Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:20])[C:7]3=[CH:21][NH:22][C:5]([C:6]=23)=[N:4][CH:3]=1.Cl.[NH:24]1[CH2:27][CH:26]([C:28]#[N:29])[CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:16]([CH3:18])([CH3:19])[CH3:17])[C:13]([N:24]3[CH2:27][CH:26]([C:28]#[N:29])[CH2:25]3)=[O:14])[C:8](=[O:20])[C:7]3=[CH:21][NH:22][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: N#CC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)[C@H](C(=O)N1CC(C#N)C1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 13.6 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoic acid (25 mg, 0.078 mmol) under nitrogen. THF (0.5 mL), azetidine-3-carbonitrile hydrochloride (18.45 mg, 0.155 mmol), HATU and 4-methylmorpholine (11.79 mg, 0.117 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 15-40%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow semi-solid (4.1 mg, 13.7%). 1H NMR (400 MHz, CD3OD) δ 1.17 (s, 9 H) 3.50-3.78 (m, 1 H) 4.17 (br. s., 1 H) 4.25-4.37 (m, 1 H) 4.41-4.69 (m, 2 H) 5.17-5.30 (m, 2 H) 5.44 (s, 1 H) 7.87 (br. s., 1 H) 8.25 (s, 1 H). [M+H] calc'd for C19H20ClN5O2, 386; found, 386.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.[NH2:19][CH:20]1[CH2:24][CH2:23][N:22](NC(OC(C)(C)C)=O)[CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:19][CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: CC(C)(C)OC(=O)NN1CCC(N)C1
Product: Clc1ccc2c(c1)N=C(NC1CCNC1)c1ccccc1N2
Yield: 11.2 %

Procedure:
8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (100 mg, 0.22 mmol) and 3-amino-1-N-(tert-butoxycarbonylamino)pyrrolidine (73 mg, 0.4 mmol) were reacted according to GP8 to give 7.7 mg of the title compound (166JO74). MS (ESI) 313 (MH+). Purity for MH+ (UV/MS) 100/90.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14](=[O:15])[NH:13][CH:12]=[CH:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.C1C(=O)N([Br:23])C(=O)C1>CN(C=O)C>[Br:23][C:11]1[C:7]2[NH:8][C:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:6]=2[C:14](=[O:15])[NH:13][CH:12]=1
Reactant: O=c1[nH]ccc2[nH]c3cc(Cl)ccc3c12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=c1[nH]cc(Br)c2[nH]c3cc(Cl)ccc3c12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 7-chloro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (123.5 g, 565 mmol) in DMF (941 ml) was added NBS (111 g, 621 mmol) in one portion at 5° C. The reaction exothermed. When the exotherm subsided, the ice bath was removed and the reaction was agitated at ambient temp for 40 min. The reaction mixture was poured into water (2 L) and the precipitate was filtered and washed with water. The cake was slurried in MeOH (4 L), heated to 65° C. for 1 h, and filtered through a fritted glass. The filtrate was treated with activated charcoal, heated to 65° C. for 1 h, filtered through a pad of Celite, washed with hot MeOH (2 L), and concentrated until the volume became about 300 mL. The residue was cooled to 0° C., and the precipitate was filtered, washed with MTBE, and dried to give the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 12.11 (s, 1H); 11.54 (s, 1H); 8.07 (d, 1H); 7.63 (s, 1H); 7.55 (d, 1H); 7.27 (dd, 1H). LRMS (APCI) calc'd for (C11H6BrClN2O) [M+H]+, 296.9. found 296.9.
