Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:21]=[CH:20][N:19]=[CH:18]1>>[N:17]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:11]3[C:10]4[C:14](=[CH:15][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)[NH:13][C:12]3=[O:16])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCn1ccnc1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c(C)c1C(=O)NCCCn1ccnc1
Yield: 43 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (8 mg, 0.04 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-imidazol-1-ylpropyl)amide (10 mg) to give 7.3 mg (43%) of the title compound as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OCCCO2)=[C:17]([F:27])[C:16]=1[O:28][CH3:29].[F-].[Cs+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([O:28][CH3:29])[C:17]=2[F:27])[N:6]=1)=[O:4]
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: COC(=O)c1nc(Cl)nc(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Cl
Temperature: 80 °C
Yield: 53.3 %

Procedure:
6-Amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester (888 mg, 4 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane (1.47 g, 6 mmol), bis(triphenylphosphine)palladium(II) dichloride (280 mg, 0.4 mmol), and cesium fluoride (1.21 g, 8 mmol) were combined in 8 mL of 1,2-dimethoxyethane and 8 mL of water. The reaction mixture was heated at 80° C. for 3 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated. The product was purified by column chromatography (ethyl acetate/hexane gradient) then purified again by column chromatography (methylene chloride/ethyl acetate gradient) to yield 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester (738 mg, 53.5% yield): 1H NMR (CDCl3): δ 7.64 (dd, 1H), 7.22 (dd, 1H), 5.64 (br s, 2H), 4.01 (s, 3H), 3.99 (d, 3H).
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[CH:27]([O:30][C:31]1[CH:32]=[CH:33]C(C#N)=[N:35][CH:36]=1)([CH3:29])[CH3:28]>C1COCC1>[CH:27]([O:30][C:31]1[CH:32]=[CH:33][C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)=[N:35][CH:36]=1)([CH3:29])[CH3:28]
Reactant: CC(C)Oc1ccc(C#N)nc1
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2c(O)nc(-c3ccc(OC(C)C)cn3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (4.43 g, 20 mmol) in THF (100 ml) at −78° C., tert-butyllithium 1.7 M in pentane (17.65 ml, 30.0 mmol) solution was added dropwise. The reaction mixture was stirred for 0.5 h before addition of 5-isopropoxypicolinonitrile (3.41 g, 21.00 mmol) in THF (2 mL). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid (5 g) was collected and washed with water to give the product 3-(5-isopropoxypyridin-2-yl)-6-methoxyisoquinolin-1-ol 4 g as a white solid. MS: MS m/z 311.11 (M++1).
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1O.[OH-].[Na+].S([O:18][CH3:19])(OC)(=O)=O.[C:20](O)(C)(C)C>>[CH3:20][O:9][C@H:6]1[C@H:4]2[O:5][CH2:1][C@H:2]([O:18][CH3:19])[C@H:3]2[O:8][CH2:7]1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Product: CO[C@H]1CO[C@H]2[C@@H]1OC[C@H]2OC
Yield: 93 %

Procedure:
292.3 g (2 mol) of 1,4; 3,6-dianhydrosorbitol and 800 ml of tert.-butanol were heated to 55° to 65° C. with stirring and then two separate dropping funnels were used to simultaneously add 572 g (7.14 mol) of aqueous 50% sodium hydroxide solution and 631 g (5 mol) of dimethyl sulfate dropwise at this temperature while keeping the reaction mixture always alkaline. The mixture was then stirred for three hours at about 60° C. and then most of the tert.-butanol was distilled off. The residue was mixed with 2,600 ml of water and the resulting solution was extracted three times with 500 ml portions of methylene chloride. The combined organic phases were dried over potassium carbonate and evaporated first at atmospheric pressure and then distilled under water jet vacuum to obtain 324 g (93% yield) of dimethyl isosorbide with a boiling point of 118° to 120° C. at 20 mbar.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][S@@:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:10].C([O:26][C:27](=O)[C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33](=[O:49])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:48])[CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)C1C=CC=CC=1>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S@:9]([CH2:8][C:27]([C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33](=[O:49])[C@@H:34]2[CH2:38][CH2:37][CH2:36][N:35]2[C:39](=[O:48])[CH2:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:26])=[O:10])=[CH:12][CH:13]=1
Reactant: COc1ccc([S@](C)=O)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc([S@@](=O)CC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To diisopropylamine (0.13 ml) in THF (8 ml) was dropwise added 1.62M n-butyllithium-hexane solution (1.2 ml) at -78° C., followed by stirring at 0° C. for 0.5 hour. The reaction mixture was cooled to -30° C., dropwise added with (S)-(-)-4methoxyphenyl methyl sulfoxide (157 mg) in THF (8 ml), and stirred at 0° C. for 0.5 hour. The reaction mixture was cooled to -78° C., added with N-(3-phenylpropionyl)-L-prolyl-L-proline benzyl ester (400 mg) in THF (8 ml) quickly, and stirred for 0.5 hour. The reaction mixture was treated as in Example 13-A) and the residue obtained was purified by medium pressure liquid chromatography (silica gel, eluate; chloroform:methanol=99:1) to give 195 mg of the title compound (See Table 5).
