Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[ClH:24].[ClH:24].[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([OH:22])[CH2:20][CH2:21]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(CCN2CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ester 23 (2.2 g, 6.72 mmol) is dissolved in 4M HCl in dioxane at 0° C. and stirred at room temperature for 3 hours. After evaporation of the solvent the product is dried at high vacuum.
Reaction SMILES: [CH:1]([OH:3])=[O:2].[F:4][CH:5]([F:36])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]1[N:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[N:26][C:27]([C:30]4([OH:34])[CH2:33][NH:32][CH2:31]4)=[N:28][CH:29]=3)[C:21]([F:23])=[CH:22][C:17]2=[N:16][C:15]=1[CH3:35].C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[CH:1]([OH:3])=[O:2].[F:36][CH:5]([F:4])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]1[N:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[N:26][C:27]([C:30]4([OH:34])[CH2:33][N:32]([CH3:39])[CH2:31]4)=[N:28][CH:29]=3)[C:21]([F:23])=[CH:22][C:17]2=[N:16][C:15]=1[CH3:35]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nc2cc(F)c(-c3cnc(C4(O)CNC4)nc3)cn2c1Cc1ccccc1OC(F)F
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O=CO
Product: Cc1nc2cc(F)c(-c3cnc(C4(O)CN(C)C4)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.5 %

Procedure:
To a suspension of Example 325 (81%, 195 mg, 0.3 mmol) in ethanol (4 mL) was added 37% aqueous formaldehyde solution (0.1 mL, 1.33 mmol) and the resulting solution was stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (160 mg, 0.76 mmol) was added in one portion, followed by acetic acid (0.1 mL), and the whole mixture was stirred at room temperature under nitrogen for 2 h. The reaction mixture was diluted and neutralised with saturated sodium bicarbonate solution (15 mL). The crude material was then extracted into dichloromethane (2×20 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated under vacuum. The resulting brown oil (140 mg) was purified by preparative HPLC (Method A) to afford the title compound (27 mg, 17%) as a colourless solid. δH (500 MHz, CD3OD) 9.05 (d, J 1.4 Hz, 2H), 8.38-8.35 (m, 2H), 7.41 (d, J 10.9 Hz, 1H), 7.33-7.27 (m, 1H), 7.18 (d, J 7.9 Hz, 1H), 7.14 (td, J 7.6, 0.9 Hz, 1H), 7.10 (dd, J 7.6, 1.7 Hz, 1H), 6.91 (t, J 74.0 Hz, 1H), 4.72 (d, J 11.3 Hz, 2H), 4.42 (s, 2H), 4.35 (d, J 11.4 Hz, 2H), 3.08 (s, 3H), 2.42 (s, 3H). Method D HPLC-MS: MH+ m/z 470, RT 1.09 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Ca+2].[OH-]>O>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[CH:11][C:12](=[O:13])[CH3:14]
Reactant: Cc1cccc(C)c1C=O
Reactant: CC(C)=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)cccc1C
Yield: 90 %

Procedure:
13.4 g (0,1 mol) of 2,6-dimethylbenzaldehyde, 100 ml of acetone, 100 ml of water and 2 g of calcium hydroxide are mixed together and refluxed for about 20-25 h with agitation. The precipitate is filtered off from the cold reaction mixture. 1 l of ice water is added to the filtrate with agitation. The product is crystallized at a yield of about 90%. M.p. of the recrystallized product: 34°-35° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:19])([F:18])[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[Br:17]>S(=O)(=O)(O)O>[N+:1]([C:9]1[C:8]([Br:17])=[C:7]([C:6]([F:5])([F:18])[F:19])[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=1)([O-:4])=[O:2]
Reactant: FC(F)(F)c1ccc(Br)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Concentrated nitric acid (2.6 ml) was cautiously added to a solution of 2,4-bis(trifluoromethyl)bromobenzene (16 g) in concentrated sulphuric acid (48 ml), and the mixture was heated to 80° C. for 6 hours. After cooling to ambient temperature and allowing to stand overnight, the reaction mixture was cautiously poured onto ice, and extracted with ethyl acetate. The organic extracts were washed with water and brine and dried over magnesium sulphate. Evaporation of the solvent, under reduced pressure, gave 6-nitro-2,4-bis(trifluoromethyl) bromobenzene as a yellow liquid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1.Cl>ClCCCl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:10]([C:9]2[CH:13]=[CH:14][C:6]([F:5])=[CH:7][CH:8]=2)=[O:11])=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1cccc(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(Br)ccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.3 %

