Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]1[C:33]([F:42])=[C:34]([C:38]([Cl:41])=[CH:39][CH:40]=1)[C:35](O)=[O:36])=[O:29])([CH3:26])([CH3:25])[CH3:24].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:41][C:38]1[CH:39]=[CH:40][C:32]([CH2:31][NH:30][C:28](=[O:29])[O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:33]([F:42])[C:34]=1[C:35](=[O:36])[NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cccc(C(F)(F)F)c4)ncnc23)c1F
Yield: 47.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-7, 87 mg, 0.285 mmol), 3-(((tert-butoxycarbonyl)amino)methyl)-6-chloro-2-fluorobenzoic acid (130 mg, 0.428 mmol), oxalyl chloride (81 mg, 0.64 mmol), DMF (1 drop) and DIPEA (111 mg, 0.86 mmol) in CH2Cl2 (4 mL) to afford 80 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.66 (s, 1H), 10.14 (s, 1H), 8.82 (d, 1H), 8.71 (s, 1H), 8.36 (m, 2H), 8.23 (d, 1H), 7.73 (t, 1H), 7.66 (t, 1H), 7.51 (m, 2H), 7.42 (m, 2H), 4.18 (d, 2H), 1.40 (s, 9H); MS [M+H]+: 590.08.
Reaction SMILES: CC(O)=[O:3].O.[F:6][C:7]([F:13])([F:12])[CH2:8][C:9](=[O:11])[CH3:10]>O1CCOCC1>[F:6][C:7]([F:13])([F:12])[CH2:8][C:9](=[O:11])[CH:10]=[O:3]
Reactant: CC(=O)CC(F)(F)F
Reactant: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: O=CC(=O)CC(F)(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of SeO2 (4.23 g, 38.1 mmol) in dioxane (25 mL) was added AcOH/H2O (1 mL/1 mL). 4,4,4-Trifluorobutan-2-one (3.81 mL, 31.7 mmol) was added dropwise to the above reaction mixture. The resulting solution was stirred overnight at 100° C. The solution was used in the next step without any further work-up or purification.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17])#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:17])#[N:12]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: c1ccc2c(c1)CCCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)N2CCCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
1,2,3,4-tetrahydroquinoline (4.2 g, 31 mmol) was added dropwise to a solution of 3-cyanobenzoyl chloride (5.2 g, 31 mmol) and triethylamine (3.1 g, 31 mmol) in dichloromethane (125 ml) while cooling in an ice/water bath. The mixture was allowed to warm to RT and stirred for 18 h. It was washed with 0.3M potassium hydrogen sulphate solution, saturated sodium hydrogen carbonate solution and brine. The organic phase was filtered through phase separation paper and reduced to yield 1-(3-cyanobenzoyl)-1,2,3,4-tetrahydroquinoline (7.1 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:19]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1.NC(N)=[O:27].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:19]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N+:11]=1[O-:27]
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCC(C)C)c1
Reactant: NC(N)=O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1cc(OCC(C)C)c(-c2cc(OC)ccc2F)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 6-(2-fluoro-5-methoxyphenyl)-5-isobutoxynicotinate (758 mg) in acetonitrile (9.4 mL) were added urea-hydrogen peroxide adduct (555 mg) and trifluoroacetic anhydride (793 μL) at 0° C., and the mixture was gradually warmed to room temperature and stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was filtered, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (631 mg) as a pale-yellow oil.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C@@H:10]([OH:13])[CH2:11][OH:12].[Cl:14][CH2:15][C:16](Cl)=[O:17]>CC#N.CO>[Cl:14][CH2:15][C:16]([NH:8][CH2:9][C@@H:10]([OH:13])[CH2:11][OH:12])=[O:17]
Reactant: O=C(Cl)CCl
Reactant: NC[C@@H](O)CO
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: O=C(CCl)NC[C@@H](O)CO
Reaction time: 16 h
Yield: 77.6 %

