Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([CH3:16])([S:7]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])[CH3:6])C.O.[OH-].[Li+]>C1COCC1.O.O>[CH3:16][C:5]([S:7]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8])([CH3:6])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
To a solution of 240 mg (0.93 mmol) of 2-methyl-2-(pyridine-3-sulfonyl)-propionic acid ethyl ester in THF/water (4/1, 10 mL) were added 76 mg (1.8 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The reaction was further diluted with water (20 mL) and then washed with DCM (2×15 mL). The basic aqueous layer was cooled in an ice bath and acidified with 1M aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with isopropanol/chloroform (1/1, 3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 213 mg of 2-methyl-2-(pyridine-3-sulfonyl)-propionic acid.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:17])[CH:13]=2)[N:8]=1.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:17])[C:13]=2[N+:18]([O-:20])=[O:19])[N:8]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2nc(Cl)ccc2c1
Agent: O=S(=O)(O)O
Product: Cc1ccc2nc(Cl)ccc2c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 98 %

Procedure:
Sulfuric acid(7.2 mL) was added to 2-chloro-6-methyl-quinoline (1.15 g, 6.5 mmol). To the resulting solution was added nitric acid(3.1 mL), and the mixture was heated at 100° C. for 20 minutes. After cooling, the mixture was poured into ice-water. The resulting yellow solid was collected by filtration and dried under vacuum to give 2-chloro-6-methyl-5-nitro-quinoline (1.42 g, 98%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][NH2:13]>O>[NH:12]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[NH2:13]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Product: NNc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A stirred solution of 4-chlorobenzenesulfonamide (38.33 g, 200 mmol) and anhydrous hydrazine (31.4 mL, 1.0 mol) was heated at reflux for 30 hours. After cooling to room temperature, the mixture was poured into water (500 mL) with swirling. The resulting precipitate was collected by filtration, washed thoroughly with water several times, air-dried, and dried under vacuum to give the title compound (35.5 g, 95% yield) as a white solid. Mp 169-171° C. 1H NMR (300 MHz, THF-d8) δ 7.59 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 6.62 (br, 1H), 5.99 (br, 2H), 3.87 (br, 2H). Mass spectrum (API-TIS) m/z 188 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][N:13]1C(=O)C3C(=CC=CC=3)C1=O)=[CH:7][CH:6]=2>CO.O.NN>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2ncc(Br)cc2c1
Agent: NN
Solvent: CO
Solvent: O
Product: NCc1ccc2ncc(Br)cc2c1

Procedure:
A solution of 2-(3-Bromo-quinolin-6-ylmethyl)-isoindole-1,3-dione (635 g, 1.73 mmol) in 15 mL of methanol and 1 mL of hydrazine monohydrate was heated at 80° C. for 2 h. After cooling, the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound. LCMS (method A): [MH]+=237/239, tR=2.795 min.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH:30]([C:38](O)=[O:39])[CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([CH:30]5[CH2:31][C:32]6[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=6)[O:28][CH2:29]5)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)C1COc2ccccc2C1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1COc2ccccc2C1

Procedure:
The title compound, white solid (26 mg, 64.9%), MS (ISP) m/z=492.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and chroman-3-carboxylic acid.
Reaction SMILES: C=C(O[C@H:7]1[C@H:12]([OH:13])[CH:11]=[CH:10][C:9]([C:14]([OH:16])=[O:15])=[CH:8]1)C(O)=O.C1([CH2:23][C:24](=[O:28])[C:25]([O-:27])=[O:26])C=CC=CC=1>>[CH:11]1[CH:12]([OH:13])[CH:7]=[CH:8][C:9]([C:14]([OH:16])=[O:15])([CH2:23][C:24]([C:25]([OH:27])=[O:26])=[O:28])[CH:10]=1
Reactant: C=C(O[C@@H]1C=C(C(=O)O)C=C[C@H]1O)C(=O)O
Reactant: O=C([O-])C(=O)Cc1ccccc1
Product: O=C(O)C(=O)CC1(C(=O)O)C=CC(O)C=C1

