Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[N:18])=[CH:7][CH:6]=1)C(C)=O.[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([NH2:1])=[CH:6][C:7]=1[N+:19]([O-:21])=[O:20])#[N:18]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(-c2ccccc2C#N)cc1
Agent: O=S(=O)(O)O
Product: N#Cc1ccccc1-c1ccc(N)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
4'-Acetamino-2-cyanobiphenyl (0.265 moles, 62.47 g.) was added at -15° to -20° C. to 600 ml of concentrated sulfuric acid. While maintaining the temperature below -15° C., nitric acid (0.278 moles, 17.5 g of 90%) in 200 ml of concentrated sulfuric acid was added dropwise. The reaction was stirred for 30 minutes following the addition and then for 3 hours at room temperature. The reaction was poured onto ice with vigorous stirring. The precipitate was filtered and dried. The solid was stirred in methanol (6 liters) and 2N sodium hydroxide (11 liters) for 6 hours, filtered and dried. The reaction produced 60 g of 4-(2-Cyanophenyl)-3-nitroaniline. (MS)
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][O:3]1.Cl.[C:19]([O:23][C:24](=[O:27])[CH2:25][NH2:26])([CH3:22])([CH3:21])[CH3:20]>CO>[C:19]([O:23][C:24](=[O:27])[CH2:25][N:26]1[C:2](=[O:3])[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(OCc1ccccc1)c1ccc(=O)oc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)Cn1cc(C(=O)OCc2ccccc2)ccc1=O
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of benzyl 2-oxo-2H-pyran-5-carboxylate (906 mg, 3.94 mmol) and glycine tert butyl ester hydrochloride (726 mg, 4.33 mmol) in MeOH (20 mL) was treated with TEA (1.642 mL, 11.81 mmol). The reaction was stirred at 23° C. under nitrogen. After 1 h, the solution was concentrated in vacuo and purified by silica gel chromatography (eluent: 10-50% EtOAc/hexane), affording the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.11 (d, J=2.35 Hz, 1H), 7.90 (dd, J=9.59, 2.54 Hz, 1H), 7.31-7.54 (m, 5H), 6.55 (d, J=9.59 Hz, 1H), 5.30 (s, 2H), 4.56 (s, 2H), 1.48 (s, 9H). MS (ESI, positive ion) m/z: 366.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])[C:5]([C:13]#[N:14])=[C:4]([S:15][CH3:16])[N:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]C[S-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])[C:5]([C:13]#[N:14])=[C:4]([S:15][CH2:16][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[N:3]=1
Reactant: C=C(OCC)c1nc(N)nc(SC)c1C#N
Reactant: [S-]CCc1ccccn1
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(OCC)c1nc(N)nc(SCCc2ccccn2)c1C#N
Temperature: 100 °C
Yield: 1.4 %

Procedure:
To a stirred suspension of 200 mg (0.85 mmol) 2-amino-4-(1-ethoxy-vinyl)-6-methylsulfanyl-pyrimidine-5-carbonitrile in 16 ml dioxane was added 546 mg (3.38 mmol) sodium 2-pyridin-2-yl-ethanethiolate and the mixture heated at 100° C. for 1 hour. The reaction mixture was then concentrated in vacuo and the residue triturated in ether. The crystals were removed by filtration and the mother liquor concentrated in vacuo. The residue was then recrystallised from ethyl acetate/hexane and the crystals additionally purified by HPLC to afford 4.0 mg (1%) 2-amino-4-(1-ethoxy-vinyl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile as an off-white crystalline solid. ES-MS m/e (%): 328 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[CH3:11][NH2:12].Cl>C(O)C>[CH3:11][NH:12][C:5]1([C:8]([OH:10])=[O:9])[CH:6]=[CH:7][CH:2]=[N:3][NH:4]1
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: CN
Agent: Cl
Solvent: CCO
Product: CNC1(C(=O)O)C=CC=NN1
Temperature: 100 °C

