Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH3:8])[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.[OH-].[K+].Cl[CH:16]([F:18])[F:17].O>CC(O)C>[F:17][CH:16]([F:18])[O:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:9]([F:11])([F:10])[F:12])[C:5]=1[CH3:8]
Reactant: FC(F)Cl
Reactant: Cc1c(C(F)(F)F)nn(C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Into 78.6 g (436.4 mmol) of 1,4-dimethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in 500 ml of 2-propanol was added 153.1 g (2728.6 mmol) of powdery potassium hydroxide at room temperature, followed by stirring. Furthermore, an excess amount of chlorodifluoromethane was introduced into the reaction solution under stirring. Thereafter, the reaction temperature once rose to 70° C. by exothermic heat and then returned to room temperature after 2 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was distilled to obtain 88.9 g (yield: 88.5%) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole as a colorless transparent liquid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](Cl)=[O:9])[CH:4]=1.[OH2:11]>CC(C)=O>[Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:9])=[O:11])[CH:4]=1
Reactant: O=C(Cl)c1cc(CBr)on1
Reactant: O
Solvent: CC(C)=O
Product: O=C(O)c1cc(CBr)on1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The distilled 5-(bromomethyl)-3-isoxazolecarbonyl chloride (1 g) is dissolved in 2 ml of acetone, cooled to 0° C. and 3 ml of water is added to the solution. The solution is allowed to stand at room temperature for one hour and then the solvent is removed under reduced pressure giving 0.9 g of the acid. It is dried over P2O5 for three days and has mp 143°-148° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1/C=C/N(C)C
Temperature: 115 °C
Reaction time: 17 h

Procedure:
A mixture of methyl 2-methyl-3-nitrobenzoate (5.0 g, 25.6 mmol) and N,N-dimethylformamide dimethyl acetal (9.18 g, 77 mmol) in DMF (30 mL) was stirred at 115° C. for 17 h. The volatiles were removed under reduced pressure to give (E)-methyl 2-(2-(dimethylamino)-vinyl)-3-nitrobenzoate as brown oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine as described in Example 1 to give 2-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (400 MHz, DMSO) 1.56 (6H, s), 7.73 (1H, dd, J 11 and 9), 7.81-7.90 (3H, m), 8.09 (1H, dd, J 7 and 2), 8.42 (1H, dd, J 7 and 1), 8.55 (1H, s), 8.81 (1H, dd, J 5 and 1), 9.06 (1H, s), 9.39 (1H, d, J 7).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[C:19]3[CH2:25][CH:24]4[N:26]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:21]([CH2:22][CH2:23]4)[CH2:20]3)[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[NH:4].[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>O1CCOCC1>[F:30][C:28]([F:31])([F:29])[C:27]([N:26]1[CH:21]2[CH2:22][CH2:23][CH:24]1[CH2:25][C:19](=[C:9]1[C:8]3[CH:7]=[CH:6][C:5]([C:3]4[NH:4][C:33](=[O:34])[O:1][N:2]=4)=[CH:18][C:17]=3[O:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:20]2)=[O:32]
Reactant: N=C(NO)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3cc(-c4noc(=O)[nH]4)ccc31)C2)C(F)(F)F
Temperature: 110 °C
Reaction time: 0.67 h

Procedure:
To a solution of compound 6a (0.1 g, 0.23 mmol) in 1,4-dioxane (4 mL) was added 1,1′-carbonyldiimidazole (CDl, 0.055 g, 0.34 mmol). The mixture was stirred at 110° C. for 40 min under a nitrogen atmosphere. After being cooled, the reaction was concentrated. The crude compound 6b was used in the next reaction without further purification. MS m/z (MH+) 469.8.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1)#[N:2].[Cl:15][C:16]([Cl:20])([Cl:19])[C:17]#[N:18].[Al](Br)(Br)Br>>[Cl:15][C:16]([Cl:20])([Cl:19])[C:17]1[N:18]=[C:17]([C:16]([Cl:20])([Cl:19])[Cl:15])[N:18]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[N:2]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: N#Cc1ccc(SCCC(=O)O)cc1
Agent: Br[Al](Br)Br
Product: O=C(O)CCSc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Temperature: 60 °C

