Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:66][N:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1>C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([N:70]4[CH2:71][CH2:72][N:67]([CH3:66])[CH2:68][CH2:69]4)=[O:31])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(C(=O)O)cc2)cc(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(C(=O)N3CCN(C)CC3)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic acid (162 mg; 0.34 mmol; 1 eq.), EDC-HCl (71.10 mg; 0.37 mmol; 1.10 eq.) and HOBT (50.11 mg; 0.37 mmol; 1.10 eq.) were taken up in DCM (6 ml) then DIEA (84.89 μl; 0.51 mmol; 1.50 eq.) and 1-methylpiperazine (37.52 μl; 0.34 mmol; 1 eq.) were added. The mixture was stirred at rt for 5 h. The solution was washed successively with a saturated solution of NaHCO3, NH4Cl and NaCl. The organic phase was dried over MgSO4 and concentrated to near dryness to afford 171 mg (90%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 10.06 (br s, 1H), 8.80 (s, 1H), 8.13 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 7.44-7.41 (m, 1H), 7.39-7.34 (m, 1H), 7.31 (br d, 2H), 7.21-7.14 (m, 2H), 6.15 (t, J=2.3 Hz, 1H), 3.76 (s, 6H), 3.65-3.35 (m, 4H), 3.10-2.85 (m, 4H), 2.63 (s, 3H). HPLC (max plot) 97.1%; Rt 3.55 min. LC/MS: (ES+): 563.4, (ES−): 561.2.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].Cl.[C:21]1([C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:27]([CH:29]1[CH2:34][CH2:33][N:32]([S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:31][CH2:30]1)(=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Agent: Cl
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCC(C(=O)c4ccccc4)CC3)s2)c(C)[nH]c1=O
Yield: 85 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with phenyl-piperidin-4-yl-methanone hydrochloride as described in Step 5, Example 24 to give the title compound as a yellow solid (85% yield). LC/MS: RT 3.27 min, m/e 471 (M+H); 1H NMR (CDCl3, δ, ppm): 11.95 (1H, s), 7.89 (2H, dd), 7.55-7.60 (1H, m), 7.44-7.52 (3H, m), 7.33 (1H, s), 7.01 (1H, d), 3.79-3.84 (2H, m), 3.27-3.36 (1H, m), 2.73-2.82 (2H, m), 2.60 (2H, q), 2.48 (3H, s), 1.89-2.05 (4H, m), 1.24 (3H, t).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:27])[N:8]([C:10]2[CH:11]=[CH:12][C:13]3[C:17]([CH:18]=2)=[N:16][N:15]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:14]=3)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:37][C:38]([Cl:45])([Cl:44])[CH2:39][O:40][C:41](Cl)=[O:42]>C1COCC1>[Cl:37][C:38]([Cl:45])([Cl:44])[CH2:39][O:40][C:41](=[O:42])[NH:27][C:7]1[N:8]([C:10]2[CH:11]=[CH:12][C:13]3[C:17]([CH:18]=2)=[N:16][N:15]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:14]=3)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3cn(CCN4CCOCC4)nc3c2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc3cn(CCN4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
To a solution of Intermediate 24b (86 mg, 0.23 mmol) in THF (10 mL) was added DIPEA (80 μL, 0.46 mmol), followed by the dropwise addition of a solution of 2,2,2-trichloroethylchloroformate (32 μL, 0.23 mmol) in THF (2 mL). The mixture was stirred at RT for 4 h, then partitioned between EtOAc/water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification by FCC, using 0-20% MeOH in EtOAc, gave the title compound (32 mg, 26%) as a yellow solid. LCMS (Method 4): Rt 2.64, 0.2 m/z 543, 545 [MH+].
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8]/C=C\[Sn](CCCC)(CCCC)CCCC)[CH3:7].N#N.CO.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH3:47])[C:36]=2[CH:48]=O)=[CH:31][CH:30]=1>C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH3:47])[C:36]=2/[CH:48]=[CH:7]/[CH:6]=[O:8])=[CH:31][CH:30]=1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1/C=C/C=O
Temperature: -78 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
n-BuLi (1.6M in hexanes, 1.52 ml, 2.43 mmol) was added to a solution of cis-1-ethoxy-2-(tri-n-butylstannyl) ethylene (1.06 gm, 2.94 mmol) in dry THF (7.5 ml) at -78° C. The mixture was stirred for 11/4 hours, then cooled to -100° C. (liquid N2 /methanol) and treated with a solution of 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxaldehyde (707 mg, 2.43 mmol) in THF (3.0 ml). Forty-five minutes after the addition, the temperature was raised to -78° C. and the mixture was stirred for an additional 50 minutes. The solution was then stirred in an ice bath for 5 minutes and subsequently quenched with H2O (8 ml) and 10% HCl (8 ml). After stirring at room temperature for 1.5 hours, the mixture was made basic with 10% NaOH (10 ml) and extracted twice with Et2O. The combined Et2O layers were washed with H2O and brine, dried (Na2SO4), filtered and stripped to yield a solid. The solid was washed with cold Et2O. The Et2O washings were stripped and triturated with cold hexane to give additional solid, which was pooled with the above solid to give 586 mg (76%) (E)-3-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-2-propenal. Analytically pure material was obtained by recrystallization from hot hexane/EtOAc.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:15]=[C:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:23]([N:12]1[C:11](=[O:20])[CH2:10][C:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:14](=[CH:15][CH2:16][CH2:17][CH2:18]2)[C:13]1=[O:19])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCBr
Reactant: COc1cccc(C23CCCC=C2C(=O)NC(=O)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)CC2(c3cccc(OC)c3)CCCC=C2C1=O
Yield: 67.5 %