Procedure:
3-Chloropyridazine-6-carboxylic acid (2.5 g) (R. F. Homer, H. Gregory, W. G. Overend and L. F. Wiggins, J. Chem.Soc (1948) 2195-9) was treated with 8M methylamine in ethanol (2.16 ml) and heated at 100° C. in a sealed bomb for 18 hours. The solution was acidified to pH 4 with 5N HCl and the precipitate filtered off to provide title compound (0.58 g). MS (−ve ion chemical ionisation) ml/z 152 ([M-H]−, 100%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:23]([OH:24])[C@@H:22]([CH2:25][OH:26])[O:21][C@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C@@H:6]1[O:27][C@H:28]1[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:29]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:3])[CH3:2].[S:63]([O-])(=[O:66])(=[O:65])[CH3:64]>>[C:1]([O:4][C@H:5]1[C@H:23]([OH:24])[C@@H:22]([CH2:25][O:26][S:63]([CH3:64])(=[O:66])=[O:65])[O:21][C@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C@@H:6]1[O:27][C@H:28]1[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:29]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)[O-]
Reactant: COC(=O)CCCCCCCCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](OC(C)=O)[C@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Product: COC(=O)CCCCCCCCO[C@H]1O[C@H](COS(C)(=O)=O)[C@@H](O)[C@H](OC(C)=O)[C@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 85.3 %

Procedure:
Compound 24 (570 mg, 0.66 mmol) was converted into its methane sulfonyl derivative exactly as described for the preparation of 10 to give 25 (530 mg, 85.3%) as a syrup after chromatography on silica gel using (hexane:ethyl acetate; 3:2) as eluant; [α]D +76.6° (c 0.57, chloroform). 1H-n.m.r. (CDCl3): δ5.19(t, 1H, J2,3 =J3,4 10.0 Hz, H-3), 4.90(d, 1H, J1',2' 3.8 Hz, H-1'), 4.82(d, 1H, J1,2 3.8 Hz, H-1), 3.57(s, 3H, OCH3), 3.00(s, 3H, CH3SO2), 2.23 and 2.03(s, 3H each, 2×Ac).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:13]=1>>[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)/[C:20]2=[O:29])=[CH:16][CH:17]=1
Reactant: Clc1ccc(I)cc1
Reactant: COC(=O)c1ccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodobenzene (commercially available) and 4-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 7.97 (d, 1H), 7.25-7.43 (m, 12H), 7.07 (dt, 1H), 6.71 (dt, 1H), 6.61 (d, 1H), 6.54 (d, 1H), 4.97 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[O:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Reactant: Oc1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3cn[nH]c3c2)cc1Cl
Temperature: 90 °C

Procedure:
To a stirred solution of 2-chloro-4-fluoro-1-nitrobenzene (3 mmol) in DMF (5 mL) was added 6-hydroxyindazole (3 mmol) and K2CO3 (6 mmol). The contents were heated at 90° C. for 6 h. The reaction mixture was cooled to RT, and the contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 6-(3-chloro-4-nitrophenoxy)-1H-indazole as a yellow solid, which was used for further transformation without any purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C#N)cc1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(C#N)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-cyano-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=259.0.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N:21]2[CH:25]=[CH:24][N:23]=[C:22]2[S:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:13][CH:12]=1)#[N:10]>ClCCl>[Br:1][C:25]1[N:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)[C:22]([S:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23][CH:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CSc1nccn1-c1ccc(C#N)c2ccccc12
Solvent: ClCCl
Product: CCOC(=O)CSc1ncc(Br)n1-c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
N-bromosuccinimide (5.48 g, 30.82 mmol) was added in three portions to a solution of ethyl 2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate (10.40 g, 30.82 mmol) in dichloromethane (150 mL) at 0° C. and then stirred at room temperature for 18 h. The mixture was washed with water (2×50 mL), saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-50% EtOAc/hexanes) provided ethyl 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate as an off-white solid (9.18 g, 71.5%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][O:15][CH3:16])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][O:15][CH3:16])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COCCC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: COCCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Reaction time: 24 h