Procedure:
To a suspension of AlCl3 (14.7 g, 110 mmol) in 250 mL of 1,2-dichloroethane was added 4-fluorobenzoyl chloride (11.8 mL, 100 mmol) at rt. The resulting mixture was stirred at rt for 15 min. and 3-bromoanisole (16.8 g, 90.0 mmol) in 20 mL of 1,2-dichloroethane was added. After 1 h at rt, the brown solution was poured into ice. 2N HCl was added to the aqueous layer followed by an extraction with CH2Cl2. The combined organics were dried (MgSO4), filtered and concentrated. The residue was subjected to chromatography on silica gel (EtOAc/hexane 5:95 to 7:93) affording 5.1 g of a solid that was triturated with 20 mL of EtOAc/hexane (10:90). The title compound was obtained from filtration, and additional product was recovered from the mother liquors.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](O)=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.S(Cl)([Cl:27])=O>CN(C=O)C>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([Cl:27])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: CC(Oc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1)C(=O)Cl

Procedure:
To 17.11 g. (0.05 mole) of 2-[[4-[4-(trifluoromethoxy)phenoxy]phenoxy]]propanoic acid is added 1 ml. of DMF, followed by 50 ml. of thionyl chloride. After evolution of HCl ceases, the thionyl chloride excess is removed in vacuum. The residue is extracted with methylene chloride and the methylene chloride solution washed with ice water, dried, and the solvent removed, leaving 2-[[4-[4-(trifluoromethoxy)phenoxy]-phenoxy]]propanoyl chloride.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24]>C(#N)C.C(OCC)C>[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH:24][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: COC(CN)OC
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1NCC(OC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of methyl 2-phenyl-2-bromoacetate (53.8 g) in acetonitrile (450 ml) was treated with triethylamine (45.2 ml). The mixture was then cooled in an ice-bath and treated, dropwise during 15 minutes, with a solution of aminoacetaldehyde dimethylacetal (37.8 ml) in acetonitrile (80 ml), keeping the temperature below 45° C. The mixture was stirred at room temperature for 2 hours and then left to stand for 48 hours. The mixture was then diluted with diethyl ether (800 ml) and washed with water (3×250 ml). The ethereal was dried over magnesium sulphate and evaporated, to give methyl 2-(2,2-dimethoxyethylamino)phenylacetate (55.5 g), in the form of a colourless oil [N.M.R. (in CDCl3) 2.10 (1H, b), 2.57-2.79 (2H, m), 3.34 (3H, s), 3.37 (3H, s), 3.68 (3H, s), 4.50 (1H, t, J=6 Hz), 7.35 (5H, m)].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([CH3:16])[CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1.[OH:17][CH2:18][C@@H:19]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH:21]([CH3:23])[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:22][CH:21]([CH3:23])[CH2:20][C@H:19]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:18][O:17][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([CH3:16])[CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1cc2c(cn1)COc1cc(Cl)ccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1cc2c(cn1)COc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Temperature: 110 °C