Reaction SMILES: N[C@H](C(CBr)=[O:8])CC(C)C.[NH:11]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@H:12]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:32](N[C@H](C(CCl)=O)CC(C)C)=[O:33])[CH2:28]C(C)C)=[O:25])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH:11]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@H:12]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:32]([OH:8])=[O:33])[CH3:28])=[O:25])=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Reactant: CC(C)C[C@H](N)C(=O)CBr
Product: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
A mixed anhydride of Z-Phe-Gly-Ala-OH (0.41 g, 0.95 mmol) was prepared and coupled to H-LeuCH2Br.HBR substantially according to the procedure described for preparation of Z-Phe-Gly-Leu-LeuCH2Cl, above. The resulting product was crystallized from ethyl acetate:hexane to yield 0.30 g. Product was recrystallized from the same solvents to yield 0.07 g, m.p. 135.5°-138° (dec.).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:13])([C:10]([OH:12])=O)[CH2:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)#[N:2].[CH3:21][NH:22][O:23][CH3:24].C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:13])([C:10]([N:22]([O:23][CH3:24])[CH3:21])=[O:12])[CH2:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)#[N:2]
Reactant: CNOC
Reactant: Cc1ccc(C2=C(C#N)C(=O)NC(C)(C(=O)O)C2)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CON(C)C(=O)C1(C)CC(c2ccc(C)cc2)=C(C#N)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
Intermediate 108C (0.25 g, 0.925 mmol) was dissolved in DCM (15 mL) in a 25 mL 1 neck rb flask that was equipped with a magnetic stirrer and an Ar inlet. N,O-Dimethylhydroxylamine (0.062 g, 1.017 mmol), EDC (0.195 g, 1.017 mmol) and N-methylmorpholine (0.112 mL, 1.017 mmol) were added and the reaction mixture was stirred at rt overnight. The reaction solvent was removed under vacuum. The residue was dissolved in EtOAc (10 mL) and washed with water (5 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to a dark solid. The crude product was purified by silica gel chromatography (40 g silica gel, eluted with 0-100% EtOAc in hexanes) to give the desired product (0089 g, 31%) as a white solid. LCMS Anal. Calc'd for C17H19N3O3 313.3, found [M+H] 314.1. 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 3.81 (s, 3H), 3.69-3.75 (m, 1H), 3.22 (s, 3H), 2.72 (d, J=17.6 Hz, 1H), 2.42 (s, 3H), 1.63 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])N=CC=1C(=O)C1C=CC(C)=CC=1.[C:29]1([Mg]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl.[OH-:38].[Na+]>C1COCC1>[NH2:6][C:7]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[CH:2]=[N:1][C:18]=1[C:17](=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Br[Mg]c1ccccc1
Reactant: [OH-]
Reactant: Cc1ccc(C(=O)c2cnn(-c3cc(C(=O)NC4CC4)ccc3C)c2N)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc(C(=O)c2ccccc2)c1N
Reaction time: 1 h

Procedure:
To a solution of 3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide 3 (56.4 mg, 0.2 mmol) in dry THF (10 ml) under nitrogen was added phenylmagnesium bromide (1M, 1 mL) at room temperature. After 1 h, HCl solution (3N, 10 ml) was added and the mixture was stirred overnight. The solution was neutralized with dilute aqueous NaOH. The mixture was extracted with ethyl acetate (100 mL×2), washed with water and dried over Na2SO4. Evaporation of the solvent gave a residue which was purifiedd by HPLC to give 3-(5-Amino-4-benzoyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide as a while solid (56 mg, 78%). LCMS (4 minute gradient) tR=2.07 min; MS m/z 361.17 [M+H]+