Procedure:
One assay commonly used to measure chorismate mutase activity is based on the spectrophotometric estimation of phenylpyruvate obtained by acid conversion of the reaction product of prephenate. Metzenberg and Mitchell (1954) Arch Biochem and Biophys 243:374. In this assay, phenylpyruvate is estimated by the absorbance of either the enol-tautomer in alkaline solution (E=17,500 M−1 cm−1 at 320 nm in 1 M NaOH) or the enol-borate complex in either a concentrated solution of sodium borate and arsenate or phosphate (E=9292 M−1 cm−1 at 300 nm). Alternatively, the disappearance of chorismate may be assayed spectrophotometrically. Nishioka and Woodin (1972) Anal Biochem 45:617. The details of these assays and their advantages and disadvantages are described in Gilchrist and Connelly (1987) Methods in Enzymology 142:450-463.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]([OH:18])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].B(O)(O)[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[OH:18][CH:12]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=[C:2]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:11]=1
Reactant: COC(=O)c1cc(Br)cc(C(O)c2nccs2)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(C(O)c2nccs2)c1
Temperature: 95 °C

Procedure:
To a mixture of methyl 3-bromo-5-(hydroxy(thiazol-2-yl)methyl)benzoate (320 mg, 0.98 mmol), p-tolylboronic acid (0.16 g, 1.2 mmol), potassium carbonate (0.20 g, 1.5 mmol), 1,4-dioxane (5 mL), and water (0.5 mL, 0.03 mol) under argon was added tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.052 mmol). The reaction mixture was heated at 95° C. for 8 h. After cooling, the mixture was treated with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.[CH2:87]([O:89][C:90](=[O:93])[CH2:91][NH2:92])[CH3:88]>>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([NH:92][CH2:91][C:90]([O:89][CH2:87][CH3:88])=[O:93])=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: CCOC(=O)CN
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Yield: 161.3 %

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (533 mg) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with glycine ethyl ester hydrochloride (242 mg) in a similar manner as described in Example 24-(i) to give the titled compound (600 mg) as a colorless powder.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([C:13]3([C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([C:13]3([C:17]3[CH:18]=[C:19]([NH:23][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(c2cccc(N)c2)C2CN(CCCC3CCCCC3)CC21
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(C2(C)C3CN(CCCC4CCCCC4)CC32)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.9 %

Procedure:
To a solution of 3-[3-(3-cyclohexylpropyl)-6-methyl-3-azabicyclo[3.1.0]-hex-6-yl]phenylamine (Preparation 10, 25 mg, 0.08 mmol) in dichloromethane (2 ml) at 0° C. under nitrogen was added pyridine (20 μl, 0.24 mmol) then dropwise over 5 minutes ethanesulfonylchloride (25 μl, 34 mg, 0.26 mmol). The mixture was allowed to warm to room temperature and was stirred for 1.5 h. Further ethanesulfonylchlonide (25 μl, 34 mg, 0.26 mmol) was added and the mixture was stirred for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (21 mg, 65%).
Reaction SMILES: C(O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+].O.[Si:12]([O:19][C@@H:20]1[C@H:24]([CH2:25][O:26][Si](C(C)(C)C)(C)C)[CH2:23][C@@H:22]([O:34][C:35]2[CH:40]=[C:39]([Cl:41])[N:38]=[CH:37][N:36]=2)[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Si:12]([O:19][C@H:20]1[CH2:21][C@H:22]([O:34][C:35]2[CH:40]=[C:39]([Cl:41])[N:38]=[CH:37][N:36]=2)[CH2:23][C@H:24]1[CH2:25][OH:26])([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](Oc2cc(Cl)ncn2)C[C@H]1CO
Temperature: -45 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
In a 2 L round-bottomed flask, 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]-oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (14) (20.5 g, 0.0433 mol was dissolved in ethanol (647.2 mL, 11.08 mol), and cooled to an internal temp of −45° C. To this was added a precooled (−20° C.) solution of 2% conc. HCl in EtOH (326 mL, 0.0516 mol, prepared by diluting 6.5 mL conc. HCl in 319.5 mL ethanol). The reaction mixture was warmed to −25° C. (to prevent pressure buildup upon capping the flask), and then capped and placed in a freezer at −35° C. The reaction was left to stand at −35° C. for 18 hours. The reaction was quenched with sodium carbonate (13.78 g, 0.1300 mol) (˜3 equiv relative to HCl) as a solution in water (40 mL, 2 mol). The volatiles were removed in vacuo, and the reaction mixture was diluted with CH2Cl2 (750 mL). The solids were filtered and set aside, and the volatiles were removed from the filtrate in vacuo. The resulting aqueous mixture with was diluted with EtOAc (500 mL) and water (200 mL) and transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted 2×250 mL with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (applied to column with ˜50 mL CH2Cl2, 400 g column, eluent 0-40% EtOAc:hexanes over 40 min to afford {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-chloropyrimidin-4-yl)oxy]cyclopentyl}methanol (11.2 g, 72%). LCMS: (FA) ES+ 359; 1H NMR (400 MHz, CDCl3) δ 8.56 (app d, J=0.6, 1H), 6.70 (app d, J=0.8, 1H), 5.62-5.54 (m, 1H), 4.56 (dd, J=5.6, 10.9, 1H), 3.86-3.78 (m, 1H), 3.70 (ddd, J=6.0, 7.6, 11.3, 1H), 2.48 (dd, J=4.6, 7.6, 1H), 2.42-2.31 (m, 1H), 2.23 (ddd, J=6.3, 9.8, 14.2, 1H), 2.15-2.09 (m, 2H), 1.89 (ddd, J=1.9, 8.0, 14.3, 1H), 0.91 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)[S:8][C:7]=2[CH:26]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][C:9]1[S:8][C:7]2[CH:26]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2cc(OC)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccccc2N)sc2cc(OC)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 6-methoxy-2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-aminoanilino)-6-methoxybenzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]([F:10])([F:9])[F:8])=[CH:5][CH:6]=1.[Br:11]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:11][CH2:1][C:2]1[O:3][C:4]([C:7]([F:10])([F:9])[F:8])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(F)F)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1ccc(CBr)o1
Yield: 78.6 %