Reaction SMILES: Cl.[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:45])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37](=O)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:29][CH2:28]2)[CH:22]=1)=[O:19].CC(O)=O.C([O-])([O-])=O.[K+].[K+]>O.[Cl-].[Cl-].[Zn+2]>[C:2]1([N:8]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:36]([CH2:35][CH2:34][CH2:33][N:30]3[CH2:31][CH2:32][CH:27]([C:23]4[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:45])[CH3:16])[CH:26]=[CH:25][CH:24]=4)[CH2:28][CH2:29]3)=[C:37]2[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Temperature: 80 °C
Yield: 20.4 %

Procedure:
A mixture of 1,1-diphenylhydrazine hydrochloride (10.3 mg, 0.0470 mmol), 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidinyl]phenyl}propanamide (14.7 mg, 0.0362 mmol), ZnCl2 (14.85 mg, 0.109 mmol), and HOAc (0.5 mL) was heated for 4 h at 80° C. The resulting crude mixture was diluted with water (10 mL), the aqueous layer was neutralized with saturated K2CO3 and extracted with CH2Cl2 (3×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide (4.1 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 7.71–7.65 (m, 1H), 7.42 (d, 1H, J=7.4 Hz), 7.39 (s, 1H), 7.36–7.15 (m, 15H), 6.94 (d, 1H, J=7.8 Hz), 3.12 (d, 2H, J=11.2 Hz), 2.90 (t, 2H, J=7.8 Hz), 2.59–2.45 (m, 3H), 2.19–1.91 (m, 7H), 1.82 (d, 2H, J=13.5 Hz), 1.24 (d, 6H, J=6.9 Hz); ESMS m/e: 555.3 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11](=[O:14])([O-])[O-].[K+].[K+].O>CS(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:8]([C:3]1[C:2]([N:4]2[CH2:5][CH2:11][O:14][CH2:2][CH2:3]2)=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ncccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ncccc1N1CCOCC1

Procedure:
To a solution of 3-bromo-2-nitropyridine (207 mg, 1 mmol) in DMSO (2 mL) was added at room temperature under stirring and under an atmosphere of nitrogen morpholine (95.8 mg, 95.8 μL, 1.1 mmol), tetrabutyl ammonium iodide (18.5 mg, 50.0 μmol) and potassium carbonate (152 mg, 1.1 mmol). The reaction was stirred at 80° C. over night. Water was added and the aqueous phase was extracted twice with diethyl ether. The combined organic layers were washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a yellow oil (57 mg, 27%) after column chromatography on silica gel using a gradient from heptane/ethyl acetate 4:1 to 1:1 (v/v) as eluent.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Sn](Cl)Cl>CO>[CH:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1NC1CCCCC1
Agent: Cl[Sn]Cl
Solvent: CO
Product: Nc1ccccc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
Cyclohexyl-(2-nitro-phenyl)-amine from Example E26.1 (3.0 g, 13.6 mmol) was dissolved in methanol (100 ml) and tin (II) chloride (12.9 g, 68.1 mmol) was added. The mixture was stirred for 20 h at room temperature then heated at reflux for 18 h and concentrated in vacuo. The residue was placed in EtOAC (100 ml), cooled down to 0° C. and pH was adjusted to 14 with conc. NH3. The precipitate was filtered off and washed with EtOAc. The filtrate was washed with 2M NH3, water then brine, dried and concentrated in vacuo to yield the title compound (2.25 g, 86%).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:29])[CH2:5][C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH:8]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:20])[N:7]=1.[I-].[Na+].Cl[CH2:33][C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][N:35]=1>CN(C)C=O>[CH3:3][CH:4]([CH3:29])[CH2:5][C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:33][C:34]2[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][N:35]=2)[C:9](=[O:17])[CH:8]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:20])[N:7]=1
