Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:13]=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][C:17]=4[C:18]=3[CH2:19][CH2:20][C@:4]12[CH3:5])#[CH:2].C(=O)([O-])[O-].[Ca+2].[H][H]>C1C=CC=CC=1>[CH2:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:13]=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][C:17]=4[C:18]=3[CH2:19][CH2:20][C@:4]12[CH3:5])[CH3:2]
Reactant: C#C[C@]1(O)CC[C@H]2C3=C(CC[C@@]21C)c1ccc(OC)cc1CC3
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccccc1
Product: CC[C@]1(O)CC[C@H]2C3=C(CC[C@@]21C)c1ccc(OC)cc1CC3
Yield: 63.5 %

Procedure:
Add dl-17α-ethynyl-3-methoxyestra-1,3,5(10),8-tetraen-17-ol (7 g) in benzene (75 ml) to a suspension of prehydrogenated 2% palladised calcium carbonate (3 g) in benzene (50 ml), and shake in an atmosphere of hydrogen until two molecular equivalents of hydrogen (1,030 ml) have been absorbed. Filter the catalyst, evaporate the solvent and recrystallize the residue twice from methanol to obtain dl-17α-ethyl-3-methoxyestra-1,3,5(10),8-tetraen-17-ol (4.5 g), m.p. 105°-120°; ultraviolet absorption maximum 278 mμ (ε12,000); infrared absorption peaks at 2.95 μ, 6.25 μ.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH:12]([C:18]([CH3:20])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:12]([C:18]([CH3:20])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Oc1ccc(Cl)cc1)C(C)=O
Temperature: 80 °C
Yield: 37 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (40 g, 1 mol) was washed with dry petroleum ether and suspended in dry toluene (700 ml). The suspension was stirred under argon and carefully treated with a solution of 4-chlorophenol (128.6 g, 1 mol) in dry toluene (300 ml) added dropwise. The resulting suspension was stirred for 1 hour, warmed to 80° C. and treated with ethyl 2-chloroacetoacetate (165 g, 1 mol) added dropwise to maintain the internal temperature between 80°-85° C. The resulting solution was stirred at 80° C. for 4 hours, cooled and carefully treated with ice. The organic phase was washed with water (3×200 ml), 10% sodium hydroxide (2×75 ml), 75 ml), water (20 ml) and brine (100 ml), dried with magnesium sulfate, filtered and concentrated. The resulting oil was distilled in vacuo [bp 126°-132° C. (0.1 mm)]to give 95 g (37%) of ethyl 2-(4-chlorophenoxy)-acetoacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][CH:10]=1.[C:22]([O:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28])(=[O:24])[CH3:23]>>[C:22]([O:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[O:11][CH:10]=[C:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])[C:13]=2[CH:14]=1)=[O:19])=[O:28])(=[O:24])[CH3:23]
Reactant: NNC(=O)c1ccc2occ(-c3cc(F)ccc3F)c2c1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Product: CC(=O)OC(C)(C)C(=O)NNC(=O)c1ccc2occ(-c3cc(F)ccc3F)c2c1
Yield: 85 %

Procedure:
In the same manner as in Reference Example 129 and using 3-(2,5-difluorophenyl)-1-benzofuran-5-carbohydrazide instead of 3-bromo-1-benzofuran-5-carbohydrazide and 2-chloro-1,1-dimethyl-2-oxoethyl acetate instead of (1S)-2-chloro-1-methyl-2-oxoethyl acetate, the title compound (yield 85%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:2]1.[Li+].[CH3:16][CH:17]([N-]C(C)C)C.C(I)C>C1COCC1>[CH2:16]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:2]1)[CH3:17]
Reactant: COC(=O)CC1=CCc2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1C=C(CC(=O)OC)c2ccccc21
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl inden-3-ylacetate from Example 13, Step 1 (1 g, 5.32 mmol) in THF (10 mL) at -70° C. was added dropwise a solution of LDA (12.2 mL, 0.87M, 2 eq.) in THF. The resulting orange solution was stirred for 30 minutes at -70° C. and then ethyl iodide (0.47 mL, 5.85 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was left to warm to room temperature while a precipitate appeared. The reaction mixture was then quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with 1N HCl, then with brine, dried over MgSO4 and evaporated to dryness. The oily residue was chromatographed on silica gel eluting with a 1:19 mixture of ethyl acetate-hexane to afford pure title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH:12]=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH2:17][CH3:18])=[O:15]>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1(/[CH:12]=[CH:19]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C=O)CC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/C1(NC(=O)OC(C)(C)C)CC1
Yield: 61 %

