Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23](O)=[O:24])=[CH:13][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.[H-].[Na+]>C1COCC1.C1C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([C:31]([F:30])([F:39])[F:40])=[CH:33][CH:34]=3)=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(C(F)(F)F)cc1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 12.5 %

Procedure:
The title compound was prepared following the procedure as described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.276 mmol), benzene (4 mL), thionyl chloride (5.0 mL), 4-(trifluoro methyl) aniline (0.133 g, 0.828 mmol), THF (5.0 mL) and 60% NaH (0.033 g, 0.825 mmol). The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.018 g of the desired product. 1HNMR (DMSO-d6): δ 2.72 (s, 3H), 7.41 (s, 2H), 7.63 (s, 2H), 7.73 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 2H), 9.47 (s, 1H), 11.39 (s, 1H), 11.60 (s, 1H); MS [M+H]+: 520.39.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:13])[C:4](=[O:12])[C:5]2[C:10]([CH3:11])=[N:9][O:8][C:6]=2[N:7]=1.[OH-].[Na+].CN(C=O)C.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>C(O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][S:1][C:2]3[N:3]([CH3:13])[C:4](=[O:12])[C:5]4[C:10]([CH3:11])=[N:9][O:8][C:6]=4[N:7]=3)=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: Cc1noc2nc(S)n(C)c(=O)c12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1noc2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a solution of 6-mercapto-3,5-dimethylisoxazolo-[5,4-d]pyrimidin-4(5H)-one (800 mg) and sodium hydroxide (165 mg) in 50% ethanol (10 ml)-DMF (10 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (1.25 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to provide the title compound as colorless solid (470 mg). 1H-NMR (CDCl3) 8: 2.57(3H,s), 3.55(3H,s), 4.59(2H,s), 7.46(2H,d,J=8.6Hz), 7.58(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.76(2H,d,J=8.6Hz).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][CH2:7][CH2:8][C:9]1[C:10]([Cl:19])=[N:11][C:12]2[N:13]([N:16]=[CH:17][CH:18]=2)[C:14]=1[Cl:15].[N+:20]([O-])([OH:22])=[O:21]>>[Cl:6][CH2:7][CH2:8][C:9]1[C:10]([Cl:19])=[N:11][C:12]2[N:13]([N:16]=[CH:17][C:18]=2[N+:20]([O-:22])=[O:21])[C:14]=1[Cl:15]
Reactant: O=[N+]([O-])O
Reactant: ClCCc1c(Cl)nc2ccnn2c1Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnn2c(Cl)c(CCCl)c(Cl)nc12
Temperature: 0 °C
Yield: 95.5 %

Procedure:
To 100 ml of concentrated sulfuric acid cooled to 0° C. with ice water, were added 50 ml of 90% nitric acid gradually so as not to raise the temperature. After the resultant mixed acid was stirred for a while, 13.80 g of the compound prepared in Example 49 as remained crystals were added gradually so as not to raise the temperature also. The resultant mixture was stirred for 4 hours while maintaining the temperature at 0° C. Since spots attributable to the raw materials on TLC disappeared, the stirring was stopped, and the reaction mixture was poured into ice water. Crystals deposited were collected by filtration and air-dried to obtain 15.61 g (yield: 95.5%) of the intended product. Yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([CH3:17])[C@:13]([CH2:19][CH2:20][C:21]([NH:23][C:24]4[S:25][CH:26]=N[N:28]=4)=[O:22])([CH3:18])[CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.N[C:30]1SC=NN=1.NC1SC=CN=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([CH3:17])[C@:13]([CH2:19][CH2:20][C:21]([NH:23][C:24]4[S:25][CH:26]=[CH:30][N:28]=4)=[O:22])([CH3:18])[CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: CC1=Cc2c(cnn2-c2ccc(F)cc2)C[C@]1(C)CCC(=O)Nc1nncs1
Agent: Nc1nccs1
Product: CC1=Cc2c(cnn2-c2ccc(F)cc2)C[C@]1(C)CCC(=O)Nc1nccs1