Procedure:
To a solution of 2-methyl-5-(trifluoromethyl)furan (4 g, 26.6 mmol) in chloroform (60 ml) were added N-bromosuccinimide (5.2 g, 29.3 mmol) and 2,2′-azobis(isobutyronitrile) (220 mg, 1.33 mmol). The reaction solution was heated under reflux for 15 min. The reaction solution was cooled, poured into water (200 ml) and was extracted with chloroform. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 2-(bromomethyl)-5-(trifluoromethyl)furan (4.79 g, 78%).
Reaction SMILES: [NH2:1][OH:2].Cl[C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH3:21])[N:11]=[C:12]([C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:5]=12>CO.C(O)C>[OH:2][NH:1][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH3:21])[N:11]=[C:12]([C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:5]=12
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Reactant: NO
Solvent: CCO
Solvent: CO
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(NO)ncnc21
Reaction time: 0.5 h

Procedure:
A solution containing 0.7 grams of anhydrous hydroxylamine in 50 milliliters of methanol was added to a solution containing 1.4 grams of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine dissolved in 600 milliliters of ethanol, at a temperature of 30°C. and the mixture was allowed to stand for 30 minutes at room temperature. The mixture was gently heated at reflux for a further 15 minutes and cooled. The crystalline product was washed with ether and dried. Recrystallisation from dimethylformamide gave 4-hydroxyamino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, having melting point 294°C.
Reaction SMILES: [C:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([N:28]=[C:29]=[O:30])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([N:28]1[C:20](=[O:21])[C@H:9]2[N:8]([C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)[C:29]1=[O:30])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN=C=O
Reactant: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccccc2)N1
Product: CCCCN1C(=O)[C@@H]2Cc3c([nH]c4ccccc34)[C@H](c3ccccc3)N2C1=O

Procedure:
The same method as employed in the preparation of Example 1 but starting from trans methyl 1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate and butyl isocyanate gave after recrystallisation from 2-propanol, the title compound as white crystals m.p.: 240-243° C. Analysis for C23H23N3O2: Calculated: C,73.97;H,6.21;N,11.25;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:32]1([NH2:39])[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[NH:33]1>O1CCOCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:36]4[N:35]=[C:34]([NH2:38])[N:33]=[C:32]([NH2:39])[CH:37]=4)=[CH:18][CH:19]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: NC1=NC=CC(N)(Cl)N1
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4ccc(Cl)c(C(F)(F)F)c4)[nH]3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 46.3 %