Procedure:
The reaction mixture of 22 g of 3-(4-cyanophenyl thio)propionic acid, 150 g of trichloroacetonitrile, and 2 g of AlBr3 was heated to 60° C. in order to dissolve the initially undissolved starting materials, and was bubbled by dry HCl at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[C:13]([N:16]1[CH:21]([CH3:22])[CH2:20][N:19]([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:18][CH:17]1[CH3:31])(=[O:15])[CH3:14].S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[C:13]([N:16]1[CH:21]([CH3:22])[CH2:20][N:19]([C:23]2[CH:24]=[CH:25][C:26]([C:27]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([F:11])=[CH:8][C:7]=4[F:12])[N:1]=3)=[CH:29][CH:30]=2)[CH2:18][CH:17]1[CH3:31])(=[O:15])[CH3:14]
Reactant: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Reactant: NC(=O)c1c(N)cc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)N1C(C)CN(c2ccc(-c3nc4cc(F)cc(F)c4c(=O)[nH]3)cc2)CC1C
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-amino-4,6-difluoro-benzamide (0.66 g, 3.84 mmol) and 4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-benzaldehyde (1.00 g, 3.84 mmol) in N,N-dimethyl acetamide (20 mL), was added sodium hydrogen sulfite (58.5 wt %, 1.04 g, 5.76 mmol) and p-toluenesulfonic acid monohydrate (0.88 g, 4.61 mmol) and the reaction mixture was stirred at 115° C. for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered off, to give 2-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-5,7-difluoro-3H-quinazolin-4-one as a yellow solid, which was used in the next step without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([N:32]1[N:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]2=[C:34]([C:41]([OH:43])=O)[C:33]1=[O:44])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:45][O:46][C:47]1[CH:56]=[C:55]2[C:50]([C:51]([O:57][C:58]3[CH:59]=[CH:60][C:61]([NH2:64])=[N:62][CH:63]=3)=[CH:52][CH:53]=[N:54]2)=[CH:49][CH:48]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.O>[CH2:25]([N:32]1[N:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]2=[C:34]([C:41]([NH:64][C:61]2[CH:60]=[CH:59][C:58]([O:57][C:51]3[C:50]4[C:55](=[CH:56][C:47]([O:46][CH3:45])=[CH:48][CH:49]=4)[N:54]=[CH:53][CH:52]=3)=[CH:63][N:62]=2)=[O:43])[C:33]1=[O:44])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)c1c(=O)n(Cc2ccccc2)n2ccccc12
Reactant: COc1ccc2c(Oc3ccc(N)nc3)ccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(=O)n(Cc5ccccc5)n5ccccc45)nc3)ccnc2c1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
A mixture of HATU (760 mg, 2.0 mmol), crude 1-benzyl-2-oxo-1,2-dihydropyrazolo[1,5-a]pyridine-3-carboxylic acid (268 mg, 1.0 mmol), 5-(7-methoxyquinolin-4-yloxy)pyridin-2-amine (220 mg, 1.0 mmol), and triethylamine (2000 μl, 14 mmol) in DMF (3 mL) plus CHCL3 (3 mL) was stirred at 60° C. for 4 days. Then, the mixture was diluted with EtOAc (10 mL) and H2O (5 mL). The organic layer was washed with NaOH (1 N), H2O, NaHCO3, and dried over Na2SO4. The organic residue was purified on silica and further purified by trituration with EtOAc in ether (5%), resulting a light green powder. Calc'd for C30H23N5O4: 517; MS (ESI pos. ion) m/z: 518
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][NH2:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12]>C1COCC1>[CH3:1][O:2][C:3]1[C:4]2[N:5]([C:11](=[O:12])[NH:10][N:9]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cccnc1NN
Solvent: C1CCOC1
Product: COc1cccn2c(=O)[nH]nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a stirred solution of (3-methoxypyridin-2-yl)hydrazine (2.7 g, 19.4 mmol) in THF (70 mL) was added 1,1′-carbonyldiimidazole (15.75 g, 90.1 mmol) at RT. After 16 hours, the resultant solid was collected by filtration and washed with THF. The solid was dissolved in a mixture of MeOH (120 mL) and water (20 mL) and stirred at RT for 10 minutes before evaporating to dryness. The resultant residue was subjected to flash chromatography (SiO2, gradient 3 to 5% MeOH in CHCl3) to afford the title compound (2.81 g, 88%) as a white solid. LCMS (Method A): RT=2.08 min, [M+H]+=166.
Reaction SMILES: N([O-])=O.[Na+].[N+:5]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH2:18])[C:9]=1[NH2:10])([O-:7])=[O:6].C(=O)(O)[O-].[Na+].[N-:30]=[N+:31]=[N-].[Na+]>Cl.O>[N:10]([C:9]1[C:8]([N+:5]([O-:7])=[O:6])=[CH:14][CH:13]=[CH:12][C:11]=1[O:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[CH2:18])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: C=C(COc1cccc([N+](=O)[O-])c1N)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: C=C(COc1cccc([N+](=O)[O-])c1N=[N+]=[N-])c1ccccn1
Reaction time: 0.08 h