Procedure:
A mixture of 8-chloro-2-methyl-5H-chromeno[3,4-c]pyridine (0.2 g, 0.863 mmol), (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (0.225 g, 1.036 mmol), palladium(II) acetate (5.81 mg, 0.026 mmol), Cs2CO3 (0.422 g, 1.295 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.022 g, 0.052 mmol) in toluene (5 mL) was heated to 110° C. for 18 h. After cooling, the mixture was filtered through celite and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (70% EtOAc in pet. ether) to afford (S)-tert-butyl (4-methyl-1-((2-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate, as a semi-solid (0.12 g, 0.291 mmol, 34% yield). LCMS (ESI) m/e 413.4 [(M+H)+, calcd for C24H33N2O4 413.2]; LC/MS retention time (Method D): tR=2.42 min.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].N1C=CC=CC=1>C(Cl)Cl>[Si:6]([O:5][CH2:1][CH2:2][C:3]#[CH:4])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C#CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-butyne-1-ol (5.0 g; 71.3 mmol) in ca. 75 ml of methylene chloride was added tert-butydimethylsilyl chloride (10.8 g; 71.6 mmol) and 7 ml of pyridine. The mixture was allowed to stir overnight at room temperature, diluted with methylene chloride, washed with water, 1M HCl, brine and dried (Na2SO4). Concentration in vacuo afforded the title compound as a colorless liquid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:66]1[CH:75]=[CH:74][CH:73]=[C:72]2[C:67]=1[CH:68]=[CH:69][C:70]([CH3:76])=[N:71]2)(=O)=O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:76][C:70]1[CH:69]=[CH:68][C:67]2[C:72](=[CH:73][CH:74]=[CH:75][C:66]=2[N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)[N:71]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1ccc2c(OS(=O)(=O)C(F)(F)F)cccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(N3CCN[C@H](C)C3)cccc2n1
Temperature: 25 °C
Yield: 58 %

Procedure:
(2R)-2-Methylpiperazine (0.550 g; 2 eq), caesium carbonate (1.78 g; 2 eq), palladium acetate (0.123 g; 0.2 eq) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.513 g; 0.3 eq) were added to a solution of 2-methyl-5-quinolinyl trifluoromethanesulfonate (D1) (0.8 g; 1 eq) in toluene (30 mL) under an inert atmosphere. The reaction mixture was stirred at reflux under nitrogen for 3 hours. The reaction cooled to room temperature, quenched using saturated aqueous ammonium chloride solution (15 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, eluting with dichloromethane-methanol (95:5) affording the title compound in 58% yield (0.383 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Br>>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: N#Cc1ccc(O)cc1F
Product: COC(=O)c1ccccc1COc1ccc(C#N)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 40, intermediate e, from 2-fluoro-4-hydroxy-benzonitrile (CAS Reg. No. 82380-18-5) and 2-bromomethyl-benzoic acid methyl ester (CAS Reg. No. 2417-73-4). Off-white solid (91%). MS (Turbo Spray): m/z=286.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:4]=1[F:16])#[N:2]>CO.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:4]=1[F:16])#[N:2]
Reactant: CCOC(=O)/C=C/c1ccc(C#N)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Step B (1.3 g, 5.9 mmol) in 30 mL of methanol was added 10% palladium on carbon (130 mg). The solution was stirred at room temperature under an atmosphere of hydrogen for 2 hours, then purged with argon. The mixture was filtered through celite, the filter pad was washed with methanol, and the filtrate was concentrated in vacuo. The crude product was purified on a C18 preparative HPLC column to give the titled product after conversion to the free base.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([C:18](OC)=[O:19])=[CH:14][C:13]4=[O:22])=[CH:8][N:7]3[C:23]=2[CH3:24])[CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:13]4=[O:22])=[CH:8][N:7]3[C:23]=2[CH3:24])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccn(-c2ccc3nc(C4CC4)c(C)n3c2)c(=O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(CO)cc3=O)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
To a solution of methyl 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate (600 mg) in DCM (10 ml) was added diisobutylaluminum hydride (1.76 M in toluene, 2.1 ml) at 78° C. The mixture was stirred at same temperature for 3 h, and allowed to warm to room temperature for 4 h. The mixture was quenched with a mixture of MeOH and water, and filtered through celite. The filtrate was concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (200 mg) as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].F[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1>>[CH3:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:16]=1
Reactant: Cc1ccnc(F)c1
Reactant: N#Cc1cccc(O)c1
Product: Cc1ccnc(Oc2cccc(C#N)c2)c1