Reactant: Cc1cccc(NC(=O)NC2N=C(CC(C)C)c3ccccc3NC2=O)c1
Reactant: Cc1cccnc1CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)NC2N=C(CC(C)C)c3ccccc3N(Cc3ncccc3C)C2=O)c1
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a suspension of sodium hydride (0.027 g of a 64% dispersion in mineral oil) in N,N-dimethylformamide (3 ml) was added gradually N-[(3RS)-2,3-dihydro-5-(2-methylpropyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (0.200 g) at ambient temperature and the mixture was stirred for 1 hour under the same conditions. To the mixture was added sodium iodide (0.107 g) and followed dropwise a solution of 2-chloromethyl-3-methylpridine (0.093 g,) in N,N-dimethylformamide (2 ml) at the same temperature. The resultant mixture was concentrated in vacuo and the residue was taken up with ethyl acetate and water. The aqueous layer was extracted with another ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a crude compound. The crude compound was recrystallized with isopropyl ether and chloroform to give N-[(3RS)-2,3-dihydro-5-(2-methylpropyl)-1-(3-methylpyridin-2-yl)methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (0.23 g) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[OH:20][CH2:21][C:22]([NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2)=[O:23]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=[C:28]2[C:27]3[C:31](=[CH:32][CH:33]=[C:25]([NH:24][C:22](=[O:23])[CH2:21][OH:20])[CH:26]=3)[NH:30][C:29]2=[O:34])=[CH:6][CH:7]=1
Reactant: O=C(CO)Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Product: O=C(CO)Nc1ccc2c(c1)C(=Cc1[nH]c3c(c1-c1ccc(F)cc1)C(=O)NCC3)C(=O)N2
Yield: 47 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 2-hydroxy-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide as starting materials to give N-{3-[3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-2-hydroxy-acetamide (50 mg, 47.0%) as a red solid.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:18](=[O:19])[O:17][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](OC(=O)CC)(=O)[CH2:27]C>>[C:16]([NH:15][CH:14]([CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18](=[O:19])[CH2:26][CH3:27])(=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1OC(c2ccccc2)N=C1CCCCNC(=O)c1ccccc1
Reactant: CCC(=O)OC(=O)CC
Product: CCC(=O)C(CCCCNC(=O)c1ccccc1)NC(=O)c1ccccc1

Procedure:
Reaction of 4-(4-benzamidobutyl)-2-phenyl-5-oxazolone according to the procedure of Example 1 (ii) but using propionic anhydride in place of acetic anhydride yields 4,8-dibenzamidooctan-3-one which on hydrolysis according to the procedure of Example 1 (iii) gives 4,8-diaminooctan-3-one. Reaction of this product with potassium thiocyanate according to the procedure of Example 1 (iv) gives the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH3:16][CH:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:21][CH:17]([CH3:16])[C:18]#[C:19][CH3:20])[N:3]=[CH:4][N:5]=1
Reactant: CC#CC(C)O
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(C)Oc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
In 5 ml of N,N-dimethylformamide were dissolved 135 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 60 mg of 3-pentyn-2-ol, to which 29 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 5 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 130 mg of 4-(2,3-difluorophenyl)-6-(1-methyl-2-butynyloxy)pyrimidine (the present compound (167)).