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].O.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:2]([NH:1][C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:19])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g (4.8 mmol) of methyl(S)-2-amino-3-(4-methoxyphenyl)propionate (cf. preparation 2-1) is diluted in 30 mL of dichloromethane. The solution is cooled in a bath of cold water, and 1.4 g (7.2 mmol) of 4-nitrophenyl chloroformate and 1.2 mL (7.2 mmol) of diisopropylethylamine are then added. After warming to room temperature, the reaction medium is stirred for 2 hours. The solution is poured into water and then extracted with dichloromethane. The organic phase is dried and then evaporated. The crude product obtained is used in the following step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[N:7]2)[CH2:23][CH2:22]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc(N2CCN(CCCCn3nnc4ccccc43)CC2)nc1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-pyrimidinyl)piperazine (4.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.8 g compound (I-45) with a yield of 67.1%. ESI-MS [M+H]+: m/z 337.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][CH2:16][C:10]2([O:14][C:13](=[O:15])[NH:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][CH2:16][C:10]2([O:14][C:13](=[O:15])[N:12]([C:20]3[CH:25]=[N:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CNC(=O)O2)C1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)CN(c1ccc([N+](=O)[O-])nc1)C(=O)O2
Yield: 81.5 %

Procedure:
Following general N—C coupling procedure 1, 2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester (0.546 g, 2.130 mmol) (Reference: German Patent DE10 2005 030051A1 (28 Dec. 2006)), was combined with 5-bromo-2-nitropyridine (0.432 g, 2.130 mmol, 1.0 eq) which gave 3-(6-Nitro-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester as a brown solid (0.709 g, 1.735 mmol) in 81% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (br. s., 9H) 1.55-1.73 (m, 2H) 1.89-2.17 (m, 3H) 3.41 (br. s., 2H) 3.65 (br. s., 2H) 3.78-3.88 (m, 1H) 3.95 (d, J=8.03 Hz, 1H) 8.34 (d, J=9.03 Hz, 1H) 8.54 (br. s., 1H) 8.61 (dd, J=9.03, 3.01 Hz, 1H) MS m/z 379.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[Li+].CS([Cl:35])(=O)=O>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH2:18][Cl:35])=[CH:16][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: ClCc1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
A mixture of 4-(7-chloroquinolin-2-ylmethoxy)benzyl alcohol (2.80 g, 9.33 mmol), triethylamine (3.12 g, 30.9 mmol), lithium chloride (0.850 g, 20.0 mmol), and 4-(N,N-dimethylamino)pyridine (10 mg) in DMF (40 mL) was cooled to -10° C. Methanesulfonyl chloride (3.40 g, 29.7 mmol) was added dropwise and the resulting mixture was stirred for 15 minutes. The mixture was warmed to room temperature and stirred for an additional 4 hours, then diluted with ethyl acetate. The resulting solution was washed once with water, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography of the residue (silica gel, ethyl acetate/hexane gradient) provided 1.60 g (54%) of the intermediate.
Reaction SMILES: [C:1]1([NH:7]/[C:8](/[CH3:13])=[CH:9]\[C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](#[N:17])[CH2:15][CH3:16]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:15]([C:14]1[C:9]([C:10](=[O:12])[CH3:11])=[C:8]([CH3:13])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:17]=1)[CH3:16]
Reactant: CC(=O)/C=C(/C)Nc1ccccc1
Reactant: CCC#N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCc1nn(-c2ccccc2)c(C)c1C(C)=O

Procedure:
According to AVV A, (Z-4-phenylaminopent-3-ene-2-one (175.2 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 24 hours at 120° C. After the brown oily raw product (157.3 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 94:6→0:100), the desired product was obtained in the form of a yellow oil (57.2 mg, 0.25 mmol, 25%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27]([C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)(=[O:29])[CH3:28]>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([S:36]([C:32]5[CH:31]=[C:30]([C:27](=[O:29])[CH3:28])[CH:35]=[CH:34][CH:33]=5)(=[O:38])=[O:37])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Reactant: CC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cccc(S(=O)(=O)N2CCN3C[C@H](Oc4cnc(C5CC5)cn4)C[C@H]3C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To (7R,8aS)-7-[(5-cyclopropylpyrazin-2-yl)oxy]octahydropyrrolo[1,2-a]pyrazine (1 mmol, Example 27B) and triethylamine (1.5 mmol) in dichloromethane (6 mL) was added 3-acetylbenzene-1-sulfonyl chloride (1.1 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 18 hours. The mixture was concentrated, and the residue was purified by chromatography on silica gel (ethyl acetate) to give the title compound (370 mg) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 (m, 2H), 0.91 (m, 2H), 1.75 (m, 1H), 1.89 (m, 1H), 2.06 (m, 2H), 2.19 (m, 2H), 2.30 (m, 3H), 3.67 (s, 2H), 2.97 (m, 1H), 3.54 (m, 1H), 3.65 (m, 1H), 3.80 (m, 1H), 5.19 (m, 1H), 7.83 (m, 1H), 8.00 (m, 1H), 8.15 (m, 3H), 8.30 (m, 1H); MS (ESI) m/z 444 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[C:16]#[CH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:21]=1>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[C:16]#[C:17][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:25]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(CCN2CCCC2)cc1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(CCN2CCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 2.1.e. from propynoic acid-(4′-chlorobiphenyl-4-yl)amide and 1-[2-(4-iodophenyl)ethyl]pyrrolidine. Yield: 70 mg (32.8% of theory); melting point: 217-218 C; C27H25ClN2O (M=428.96); calc.: molecular ion peak (M+H)+: 429/431; found: molecular ion peak (M+H)+: 429/431; Rf value: 0.3 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([O:23][CH3:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[Li]CCCC.CN(C=O)C>>[CH3:24][O:23][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([CH:8]=[O:9])=[CH:14][CH:15]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: COC1(c2ccc(Br)cc2)CCC1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COC1(c2ccc(C=O)cc2)CCC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 1-bromo-4-(1-methoxycyclobutyl)-benzene (140 mg, 0.58 mmol), n-BuLi (363 μl, 1.6M solution in hexane, 0.58 mmol) and DMF (90 μl, 1.16 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 4-(1-methoxycyclobutyl)-benzaldehyde (76 mg, 69%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 10.03 (s, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 2.96 (s, 3H), 2.45-2.39 (m, 4H), 1.99 (m, 1H), 1.73 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[C:10]([CH3:11])=[N:9][N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[NH2:19][CH2:20][C:21]1[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]=2[N:7]=1
Reactant: Cc1nn(C(C)(C)C)c2nc(Cl)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (320 mg, 1.195 mmol) in DMSO (7 mL) were added 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (338 mg, 1.793 mmol), N-methylmorpholine (0.526 mL, 4.78 mmol), 1-hydroxy-7-azabenzotriazole (325 mg, 2.391 mmol) and EDC (458 mg, 2.391 mmol), and the reaction mixture was stirred overnight. The reaction mixture was quenched with water (20 mL) and stirred for 10 min. The precipitate was collected by filtration and further dried under high vacuum to give the product as a solid, 450 mg (94%). LCMS E-S (M+H)=402.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (s, 9H), 2.12 (s, 3H), 2.22 (s, 3H), 2.37 (s, 3H), 4.33 (d, J=4.80 Hz, 2H), 5.88 (s, 1H), 7.09-7.21 (m, 1H), 8.77 (t, J=4.93 Hz, 1H), 11.53 (s, 1H).
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[C:6]([CH:10]3[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14](O)([C:21]([F:24])([F:23])[F:22])[NH:13][C:12]([CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[C:11]3[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:7][CH:8]=[CH:9][C:2]=12.FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>ClCCl>[N:1]1[O:5][N:4]=[C:3]2[C:6]([CH:10]3[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([C:21]([F:24])([F:23])[F:22])[NH:13][C:12]([CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[C:11]3[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(O)(C(F)(F)F)C(C(=O)OCC)C1c1cccc2nonc12
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1=C(C(OCC)OCC)NC(C(F)(F)F)=C(C(=O)OCC)C1c1cccc2nonc12

Procedure:
A solution of diethyl 4-(4-benzofurazanyl)-2-diethoxymethyl-1,4,5,6-tetrahydro-6-hydroxy-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (9.0 g, 17 mmoles), trifluoroacetic anhydride (4.77 ml, 34 mmoles) and pyridine (4.05 ml, 51 mmoles) in dry dichloromethane (100 ml) was stirred at room temperature. After 3 hours the solution was washed with water, 10% aqueous hydrochloric acid solution, brine and dried (MgSO4). Evaporation of the solvent left crude sub-title compound as an oil (8.8 g). Nmr (CDCl3) δ 6.1 (s,H), 5.6(s,H).