Procedure:
The procedure in Example 9, Part A, was followed in which 4a-(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (12 g, 0.05 moles) in 150 ml of anhydrous dimethylformamide was added to a 55% suspension of sodium hydride in mineral oil (2.4 g) in 100 ml of dimethylformamide at 70°; n-hexyl bromide (9.1 g) was added, the reaction heated at 70° for 18 hrs. The crude material obtained from this procedure was chromatographed to yield 12 g of product.
Reaction SMILES: [NH:1]1[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C[Si](N[Si](C)(C)C)(C)C.C[Si](Cl)(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C(O[C@@H:39]1[O:51][C@H:50]([CH2:52][O:53]C(=O)C)[C@@H:45]([O:46]C(=O)C)[C@H:40]1[O:41]C(=O)C)(=O)C>C(#N)C>[C@@H:39]1([N:1]2[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]2=[O:3])[O:51][C@H:50]([CH2:52][OH:53])[C@@H:45]([OH:46])[C@H:40]1[OH:41]
Reactant: Nc1nc[nH]c(=O)n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 2.5 °C
Reaction time: 20 h

Procedure:
A mixture of 5-azacytosine, HMDS, and TMSCl in acetonitrile is heated to reflux for 20 hours under an inert atmosphere. TMS-triflate and 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose are then added directly to the silylated 5-azacytosine in acetonitrile. The addition is performed at ambient temperature and under an inert atmosphere. The reaction mixture is maintained under stirring for 20 hours, then the acetonitrile is removed under vacuum. The solids are then dissolved in dichloromethane, and the mixture is poured over a pre-cooled (0-5° C.) sodium bicarbonate solution (10%). The resulting mixture is extracted with dichloromethane. The combined organic extract is washed with cooled (0-5° C.) 10% sodium bicarbonate and brine, then dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuum to dryness. The off-white foam is dissolved in methanol and treated with a solution of 25% sodium methoxide in methanol. The suspension is stirred at ambient temperature for 15 hours, then the solid is filtered off, washed with methanol and anhydrous ether, then dried in vacuum. The crude 5-azacytidine is further purified from DMSO and methanol (for details see Example 4).
Reaction SMILES: [CH2:1]1[C:12]2[CH:4]([N:5]=[C:6]3[C:11]=2[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH2:3][CH2:2]1.[NH2:13]N.O.NN>>[NH2:13][CH:1]1[C:12]2[CH:4]([N:5]=[C:6]3[C:11]=2[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: NN
Reactant: c1ccc2c(c1)=NC1CCCC=21
Solvent: O
Product: NC1CCC2N=c3ccccc3=C12

Procedure:
Alternatively, in Scheme 2, Step G, the phthalimide group of the tetrahydrocyclopenta[b]indole of formula (8) is cleaved with hydrazine or hydrazine hydrate to provide an aminotetrahydrocyclopenta[b]indole of formula (9) as previously described in Step B. Subsequently, the resulting free amine is converted to the p-toluenesulfonic acid salt in ethanol.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:8][C:7]2=O)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:25])=O.O>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2[Cl:25])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c1N=C(C(=O)OC)CC2=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12