Procedure:
3-Hydroxy-benzonitrile was reacted with 2-fluoro-4-methylpyridine according to the method of Example 78A to provide the title compound. MS (DCI/NH3) m/z 211 (M+1)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]([CH2:20]O)[CH:15]=2)[CH:9]=[CH:10][C:11]=1[Cl:12]>C(Cl)(Cl)Cl>[Cl:3][CH2:20][C:16]1[N:17]=[CH:18][N:19]=[C:14]([NH:13][C:8]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=2)[CH:15]=1
Reactant: OCc1cc(Nc2ccc(Cl)c(Cl)c2)ncn1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cc(Nc2ccc(Cl)c(Cl)c2)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (0.184 mL, 2.52 mmol) was added dropwise to a stirred solution of (6-((3,4-dichlorophenyl)amino)pyrimidin-4-yl)methanol (0.17 g, 0.629 mmol) in chloroform at 0° C. The mixture was allowed to warm to room temperature and further stirred for 18 h. After concentration, the crude product 6-(chloromethyl)-N-(3,4-dichlorophenyl)pyrimidin-4-amine (0.08 g, 75%) was used in the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (1H, br. s.), 8.81 (1H, s), 8.20 (1H, s), 7.64 (2H, s), 7.11 (1H, s), 4.76 (2H, s). LCMS: R.T.=3.48; [M+H]+=287.91.
Reaction SMILES: Cl[CH:2](Cl)[C:3]([O:5][CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])=O.[CH:29](O)(C)C>>[CH:3]([O:5][CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])([CH3:29])[CH3:2]
Reactant: CC(C)O
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(Cl)Cl)CS[C@H]12
Product: CC(C)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
3-Dichloroacetoxymethyl-7β-(2'-thienylacetamido)-ceph-3-em-4-carboxylic acid (12.0 g., 25.8 m.mole.) was refluxed in isopropanol (100 ml.) for 45 minutes. After filtration through a pad of Kieselguhr, the isopropanol solution was poured into water (1000 ml.) and the pH adjusted to 8.5. The solution was extracted with ethyl acetate (2 × 100 ml.) and the extracts discarded. The solution was then acidified to pH 1.5 with 2N-hydrochloric acid and extracted with ethyl acetate (3 × 100 ml.). The ethyl acetate extracts were dried over magnesium sulphate and evaporated. The residue (8.5 g.) was dissolved in a mimimum of hot ethanol, from which the title compound separated on cooling (1.5 g., 15%). This material recrystallised from ethanol as colourless prisms, m.p. 169°-171° (d), [α]D28 + 87° (c 1.0, tetrahydrofuran), λλmax (ethanol) 237 nm (ε 14,500), 260 nm (ε 7,900), νmax (Nujol) 1775 (β-lactam), 1728 (COOH), 1668 and 1535 cm.-1 (CONH), N.M.R. (D2O, with sodium bicarbonate) 5.64 and 5.95 (quartet: J = 16 Hz, -CH2OCH(CH3)2), 6.31, 8.87τ )-CH2 -OCH (CH3)2 respectively). (Found: C, 51.6; H, 5.1; N, 6.7; S, 16.3. C17H20N2O5S2 requires C, 51.5; H, 5.1; N, 6.1; S, 16.2%). Rf 0.32 (system B), 0.65 (system C).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[Cl:12][C:13]1[C:25]([CH3:26])=[C:24]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([C:27](O)=[O:28])[C:22]=3[NH:23]2)=[CH:15][CH:14]=1.Cl>C(OCC)(=O)C>[Cl:12][C:13]1[C:25]([CH3:26])=[C:24]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([CH2:27][OH:28])[C:22]=3[NH:23]2)=[CH:15][CH:14]=1
Reactant: Cc1c(Cl)ccc2c1[nH]c1c(C(=O)O)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)ccc2c1[nH]c1c(CO)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A suspension of 0.3 g. of lithium aluminum hydride in 5 ml. of absolute tetrahydrofuran is combined dropwise with 0.560 g. of the ethyl ester of 7-chloro-8-methylcarbazole-1-carboxylic acid, dissolved in 10 ml. of absolute tetrahydrofuran; the mixture is agitated for one hour at room temperature. Then, the reaction mixture is heated for one hour under reflux, allowed to cool, diluted with 20 ml. of ethyl acetate, mixed under cooling dropwise with hydrochloric acid, and the organic phase is separated, washed, and concentrated under vacuum. The residue is recrystallized from toluene, thus obtaining, in a 95% yield, 7-chloro-1-hydroxymethyl-8-methylcarbazole, m.p. 187° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([SH:13])=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=1>C(O)C>[OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([S:13][C:21]2[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=2)=[N:4][N:3]=1
Reactant: Oc1nnc(S)n1-c1ccccc1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1cnc(Sc2nnc(O)n2-c2ccccc2)s1
Yield: 18.7 %

