Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2O.P(Cl)(Cl)([Cl:25])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[Cl:25]
Reactant: Oc1c(-c2ccccc2)c(C(F)(F)F)nc2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1nc2ccc(Br)cc2c(Cl)c1-c1ccccc1

Procedure:
A solution of 6-bromo-3-phenyl-2-(trifluoromethyl)quinolin-4-ol (8.29 g, 22.5 mmol, Intermediate 34, step a) in phosphoryl trichloride (25 mL, 269 mmol) was heated at 110° C. for 2 hours, and concentrated in vacuo. Dichloromethane and ice-water were added, and the mixture was basified at 4° C. with conc. NH4OH until pH ˜10. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (120 g silica gel column, 2-9% EtOAc in heptane) to give the title compound as a light yellow solid.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH2:17])[CH3:13]>>[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH:17][C:8]([C:7]1[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=1[CH:1]=[O:2])=[O:10])[CH3:13]
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Yield: 94.4 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (3.0 g, 19.6 mmol) reacted with N,N-diethylethylenediamine (3.03 mL, 21.5 mmol) to give 4.65 g (94%) of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide.
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: CC(C)[C@H](N)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
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: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][CH:10]=2)[C:5]([Cl:28])=[CH:4][N:3]=1.Cl.CCOCC>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:13][CH:14]=2)[C:5]([Cl:28])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3nc(Cl)ncc3Cl)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Clc1ncc(Cl)c(Nc2ccc([C@H]3CNCCO3)cc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 198.3 %

Procedure:
(S)-tert-Butyl 2-(4-(2,5-dichloropyrimidin-4-ylamino)phenyl)morpholine-4-carboxylate (45 mg, 0.106 mmol) was dissolved in dioxane (0.5 ml) and a solution of HCl in dioxane (4 M, 0.3 ml, 1.27 mmol) was added. The reaction mixture was stirred at 60° C. for 2 hours. After cooling, ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2,5-dichloro-N-(4-(morpholin-2-yl)phenyl)pyrimidin-4-amine hydrochloride (38 mg, 99%) as a white solid. MS (ISP): 325.1 ([{35Cl}M+H]+), 327.1 ([{37Cl}M+H]+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)Cl>[O:7]=[C:2]1[NH:1][CH2:6][CH2:5][N:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:3]1
Reactant: O=C1CNCCN1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCNC(=O)C1
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a solution of 2-piperazinone (5.0 g, 50.0 mmol) and triethylamine (11.09 g, 110.0 mmol) in DCM (15 mL) is added ethyl chloroformate (5.9 g, 55.0 mmol) at room temperature and the reaction mixture is stirred for 2 h. The reaction is quenched with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers are dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue is triturated with Et2O to give the title compound (5.0 g, 29.05 mmol) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 1.19 (t, 3H), 3.16-3.19 (m, 2H), 3.48-3.51 (m, 2H), 3.85 (s, 2H), 4.05 (q, 2H), 8.06 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][O:5][C:6]([CH3:10])([CH3:9])[C:7]#[CH:8].S(=O)(=O)(O)[OH:13]>CO.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH3:10][C:6]([CH3:9])([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])[C:7](=[O:13])[CH3:8]
Reactant: O=S(=O)(O)O
Reactant: C#CC(C)(C)OCC(=O)OC
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CO
Product: COC(=O)COC(C)(C)C(C)=O
Temperature: 25 °C

Procedure:
The product from Example 66A (10.0 g, 64 mmol) in methanol (320 mL) was treated with mercury(II) acetate (2.0 g, 6.4 mmol) and sulfuric acid (0.5 mL). After refluxing for 1.5 hours, the mixture was allowed to cool to ambient temperature, concentrated to a volume of 100 mL, poured into 1N HCl (300 mL) and extracted with dichloromethane (3×300 mL). The organic layers were combined, washed with aqueous NaHCO3, washed with brine, dried over Na2SO4 and concentrated to provide the title compound (10.3 g).
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CN([CH:15]=[C:16]1[CH2:20][CH2:19][O:18][C:17]1=[O:21])C.CO>C(OCC)(=O)C>[OH:18][CH2:19][CH2:20][C:16]1[C:17](=[O:21])[N:2]2[CH:3]=[CH:4][C:5]3[C:10]([C:1]2=[N:11][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: Nc1nccc2ccccc12
Reactant: CN(C)C=C1CCOC1=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1c(CCO)cnc2c3ccccc3ccn12
Temperature: 200 °C
Yield: 75 %