Procedure:
The product of step (b) (3 g, 0.0099 mole) was dissolved in dry benzene (50 mls), treated with phosphoryl chloride (2.5 mls) and refluxed for 1 hour. The reaction mixture was cooled, poured into water and extracted with ether, which was then washed with water and dried over magnesium sulphate. The solvent was evaporated to leave 2.8 g of yellow-brown solid. Recrystallisation from cyclohexane gave yellow needles mp 163°-164°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][C:11]([S:14][C:15]3[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=3)=[CH:10][C:9]=2[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:5][CH:6]=1.Cl.Cl[CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][CH2:31][O:21][C:17]1[CH:16]=[C:15]([S:14][C:11]2[CH:10]=[C:9]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:8]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)=[N:13][CH:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1csc(Nc2ncc(Sc3cccc(O)c3)cc2Oc2ccccc2)n1
Reactant: CN(C)CCCCl
Agent: Cl
Product: Cc1csc(Nc2ncc(Sc3cccc(OCCCN(C)C)c3)cc2Oc2ccccc2)n1

Procedure:
Prepared according to the method of Example 60 using 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)phenol and 3-chloro-N,N-dimethylpropan-1-amine hydrochloride. 1H NMR (d6-DMSO) δ 9.55 (s, 1H), 8.28 (dd, 1H), 7.49 (dd, 1H), 7.29 (m, 2H), 7.11 (t, 1H), 7.00 (t, 1H), 6.85 (m, 2H), 6.65 (m, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.38 (m, 1H), 3.70 (m, 2H), 2.21 (s, 3H), 2.04 (s, 6H) 1.96 (t, 2H), 1.44 (m, 2H); Mass spectrum (esi) m/z=−493.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:8]=2[C:9]#[N:10])[CH:6]=1.[CH3:19][N+:20]([CH3:22])=[CH2:21].[I-]>CN(C=O)C>[CH3:19][N:20]([CH2:22][C:6]1[N:5]([C:7]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][C:8]=2[C:9]#[N:10])[CH:4]=[N:3][C:2]=1[CH3:1])[CH3:21]
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2C#N)cn1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(C(F)(F)F)cc2C#N)c1CN(C)C
Yield: 53 %

Procedure:
As described for example 84b, 2-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzonitrile (+regioisomer) was reacted with Eschenmoser's salt in DMF for 16 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography afforded the title compound as a yellow oil that was sufficiently pure to be used in the next step (yield: 53%). MS: m/e=309.3 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][O:32][CH2:33][CH3:34])[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.Cl[C:36]([O:38][CH2:39][CH2:40][CH2:41]C)=[O:37]>ClCCl>[CH2:33]([O:32][CH2:31][C:20]1[N:21]([CH2:22][C:23]([CH3:25])([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH3:24])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:8][C:36](=[O:37])[O:38][CH2:39][CH2:40][CH3:41])[C:18]=2[N:19]=1)[CH3:34]
Reactant: CCCCOC(=O)Cl
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)Nc1nc2ccccc2c2c1nc(COCC)n2CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
Triethylamine (2.67 mL, 5 eq) was added to a chilled (ice/water bath) suspension of N-{2-[4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (1.5 g, 1 eq) in dichloromethane (150 mL). A solution of butyl chloroformate (1.73 g, 3.3 eq) in dichloromethane (5 mL) was added dropwise to give a clear solution. The reaction mixture was allowed to come to ambient temperature with stirring for 24 hours. The reaction mixture was washed sequentially with water (150 mL), 4% sodium carbonate (150 mL), water (150 mL), and brine (150 mL). The organic layer was concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a linear gradient of 0-20% CMA in chloroform, 1500 mL) followed by recrystallization from diethyl ether to provide 1.23 g of propyl 2-ethoxymethyl-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-4-ylcarbamate as a white powder, mp 125-127° C. Anal calcd for C23H33N5O5S: C, 56.19; H, 6.77; N, 14.25. Found: C, 56.35; H, 6.65; N, 14.24.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:13])=[O:12].[Na+:14].[CH2:15]([CH2:17][NH2:18])[OH:16].Cl>O>[OH:16][CH2:15][CH2:17][NH:18][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:13])=[O:12].[Na+:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)[O-])c1
Reactant: NCCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(NCCO)c(S(=O)[O-])c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
122 g of sodium 2-chloro-5-nitrobenzenesulphinate are kneaded together with 150 g of ethanolamine, and the mixture is gradually heated to 100° C. After 30 minutes at 100° C. 500 ml of water are added, the reaction solution is neutralised with hydrochloric acid, and the sodium 2-(2-hydroxyethyl)amino-5-nitrobenzenesulphinate is isolated as above, by salting out.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:33][OH:34].C([O-])(O)=O.[Na+]>>[OH:34][N:33]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(C#CCCC(=O)O)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(C#CCCC(=O)O)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 5-{4-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-pent-4-ynoic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (4.2:1) as a colorless oil, MS (ESI−): m/z=425.1862 ([M−H]−).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN1C(=O)CCC1>[CH:14]1([NH:20][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NC1CCCCC1
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc([N+](=O)[O-])c(NC2CCCCC2)c1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A mixture of 3-fluoro-4-nitrobenzoic acid (0.35 g, 1.891 mmol) and cyclohexylamine (2.17 mL, 18.91 mmol) in NMP (10 mL) was stirred under Ar at 85° C. for 6 h. The solvent was evaporated under high vacuum. The residue was purified by chromatography using CH3Cl-MeOH (10:1) as the eluent to give the title intermediate in a quantitative yield. MS: 263.11 (M−H+).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[CH2:1]([NH:7][C:28]([C:17]1[N:18]([CH3:27])[C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=2)[N:16]=1)=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Reactant: CCCCCCN
Product: CCCCCCNC(=O)c1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C

