Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[C:17]12([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:30][CH2:29][C:28]([NH:27][C:17]23[CH2:24][CH:23]4[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]4)[CH2:18]2)[CH2:26]3)=[O:31])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SCCC(=O)NC23CC4CC(CC(C4)C2)C3)cc(C(C)(C)C)c1O

Procedure:
Following the method of Example 4, 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole), the title compound of Example 5 (1.03 g, 0.005 mole) and triethylamine (0.5 ml) were stirred in methanol (100 ml) for 12 hours at room temperature under argon. The solvent and triethylamine were removed on a rotary evaporator and the product purified by chromatography on silica, recrystallized from ethyl aceate/hexane, filtered and dried in vacuo, m.p. ca 172.5°-173.5° C. Analysis calc. for C27H41NO2S(443.69):
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[C:5]([C:7]1[C:8]([I:19])=[C:9]([C:13]([I:18])=[C:14]([NH2:17])[C:15]=1[I:16])[C:10]([Cl:12])=[O:11])=[O:6])[CH:2]=[CH2:3].[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>CC(N(C)C)=O>[CH2:1]([N:4]([CH3:20])[C:5]([C:7]1[C:15]([I:16])=[C:14]([NH:17][C:26]([CH2:25][O:24][C:21](=[O:23])[CH3:22])=[O:27])[C:13]([I:18])=[C:9]([C:10]([Cl:12])=[O:11])[C:8]=1[I:19])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(=O)OCC(=O)Cl
Reactant: C=CCN(C)C(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Solvent: CC(=O)N(C)C
Product: C=CCN(C)C(=O)c1c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
3-(Allyl-methyl-carbamoyl)-5-amino-2,4,6-triiodo-benzoyl chloride (8) (5 g, 7.93 mmol) was dissolved in dry DMA (20 mL) was acetoxyacetyl chloride (1.7 mL, 15.9 mmol) was added dropwise. The reaction mixture was stirred at overnight at RT, with nitrogen bubbling through the reaction mixture. The reaction was monitored by TLC on silica gel plates eluting with ethyl acetate: petrol (1:1). (6) had an Rf of 0.62 and 0.76 whilst there were two new spots at 0.32 and 0.22. The solution was diluted with ethyl acetate (˜100 mL) and washed with ice water/brine (50:50, 20 ml×5). The organics were dried over MgSO4, filtered, concentrated and dried under high vacuum to give the desired compound (5.26 g, 91%). The structure was confirmed by 1H and 13C NMR, and purity by LCMS.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:27]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[O:17])=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)N=C=O
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Product: CC(C)NC(=O)NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 20 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carboxamide and isopropyl isocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[C-:14]#[N:15].[Na+]>CS(C)=O.O>[C:10]([C:4]1[CH:5]=[C:6]([CH2:8][C:14]#[N:15])[CH:7]=[C:2]([Br:1])[C:3]=1[OH:13])(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(CCl)cc(Br)c1O
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1cc(CC#N)cc(Br)c1O
Reaction time: 15 h
Yield: 58 %