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide (110 mg, 0.348 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (279 mg, 1.39 mmol) in n-BuOH (5 mL) was stirred at 160° C. for 24 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (1×20 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by C-18 reverse phase chromatography (Biotage 25M+ column) on Biotage SP4 unit eluting with 10-85% CH3CN gradient (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(3-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate as a solid. This material was dissolved in TFA (3 mL) and stirred at room temperature for 20 minutes. TFA was then removed in vacuo, and the residue was dissolved in a few drops of methanol and purified by C-18 reverse phase chromatography (Biotage C-18, 12M+ column) on Biotage SP4 unit eluting with 1-50% CH3CN/water gradient (14 CV). The product isolated was dissolved in CH2Cl2 (1 mL), and 2M HCl in ether (2 mL) was added. The solid was dissolved in MeOH, evaporated from CH2Cl2 (3×2 mL) and dried under high vacuum to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide hydrochloride (28 mg, 20% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.80 (s, 1H), 9.34 (s, 1H), 8.23 (br s, 4H), 7.57 (br s, 1H), 3.64 (t, 2H), 3.55-3.49 (m, 2H), 3.42-3.55 (m, 2H), 3.27 (s, 3H), 3.08-3.03 (m, 1H), 2.62 (t, 2H), 2.15-2.09 (m, 1H), 1.88-1.81 (m, 1H), 1.75-1.67 (m, 1H), 1.53-1.45 (m, 1H); LCMS (APCI+) m/z 396, 398 (M+H)+, Retention time=2.09 minutes (Method 2).
Reaction SMILES: Cl[C:2]1[CH2:7][C@H:6]2[C@H:8]3[C@:18]([F:22])([C@@H:19]([OH:21])[CH2:20][C@:4]2([CH3:5])[C:3]=1[S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]1)[CH2:10][CH2:9]3.[CH3:29][O-:30].[Na+]>CO>[CH2:27]([S:24]([C:3]1[C@:4]2([CH2:20][C@H:19]([OH:21])[C@@:18]3([F:22])[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:16]3([CH3:17])[CH:15]=[CH:14][C:13](=[O:23])[CH:12]=4)[C@@H:6]2[CH2:7][C:2]=1[O:30][CH3:29])[CH3:5])(=[O:26])=[O:25])[CH3:28]
Reactant: CCS(=O)(=O)C1=C(Cl)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCS(=O)(=O)C1=C(OC)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Yield: 39.6 %

Procedure:
A suspension of (11β)-16-chloro-17-(ethylsulfonyl)-9-fluoro-11-hydroxyandrosta-1,4,16-trien-3-one (1.29 g; prepared as described above) in anhydrous methanol (190 ml) containing sodium methoxide (800 mg) is refluxed for 3 hours. The resulting solution is concentrated in vacuo, diluted with water, saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried (anhydrous Na2SO4) and evaporated to afford the crude material (1.2 g). This is chromatographed over silica gel (60 g) to isolate the title compound (505 mg), melting point 288°-289° C., after crystallization from acetone-hexane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH:32]2[CH2:34][CH2:33]2)[C:27]2[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=2[C:25]2[CH:39]=[CH:40][CH:41]=[CH:42][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18]>CO.C(Cl)(Cl)Cl>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH:32]2[CH2:33][CH2:34]2)[C:27]2[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=2[C:25]2[CH:39]=[CH:40][CH:41]=[CH:42][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: CC(C)[C@H](N)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-T), the title compound was prepared. The reaction was monitored by tlc (Rf=0.3, 2.5% MeOH/CHCl3) and product was purified by chromatography (silica, 2.5% MeOH/CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([N:12]1[C:17]3[N:18]=[C:19](S(C)=O)[N:20]=[CH:21][C:16]=3[CH:15]=[CH:14][C:13]1=[O:25])[CH2:9][CH2:8]2.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([N:12]1[C:17]3[N:18]=[C:19]([NH:37][C:36]4[CH:35]=[CH:34][C:33]([N:30]5[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]5)=[CH:39][CH:38]=4)[N:20]=[CH:21][C:16]=3[CH:15]=[CH:14][C:13]1=[O:25])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(n1c(=O)ccc3cnc(S(C)=O)nc31)CC2
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: ClCCl
Product: COc1cccc2c1C(n1c(=O)ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nc31)CC2
Yield: 8.6 %