Procedure:
The title compound was prepared in a manner analogous to the preparation of the title compound of Example 171, replacing and 2-amino-1,3,4-thiadiazole with 2-aminothiazole. MS found: (M+H)+=397. 1H NMR (400 MHz, chloroform-D) δ ppm 1.20 (s, 3 H) 1.79-1.90 (m, 2 H) 1.91 (s, 3 H) 2.53-2.68 (m, 3 H) 2.79 (d, J=16.00 Hz, 1 H) 6.23 (s, 1 H) 7.06 (d, J=4.07 Hz, 1 H) 7.17 (t, J=8.65 Hz, 2 H) 7.39-7.50 (m, 4 H).
Reaction SMILES: C(O/[CH:4]=[C:5]1\[C:6](=[O:24])[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[N:8]=[C:9]\1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1F)C.C(=O)([O-])[O-].[K+].[K+].[NH:31]1[C:39]2[C:34](=[CH:35][C:36]([CH2:40][NH2:41])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1>O>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:7]1[C:6](=[O:24])[C:5]2=[CH:4][N:41]([CH2:40][C:36]3[CH:35]=[C:34]4[C:39](=[CH:38][CH:37]=3)[NH:31][CH:32]=[CH:33]4)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9]2=[N:8]1
Reactant: NCc1ccc2[nH]ccc2c1
Reactant: CCO/C=C1\C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=c1c2cn(Cc3ccc4[nH]ccc4c3)c3ccccc3c-2nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(4Z)-4-[(Ethoxy)methylidene]-2,5-bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one (236 mg, 0.720 mmol), potassium carbonate (100 mg, 0.720 mmol, 1 equiv) and 1-(1H-indol-5-yl)methanamine (105 mg, 0.720 mmol, 1 equiv) were combined and placed into a preheated oil bath at 100° C. open to the air for 2.5 hours. The mixture was cooled to ambient temperature, poured into water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound: 1H-NMR (500 MHz, d6-DMSO) δ 11.14 (1H, s), 9.12 (1H, s), 8.18 (1H, d, J=8.0 Hz), 7.89 (1H, d, J=9.0 Hz), 7.62-7.58 (2H, m), 7.53 (1H, s), 7.51 (1H, t, J=7.7 Hz), 7.48-7.38 (3H, m), 7.36-7.32 (2H, m), 7.09 (1H, d, J=8.6 Hz), 6.40 (1H, br m), 5.78 (2H, m) ppm; low resolution mass spectrometry (ES+) m/z 409.1449 [(M+H)+; calculated for C25H18FN4O: 409.1459].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>C(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])=[S:16])=[N:3][CH:4]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1ccc(Br)cn1
Solvent: ClCCl
Product: CCOC(=O)NC(=S)Nc1ccc(Br)cn1
Temperature: 20 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2-amino-5-bromopyridine (200.0 g, 1.156 mol) in DCM (2.0 L) cooled to 5° C. was added ethoxycarbonyl isothiocyanate (134.9 mL, 1.156 mol) dropwise over 15 min. The reaction mixture was then allowed to warm to room temperature (20° C.) and stirred for 16 h. Evaporation in vacuo gave a yellow solid which was collected by filtration, thoroughly washed with petrol (3×500 mL) and air-dried to afford the title compound (351.5 g, quantitative). No further purification was required.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1cccc(O)c1
Yield: 893.9 %