Procedure:
A heterogenous mixture containing 14.4 g of 1-isoquinolinamine (0.1 m) and 14.12 g of dihydro-3-[(dimethylamino)methylene]-2(3H)-furanone was heated to 200° C. for 4 hours to yield a homogenous yellow orange solution which solidified upon cooling to ambient temperature. The solidified reaction mixture was titurated with methanol and ethyl acetate to yield 3-(2-hydroxyethyl)-4H-pyrimido[2,1-a]isoquinolin-4-one as a tan solid (18.0 g; 75% yield) of the formula ##STR26## having a melting point of 185.2°-187.0° C. and the following elemental analysis:
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[Cl:18][C:19]1[N:20]=[CH:21][N:22]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][C:36]2[CH:41]=[C:40]([CH:42]=O)[CH:39]=[C:38]([Cl:44])[CH:37]=2)[C:29]=1[F:45])=[O:25]>C1COCC1.CCOC(C)=O>[Cl:18][C:19]1[N:20]=[CH:21][N:22]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][C:36]2[CH:41]=[C:40](/[CH:42]=[CH:3]/[C:1]#[N:2])[CH:39]=[C:38]([Cl:44])[CH:37]=2)[C:29]=1[F:45])=[O:25]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C=O)c2)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(/C=C/C#N)c2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (56.1 mg, 0.317 mmol) in THF (5 mL) at 0° C. was added potassium t-butoxide (1.0 M solution in THF) (0.317 ml, 0.317 mmol) and the mixture was stirred at 0° C. for 30 minutes. Next, 4-chloro-N-({4-chloro-3-[(3-chloro-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (165 mg, 0.288 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(E)-2-cyanoethenyl]phenyl}oxy)-2-fluorophenyl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (113 mg, 0.190 mmol, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (t, 1H), 7.95 (s, 1H), 7.54 (d, 2H), 7.41-7.48 (m, 1H), 7.36 (t, 1H), 7.23 (s, 1H), 6.97 (s, 1H), 6.58 (d, 1H), 5.47 (s, 2H), 4.45 (d, 2H), 3.36 (t, 2H), 0.72 (t, 2H), −0.12 (s, 9H).
Reaction SMILES: [C:1]([C@H:5]1[C:32](=[O:33])[N:31]2[CH2:34][C@@H:28]([CH2:29][C@H:30]2[C:35]([O:37][CH3:38])=[O:36])[O:27][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([OH:26])=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:39][C@H:9]2[O:8][C:7](=[O:40])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[C:41]([N:48]1[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]1)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>>[C:44]([O:43][C:41]([N:48]1[CH2:53][CH2:52][CH:51]([O:26][C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]3[O:27][C@H:28]4[CH2:34][N:31]([C:32](=[O:33])[C@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[NH:6][C:7](=[O:40])[O:8][C@@H:9]5[CH2:39][C@H:10]5[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]=23)[C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:29]4)[CH2:50][CH2:49]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCN(C(=O)OC(C)(C)C)CC1)O2

Procedure:
The title compound was prepared using the same method as described in Example 210, Step 1 with methyl (1aR,5S,8S,10R,22aR)-5-tert-butyl-17-hydroxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-8-carboxylate (Example 113, Step 5) and 1-Boc-4-hydroxypiperidine. LRMS (ES+) m/z 737.5 (M+H)+.
Reaction SMILES: [C:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)(=O)[CH2:2][CH2:3][CH3:4].[CH:18]([NH2:20])=[O:19]>C(O)=O>[CH:18]([NH:20][CH:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4])=[O:19]
Reactant: NC=O
Reactant: CCCC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: O=CO
Product: CCCC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 5 h