Procedure:
Triethylamine (1.83 mL, 13.2 mmol) was added to a solution of (R)-3-amino-1,2-propanediol (1.00 g, 11.0 mmol) in a mixture CH3CN/MeOH (36 mL/16 mL) at −10° C. under nitrogen. Chloroacetyl chloride (0.98 ml, 12.0 mmol) was added dropwise at −10° C. over 30 min. The reaction mixture was allowed to reach room temperature and stirred for 16 h. The mixture was concentrated and purified by flash column chromatography on silica gel, eluting with methanol/ethyl acetate (8/92), to give the title compound as a white solid (1.43 g, 78%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][N:13]([CH3:24])[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[NH:17][C:18](=[O:20])[CH3:19]>>[C:18]([NH:17][C:16]1[CH:15]=[C:14]([N:13]([CH3:12])[CH3:24])[CH:23]=[CH:22][C:21]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5])(=[O:20])[CH3:19]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(=O)Nc1cccc(N(C)C)c1
Product: CC(=O)Nc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O

Procedure:
Condensation of phthalic anhydride and m-(dimethylamino)acetanilide by the method of part A of Example 1 affords 2-(2-acetamido-4-(dimethylamino) benzoyl)benzoic acid (II: Y'2 = CH3CONH, Y'4 = (CH3)2N, Z4 = Z'5 = Z'6 = Z7 = H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[N:10][CH:9]=[C:8]2[C:13]([O:15][CH3:16])=[O:14].[F-:17]>C1C=CC=CC=1>[F:17][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[N:10][CH:9]=[C:8]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cnnc2c(CCl)cccc12
Reactant: [F-]
Solvent: c1ccccc1
Product: COC(=O)c1cnnc2c(CF)cccc12

Procedure:
A mixture of 0.35 g of 58B, 3.0 g of Amberlyst A26 fluoride resin and 5 ml of benzene was stirred vigorously at mild reflux in a nitrogen atmosphere overnight. The resulting mixture was filtered, and the filtrate was stripped of solvent. The residue was chromatographed over silica gel, using a 1:99 v:v mixture of ethyl acetate and methylene chloride as eluent, to give 58, as a yellow solid, m.p.: 104°-105° C.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.Cl[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.O>[C:20]1([C:17]2[CH:18]=[CH:19][C:13]3[O:12][C:11]([N:4]4[CH:5]5[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]5)[CH2:2][CH2:3]4)=[N:15][C:14]=3[CH:16]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1nc2cc(-c3ccccc3)ccc2o1
Reactant: C1CN2CCC(CC2)N1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccc3oc(N4CCN5CCC4CC5)nc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.3 %

Procedure:
1,4-Diazabicyclo[3.2.2]nonane (504 mg, 4.0 mmol) was added to a mixture of 2-chloro-5-phenylbenzoxazole (919 mg, 4.0 mmol), sodium tert-butoxide (423 mg, 4.4 mmol) and toluene (4 mL) at RT. The mixture was stirred at RT for 16 h and water (10 mL) and ethyl acetate (10 mL) were added. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated and the residue was purified by chromatography (Biotage, 40S) eluting with 4% MeOH in CHCl3, with 20 drops of NH4OH per liter of eluent to afford 540 mg (42%) of the title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 7.60-7.56 (m, 3H), 7.42 (t, 2H, J=7.7 Hz), 7.33-7.20 (m, 3H), 4.51 (s, 1H), 3.92 (t, 2H, J=5.8 Hz), 3.17-2.97 (m, 6H), 2.20-2.07 (m, 2H), 1.84-1.75 (m, 2H), 13C NMR (CDCl3, 100 MHz) δ 162.2, 148.6, 144.3, 141.9, 137.9, 129.0, 127.5, 127.1, 119.8, 114.8, 108.8, 57.3, 50.4, 46.5, 44.4, 27.0; MS (Cl) m/z 320.1 (M+1) The hydrochloride salt was prepared by diluting the title compound in ethyl acetate and adding a 2.5 N HCl in ethyl acetate solution: mp>300° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])=[C:4]([CH3:16])[CH:3]=1.C(C(O)=O)(F)(F)F>C(Cl)Cl.C1(OC)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(F)ccc1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(F)ccc1CC(=O)O
Reaction time: 16 h