Procedure:
A suspension of 3-hydroxyphenylacetic acid (5.4 g) and para-toluensulfonic acid (650 mg) in 80 ml of ethanol is refluxed for 4 hours, then the solvent is evaporated off and the residue is dissolved in ethyl acetate and washed twice with a saturated aqueous solution of sodium hydrogencarbonate. The organic phase is dried over sodium sulfate and the solvent is evaporated off to give 6.08 g of the product as a yellow oil.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[N:10][NH:9][C:8]1=[S:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([O:32][CH3:33])[CH:26]=[C:25]3[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=2)=[O:21])=[CH:16][CH:15]=1.O>C1COCC1>[Cl:40][C:36]1[CH:35]=[C:34]([C:25]2[C:24]3[C:29](=[CH:30][CH:31]=[C:22]([C:20]([C:17]4[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=4)([C:11]4[N:7]([CH3:6])[C:8]([SH:12])=[N:9][N:10]=4)[OH:21])[CH:23]=3)[N:28]=[C:27]([O:32][CH3:33])[CH:26]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Reactant: Cn1cn[nH]c1=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nnc(S)n3C)ccc2n1
Temperature: -70 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
BuLi (0.233 mol) was added dropwise at −70° C. to a solution of 2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.0612 mol) in THF (350 ml) under N2 flow. The mixture was stirred at −70° C. for 1 hour and then brought to 0° C. The mixture was stirred at 0° C. for 45 minutes and then cooled to −70° C. A solution of intermediate (56) (0.0612 mol) in THF (150 ml) was added. The mixture was then brought to 0° C., poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: Cyclohexane/EtOAc 70/30; 15–35 μm). The pure fractions were collected and the solvent was evaporated, yielding 11.06 g (35%) of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(5-mercapto-4-methyl-4H-1,2,4triazol-3-yl)-2-methoxy-6-quinolinemethanol (intermediate 57), mp. >260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([O:18][CH2:19][C:20]#[N:21])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([CH2:22][NH:23][C:24]([C:26]2[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]=2[CH2:35][CH2:36][CH2:37][CH3:38])=[O:25])=[CH:13]3)=[CH:4][CH:3]=1.[N-:39]=[N+:40]=[N-:41].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([O:18][CH2:19][C:20]3[NH:41][N:40]=[N:39][N:21]=3)=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([CH2:22][NH:23][C:24]([C:26]2[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]=2[CH2:35][CH2:36][CH2:37][CH3:38])=[O:25])=[CH:13]3)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(Cl)cc3)c(OCC#N)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(Cl)cc3)c(OCc3nnn[nH]3)ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid [5-(4-chloro-phenyl)-6-cyanomethoxy-naphthalen-2-ylmethyl]-amide (152 mg, 0.29 mmol), prepared in the previous step, sodium azide (59 mg, 0.90 mmol) and ammonium chloride (85 mg, 1.58 mmol) in 10 mL of DMF was stirred under nitrogen at 100° C. for 24 h (overnight). If starting material remains additional sodium azide and ammonium chloride are added and the stirring continued at 100° C. until the reaction is complete. The reaction was diluted with 50 mL of water, made basic by the addition of 1 N NaOH and extracted multiple times with ethyl acetate. The aqueous layer was acidified. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (149 mg, 91%) as a white solid, mp 208-211° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19].Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[CH:22]=[CH:21][CH:20]=2)=[C:8]([CH2:17][CH2:18][CH3:19])[C:9]=1[OH:16])(=[O:15])[CH3:14]
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(OCc2cccc(Nc3ccc(C#N)cc3)c2)ccc(C(C)=O)c1O
Temperature: 100 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
Combine 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.00 g, 3.34 mmol), 4-bromo-benzonitrile (553 mg, 3.03 mmol), cesium carbonate (1.39 g, 4.25 mmol), and 18-crown-6 (80 mg, 0.304 mmol) in toluene (25 mL) and stir. Purge reaction vessel with argon. Add BINAP [rac-2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl] (284 mg, 0.456 mmol), and palladium acetate (68 mg, 0.304 mmol). Purge reaction vessel with argon. Heat to 100° C. After 18 hours, cool to ambient temperature. Add 10% aqueous citric acid, and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate to dryness. Purify the resulting residue by flash chromatography eluting with 30% ethyl acetate:hexanes to yield the title compound as a yellow solid (760 mg, 63%): 1H NMR (CDCl3) δ 0.92 (t, 3H), 1.58 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H), 5.15 (s, 2H), 6.07 (bs, 1H), 6.47 (d, 1H), 6.98 (d, 2H), 7.13 (t, 2H), 7.23 (m, 1H), 7.38 (t, 1H), 7.49 (d, 2H), 7.58 (d, 1H), 12.75 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][CH:14]([CH:17]=O)[CH:15]=O>>[Br:13][C:14]1[CH:15]=[C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][NH:9][C:10]2=[N:12][CH:17]=1
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: O=CC(Br)C=O
Product: Brc1cnc2[nH]nc(-c3ccccc3)c2c1
Yield: 13 %