Procedure:
A solution of 1-(3-Bromo-5-chloromethyl-2-hydroxy-phenyl)-ethanone 212 (7.6 mmol) in 6 mL DMSO is added dropwise to a suspension of 8.2 mmol of NaCN in 4 mL DMSO. The mixture is stirred for 12-18 h and diluted with 80 mL water to yield a solid. The solid is isolated and recrystallized from ethanol to yield (3-acetyl-5-bromo-4-hydroxy-phenyl)-acetonitrile 213 in a 58% yield.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([CH2:14][C:15]1[C:16]([NH2:22])=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=1)[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[H-].[Na+]>CS(C)=O.O>[Br:21][C:19]1[CH:18]=[N:17][C:16]2[NH:22][C:3](=[O:2])[CH2:4][N:5]([CH2:6][CH2:7][N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH2:14][C:15]=2[CH:20]=1
Reactant: COC(=O)CN(CCN1CCOCC1)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CN(CCN2CCOCC2)Cc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
A solution of [(2-amino-5-bromo-pyridin-3-ylmethyl)-(2-morpholin-4-yl-ethyl)amino]acetic acid methyl ester (0.34 g, 0.88 mmol) in DMSO (10 mL) was treated with NaH (60% dispersion in mineral oil, 35 mg, 0.88 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (20 mL), and then extracted with EtOAc (4×50 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. The resulting pale yellow oil was purified by flash column chromatography (silica gel, CH2Cl2,/MeOH, 97:3 to 90:10) to give the title compound (0.24 g, 57%) as an off-white solid: MS (ESI) m/e 355 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]([CH3:33])([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:5][C:6]1[S:7][C:8]([CH2:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>CCO.O>[CH3:33][C:4]([O:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([CH2:5][C:6]1[S:7][C:8]([CH2:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])=[CH:9][CH:10]=1)[C:3]([OH:34])=[O:2]
Reactant: COC(=O)C(C)(Cc1ccc(CCCc2nc(-c3ccccc3)oc2C)s1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCCc1ccc(CC(C)(Oc2ccccc2)C(=O)O)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
2-Methyl-3-{5-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-thiophen-2-yl}-2-phenoxy-propionic acid methyl ester 400 mg) was dissolved in EtOH (10 mL), and then 5 N NaOH (3 mL) was added. This mixture was allowed to stir at 60° C. for 1 h. The mixture was cooled to room temperature and then acidified to pH=2 by the dropwise addition of 5 N HCl. This acidic mixture was diluted with H2O (10 mL) and then extracted with CH2Cl2 (2×25 mL). The organic layers were combined, dried over NaCl, and solvent removed in vacuo which provided 354 mg (92%) of desired acid: 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 2H), 7.39 (m, 4H), 7.23 (m, 1H), 7.03 (t, 1H), 6.95 (d, 2H), 6.70 (d, 1H), 6.62 (d, 1H), 3.40 (d, 1H), 3.30 (d, 1H), 2.80 (t, 2H), 2.52 (t, 2H), 2.27 (s, 3H), 2.02 (m, 2H), 1.44 (s, 3H); MS (EI) 462.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:28]=[C:27]([C:26]2[CH:29]=[CH:30][CH:31]=[C:32]([N+:33]([O-:35])=[O:34])[C:25]=2[Cl:24])[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Reactant: N#Cc1cccc([N+](=O)[O-])c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cccc([N+](=O)[O-])c1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.90 g), 2-chloro-3-nitrobenzonitrile (1.19 g), anhydrous aluminum chloride (0.70 g) and o-dichlorobenzene (20 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.19 g of desired compound (melting point: 112.0°-114.0° C.).
Reaction SMILES: C(OC([NH:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]([CH2:27][C:28]2[C:33](C(O)=O)=[CH:32][CH:31]=[CH:30][N:29]=2)[C:10]1=[O:37])=O)(C)(C)C.O.ON1C2C=CC=C[C:43]=2N=N1.[OH-].[NH4+].N1C(=O)C=NC=C2C=CC=CC=12>O1CCCC1>[NH2:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]([CH2:27][C:28]2[CH:33]=[C:32]([CH3:43])[CH:31]=[CH:30][N:29]=2)[C:10]1=[O:37]
Reactant: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2N(Cc2ncccc2C(=O)O)C1=O
Reactant: On1nnc2ccccc21
Agent: O=c1cncc2ccccc2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(CN2C(=O)C(N)N=C(c3ccccc3F)c3ccccc32)c1
Reaction time: 2 h

Procedure:
A solution of (3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1-(3-hydroxycarbonylpyridin-2-yl) methyl-1H-1,4-benzodiazepin-2-one (0.71 g) in tetrahydrofuran (20 ml) was treated with dicyclohexylcalbodiimide (0.29 g) and 1-hydroxybenzotriazole monohydrate (0.215 g) at room temperature. The mixture was stirred for 2 hours at the same condition. To the mixture was added dropwise a solution of ammonium hydroxide (28% ammonia in water, 0.359 g) in tetrahydrofuran (1 ml) at ambient temperature under stirring. The mixture was stirred overnight at ambient temperature. The resultant mixture was concentrated in vacuo, and the residue was taken up with ethyl acetate. The organic layer was washed with a brine and dried over sodium sulfate. Filtration and evaporation gave a crude product. The crude product was purified by column chromatography on silica gel with a mixture of chloroform and methanol to afford (3RS)-1-(3-aminocarbonylpyridin-2-yl)methyl-3-tert-butoxycarbonyl-amino-2,3-dihydro-5-(2-fluorophenyl)-1H,-1,4-benzodiazepin-2-one (0.32 g) as a yellow form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:74][C:75]([F:79])([F:78])[CH2:76][NH2:77]>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:30][CH2:31][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:33][CH2:34]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:77][CH2:76][C:75]([F:79])([F:78])[F:74])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCC(F)(F)F)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2,2,2-trifluoroethanamine (6.56 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (24.6 mg, 68%). LC-MS m/z 655 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:25](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:26].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:25]([NH:15][C:14]1[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:22]=[C:10]2[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:13]=1)[CH3:26]
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reaction time: 22 h
Yield: 117.3 %