Procedure:
The pure ester was dissolved in 60 ml of CH2Cl2 was added 6 drops of anisole and 60 ml of CF3CO2H and the solution was atirred at rt for 16 hr. Upon removal of volatiles, the residue was dried three times by dissolving in toluene to afford 20.02 g of the title compound. 1H-NMR (CDCl3): δ 2.35 (s, 3H), 3.67 (s, 2H), 6.92-6.95 (m, 2H), 7.19 (d of d, 1H, J=8.2, 5.7 Hz) ppm.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[NH:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=3)=[O:25])=[C:19]([C:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=3)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.CCO.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[NH2:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[NH:27][CH:28]=[C:29]([C:31]#[N:32])[N:30]=3)=[O:25])=[C:19]([C:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=3)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CN)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of [2-(4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (as prepared in the previous step, 0.41 g, 0.77 mmol) in CH2Cl2 (20 mL) was treated with EtOH (0.2 mL) and TFA (6 mL). The mixture stirred at room temperature for 45 min, and the solvents were evaporated in vacuo. The crude material was used directly in the next step. LC-MS (ESI, m/z): Calcd. for C24H28N6O2 433.2 (M+H), found 433.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20](=[O:25])C(F)(F)F)=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].[OH2:28]>CN(C=O)C.COC(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]([OH:25])=[O:28])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C(c1cn(Cc2cc(F)cc(F)c2)c2cc(Cl)ccc12)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: O=C(O)c1cn(Cc2cc(F)cc(F)c2)c2cc(Cl)ccc12
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
To a solution of 2.2 g (6.5 mmol) 1-[6-chloro-1-(3,5-difluoro-benzyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone in 65 ml DMF were added 1.7 g (36 mmol) sodium hydride (50% in oil) at room temperature. After stirring for 5 min. 0.59 ml (33 mmol) water were added dropwise. Stirring was continued at room temperature for 45 min. The reaction mixture was diluted with 150 ml of tert-butyl methyl ether and extracted with two 150-ml portions of a 1 M aqueous solution of sodium hydroxide. The combined aqueous layers were acidified to pH 1 with concentrated hydrochloric acid solution and extracted with three 150-ml portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dried in high vacuo at 80° C. to give 2.0 g (95%) of the crude title compound as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19]>CO>[CH3:17][S:18]([CH2:21][CH2:22][N:13]1[CH2:14][CH2:15][CH2:16][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)(=[O:20])=[O:19]
Reactant: C=CS(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(N2CCCNCC2)cc1
Solvent: CO
Product: CS(=O)(=O)CCN1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-Nitro-phenyl)-[1,4]diazepane (4.90 g), Methansulfonyl-ethene (2.35 g) and Methanol (50 mL) was stirred for 2 h at room temperature. The volatiles were removed in vacuo. The product with the molecular weight of 327.40 (C14H21N3O4S) was obtained in this way; MS (ESI): 328 (M+H+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([NH2:11])[C:8]([O:12][CH3:13])=[C:7]2[C:3]=1[C:4]1[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:5]=1[NH:6]2.[CH2:19]([S:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH3:20].O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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>[CH2:19]([S:21]([C:24]1[CH:29]=[C:28]([C:2]2[CH:10]=[C:9]([NH2:11])[C:8]([O:12][CH3:13])=[C:7]3[C:3]=2[C:4]2[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:5]=2[NH:6]3)[CH:27]=[CH:26][CH:25]=1)(=[O:22])=[O:23])[CH3:20]
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Reactant: COc1c(N)cc(Br)c2c1[nH]c1ncc(C)cc12
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: CCOC(C)=O
Product: CCS(=O)(=O)c1cccc(-c2cc(N)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 140 °C
Yield: 81.9 %