Procedure:
1-Tert-butoxycarbonylaminocyclopropane carbaldehyde (10.99 g, 59.3 mmol) and (carbethoxymethylene) triphenylphosphorane (27.6 g, 75.2 mmol) were dissolved in dichloromethane (300 ml) and heated under reflux for 4 hours. After evaporating the solvent, the resulting residue was applied to a silica gel chromatography column and eluted with an eluant of n-hexane:ethyl acetate=9:1, to thereby obtain 9.23 g (61%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[C:15]([OH:24])[CH:16]=[CH:17][C:18]=3[OH:23])[C:13](=[O:25])[C:12]=2[C:11]([NH:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])=[CH:10][CH:9]=1.[F:33][C:34]([F:41])([F:40])[C:35]([O:37]CC)=O>CO>[OH:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[C:15]([OH:24])[CH:16]=[CH:17][C:18]=3[OH:23])[C:13](=[O:25])[C:12]=2[C:11]([NH:26][CH2:27][CH2:28][N:29]([CH2:30][CH2:31][OH:32])[C:35](=[O:37])[C:34]([F:33])([F:40])[F:41])=[CH:10][CH:9]=1)[C:35](=[O:37])[C:34]([F:41])([F:40])[F:33]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCNCCO)ccc(NCCNCCO)c21
Solvent: CO
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCN(CCO)C(=O)C(F)(F)F)ccc(NCCN(CCO)C(=O)C(F)(F)F)c21

Procedure:
A suspension of 1.50 g. of 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone in 75 ml. of ethyl triflouroacetate and 75 ml. of methanol is stirred for 10 minutes. Evaporation of the resulting solution in vacuo at 30° C. leaves a residue which is washed and macerated with methylene chloride, giving 2.11 g. of blue-black solid, m.p. 162° C.
Reaction SMILES: Cl.[NH2:2]O.[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:24])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:11]([CH3:15])[O:12]2)=[CH:7][C:6]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>N1C=CC=CC=1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:11]([CH3:15])=[N:2][O:24][C:9]=2[C:8]2[CH:7]=[C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:5]([OH:4])=[CH:14][C:13]=2[OH:12])=[CH:17][CH:18]=1
Reactant: NO
Reactant: COc1ccc(-c2c(C)oc3cc(O)c(-c4ccccc4)cc3c2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2c(C)noc2-c2cc(-c3ccccc3)c(O)cc2O)cc1
Yield: 73.9 %

Procedure:
Hydroxylamine hydrochloride (75 mg, 1.08 mmol) was added to a suspension of 7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-6-phenyl-chromen-4-one (105 mg, 0.29 mmol) in pyridine (2 ml) and the mixture heated under reflux for ˜6 hrs., to give a pale yellow solution. The solution was allowed to cool and water (20 ml) added. The mixture was extracted with diethyl ether (2×10 ml). The combined extracts were washed with water (2×20 ml) and saturated aqueous sodium chloride solution (10 ml). The solution was dried over anhydrous magnesium sulphate and concentrated. The crude products were purified by column chromatography, silica, eluting with ethyl acetate/hexane (1:1), to give the title compound as an off-white powder (80 mg)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:23])=[C:21]([Cl:22])[C:16]=4[C:15](=[O:24])[N:14]4[CH2:25][CH2:26][C@H:13]4[C:12]=23)[N:4]=1.C(N(C(C)C)[CH:30]([CH3:32])[CH3:31])C.[CH2:36](Br)[CH:37]=[CH2:38]>C(Cl)Cl>[CH2:32]([N:1]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:23])=[C:21]([Cl:22])[C:16]=4[C:15](=[O:24])[N:14]4[CH2:25][CH2:26][C@H:13]4[C:12]=23)[N:4]=1)[CH2:38][CH:37]=[CH2:36])[CH:30]=[CH2:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Reactant: C=CCBr
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Yield: 69.2 %