Reaction SMILES: Br[CH:2]([F:28])[C:3]([F:27])([F:26])[S:4][C:5]1[NH:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:7]2[N:6]=[C:5]([S:4][C:3]([F:27])([F:26])[CH2:2][F:28])[NH:9][C:8]=2[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2nc(SC(F)(F)C(F)Br)[nH]c2-c2ccc(OC)cc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(SC(F)(F)CF)[nH]c2-c2ccc(OC)cc2)cc1

Procedure:
To a solution of 2-(2-bromo-1,1,2-trifluoroethylthio)-4,5-bis(4-methoxyphenyl)imidazole (14.2 g., 0.03 mole) in 150 ml. toluene is added tri-n-butyltin hydride (9.0 g., 0.03 mole). The mixture is refluxed for four hours. Another 9.0 g. (0.03 mole) of tri-n-butyltin hydride is added and the mixture is refluxed overnight. The mixture is then added directly to a column of 2 lb. of silica gel (SilicAR® CC-7). Elution with toluene followed by toluene/ethyl acetate (95/5) gives 6.5 g. of crystalline product. A recrystallization from methylcyclohexane gives 5.6 g. of pure product, m.p. 143.5°-145°.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6].[CH3:33]I.O>CN(C)C=O>[CH2:3]([O:7][C:8]1[C:13]([CH2:14][O:15][CH3:33])=[CH:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[C:10]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1COC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (11 mg 4.5 mMol) is added to a stirring solution of 2-butoxy-6-(4-fluorophenyl)-3-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]pyridine (Example 29) (128 mg, 0.3 mMol) in dimethylformamide (50 mL). After 1 hour, methyl iodide (85 mg, 0.6 mMol) is added and the reaction mixture is stirred for 20 hours at room temperature. Water (1 mL) is added dropwise and the mixture is concentrated to an oily solid. The titled material is purified by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([F:30])[CH:11]=[C:12]2[C:17]=1[O:16][CH:15]([CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:14][CH2:13]2.[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:18][CH:15]1[CH2:14][CH2:13][C:12]2[C:17](=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:9]=[C:10]([F:30])[CH:11]=2)[O:16]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1CCc2cc(F)cc(-c3ccccc3Cl)c2O1
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
A solution of toluene-4-sulfonic acid 8-(2-chloro-phenyl)-6-fluoro-chroman-2-ylmethyl ester (253 mg, 0.566 mmol) and sodium azide (147 mg, 2.264 mmol) in anhydrous dimethyl sulfoxide (8 mL) was heated to 70° C. under nitrogen for 20 hours. The cooled reaction mixture was quenched by the addition of water (30 mL) and the resulting suspension stirred vigorously for 10 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 170 mg (95%) of 2-azidomethyl-8-(2-chloro-phenyl)-6-fluoro-chroman a colorless syrup.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:11]([O:18][CH:19]1[CH2:24][CH2:23][C:22]([CH3:28])([C:25](Cl)=[O:26])[CH2:21][CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al](Cl)(CC)CC.CCOCC>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:11]([O:18][CH:19]1[CH2:24][CH2:23][C:22]([C:25]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=3)[NH:8][CH:9]=2)=[O:26])([CH3:28])[CH2:21][CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C(=O)Cl)CCC(OCc2ccccc2)CC1
Reactant: Brc1cnc2[nH]ccc2n1
Agent: CC[Al](Cl)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCC(OCc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
A solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (531 mg, 2.68 mmol) and 4-benzyloxy-1-methyl-cyclohexanecarbonyl chloride (2.15 g, 8.05 mmol) in anhydrous Toluene (16 ml) was treated with Et2AlCl (1M in Hexanes, 5.36 ml, 5.36 mmol), dropwise. The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, quenched with sat. NaHCO3, and extracted with ethyl acetate (3×). The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a dark brown oil. Silica gel chromatography using 0-50% Et2O in DCM as eluant provided 205 mg (18%) of (4-benzyloxy-1-methyl-cyclohexyl)-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanone as a pale yellow solid. M−H=426.