Procedure:
A solution of 0.29 g (0.001 mol) 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine in 50 ml dimethylformamide was treated with 0.05 g (0.001 mol) sodiumhydride(55%) for 15 minutes at room temperature. Then 0.22 g (0.001 mol) ethyl-p-toluenesulfonate were added and stirring was continued for 22 hours. Saturated aqueous sodiumbicarbonate was added and the mixture was extracted with dichloromethane. Evaporation of the solvent and chromatography on silicagel with dichloromethane/methanol 96/4 gave 0.37 g(17%) ethyl-(2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-amine as beige crystals. MS m/e (%): 316 (M+H+, 100).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][C:32]1[C:37]([C:38]#[N:39])=[CH:36][CH:35]=[C:34]([NH:40][CH2:41][CH2:42][NH2:43])[N:33]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:31][C:32]1[C:37]([C:38]#[N:39])=[CH:36][CH:35]=[C:34]([NH:40][CH2:41][CH2:42][NH:43][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH:18]5[CH2:20][CH2:19]5)[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:33]=1
Reactant: Clc1ccc(-c2cc3nc(C4CCN(C5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Reactant: N#Cc1ccc(NCCN)nc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(C5CC5)CC4)nn23)nc1N
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-cyclopropylpiperidin-4-yl)-[1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 45A), 30 mg (0.14 mmol) of 2-amino-6-[(2-aminoethyl)amino]pyridine-3-carbonitrile dihydrochloride (Example 9A) and 0.125 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 43 mg (64% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:21])[C@@H:4]2[CH2:19][C:18](=[O:20])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8].[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C(Cl)Cl>[OH:21][CH:3]1[C@@H:4]2[CH2:19][C:18](=[O:20])[N:5]2[C:6]([C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])=[O:8])=[C:2]1[CH3:1]
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C[C@H]2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C[C@H]2C1O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Pivaloyloxymethyl 2-diazo-3-methyl-1-betaoxoceph-3-em-4-carboxylate (150 mg., 0.42 mmoles) was converted to a methylene chloride solution of pivaloyloxymethyl 2-methyl-1-oxocarbapen-2-em-3-carboxylate by the method of Example 1. Without isolation, and while continuing to maintain the temperature at -78° C., tetrabutylammonium borohydride (26.4 mg., 0.092 mmole) was added and the mixture stirred for 30 minutes. The reaction was quenched with acetic acid (0.58 equivalent), extracted twice with aqueous buffer (pH 7), dried over anhydrous sodium sulfate and filtered to yield a methylene chloride solution of pivaloyloxymethyl 1-hydroxy-2-methylcarbapen-2-em-3-carboxylate [ir (CH2Cl2) 1780, 1745 cm-1 ; Rf 0.25, (4:1 chloroform:ethyl acetate)]. If desired, this product is further isolated by evaporation in vacuo, keeping the temperature as low as possible to minimize degradation.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:28][CH3:29])[C:26]=1[OH:27])[CH:22]=[O:23].Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][OH:23])[CH:24]=[C:25]([O:28][CH3:29])[C:26]=1[O:27][CH:37]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:31]=1)[C:38]([O:40][CH3:41])=[O:39]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: COC(=O)C(Oc1c(Cl)cc(CO)cc1OC)c1ccccc1
Yield: 64.6 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 0.50 g (2.62 mmol) of 3-chloro-4-hydroxy-5-methoxybenzaldehyde was alkylated with 0.668 g (2.92 mmol) of methyl 2-bromophenylacetate to afford 0.570 g (64%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]2[CH:16]=CC=C[CH:12]=2)=[O:9])[CH:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:3]=1.[CH3:23]C(C)([O-])C.[K+].CCOC(C)=O>C1COCC1>[C:11]([O:10][C:8]([N:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:9])([CH3:12])([CH3:16])[CH3:23]
Reactant: CCCCCCC1C=C(Cl)C=CN1C(=O)Oc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCC1C=C(Cl)C=CN1C(=O)OC(C)(C)C
Temperature: -42 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-Chloro-1-(phenoxycarbonyl)-2-n-hexyl-1,2-dihydropyridine (7.42 g, 23.2 mmol) in 250 ml of THF at −42° C. was added dropwise over 15 minutes a 1.0M solution of potassium t-butoxide (93 mL, 92.87 mmol). The resulting orange solution was stirred for 1 h at −42° C. The cooling bath was removed, and the reaction mixture was allowed to stir for 20 min while being slowly warmed to room temperature. Water (50 ml) and ether (70 ml) were added and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with cold 1.0 N NaOH (2×35 ml), and brine. The organic phase was dried over MgSO4, filtered through Celite, and concentrated in vacuo to give the crude product. Column chromatography with 5% EtOAc in hexanes afforded 5.9 g (81% from previous reaction) as a clear colorless oil that was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 6.85-6.63 (dd, 1H), 5.55 (br s, 1H), 5.23-5.12 (m, 1H), 4.87-4.56 (m, 1H), 1.72-1.25 (m, 19H), 0.89-0.85 (t, 3H).
Reaction SMILES: [CH:1]([N:4]=[C:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:15](Cl)([Cl:17])=[O:16]>C(Cl)Cl>[C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:15]([Cl:17])=[O:16])([CH3:7])=[CH2:6]
Reactant: O=C(Cl)Cl
Reactant: CC(C)=NC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)N(C(=O)Cl)C(C)C