Procedure:
26.6 g (71 mmol) of crude (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 400 ml of methylene chloride, 85 ml (496 mmol) of N-ethyldiisopropylamine and 34.5 g (285 mmol) of allyl bromide were stirred at room temperature for 20 hours. The reaction solution was washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on 2 kg of silica gel while eluting with ethyl acetate. The uniform fractions were evaporated and recrystallized from toluene and n-hexane. There were obtained 22.34 g (69%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 103°-104°.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([O:20][C:21]2[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=4)=[C:28](I)[O:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O>CS(C)=O.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>[CH2:7]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([O:20][C:21]2[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=4)=[C:28]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[F:39])[O:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1F
Reactant: CCc1ccc(-c2c(I)oc3ncnc(O[C@@H]4CCCN(Cc5ccccc5)C4)c23)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCN(Cc5ccccc5)C4)c23)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Add 0.68 ml of a 2 M aqueous sodium carbonate solution to a mixture of 365 mg (0.68 mmol) of 4-{[(3R)-1-benzylpiperidin-3-yl]oxy}-5-(4-ethylphenyl)-6-iodofuro[2,3-d]pyrimidine and 24 mg (0.03 mmol) of bis(triphenylphosphine)palladium(II) chloride in 15 ml of DMSO. Then add 118 mg (0.85 mmol) of (2-fluorophenyl)boronic acid and stir the mixture at 80° C. for 15 hours. Then filter the reaction mixture and purify directly by means of preparative RP-HPLC (gradient: water/acetonitrile). 291 mg (84% of theory) of the target compound are obtained.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][S:13]([NH:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:15])=[O:14]>>[NH2:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:21]3[CH:22]=[C:17]([NH:16][S:13]([CH3:12])(=[O:14])=[O:15])[CH:18]=[CH:19][CH:20]=3)[N:7]2[N:8]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: CS(=O)(=O)Nc1cccc(-c2cccc3nc(N)nn23)c1
Yield: 18 %

Procedure:
N-[3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.80 g, 8.45 mmol) and 3-methylsulfonylaminophenyl boronic acid (2.0 g, 9.30 mmol), in a manner analogous to Step 73c. The residue was purified on an 80 g Isco silica gel column using a gradient of 0-7% methanol in dichloromethane as an eluent. N-[3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide (461 mg, 18%) was isolated as a beige powder. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.94 (s, 1H), 7.72 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.51 (m, 2H), 7.38 (d, J=8.6 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.03 (br s, 2H), 3.08 (s, 3H). MS=304 (MH)+.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH:16]1[C:21]([CH2:22][C:23]([NH2:25])=[NH:24])=[CH:20][C:19]([Cl:26])=[C:18]([Cl:27])[CH:17]=1>>[OH:13][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:24]=[C:23]([CH2:22][C:21]2[CH:16]=[CH:17][C:18]([Cl:27])=[C:19]([Cl:26])[CH:20]=2)[N:25]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)Cc1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1cnc(Cc2ccc(Cl)c(Cl)c2)nc1O
Yield: 37 %