Reaction SMILES: C(O)(C)C.C(O)=O.[CH2:8]([C:10](=[CH:13][CH3:14])[CH:11]=O)[CH3:9].[NH2:15][C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:13]([C:10]1[C:8]([CH3:9])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:15][CH:11]=1)[CH3:14]
Reactant: CC=C(C=O)CC
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CC(C)O
Product: CCOC(=O)c1ncc(CC)c(C)c1C(=O)OCC
Temperature: 70 °C
Yield: 24.3 %

Procedure:
Isopropyl alcohol 300 ml and 90% formic acid 12.8 g (0.250 mol) were placed in 500 ml four-neck flask equipped with a reflux condenser. After heating the content to 70° C., a mixture of 2-ethyl-2-butenal 21.6 g (0.22 mol) and ethyl β-amino-β-ethoxycarbonylacrylate 31.1 g (0.166 mol) was added dropwise thereto with air-bubbling and refluxed for 48 hours. To this reaction mixture, conc. hydrochloric acid 10 ml was added dropwise thereto to precipitate remaining ethyl β-amino-β-ethoxy-carbonylacrylate as its hydrochloride form and filtered off at 20° C. Concentration of the filtrate gave 52.2 g of oily substance, which was subjected to silica gel column-chromatography (eluent; ethyl acetate: benzene=1:3) and 10.7 g of 5-ethyl-4-methyl-2,3-diethoxycarbonylpyridine was obtained.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].SCCC(O)=O.[CH3:16][CH:17]1CC(C)(C)[CH2:21][C:19](=[O:20])[CH2:18]1.Cl.[OH-].[Na+]>O>[CH:6]1[CH:5]=[C:4]([C:8]2[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[CH:21]=2)[C:3]([OH:9])=[CH:2][CH:7]=1
Reactant: CC1CC(=O)CC(C)(C)C1
Reactant: Cc1cccc(C)c1O
Agent: Cl
Agent: O=C(O)CCS
Agent: [Na+]
Solvent: O
Product: Oc1cccc(-c2ccccc2O)c1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
2196 g (18 mol) of 2,6-dimethylphenol, 38.2 g (0.36 mol) of β-mercaptopropionic acid and 420 g (3 mol) of dihydroisophorone (3,3,5-trimethylcyclohexan-1-one) are introduced into a stirring apparatus equipped with a stirrer, thermometer, reflux condenser and gas inlet pipe at 35° C. Dry HCl gas is introduced into this solution at 35° C. over a period of 5 h. The mixture is then left to react at 28°-30° C. for a period of about 10 hours. When 95% of the ketone has been converted (examined by GC) 2.5 l of water are added to the reaction mixture and a pH value of 6 is adjusted by the addition of a 45% NaOH solution. The reaction mixture is stirred for one hour at 80° C. and then cooled to room temperature. The aqueous phase is decanted off and the remaining residue is washed with water at 60° C. The resulting crude product is filtered off and hot-extracted three times with n-hexane and is then filtered.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=O)[CH3:2].Cl.[OH:17][NH3+:18]>N1C=CC=CC=1.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5](=[N:18][OH:17])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)[CH3:2]
Reactant: [NH3+]O
Reactant: CCOC(=O)C(=O)c1ccc(SC)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(=NO)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
22.4 g (0.1 mol) of (4-Methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester and 7.6 g (0.1 mol) of hydroxylammonium hydrochloride are dissolved in 180 ml of pyridine and the mixture is stirred at room temperature for 16 hours. The yellowish solution is diluted with water and ethyl acetate, the organic phase separated and the aqueous phase extracted several times with ethyl acetate. The combined organic extracts are washed with diluted hydrogen chloride and water and the solvent is evaporated. 24 g (100%) of crude hydroxyimino-(4-methylsulfanyl-phenyl)-acetic acid ethyl ester (66:34 mixture of the E and Z-isomers) are thus obtained and used in the next step without further purification. The structure is confirmed by the 1H-NMR spectrum (in CDCl3). δ[ppm]: 7.46 (d,2H), 7.19 (d,2H), 4.44 (E) and 4,32 (Z) (two d,2H) 2.47 (Z) and 2.46 (E) (s,3H) 1.37 (E) and 1.28 (Z) (t,3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:50]1[CH2:51][CH2:52][CH:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48][CH2:49]1)(=[O:18])[CH3:16]
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and acetyl chloride as starting materials in 43% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.02 (s, 2H), 9.40 (s, 1H), 9.01 (s, 1H), 8.31 (s, 2H), 8.20 (s, 1H), 7.65 (s, 1H), 7.31 (d, 1H), 7.08 (d, 1H), 4.38 (d, 1H), 3.81 (d, 1H), 3.00 (m, 6H), 2.52 (m, 1H), 2.32 (m, 2H), 2.00 (s, 3H), 1.75 (m, 2H), 1.20 (m, 2H). LCMS for C26H29ClN7O2 (M+H)+: m/z=506.2.