Procedure:
A 5 mL microwave vial was charged with Compound 238 (500 mg, 1.63 mmol), 3-(ethylsulfonyl)phenylboronic acid (419 mg, 1.96 mmol) and Pd(PPh3)4 (188 mg, 0.16 mmol). To the mixture was added dioxane (5 mL) and a saturated aqueous solution of K2CO3 (2.5 mL). The reaction mixture was heated at 140° C. for 20 min. in microwave. The reaction was diluted with EtOAc and washed with aqueous water and brine. The organic extracts were dried (Na2SO4) and concentrated and purified by flash chromatography to yield the title compound (528 mg, 82%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]1[C:17]([OH:19])=O.C[N:21](C)C=O>O1CCCC1.O>[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]1[C:17]([NH2:21])=[O:19]
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C1CCc2ccccc2O1
Temperature: 25 °C
Yield: 97 %

Procedure:
Oxalyl chloride (11.0 mL, 126 mmol) was added dropwise to a cooled (0° C.) solution of the compound from Example 20 (15 g, 84.3 mmol) and N,N-dimethylformamide (1 mL) in tetrahydrofuran (250 mL). Upon completion of gas evolution the mixture was warmed to room temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (450 mL). The solution was cooled to −78° C. and ammonia condensed onto the mixture. After 30 minutes the mixture was warmed to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic phase was washed with saturated aqueous sodium chloride solution (2×), dried (MgSO4), and concentrated to give a solid. The solid was triturated with 1:1 diethyl ether/hexanes and dried at 50° C. in vacuo to give a colorless solid (14.5 g, 97%). Mp 125-127° C.; 1H NMR (acetone-d6, 300 MHz) δ 7.08 (m, 3H), 6.86 (m, 2H), 6.75 (br s, 1H), 4.47 (dd, 9.2 Hz, 2.9 Hz, 1H), 2.76 (m, 2H), 2.28 (m, 1H), 0.96 (m, 1H).
Reaction SMILES: [Mg].[CH2:2](I)[CH3:3].[CH3:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]2[CH:18]=[N:19][C:20]([CH:21]=[O:22])=[C:8]2[CH2:7]1>C(I)C.C(OCC)C.O1CCCC1>[OH:22][CH:21]([C:20]1[N:19]=[CH:18][N:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[N:6]([CH3:5])[CH2:7][C:8]=12)[CH2:2][CH3:3]
Reactant: CN1Cc2c(C=O)ncn2-c2ccccc2C1=O
Reactant: CCI
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C

Procedure:
1.22 g (50.2 mmol) of magnesium shavings are covered with 60 ml of absolute diethyl ether under an argon atmosphere and treated with 2-3 drops of ethyl iodide. When the Grignard reaction starts, a solution of 4.3 ml (51 mmol) of ethyl iodide in 10 ml of absolute diethyl ether is added dropwise at the boiling point. After the magnesium has dissolved completely, the mixture is treated dropwise with a solution, warmed to 30° C., of 0.65 g (40 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde in 200 ml of absolute tetrahydrofuran. The yellow coloured suspension is heated to boiling under reflux for ca 5.5 hours, cooled to room temperature and poured into 600 ml of ice/water. The mixture is filtered over Dicalit while rinsing with tetrahydrofuran. After concentration of the filtrate in vacuo, the residue is taken up in 250 ml of chloroform. The chloroform phase is washed twice with 60 ml of water each time, dried over magnesium sulphate and concentrated. The crude product is chromatographed on silica gel using chloroform/methanol (19:1, vol/vol) for the elution. After recrystallisation from ca 40 ml of ethyl acetate, there is obtained 4,5-dihydro-3-(1-hydroxypropyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 145°-147° C.
Reaction SMILES: C1([C:7]2[C:8]([NH2:19])=[N:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=2)C=CC=CC=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[N:19]=[C:8]3[CH:7]=[CH:12][C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:10][N:9]3[CH:21]=2)=[CH:25][CH:26]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Nc1ncc(-c2ccccc2)cc1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2cn3cc(-c4ccccc4)ccc3n2)cc1
Yield: 82 %