Procedure:
5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridine x151 is synthesized according to the method described in example 20.1 using 3-phenyl-1H-pyrazol-5-amine x150 and bromomalonaldehyde x9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:28]([NH2:30])[CH3:29])=[C:18]([F:31])[CH:17]=1.C(N(CC)CC)C>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:28]([NH:30][S:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])(=[O:13])=[O:12])[CH3:29])=[C:18]([F:31])[CH:17]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CC(N)c1ccccc1-c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)c(OC)c1

Procedure:
The title compound was prepared from 2,4-dimethoxybenzenesulfonyl chloride (379 mg, 1.6 mmol), 1-(4′-chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethylamine (400 mg, 1.6 mmol), and triethylamine (246 μL, 1.7 mmol) according to the procedure and in the same manner as described in Example 105, step c resulting in the isolation of 480 mg (67%) of a white solid;
Reaction SMILES: [I-:1].F[C:3]1[CH:12]=[CH:11][C:10]2[N:9]3[C:13]4[CH:22]=[CH:21][C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[N+:14]=4[CH:23]=[C:8]3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C)C=O>[I-:1].[N:24]1([C:3]2[CH:12]=[CH:11][C:10]3[N:9]4[C:13]5[CH:22]=[CH:21][C:20]6[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=6[N+:14]=5[CH:23]=[C:8]4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Fc1ccc2c(ccc3c[n+]4c5ccccc5ccc4n32)c1
Reactant: C1COCCN1
Agent: [I-]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)ccc1n3c(ccc4cc(N5CCOCC5)ccc43)c[n+]21

Procedure:
A mixture of 1.04 g. of 10-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 3.0 ml. of morpholine and 40 ml. of dimethylformamide is heated at gentle reflux for 40 hours, treated with 1.5 g. of sodium iodide and evaporated at reduced pressure to give 10-(4-morpholinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide; m.p. >300° C. after two crystallizations from aqueous methanol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(C)C2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCC(C)C2)nc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 6.2 %