Procedure:
The title compound was prepared by the general method described by Potts, K.T.(1961) Chem. Rev. 61:87. 4-Phenyl-3-thiosemicarbazide (4.18 g) (Aldrich) was dissolved in 50 mL of pyridine and treated with 2.71 g of ethyl chloroformate at 0° C. The reaction was stirred for 2 hours and then refluxed for 18 hours. Evaporation of the solvent and trituration with water gave 2.5 g of 3-hydroxy-5-mercapto-4-phenyl-1,2,4-triazole. 3-Hydroxy-5-mercapto-4-phenyl-1,2,4-triazole (1.93 g) was stirred in 10 mL of ethanol with 1.1 equivalent of potassium carbonate in 10 mL ethanol for one hour and then reacted with 2.09 g of 2-bromo-5-nitrothiazole as in Example 1. Crystallization from ethanol and water gave 0.6 g of 3-hydroxy-5-[(5-nitrothiazol-2-yl)mercapto]-4-phenyl-1,2,4-triazole, a dark yellow solid, M.P. 188-190° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C@@H:6]([NH:12][C:13]([NH:15][C:16]3[N:21]=[CH:20][C:19]4[C:22]([C:44]5[CH:49]=[CH:48][N:47]=[C:46]([CH3:50])[CH:45]=5)=[N:23][N:24](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:18]=4[CH:17]=3)=[O:14])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C@@H:6]([NH:12][C:13]([NH:15][C:16]3[N:21]=[CH:20][C:19]4[C:22]([C:44]5[CH:49]=[CH:48][N:47]=[C:46]([CH3:50])[CH:45]=5)=[N:23][NH:24][C:18]=4[CH:17]=3)=[O:14])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(NC(=O)N[C@H]4CCOc5cc(F)ccc54)ncc23)ccn1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]c3cc(NC(=O)N[C@H]4CCOc5cc(F)ccc54)ncc23)ccn1

Procedure:
In a manner similar to that described in Scheme 6 and Example 30, (S)-1-(7-fluorochroman-4-yl)-3-(3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea was deprotected with TFA to afford 1-[(4S)-7-fluoro-3,4-dihydro-2H-chromen-4-yl]-3-[3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl]urea. MS ESI calc'd. for C22H19FN6O2[M+1]+ 419, found 419.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH:18]([N:31]1[C:39]2[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42](O)=[O:43])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:18]([N:31]1[C:39]2[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42]([NH:1][C:2]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:43])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1
Reactant: CCOC(=O)CCCOc1ccc(Cl)cc1N
Product: C/C(=C\C(=O)Nc1cc(Cl)ccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1

Procedure:
268 mg of compound 47 was obtained in a similar manner to those described in the Examples 1 and 2 using 773 mg of ethyl 4-(2-amino-4-chlorophenoxy)butyrate and 551 mg of 3-(1-benzhydrylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[CH:9][C:8]([CH3:12])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1([C:16](=O)[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>C1C=CC=CC=1>[CH:1]1([N:6]2[C:10]3[N:11]=[C:16]([CH:13]4[CH2:14][CH2:15]4)[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]=3[C:8]([CH3:12])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(N)n(C2CCCC2)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCCC1
Reaction time: 4 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 33 using 1-cyclopentyl-3-methyl-1H-pyrazol-5-amine (570 mg, 3.45 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (635 mg, 3.45 mmol), and benzene (50 mL) wherein the reaction time was 4 h. The crude product was purified via silica gel chromatography (eluent: 0 to 10% EtOAc:Hex). The final product was collected as 0.740 g (68%). LCMS E-S (M+H)=314.3 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04-1.21 (m, 4 H) 1.47 (t, J=7.20 Hz, 3 H) 1.73 (br. s., 2 H) 2.00 (d, J=2.78 Hz, 2 H) 2.08-2.16 (m, 4 H) 2.21 (s, 1 H) 2.67 (s, 3 H) 4.49 (q, J=7.16 Hz, 2 H) 5.32 (t, J=7.83 Hz, 1 H) 7.40 (s, 1 H).