Procedure:
The ketone produced as described above (37.0 g) and 98% formic acid (9 ml) were added to formamide (23.5 ml) at 170° C. and the temperature kept at 175°-180° C. for five hours. A further portion of formic acid (4.5 ml) was added and the mixture was maintained at 175°-180° C. for a further fifteen hours. The mixture was extracted with ether which on evaporation gave a thick oil which was crystallised from petroleum ether (b.p. 60°-80°) to give N-formyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine having a melting point of 103°-105° C. (Formula I R1 =propyl; R2 =H; R3 =H; R4 =CHO; R5 =4-Cl and R6 =3-Cl).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:12](OCC)(=[O:16])[CH:13]([CH3:15])[CH3:14]>C1COCC1>[CH3:14][CH:13]([CH3:15])[C:12](=[O:16])[CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9]
Reactant: CCOC(=O)C(C)C
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(=O)C(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
Benzylcyanide (1500 mg, 12.8 mmol) was dissolved in 150 ml dry THF and cooled down to 0° C. The solution was stirred at that temperature while NaH (60% in mineral oil, 663 mg) was added slowly. After the addition was completed, the mixture was stirred at 0° C. for 30 min and then the ice bath was removed and stirring continued at RT for 120 min. Ethyl isobutyrate (1785 mg, 15.4 mmol) was added at once and the reaction mixture heated at 60° C. for 2 h. The THF was removed in vacuo and the residue was then poured into ice-water. HCl 6M was added with stirring until neutral pH was reached. The mixture was extracted with EtOAc, dried over MgSO4 and concentrated in vacuo. The compound was purified by flash chromatography [silica; n-heptane-EtOAc (9:1)] to afford 4-methyl-3-oxo-2-phenyl-pentanenitrile (460 mg, 19%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8](Cl)[N:7]=1.[NH3:15].C(O)C>S([O-])([O-])(=O)=O.[Cu+2].CCOCC>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([NH2:15])[N:7]=1
Reactant: Cc1cc(Cl)nc(NCCN(C)C)c1
Reactant: N
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(N)nc(NCCN(C)C)c1

Procedure:
A mixture of 2-(2-dimethylaminoethylamino)-4-methyl-6-chloropyridine (from Example 77, Part A) (21.4 g., 0.1 mole), liquid ammonia (85 g) and copper sulfate catalyst (1.0 g) in 150 ml. ethanol is heated at 200° C. for 48 hours in a pressure vessel. The cooled reaction mixture is filtered and concentrated in vacuo. The residual oil is dissolved in 125 ml of chloroform, washed with excess sodium hydroxide and then with saturated sodium chloride solution, dried, filtered and concentrated in vacuo. The 16.0 g. of crude oil obtained is taken up in 100 ml of ether, filtered and extracted into dilute hydrochoric acid. The acidic extract is made basic and the product is extracted into ether. After drying and removing the ether in vacuo, the product (8.0 g.) is distilled. Purified material is collected at 125°-128° C. at 0.4 mm.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([NH:13]C(=O)OC(C)(C)C)[C:5]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6])#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:13][C@H:4]([CH2:3][C:1]#[N:2])[C:5]([NH:7][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H](CC#N)C(=O)NC1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC[C@@H](N)C(=O)NC1CCCC1
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of (R)-tert-butyl 3-cyano-1-(cyclopentylamino)-1-oxopropan-2-ylcarbamate and 50% TFA/DCM (10 mL) was stirred for 1 h. Following reaction, the mixture was concentrated to afford the title compound as a clear oil (TFA salt, 0.265 g, 41%). The product was pure by TLC (visualized by ninhydrin stain).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:26]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH2:31])[CH3:27]>N1C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=1)[NH:31][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)[CH3:27]
Reactant: O=C(O)c1cccnc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cccnc1
Reaction time: 8 h

Procedure:
Nicotinic acid (12.3 g, 0.1 mol) was dissolved in dry pyridine (300 mL). The solution was cooled and dicyclohexylcarbodiimide (20.6 g, 0.1 mol) was added. After dissolution, tyrosine ethyl ester hydrochloride (24.6 g, 0.1 mol) was added and the solution was stirred overnight. The precipitated dicyclohexylurea (DCU) was removed by filtration. Additional DCU was removed by triturating the oil with hot water. The product was purified with acetone. Calculated for C17H18N2O4.1/2H2O: C, 63.16; H, 5.88; N, 8.66. Found: C, 63.10; H, 5.96; N, 8.59. The product can also be named N-[1-ethoxycarbonyl-2-(4'-hydroxyphenyl)ethyl]nicotinamide.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=O.[N+]([O-])(O)=O.[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].[OH-].[Na+]>C(O)(C)C>[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:30]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[CH:4]=[CH:3][N:29]=2)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Reactant: CN(C)C=CC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1cccc(Nc2nccc(-c3ccccn3)n2)c1
Reaction time: 0.33 h