Procedure:
4-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (1.3 g, 3.66 mmol) was dissolved in 18 mL of anhydrous dioxane in a 10-20 md microwave vial (Personal Chemistry). Solid Cs2CO3 (1.19 g, 3.66 mmol, 1.0 eq) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 4-chloro-2,4-diaminopyrimidine (0.530 g, 3.66 mmol) was added. The vial was capped and microwaved at 200° C. for 25 min. Then the reaction mixture was diluted with ca. 10 mL of MeOH, transferred into a round-bottom flask and concentrated in vacuo to ca. 20 mL. The resulting reddish solution was loaded on a short pad of silica gel and eluted first with 100% ethyl acetate to remove the unreacted starting material and then with 20% MeOH in EtOAc to elute the product. The product was further purified by ISCO system (80 g pre-packed column, 40 min method, 0% to 10% MeOH gradient in ethyl acetate). Solvent was removed in vacuo to give the title product as an off-white solid (0.785 g). Yield 46.3%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[N:9]([CH:11]([C:16]([NH:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[CH3:10])=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]([NH:31][CH:32]2[CH2:34][CH2:33]2)[CH3:30])=[CH:25][CH:24]=1)#[CH:22]>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.[Cu]I.C(Cl)(Cl)Cl>[CH:32]1([NH:31][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([C:21]#[C:22][C:2]3[CH:7]=[CH:6][C:5]([C:8](=[O:20])[N:9]([CH:11]([C:16]([NH:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])[CH3:10])=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)[CH3:30])[CH2:34][CH2:33]1
Reactant: C#Cc1ccc(C(C)NC2CC2)cc1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#Cc2ccc(C(C)NC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
Intermediate 6-2 (0.11 g), PdCl2(PPh3)2 (10 mg), CuI (5.0 mg), and TEA (28 mg) were added to a chloroform (5.0 mL) solution of N-[1-(4-ethynylphenyl)ethyl]cyclopropylamine (51 mg) as obtained in Example 14-(3), and the mixture was stirred in a nitrogen atmosphere for 2 hours at room temperature, whereafter the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel chromatography (ethyl acetate) to obtain 1-[1-(cyclopropylamino)ethyl]-4-[(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)ethynyl]benzene (light yellow foam) (0.10 g, 85%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]=[C:15]2[C:20]3[CH2:21][NH:22][CH2:23][CH2:24][C:19]=3[NH:18][C:17](=[O:25])[N:16]2[CH:26]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([N:22]1[CH2:23][CH2:24][C:19]2[NH:18][C:17](=[O:25])[N:16]3[CH:26]=[C:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[F:6])[N:14]=[C:15]3[C:20]=2[CH2:21]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)N1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Propionyl chloride (39 uL, 0.4 mmol) was added to a solution of 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (124 mg, 0.4 mmol) and triethylamine (74 uL, 0.5 mmol) in DMF (2 mL) at room temperature. The reaction mixture was stirred for 50 minutes, and then poured into ice water. The precipitate was collected, washed with water and 95% ethanol, and dried to yield 9-propionyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 36) as a white solid, m.p. >310° C.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[CH:9]=[N:10][C:11](I)=[C:7]2[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:4]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C)C=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.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][CH:2]([F:23])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[C:7]2[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2c(I)ncn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
A mixture of 4-difluoromethyl-8-iodo-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (2.45 g, 5.58 mmol), trimethylsilylacetylene (1.24 ml, 8.94 mmol) and triethylamine (2.08 ml, 14.9 mmol) in N,N-dimethylformamide (10 ml) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (105 mg, 0.15 mmol), PPh3 (78 mg, 0.3 mmol) and CuI (9 mg, 0.05 mmol) were added. Stirring was continued at 90° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with ice-water (50 mL) and extracted with ethyl acetate (3×70 ml). The combined organic layers were washed with water (40 ml) and brine (40 ml), dried (MgSO4) and evaporated to give 4-difluoromethyl-2-(4-trifluoromethyl-phenyl)-8-trimethylsilanylethynyl-imidazo[1,5-a]pyrimidine(1.58 g, 69%) as a brown solid, which was dissolved in THF (15 ml) and MeOH (15 ml), while stirring at 0° C. potassium carbonate (51 mg, 0.37 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (50 ml) and extracted with TBME (2×80 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/EtOAc) followed by crystallization from diethyl ether/hexane to give 4-difluoromethyl-8-ethynyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (0.61 g, 49%) as a brown solid. MS (EI) 337.1 [(M)+]; mp 135° C.