Procedure:
Dissolving crude 3,5-diphenyl-2-amino-pyridine obtained and 5.5 g (20 mmol) of 2,4′-dibromo acetophenone into 80 milliliter of ethanol, adding 3.0 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 7 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining 6.9 g of 2-(4-bromo-phenyl)-6-phenyl-imidazo [1,2-a] pyridine (yield: 82%).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15](Cl)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:22][C:23](=[O:25])[NH2:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:23](=[O:25])[NH:24][C:15]([CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: O=C(Cl)C1c2ccccc2Sc2ccccc21
Reactant: CCCCOC(N)=O
Product: CCCCOC(=O)NC(=O)C1c2ccccc2Sc2ccccc21

Procedure:
The title compound, white solid, m.p. 151-154° C., MS: m/e 342.2 (M+H+) was prepared in accordance with the general method of example 6 from 9H-thioxanthene-9-carbonyl chloride and carbamic acid butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Br[CH2:24][CH2:25][CH3:26]>>[CH3:18][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][CH3:26])=[CH:7][N:6]=2)=[CH:10][CH:11]=1
Reactant: CCCBr
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(O)cn2)cc1
Product: CCCOc1ccc(Oc2ccc(CCC(C)NC(C)=O)cc2)nc1

Procedure:
N-{3-[4-(5-Hydroxypyridin-2-yloxy)phenyl]-1-methylpropyl}acetamide was reacted with 1-bromopropane in analogy to example 10b. Yield: 38 mg (66%), M+H+: 343.13.
Reaction SMILES: [CH3:1][N+:2]#[C-:3].C([Li])CCC.[CH2:9]([O:11][CH:12]([O:18][CH2:19][CH3:20])[C:13](OCC)=[O:14])[CH3:10].CCOC(C)=O.CCCCCC>C1COCC1>[CH2:9]([O:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]1[O:14][CH:1]=[N:2][CH:3]=1)[CH3:10]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: [C-]#[N+]C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(OCC)c1cnco1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
Prepared according to the procedure of Schollkopf (J. Am. Chem. Soc. 112 (10) 4070 (1990)). To a solution of methyl isocyanide (2.88 g, 0.0702 mol) in THF (50 mL) under argon at -78° C. was added dropwise n-butyllithium solution (1.6M in hexanes, 44 mL) over 15 mins. After stirring for an additional 20 mins at -78° C., a solution of ethyl diethoxyacetate (12.62 g, 0.0702 mol) in THF (15 mL) was added dropwise over 20 mins. The bath was allowed to warm to -30° C. over the next 2 hrs and the reaction was then stirred at 0° C. for 30 mins. The reaction was quenched at 0° C. with glacial HoAc (4.22 g, 0.0702 mol) and the solvent was removed by rotary evaporation in vacuo. The golden solid was partitioned with H2O (45 mL) and EtOAc (200 mL), and the aqueous extracted with EtOAc (2×200 mL). The combined organic was washed with satd aq NaCl, dried over Na2SO4, and concentrated in vacuo to a brown oil. Chromatography on a 300 g SiO2 flash column with a gradient of EtOAc/hexane (10%, 15%, 20%) afforded the desired compound as a colorless liquid (7.46 g, 0.0436 mol, 62%): 1H NMR (CDCl3) δ1.25 (t, J=6.9 Hz, 6H), 3.56-3.70 (m, 4H), 5.62 (s, 1H), 7.26 (s, 1H), 7.86 (s, 1H). Mass spectrum: (M+H)+ =172.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[N:14]=[C:15]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[N:30]=[N:31][NH:32][N:33]=5)[CH:24]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:5][CH:4]=1.CI.[C:36]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]3[N:14]=[C:15]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[N:30]=[N:31][N:32]([CH3:36])[N:33]=5)[CH:24]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(-c5nn[nH]n5)c4)nn23)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(-c5nnn(C)n5)c4)nn23)cc1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
To a suspension of [3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-[3-(2H-tetrazol-5-yl)-phenyl]-amine (compound T3) (111 mg, 0.25 mmol) in a mixture of DMF/acetone 1:1 (8 mL) are added methyl iodide (79 μg, 1.25 mmol) and K2CO3 (53 mg, 0.37 mmol). The mixture is stirred at room temperature over night. The reaction mixture is concentrated and water is added. The resulting precipitate is filtered and washed with methanol to yield 23 mg of the title compound as white powder.