Procedure:
Sodium nitrite (100 mg, 2 mmol) in water (4 mL, 60 mmol) was added to a solution of 2-nitro-6-[(2-pyridin-2-ylprop-2-en-1-yl)oxy]aniline (350 mg, 1.3 mmol) in 4.0 M hydrogen chloride in water (4 mL, 10 mmol) at 0° C. The reaction was stirred for 5 min and was then neutralized to pH 6-7 with solid sodium bicarbonate. Sodium azide (80 mg, 1 mmol) in water (2 mL) was added drop-wise to the mixture, followed by stirring for 30 min, over which time the reaction mixture became a thick slurry. The resulting mixture was filtered and dried to give 2-{1-[(2-azido-3-nitrophenoxy)methyl]vinyl}pyridine as a dark yellow solid (0.25 g. 83%). LCMS calculated for C14H12N5O3 (M+H)+: m/z=298.1. found: 298.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[CH2:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[O:16])[S:10][C:11]=1[CH2:12][CH3:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (200 mg, 0.57 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (181 mg, 0.57 mmol) [Prepared according to Preparation 6] and N,N-diisopropylethylamine (0.50 ml, 2.87 mmol) in Dichloromethane (4.23 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (295 mg, 0.632 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (240 mg, 0.37 mmol, 64.8% yield) as a white foam: LCMS (ES) m/e 645, 647 (M, M+2)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5](I)[CH:4]=1)=[O:2].[CH2:14]([OH:18])[CH2:15][C:16]#[CH:17]>CN(C=O)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([C:17]#[C:16][CH2:15][CH2:14][OH:18])[CH:4]=1)=[O:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1I
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C=O)cc1C#CCCO
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a degassed solution of N-(4-formyl-2-iodo-phenyl)-acetamide (0.810 g, 2.82 mmol) in DMF (25 mL) and triethylamine (5 mL) were added PdCl2(PPh3)2 (0.10 g, 0.14 mmol) and copper (I) iodide (0.16 g, 0.85 mmol). A degassed solution of but-3-yn-1-ol (0.27 g, 0.29 mmol) in DMF (8 mL) and triethylamine (2 mL) was added at 80° C. over a period of 1 hour under nitrogen. After the addition, the reaction mixture was stirred at 80° C. for 4 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4. Removal of solvent gave N-[4-formyl-2-(4-hydroxy-but-1-ynyl)-phenyl]-acetamide as a brown solid. Crude yield: 0.85 g (100%). The crude material was used in next step without further purification.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:66](=[O:67])[N:6]2[C:7]([C:53]([O:55]CC3C=CC([N+]([O-])=O)=CC=3)=[O:54])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15](C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[C@H:14]([C:30]([N:32]4[CH2:35][CH:34]([N:36](C(OCC5C=CC([N+]([O-])=O)=CC=5)=O)[C:37](=[NH:39])[CH3:38])[CH2:33]4)=[O:31])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[C:37]([NH:36][CH:34]1[CH2:33][N:32]([C:30]([C@@H:14]2[CH2:13][C@H:12]([S:11][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:66](=[O:67])[N:6]4[C:7]=3[C:53]([OH:55])=[O:54])[CH2:16][NH:15]2)=[O:31])[CH2:35]1)(=[NH:39])[CH3:38]
Reactant: [H][H]
Reactant: CC(=N)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: CC(=N)NC1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)C1
Yield: 35.3 %

Procedure:
0.77 g of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-{3-[N(4-nitrobenzyloxycarbonyl)-N-acetimidoylamino]azetidin-1-ylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] was dissolved in 15 ml of a 2:1 by volume mixture of tetrahydrofuran and water. 0.77 g of a 10% w/w palladium-on-carbon catalyst was then added to the resulting solution, after which the mixture was hydrogenated at room temperature for 2 hours in a hydrogen atmosphere. At the end of this time, the catalyst was removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was then concentrated by evaporation under reduced pressure, and the resulting residue was subjected to reverse phase column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 100 ml). The fraction containing the title compound and obtained by elution with 4% by volume aqueous acetonitrile was concentrated by evaporation under reduced pressure and freeze-dried, to give 0.13 g of the title compound as a powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]2[CH:12]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:23][CH2:24][N:25]([CH2:2][C:3]3[N:4]=[C:5]4[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][N:6]4[CH:12]=3)[CH2:26][CH2:27]2)=[C:18]([CH:21]=1)[C:19]#[N:20]
Reactant: Cc1ccc2nc(CCl)cn2c1
Reactant: N#Cc1cc(Cl)ccc1N1CCNCC1
Product: Cc1ccc2nc(CN3CCN(c4ccc(Cl)cc4C#N)CC3)cn2c1
Yield: 31.1 %