Procedure:
1 g (5.68 mmol)of 3-dimethylamino-1-(2-pyridyl)-2-propen-1-one [EP-A-233 461] is dissolved in 8 ml of isopropanol, and 1.38 g (5.68 mmol) of 3-nitrophenylguanidine nitrate are added. After the addition of 0.25 g (6.24 mmol) of sodium hydroxide, the yellow suspension is heated at reflux for 20 hours, then cooled to 0°, filtered and washed with 30 ml of isopropanol. The filtration residue is stirred in 15 ml of ethanol for 20 minutes, filtered and washed with a small amount of cold ethanol, yielding N-(3-nitrophenyl)-4-(2-pyridyl)-2-pyrimidine-amine; m.p. 213°-219°.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25].COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:25]
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifuluoroacetic acid) salt (EXAMPLE 34 Step 1) and 3-trifluoromethylbenzoic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: [N:1]([CH:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1([O:17][CH3:18])[CH2:11][N:10]([S:12]([OH:15])(=[O:14])=[O:13])[C:9]1=[O:16])=[O:6])=[N+]=[N-].[K].FC(F)(F)C(O)=O>CO.[Pd]>[NH2:1][CH:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1([O:17][CH3:18])[CH2:11][N:10]([S:12]([OH:15])(=[O:13])=[O:14])[C:9]1=[O:16])=[O:6]
Reactant: COC1(NC(=O)C(N=[N+]=[N-])c2ccccc2)CN(S(=O)(=O)O)C1=O
Agent: [Pd]
Agent: [K]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC1(NC(=O)C(N)c2ccccc2)CN(S(=O)(=O)O)C1=O
Reaction time: 1 h

Procedure:
(±)-3-[(Azidophenylacetyl)amino]-3-methoxy-2-oxo-1-azetidinesulfonic acid, potassium salt (209 mg; see Example 88) is dissolved in 60 ml of dry methanol. Anhydrous trifluoroacetic acid (0.6 ml) and 10% palladium on carbon (105 mg) are added and the mixture is hydrogenated for 1 hour. The catalyst is removed by filtration and the filtrate is evaporated in vacuo to yield 271 mg of crude product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[NH:8][C:9](=[O:18])[N:10]([CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[C:26]([O:34][CH3:35])[CH:25]=1)([O-:23])=[O:22].O>C1COCC1>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[N:8]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][C:26]=3[O:34][CH3:35])(=[O:31])=[O:32])[C:9](=[O:18])[N:10]([CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2n1C1CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)n1c(=O)n(C2CCCCCC2)c2cc(Cl)ccc21
Reaction time: 18 h
Yield: 64.4 %

Procedure:
600 mg of sodium hydride as a 60% dispersion in oil were added in portions, with stirring, to a solution of 3 g of 5-chloro-3-cycloheptyl-1,3-dihydro-2H- benzimidazol-2-one in 30 ml of THF. 3 g of 4-nitro-2- methoxybenzenesulfonyl chloride were then added and the reaction mixture was stirred for 18 hours. The reaction mixture was then poured into a water+ ice mixture, extracted with ethyl acetate and washed with water and the organic phase was dried over sodium sulfate and concentrated to dryness. 3.5 g of the expected product were obtained by crystallization from an iso ether/AcOEt mixture (60/40; v/v). M.p.=193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[CH3:27][CH:28]1[CH2:33][NH:32][CH2:31][CH:30]([CH3:34])[NH:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:32]2[CH2:31][CH:30]([CH3:34])[NH:29][CH:28]([CH3:27])[CH2:33]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: CC1CNCC(C)N1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: CC1CN(C(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)CC(C)N1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2,6-dimethylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3,5-dimethylpiperazine-1-carbonyl)benzamide. MS (Q1) 483 (M)+.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]([CH3:30])([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)[CH2:16][O:17][CH2:18][CH2:19][CH3:20]>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][C:15]([CH3:14])([CH3:30])[CH2:16][O:17][CH2:18][CH2:19][CH3:20])=[CH:29][CH:28]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: CCCOCC(C)(C)Oc1ccc(CBr)cc1
Product: CCCOCC(C)(C)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Yield: 50.3 %

Procedure:
By using 2.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 3.0 g of 4-(1,1-dimethyl-2-propoxyethoxy)benzyl bromide and similarly to the procedures in Preparation Example 13, 2.1 g of the aimed product was obtained as an oil.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([OH:16])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]1(=[O:24])[NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)(=O)C>[C:8]([CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:17]1=[O:24])(=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCCCCN1
Reactant: O=C(O)c1ccccc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1NCCCCC1C(=O)c1ccccc1

Procedure:
heating acetic anhydride, benzoic acid, and caprolactam at a temperature of about 130° to about 170° C. to form volatile acetic acid and benzoyl caprolactam;