Procedure:
The title compound was prepared by (a) of diethyl ethoxymethylenemalonate (6 g, 27 mmol) with 3',4'-dichlorophenylacetamidine (5.5 g, 27 mmol) to afford 37% of ethyl 4-hydroxy-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (2 g, 6 mmol) with POCl3 (14 g, 92 mmol) to afford 62% of ethyl 4-chloro-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 4-chloro-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (1 g, 2.8 mmol) with hydrazine (0.27 g, 8.3 mmol) to afford 99% of ethyl 4-hydrazino-2-(3',4'-dichlorophenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (0.9 g, 2.7 mmol) with citraconic anhydride (0.49 g, 4.4 mmol) in analogy to Example 21 to afford 47% (0.3 g) of the title compound; m.p. 119-121° C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][CH2:55][C:56]([O:58][CH:59]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:72][C:73]1[S:74][C:75]2[C:76]([N:81]=1)=[N:77][CH:78]=[CH:79][CH:80]=2.SC1SC2C=CN=CC=2N=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][CH2:55][C:56]([O:58][CH:59]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:72][C:73]4[S:74][C:75]5[C:76]([N:81]=4)=[N:77][CH:78]=[CH:79][CH:80]=5)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1nc2ncccc2s1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Agent: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4ncccc4s3)CS[C@@H]3C(NC(=O)/C(=N\OCC(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 71.1 %

Procedure:
Using 301 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-diphenylmethoxycarbonylmethoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 60 mg of 2-mercaptothiazolo[4,5-b]pyridine in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 2-mercaptothiazolo[4,5-c]pyridine, respectively, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 242 mg of the title compound in a yield of 71%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([NH:1][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a solution of 2-amino-5-nitropyrimidine (6.34 g, 45.3 mmol) in pyridine (100 ml) was added benzoyl chloride (5.8 ml, 49.8 mmol, 1.1 eq) dropwise over 10 minutes. The reaction mixture was refluxed for 6 hours, poured into ice (800 ml) and allowed to stand overnight. A brown solid was collected by filtration, washed with water and taken up in DCM (500 ml). The solution was washed with brine (3×200 ml), dried (MgSO4), filtered and concentrated under reduced pressure to leave a brown solid. Purification by column chromatography (1% methanol in DCM), afforded the title compound as a thick yellow oil (5.14 g, 47% yield).
Reaction SMILES: N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@H](OC2C=CC=CN=2)CN1C(C1C=CC=CC=1)C1C=CC=CC=1)O.[NH2:39][C@@H:40]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@@H:41]([C@H:43]1[CH2:47][C@@H:46]([O:48][C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)[CH2:45][N:44]1C(C1C=CC=CC=1)C1C=CC=CC=1)[OH:42].[C:77]([NH:80][C@:81]1([C@@H:130]([CH2:132][CH3:133])[CH3:131])[CH2:85][CH2:84][N:83]([C@@H:86]([CH2:121][CH2:122][C:123]2[CH:128]=[CH:127][CH:126]=[CH:125][CH:124]=2)[C:87](N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:88])[C:82]1=[O:129])(=[O:79])[CH3:78].[Li+].[OH-]>CCO.O>[C:77]([NH:80][C@:81]1([C@@H:130]([CH2:132][CH3:133])[CH3:131])[CH2:85][CH2:84][N:83]([C@@H:86]([CH2:121][CH2:122][C:123]2[CH:124]=[CH:125][CH:126]=[CH:127][CH:128]=2)[C:87]([NH:39][C@@H:40]([CH2:68][C:69]2[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=2)[C@H:41]([OH:42])[C@H:43]2[CH2:47][C@@H:46]([O:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)[CH2:45][NH:44]2)=[O:88])[C:82]1=[O:129])(=[O:79])[CH3:78]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](Oc2cccnc2)CN1C(c1ccccc1)c1ccccc1
Agent: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@H](Oc2ccccn2)CN1C(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](Oc3cccnc3)CN2)C1=O
Temperature: 25 °C