Procedure:
Following the general procedure of Example 9, Step 2, and making non-critical variations, 2-(chloromethyl)-6-methylimidazo[1,2-α]pyridine (Example 9, Step 1; 0.2792 g) and 5-chloro-2-(piperazin-1-yl)benzonitrile (Example 32, Step 1; 0.4029 g) give 0.176 g of the title compound after chromatography and crystallization from ethyl ether/dichloromethane; mp 135-136° C.; MS m/z 365, 367; IR (mineral oil) 1486, 803, 1341, 825, 1333 cm-1 ; 1H NMR (CDCl3) δ2.31, 2.78, 3.25, 3.77, 6.92, 7.00, 7.39-7.50, 7.86.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=[C:4]([Cl:17])[N:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=1.C1COCC1>O1CCOCC1>[Cl:17][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[C:2]([O:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)[N:3]=1
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Reactant: OCCc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1OCCc1ccc(F)cc1
Temperature: 150 °C
Yield: 40.6 %

Procedure:
2,6-dichloro-N-cyclohexylnicotinamide (Intermediate 1, 273 mg, 1 mmol) was stirred in 1,4-dioxane (4 ml). To this solution was added 4-fluorophenethyl alcohol (154 mg, 1.1 mmol) followed by bis-sodium hexamethyldisilylamide 1.0M in THF (1.1 ml, 1.1 mmol). The tube was sealed and subjected to microwave heating 150° C. (Biotage Initiator 300 W) for 2 hours. The solvent was evaporated and the residue was diluted with water (15 ml) and extracted with dichloromethane (2×20 ml). The combined extract was washed with brine (20 ml) dried over MgSO4, filtered and evaporated. The crude product was purified on SiO2 (40 g) eluting with ethyl acetate/isohexane 0-40% and gave 6-chloro-N-cyclohexyl-2-[2-(4-fluorophenyl)ethoxy]nicotinamide (153 mg, 40%) as a white solid
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[C:21]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccncc1
Product: CCOC(=NC(=O)c1ccncc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and isonicotinoyl chloride, there is obtained ethyl N-(isonicotinoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 120°-122° C.;
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3][CH2:4][CH2:5][C:6](=[O:12])[CH2:7][C:8]([O:10]C)=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>>[CH2:19]([N:21]([CH2:22][CH3:23])[C:8](=[O:10])[CH2:7][C:6](=[O:12])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH3:20]
Reactant: COC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Reactant: CCNCC
Product: CCN(CC)C(=O)CC(=O)CCC=C(C)CCC=C(C)C

Procedure:
5.4 g of the product of Example 3 and 10.8ml of diethylamine were stirred in a closed auto clave at 110° C. for 70 hours and after cooling, the reaction mixture was recovered and evaporated under reduced pressure. The residue was chromatographed over silica and was eluted with a 1-1 ethyl etherpetroleum ether (b.p.= 40°-75° C.) mixture to obtain 3.6 g of N,N-diethyl-7,11-dimethyl-3-oxo-6,10-dodecadienamide in the form of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].C(OC([N:36]1[CH2:41][CH2:40][CH2:39][C@H:38]([CH2:42]OS(C)(=O)=O)[CH2:37]1)=O)(C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:42][C@H:38]2[CH2:39][CH2:40][CH2:41][NH:36][CH2:37]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](COS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cn(C[C@H]2CCCNC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
A solution of the 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) in dry DMF was treated with NaH (1.1 eq) and stirred for 10 min at room temperature, then treated with (S)-3-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.1 eq) (JP 2001278872) and stirred at room temperature for 16 h then 70° for 4 h. Concentration and treatment with excess HCl in dioxane gave after purification by preparative HPLC the desired product in 39% yield.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[F:14].[C:15]([CH:17]1[CH2:19][CH:18]1[C:20](N(OC)C)=[O:21])#[N:16].O>CCCCCC.C1COCC1>[F:14][C:8]1[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=1[C:20]([CH:18]1[CH2:19][CH:17]1[C:15]#[N:16])=[O:21]
Reactant: CON(C)C(=O)C1CC1C#N
Reactant: Cc1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C2CC2C#N)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
16.5 ml (26.5 mmol) of a 1.6N solution of n-butyllithium in hexane were added dropwise to a solution of 5.00 g (26.5 mmol) of 4-bromo-3-fluorotoluene in 40 ml of THF at −78° C., and the mixture was stirred for 0.5 h. Then, at −78° C., a solution of 2.72 g (17.6 mmol) of the compound from Example 73A in 10 ml of THF was added, and the mixture was allowed to warm to RT and was stirred at RT for 2 h. Water was added, the mixture was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). 300 mg (9% of theory) of the title compound were obtained.