Procedure:
8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.29 g, 0.81 mmol) and 4-(4-methylpiperazino)aniline (0.15 g, 0.81 mmol) were stirred at 140° C. for 4 h. The reaction mixture was dissolved in dichloromethane (35 mL) and washed with 10% sodium hydroxide solution (1×15 mL) then with water (1×15 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using dichloromethane:methanol (9:1) to give 8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (32 mg, 0.07 mmol, 8.6%) as the major product. ESMS m/z 483 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 9.81 (br. s., 1H), 8.73 (s, 1H), 7.77 (d, J=9.3 Hz, 1H), 7.61 (d, J=9.0 Hz, 2H), 7.14 (t, J=7.5 Hz, 1H), 6.89 (d, J=9.0 Hz, 2H), 6.87 (br.s., 1H), 6.84 (d, J=7.3 Hz, 1H), 6.65 (d, J=8.3 Hz, 1H), 6.13 (d, J=9.3 Hz, 1H), 3.43 (s, 3H), 3.10-3.00 (m, 4H), 3.00-2.85 (m, 2H), 2.45-2.38 (m, 4H), 2.35-2.25 (m, 2H), 2.20 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([NH:20][C:21]([C:23]3[C:24]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH:17]=[CH:16][C:15]=2[Cl:38])[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([NH:20][C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][C:24]=3[NH:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH:17]=[CH:16][C:15]=2[Cl:38])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(COc2cc(NC(=O)c3cccnc3NCc3ccc(F)cc3)ccc2Cl)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(OCC2CNC2)c1)c1cccnc1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 mL of TFA/CH2Cl2 (1:1) was added 3-(2-chloro-5-{[2-(4-fluoro-benzylamino)-pyridine-3-carbonyl]-amino}-phenoxymethyl)-azetidine-1-carboxylic acid tert-butyl ester (270 mg, 0.5 mmol) at 0° C. The solution was stirred for 2 h at RT. The solvents were removed in vacuo. The residue was diluted in 30 mL of EtOAc and washed with 30 mL of saturated aqueous NaHCO3, then brine. The resulting organic phase was dried over MgSO4 and concentrated in vacuo. The title compound was purified by column chromatography (silica gel, 5% 2N NH3 in MeOH/EtOAc) and isolated as a white solid. MS (ES+): 442 (M+H)+. Calc'd for C23H22ClFN4O2-440.90.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)#[N:16]>CC(C)=O>[CH2:7]([N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]1=[N:17][C:15]#[N:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: N#CNc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CN=c1ccccn1Cc1ccccc1
Reaction time: 2.5 h
Yield: 53 %

Procedure:
7 g (50 mmole) of potassium carbonate and 6.5 ml (55 mmole) of benzyl bromide are weighted to the suspension of 6 g (50 mmole) of 2-(cyanoamino)pyridine in 100 ml of acetone, then the reaction mixture is refluxed under vigorous stirring for 2.5 hours. After cooling the inorganic salt is filtered off and the acetone filtrate is evaporated under reduced pressure. The residue is triturated with 10 ml of ether, filtered and washed twice with 5 ml of ether each to obtain 5.55 g (53.1%) of the named compound, m.p.: 142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:33])([C:25]4[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=4)[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[CH:16]=3)[N:11]([CH3:34])[C:10](=[O:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:38])=O>>[Cl:38][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([C:18]([OH:33])([C:19]2[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=2)[C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH3:34])[C:10](=[O:35])[CH:9]=[C:8]3[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:26][CH:27]=1
Reactant: Cn1cncc1C(O)(c1ccc(CO)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: O=S(Cl)Cl
Product: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of (±)-4-(3-chlorophenyl)-6-[hydroxy[4-(hydroxymethyl)phenyl](1-methyl-1H-imidazol-5yl)methyl]-1-methyl-2(1H)-quinolinone (described in Example B9) (0.000823 mol) in thionyl chloride (4 ml) was kept at room temperature for 2 hours. The solvent was evaporated till dryness. The residue was taken up in H2O. EtOAc was added. The mixture was basified with K2CO3 (10%) and extracted. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated, yielding 0.43 g (>100%) of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.Br>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCN2CCC(Cc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Agent: Br
Solvent: O
Product: Oc1ccc(CCN2CCC(Cc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of 7.7 parts of 1-[(4-fluorophenyl)methyl]-2-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methyl]-1H-benzimidazole and 150 parts of a hydrobromic acid solution 48% in water was stirred overnight at 80° C. The reaction mixture was evaporated and water was added to the residue. The whole was treated with ammonium hydroxide and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography HPLC) over silica gel using a mixture of hexane, trichloromethane and methanol (45:45:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.5 parts (35%) of 4-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]phenol; mp. 130.3° C. (504).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1.Br[C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[F:23][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:25]3[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(OCC)c3)nc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: CCOc1cccc(-c2cc(C(F)F)n3ncc(C#Cc4cccc(S(N)(=O)=O)c4)c3n2)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.19) (313 g, 1.0 mmol) and commercially available 3-bromobenzene-sulfonamide (307 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow foam (50 mg, 11%). MS (ISP) 469.3 [(M+H)+]; mp 167-168° C.