Procedure:
Using essentially the same procedure as Example 9, Step B, but using hexylamine (0.020 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][N:24]([C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: O=C(Cl)C1CC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(C(=O)C3CC3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=554.2 (M+H+), was prepared in accordance with the general method of example 38 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and cyclopropane carboxylic acid chloride.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([CH:9]=O)=[CH:4][NH:3]1.CO.Cl.[NH2:14][OH:15].C([O-])(=O)C.[K+]>O>[OH:15][N:14]=[CH:9][C:5]1[C:6](=[O:8])[NH:7][C:2](=[O:1])[NH:3][CH:4]=1
Reactant: NO
Reactant: O=Cc1c[nH]c(=O)[nH]c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=c1[nH]cc(C=NO)c(=O)[nH]1
Yield: 84.4 %

Procedure:
A mixture of 2,4-dioxo-5(1H,3H)-pyrimidinecarbaldehyde (1.79 g, 12.8 mmol), methanol (35 mL) and water (35 mL) was heated at reflux and then a mixture of hydroxylamine hydrochloride (905 mg, 13 mmol), potassium acetate (1.28 g, 13 mmol) and water (15 mL) was added. The mixture was cooled and the solids were collected, washed with water and recrystallized from water/methanol to give 5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione (1.68 g, 10.8 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:27])=[C:6]([C:8]2[C:23](=[O:24])[N:22]([O:25][CH3:26])[C:11]3[N:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:14]=[CH:15][C:10]=3[CH:9]=2)[CH:7]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](O)=[O:65])=[CH:62][C:61]=1[C:69]([F:72])([F:71])[F:70]>CN(C=O)C>[Cl:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([Cl:27])=[C:6]([C:8]3[C:23](=[O:24])[N:22]([O:25][CH3:26])[C:11]4[N:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:14]=[CH:15][C:10]=4[CH:9]=3)[CH:7]=2)=[O:65])=[CH:62][C:61]=1[C:69]([F:70])([F:71])[F:72]
Reactant: COn1c(=O)c(-c2cc(N)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COn1c(=O)c(-c2cc(NC(=O)c3ccc(Cl)c(C(F)(F)F)c3)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Temperature: 25 °C
Yield: 70 %

Procedure:
In a 3 ml vial equipped with a small triangular magnetic stirring bar was placed 6-(5-amino-2-chlorophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin -7(8H)-one (348 μmol). Triethylamine (344 μmol) was added, followed by aliquots of DMF stock solutions of HATU (320 μmol) and 4-chloro-3-(trifluoromethyl)benzoic acid (129 μmol), and the mixture was stirred at room temperature over night. The solution was transferred to maximum recovery HPLC vials and purified by prep. HPLC-MS. The collected fractions were transferred to centrifuge vials and lyophilized, giving 4-chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl) -3-(trifluoromethyl)benzamide as a solid (70%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([NH2:11])[CH:5]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:5]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1cc(N)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)cc(N=Cc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 3-amino-5-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-5-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C15H11BrClNO2 353.62, obsd. (ESI+) [(M+H)+]351.9 & 353.9.