH:47]4[CH2:51][CH2:50][S:49](=[O:53])(=[O:52])[CH2:48]4)=[O:46])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reactant: O=C=NC1CCS(=O)(=O)C1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)NC2CCS(=O)(=O)C2)CC1

Procedure:
In a manner similar to the method described in example 160, (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with 3-isocyanato-tetrahydro-thiophene 1,1-dioxide (Chembridge) to give a mixture of diasteremers. The diastereomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Whelk-O column, eluting with 40% isopropanol in carbon dioxide) to give the title compound as pre-peak. HR-MS (ES, m/z) calculated for C39H49Cl2N6O5 [(M+H)+] 783.2857, observed 783.2852.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:21]=[O:22])C>CCOCC>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH:21]=[O:22])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a 150 ml flask was added 1,4-dibromonaphthalene (2.0 g, 7.0 mmol) and anhydrous ether (50 ml). After cooling to 0° C. n-BuLi (3.1 ml of 2.5 M in hexanes, 7.7 mmol) was added dropwise and stirred for 20 minutes after which anhydrous DMF (1.62 ml, 21 mmol) was added. The reaction was then warmed to ambient temperature and after 1 h the reaction was quenched with water (10 ml), stirred for 10 minutes, and extracted with ether (3×). The ether layer was dried over anhydrous Na2SO4, passed through a silica plug, and concentrated to afford 1.02 g (62%) of product as a pure off-white solid: 1H NMR (300 MHz, DMSO-d6): δ 7.80–7.85 (2H, m), 8.10 (1H, d, J=7.7 Hz), 8.20 (1H, d, J=7.7 Hz), 8.32 (1H, m). 9.24 (1H, m), 10.42 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH3:39]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:38]([CH2:37][CH2:36][O:35][CH3:34])[CH3:39])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CNCCOC
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COCCN(C)CCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3c(OC)ccc(F)c3F)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and N-(2-methoxyethyl)methylamine (TCI America) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H35N6O5SF2[(M+H)+] 557.2352, observed 557.2357.
Reaction SMILES: O.[O:2]=[C:3]1[N:8]([Na])[C:7](=[O:10])[CH:6]=[N:5][NH:4]1.[CH2:11](Br)[CH:12]=[CH2:13]>C(O)CO>[O:2]=[C:3]1[N:8]([CH2:13][CH:12]=[CH2:11])[C:7](=[O:10])[CH:6]=[N:5][NH:4]1
Reactant: O=c1cn[nH]c(=O)n1[Na]
Reactant: C=CCBr
Solvent: OCCO
Solvent: O
Product: C=CCn1c(=O)cn[nH]c1=O
Temperature: 80 °C

Procedure:
A mixture of 6.12 g 3,5-dioxo-4-sodio-2,3,4,5-tetrahydro-1,2,4-triazine monohydrate, 5.81 g allyl bromide and 50 ml ethylene glycol was heated to 80° C. for 4 hours.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH:6]=1.[CH2:14]([O:16][CH:17]=[CH:18][C:19](Cl)=[O:20])[CH3:15]>N1C=CC=CC=1>[CH2:14]([O:16][CH:17]=[CH:18][C:19]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)=[CH:8][CH:9]=1)=[O:20])[CH3:15]
Reactant: CCOC=CC(=O)Cl
Reactant: Cc1cn(-c2ccc(N)cc2)cn1
Solvent: c1ccncc1
Product: CCOC=CC(=O)Nc1ccc(-n2cnc(C)c2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
4-(4-methyl-1H-imidazol-1-yl)aniline (15 g, 138 mmol) was dissolved in dry pyridine (80 mL), freshly distilled 3-ethoxyacryloyl chloride (19 g, 140 mmol) was then added drop-wise at 5°/0° C. The resulting mixture was stirred at 0° C. for 1 hours and at r.t. overnight. The reaction mixture was quenched with water (500 mL), the pH was adjusted to pH=10, by adding K2CO3 and the resulting solid was filtered, washed with water and dried, to provide the title product as slight orange powder (18.6 g; 75%), m.p.: 214-216° C. C15H17N3O2, MW: 271.32.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[C:29]2[C:25]([C:26](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]cc(CCC(=O)O)c1C
Yield: 86.6 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (217 mg), 239 mg 6-(2-methoxyphenyl)-2-oxindole and 3 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 348 mg (86%) of the title compound as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([OH:11])[CH:5]=1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([N+]([O-])=O)[CH:19]=[CH:18][N:17]=1.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:20]2[CH:19]=[CH:18][N:17]=[C:16]([Cl:15])[CH:21]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(O)c1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(Oc2ccnc(Cl)c2)c1
Reaction time: 1.5 h

Procedure:
4-Fluoro-3-hydroxybenzoic acid methyl ester (1.70 g, 10.0 mmol) was dissolved in dimethylformamide (9 mL) under nitrogen at room temperature. Sodium hydride (60% oil dispersion, 0.48 g, 12 mmol) was added in portions over 30 min. The reaction was stirred for 90 minutes and then cooled in an ice bath. 2-Chloro-4-nitropyridine (1.58 g, 10.0 mmol) was added in small portions over 50 min. The reaction was stirred at room temperature for 17.5 h. Water (200 ml) was added and the mixture stirred until a brown lump formed. The water was decanted and the residue dissolved in EtOAc (150 mL). The solution was washed with brine, dried (MgSO4), filtered and evaporated to give 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester. Yield: 3.10 g.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+].[CH2:38]([O:40][CH2:41][CH2:42]O)[CH3:39]>>[CH2:38]([O:40][CH2:41][CH2:42][O:8][C:6]1[CH2:5][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2](=[O:1])[CH:7]=1)[CH3:39]
Reactant: CCOC(=O)C1C(=O)CC(=O)CC1c1ccc(C)cc1
Reactant: CCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOCCOC1=CC(=O)C(C(=O)OCC)C(c2ccc(C)cc2)C1
Reaction time: 16 h

Procedure:
A mixture of ethyl 2,4-dioxo-6-p-tolylcyclohexanecarboxylate (5 g.) prepared as in Example 1, and p-toluenesulphonic acid (0.5 g.) dissolved in 2-ethoxyethanol (50 ml.) was allowed to stand at 25° C for 16 hrs. Pouring the mixture into excess aqueous Na2CO3 solution followed by ether extraction afforded a mauve coloured solution containing the product. After decolourisation of the solution with activated charcoal, evaporation of solvents and crystallisation of the residue from ether/cyclohexane afforded ethyl 4-ethoxyethoxy-2-oxo-6-p-tolyl-3cyclohexenecarboxylate m.p. 59°-60° C.