Procedure:
99 parts of acetone isopropylimine and 94 parts of triethylamine are dissolved in 400 parts of methylene chloride, and the whole reacted with 120 parts of phosgene at a temperature of 30° to 40° C., as described in Example 1. After isolation, 131 parts (81% of the theory) of N-isopropenyl-N-isopropylcarbamyl chloride is obtained having a boiling point of 69° C. at 3 mm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][N:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:9][O:8][C:5]1[C:4]([CH2:10][N:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:3][C:2]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][N:6]=1
Reactant: COc1ncc(Br)cc1CN(c1ccc(Oc2ccc(C)cc2)cc1)S(C)(=O)=O
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2ccccc2)cc1CN(c1ccc(Oc2ccc(C)cc2)cc1)S(C)(=O)=O
Temperature: 100 °C

Procedure:
A solution of N-(5-bromo-2-methoxy-pyridin-3-ylmethyl)-N-(4-p-tolyloxy-phenyl)-methanesulfonamide (0.16 g, 0.33 mmol) from Example 49 Step A and phenyl boronic acid (0.059 g, 0.49 mmol) in dioxane/H2O (2 mL/0.5 mL) was treated with Na2CO3 (0.11 g, 1.0 mmol) and PdCl2dppf.CH2Cl2 complex (23.8 mg, 0.033 mmol). The resulting mixture was heated at 100° C. overnight. The reaction mixture was brought to the usual work-up and the crude product was purified by chromatography (silica gel, 35% EtOAc/hexanes) to give the desired product. MS (EI) 475 (M+H)+.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.C([O-])([O-])=O.[Na+].[Na+].[Cl:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[C:24]([Cl:26])[CH:25]=1.Cl>O>[Cl:26][C:24]1[CH:23]=[C:22]([S:27]([N:2]2[CH2:3][CH:4]3[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:1]2[C:10]([OH:12])=[O:11])(=[O:28])=[O:29])[CH:21]=[C:20]([Cl:19])[CH:25]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=C(O)C1NCC2CCCCC21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1C2CCCCC2CN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 192.7 %

Procedure:
Octahydroisoindole-1-carboxylic acid (4.12 gm) was dissolved in a solution of water (125 mL) containing 5.32 g of Na2CO3. Upon complete dissolution, 4.93 g of 3,5-dichlorobenzenesulfonyl chloride was added. The reaction was stirred at rt over night. The reaction mixture was then washed with EtOAc (2×100 mL). The aqueous layer was isolated and acidified to pH=3 by the dropwise addition of a concentrated HCl solution. A solid precipitate formed in the aqueous layer and was filtered and dried in vacuo to afford N-(3,5-dichlorobenzenesulfonyl)-octahydro-isoindole-1-carboxylic acid (14.64 g) as a white solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][N:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C1(C)C=CC=CC=1.[C:27]1([C@@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:27]1([C@@H:33]([NH:35][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][N:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3cnccc32)n1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3cnccc32)n1)c1ccccc1
Temperature: 100 °C

Procedure:
To a flask containing 2-methanesulfonyl-4-[5-azabenzimidazol-1-yl]pyrimidine (33.8 mg) was added toluene (0.25 mL) and (S)-1-phenylethylamine (0.25 mL). The mixture was warmed to 100° C. The 2-methanesulfonyl-4-[5-azabenzimidazol-1-yl]pyrimidine did not dissolve so DMF (0.25 mL) was added and the mixture was maintained at 100° C. overnight. The reaction mixture was cooled and the solvents were removed under reduced pressure. The product was purified by preparative thin layer chromatography (eluted with 7% MeOH in CH2Cl2) to give 28 mg of the title compound. 1H NMR (500 MHz, CD2Cl2): δ 1.63 (3H, d, J=7 Hz), 5.18, (1H, br s), 5.96 (1H, br s), 6.78 (1H, d, J=5.5 Hz), 7.28 (1H, t, J=7 Hz), 7.38 (2H, t, J=7 Hz), 7.46 (2H, m), 7.62 (1H, br), 8.43 (1H, d, J=5 Hz), 8.4-8.6 (2H, m), 9.07 (1H, s).