Procedure:
To a solution of methyl 2-(4-methyl-2-(3-methylpiperidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate (0.067 g; 0.169 mmol) in methanol (4.1 mL) was added a solution of sodium hydroxide 5% (4.1 mL, 5.12 mmol) and the mixture was stirred at room temperature for 4 days. The volatiles were removed under reduced pressure, the residue dissolved in water and the pH was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N. The formed precipitate was collected by filtration. Purification by preparative HPLC (HPLC method 3) furnished 0.004 g (6%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([OH:24])[CH:4]([NH:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:5](OCC)=[O:6].[CH3:27][NH2:28]>C(O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][CH:4]([C:5](=[O:6])[NH:28][CH3:27])[CH:3]([OH:24])[C:2]([F:26])([F:25])[F:1])=[O:23])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: CCOC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)C(F)(F)F
Reactant: CN
Solvent: CCO
Product: CNC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.1 g (7.9 mmol) of ethyl 4,4,4-trifluoro-2-(4-fluoro-2-trifluoromethylbenzoylamino)-3-hydroxybutyrate were dissolved in ethanol. At RT, 20 ml of a 3.9% strength solution of methylamine in ethanol was added. After 5 h of stirring at RT, methylamine gas was introduced for 10 min and the mixture was stirred at RT for 16 h. The reaction solution was then concentrated, and the residue was washed with MTBE. This gave 1.8 g (61% of theory) of the title compound as colorless crystals (diastereomer ratio 3:1) of m.p. 212° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([C:28]2[O:32][N:31]=[C:30]([CH2:33]Cl)[N:29]=2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1[N:5]([CH2:33][C:30]2[N:29]=[C:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:36])([F:20])[F:35])[CH:23]=3)[O:32][N:31]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2
Reactant: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 using 2-(2-methylpropyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-[3-(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.22 (d, J=7.8 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.66 (m, 2H), 7.54 (d, J=8.3 Hz, 1H), 6.63 (d, J=1.2 Hz, 1H), 5.48 (s, 2H), 2.84 (d, J=7.3 Hz, 2H), 2.14 (m, 1H), 1.08 (d, J=6.6 Hz, 6H); MS (ES) m/z 493 (M+1).
Reaction SMILES: [CH3:1][CH2:2]/[C:3](=[C:11](/[CH2:19][CH3:20])\[C:12]1[CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=1)/[C:4]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1.O.[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[OH:16][C:15]1[CH:14]=[CH:13][C:12]([C:11](=[C:3]([C:4]2[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=2)[CH2:2][CH3:1])[CH2:19][CH3:20])=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]
Reactant: CC/C(=C(/CC)c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCC(=C(CC)c1ccc(O)c([N+](=O)[O-])c1)c1ccc(O)cc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 18.8 %

Procedure:
Under a nitrogen atmosphere, a suspension of diethylstilbestrol (1.0 g) in acetic acid (160 ml)-water (16 ml) was cooled to 5° C., and 70% nitric acid (0.34 g) was added dropwise thereto. Then, the resulting mixture was heated to 20° C. and stirred for 5 hours. The solvent was distilled off under reduced pressure and an aqueous sodium hydrogencarbonate solution was added to the residue, followed by two runs of extraction with ethyl acetate (150 ml). The combined organic layer was washed with water (200 ml), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=9:1) to obtain 3-(4-hydroxy-3-nitrophenyl)-4-(4-hydroxyphenyl)-3-hexene (0.22 g, yield 19%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1.[OH-].[Li+]>CO.O>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1
Reactant: COC(=O)c1cnc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3.2 g (10 mMol) of methyl 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4.5-b]pyridine-6-carboxylate in 150 ml methanol was mixed with a solution of 1.5 g lithium hydroxide in 20 ml water and stirred for 24 hours at room temperature. Then the mixture was diluted with 50 ml of water, the alcohol was distilled off and the aqueous phase was washed with ethyl acetate. After acidification with dilute hydrochloric acid the mixture was extracted several times with dichloromethane/methanol (9:1), the organic phase was dried with sodium sulphate and the solvent was distilled off. Yield: 2.1 g beige solid (70% of theory), Rf value: 0.38 (silica gel; ethyl acetate/ethanol/ammonia =50:45:5)
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1>CN(C=O)C.CCOC(C)=O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:3][CH2:4][CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)=[N:13][CH:14]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(OCCN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
280 mg (7.00 mmol, 60%) NaH are added to a solution of 0.76 mL (6.14 mmol) N-(2-hydroxyethyl)pyrrolidine in 20 mL DMF at RT. The reaction solution is stirred for 45 min at RT and then 1.35 g (5.53 mmol) 2,5-dibromopyridine are added. The solution is stirred for 16 h at 70° C. and the solvent is eliminated i.vac. The residue is taken up in 100 mL EtOAc and 50 mL water and the organic phase is extracted with 40 mL saturated NaCl solution. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (gradient: cyc/EtOAc 1:1 to EtOAc).