Procedure:
Step 13 (B): (1S,2S)-2-amino-1-((2R,4R)-1-benzhydryl-4-(pyridin-3-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-(pyridin-3-yloxy)pyrrolidin-2-yl)oxazolidin-2-one (Step 13 (A), 119 mg, 0.22 mmol) in EtOH (10 mL) was added a solution of LiOH (106 mg, 4.4 mmol) in H2O (3 mL). This reaction mixture was stirred at reflux for 4 h. After cooling down to rt, the mixture was concentrated to remove EtOH and H2O was added followed by 1N HCl solution and pH 7 buffer. The mixture was extracted with ethyl acetate and the organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-10% MeOH/chloroform) gave 25.9 mg of the title compound as an opaque oil:
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:26])[CH2:4]2)[CH3:2].Cl.Cl[CH2:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1>>[CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:29][C:30]4[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:26])[CH2:4]2)[CH3:2]
Reactant: Cc1ncccc1CCl
Reactant: CC[C@@]12C[C@H](O)[C@](O)(c3ccc(F)cc3)C[C@H]1CCc1cc(O)ccc12
Agent: Cl
Product: CC[C@@]12C[C@H](O)[C@](O)(c3ccc(F)cc3)C[C@H]1CCc1cc(OCc3cccnc3C)ccc12

Procedure:
The title compound was prepared starting from the title product of Example 28 and 3-chloromethyl-2-methylpyridine hydrochloride using the same procedure outlined for Example 2. Product was isolated by flash chromatography eluting with 35% ethyl acetate in hexane. Mass spectrum: m/e 462 (M+1).
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:19]=3)[CH2:14]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=O)C.O.[OH-].[Li+]>CO.O1CCCC1.O>[S:25]1[CH:26]=[CH:27][C:23]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][N:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([CH:5]([OH:4])[CH3:6])[N:12]=2)[CH2:22][CH2:21]3)=[CH:24]1
Reactant: CC(=O)O[C@H](C)c1nccc(N2CCc3cc(-c4ccsc4)ccc3C2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1nccc(N2CCc3cc(-c4ccsc4)ccc3C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of (R)-1-[4-(6-thiophen-3-yl-3,4-dihydro-1H-isoquinolin-2-yl)-pyrimidin-2-yl]-ethyl acetate (prepared according to the method of Example 248, Step C, 253 mg, 0.67 mmol) in a 3:1:1 mixture of methanol/tetrahydrofuran/water (5 mL) was added lithium hydroxide hydrate (84 mg, 2.0 mmol). This mixture was stirred at room temperature for 1 h, concentrated, re-suspended in water, and extracted with chloroform (4×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2% methanol/chloroform) to give a yellow solid which was further purified by recrystallization from ether/methanol to give 163 mg (72%) of the title compound as a white solid. mp: 125.5-127.5° C.; 1H NMR (CDCl3, 300 MHz) δ8.22 (d, 1H), 7.47-7.35 (c, 5H), 7.22 (d, 1H), 6.42 (d, 1H), 4.78-4.72 (c, 2H), 4.46 (br s, 1H), 3.93-3.84 (c, 2H), 2.99 (t, 2H), 1.54 (d, 3H); MS (APCI) 338 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C@@H:11]2[CH2:14][CH2:13][NH:12]2)=[O:10])=[N:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2].Cl.[O:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C(O)(=O)C.C([BH3-])#N>C1COCC1>[CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C@@H:11]2[CH2:14][CH2:13][N:12]2[CH2:28][CH:25]2[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)=[O:10])=[N:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCc1sc(NC(=O)[C@@H]2CCN2)nc1-c1ccccc1
Reactant: O=CC1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1sc(NC(=O)[C@@H]2CCN2CC2CCOCC2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of (S)-Azetidine-2-carboxylic acid (5-ethyl-4-phenyl-thiazol-2-yl)-amide; hydrochloride (100 mg; 0.309 mmol) in THF (1.5 mL) id added tetrahydro-pyran-4-carbaldehyde (70.5 mg; 0.618 mmol), acetic acid (0.071 mL; 1.236 mmol) and MP-cyanoborohydride (327 mg; 2.36 mmol/g). The reaction mixture is agitated at room temperature for 18 hours. After this time, the reaction mixture is filtered and the filtrate is washed with saturated sodium bicarbonate aqueous solution then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 386 [M+H+].