Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=1>>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([S:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:29]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1

Procedure:
The product from Example 2g (93 mg, 0.44 mmol) was reacted with the product from Example 18b (123 mg, 0.44 mmol) for 23 h following the procedure from Example 1g giving the title compound after purification of the crude product by HPLC with TFA as a trifluoroacetic acid salt solid (72 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H), 1.84 (dq, J=14.75, 7.46 Hz, 2H), 2.04 (s, 3H), 2.35 (s, 3H), 2.99 (t, J=7.35 Hz, 2H), 6.31 (d, J=6.99 Hz, 1H), 7.15 (d, J=8.09 Hz, 1H), 7.20-7.33 (m, 4H), 7.50 (d, J=8.46 Hz, 2H), 7.81 (d, J=8.46 Hz, 1H), 8.41 (d, J=6.99 Hz, 1H), 9.00 (d, J=8.46 Hz, 1H), 10.05 (s, 1H), 11.02 (s, 1H); MS (ESI+) m/z 443 (M+H)+; (ESI−) m/z 441 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Yield: 29 %

Procedure:
Ethyl 4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylate, 11-b, (150 g, 0.46 mol) in THF (1.5 L) was treated with LiOH monohydrate (58 g, 1.39 mol) in water (60 ml) at room temperature for 3 hours. The mixture was concentrated under vacuum and diluted with water (200 ml) followed by extraction with ethyl acetate. The aqueous layer was acidified to pH=2 with 10% HCl and solid crashed out from the solution which was then filtered and washed with water to afford the product, 11-c, (40 g, 29%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2].C([Li])CCC.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:22]1([S:28]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[CH:11][CH:10]=3)[C:6]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCc1ccc2[nH]cc(CCC(=O)O)c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 6.1 %

Procedure:
The indole propionic acid 14 (100 mg, 0.46 mmol) was dissolved in THF (5.0 mL) and cooled to −78° C. To this solution was added n-butyllithium (n-BuLi; 0.4 mL, 1.0 mmol, 2.4 M in hexanes) dropwise and the mixture was stirred at −78° C. for 1 hour. To this mixture was added benzenesulfonyl chloride (0.13 mL, 1 mmol) and the reaction was allowed to stir overnight and warm to room temperature. The mixture was poured into ice cold H3PO4 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography (5% MeOH/CHCl3) to give compound 6 as a white solid (10 mg; M−1=356.4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[N:6][CH:7]=1.[NH2:18][CH:19]1[CH:26]2[CH2:27][C:22]3([OH:29])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:18][CH:19]2[CH:20]3[CH2:28][CH:24]4[CH2:23][C:22]([OH:29])([CH2:27][CH:26]2[CH2:25]4)[CH2:21]3)=[O:14])=[N:6][CH:7]=1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)c1cccc(Oc2ccc(Cl)cn2)c1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(Oc2ccc(Cl)cn2)c1

Procedure:
Prepared from 3-(5-chloro-pyridin-2-yloxy)-benzoic acid and 4-amino-1-hydroxyadamantane. 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1 H), 7.68 (d, 1 H), 7.51-7.61 (m, 2 H), 7.47 (t, 1 H), 6.94 (d, 1 H), 6.23-6.36 (m, 1 H), 4.08-4.25 (m, 1 H), 2.24 (t, 3 H), 1.51-2.03 (m, 13 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[C:13]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C(O)(C(F)(F)F)=O.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CNc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
4-Formylbenzoic acid methyl ester (10.6 g, 64 mmol) was dissolved in methanol (200 mL). 4-tert-Butylaniline (9.61 g, 64 mmol) was added and the resulting suspension was refluxed for 15 min. After cooling to room temperature, TFA (5.18 mL, 68 mmol) was added followed by portion wise addition of sodium cyanoborohydride (3.26 g, 52 mmol). The resulting mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was partitioned between ethyl acetate (200 mL) and 1 N aqueous sodium hydroxide (150 and 100 mL). The organic phase was dried (magnesium sulphate) and evaporated in vacuo to afford 19.0 g (99%) of 4-[(4-tert-butylphenylamino)methyl]benzoic acid methyl ester as a solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+]([C:7]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-])=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][S:2][C:7]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: C[S-]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(F)(F)F)cc1SC
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
Sodium thiomethoxide (91 mg; 1.3 mmol; 1.3 equiv) was dissolved in water (0.34 mL). Tetrabutylammonium bromide (48 mg; 0.15 mmol; 0.15 equiv) was added. Methyl 2-nitro-4-trifluoromethylbenzoate (5a; 249 mg; 1.0 mmol) was dissolved in toluene and added to the mixture. The reaction mixture was stirred at ambient temperature for 1 h to completely consume 5a according to gas chromatography (GC) analysis. The reaction mixture was diluted with ethyl acetate and water and the layers were thoroughly mixed and then separated. The organic layer was dried over Na2SO4 and concentrated to afford 0.26 g of 6a which contained a small amount of tetrabutylammonium bromide. The crude product was filtered through a pad of flash silica gel to afford 226 mg (90%) of 6a.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[S:7](Cl)(Cl)(=[O:9])=[O:8]>[W]>[CH3:3][CH:2]1[C:1](=[O:6])[O:5][S:7](=[O:9])(=[O:8])[CH2:4]1
Reactant: CC(C)C(=O)O
Reactant: O=S(=O)(Cl)Cl
Agent: [W]
Product: CC1CS(=O)(=O)OC1=O

Procedure:
88 g. of isobutyric acid dissolved in 100 g. of sulfuryl chloride is heated at 80° C. and irradiated with a 300 watt tungsten lamp for 2 hours. Addition of ligroin precipitates an oil which has a boiling range 135°-140° at 4mm and is identified as 4-methyl-1,2-oxathiolane-5-one-2,2-dioxide by its equivalent weight, 75.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:20])[CH:3]=1.[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:20])[CH:3]=1
Reactant: COC(=O)c1cccc(-n2c(C)cc(O)cc2=O)c1C
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1C
Reaction time: 8 h

Procedure:
Methyl-3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-2-methylbenzoate (from Step 1) (42.0 g, 154 mmol) was stirred briskly at room temperature with 2,4-difluorobenzyl bromide (19.7 ml, 154 mmol) and K2CO3 (31.8 g, 231 mmol) in 250 ml of N,N-dimethylformamide. After stirring overnight, the reaction was poured into 1 L of cold water. The solution was extracted 3 times with ethyl acetate and the organic layers were dried over MgSO4, and evaporated. The product was carried on to the next step as a crude oil (60.4 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J=7.85, 1.28 Hz, 1H), 7.45-7.34 (m, 2H), 7.27-7.23 (m, 1H), 6.94-6.84 (m, 2H), 5.98 (d, J=2.68 Hz, 1H), 5.92 (dd, J=2.69, 0.81 Hz, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 2.28 (s, 3H), 1.81 (s, 3H); LC/MS, tr=2.96 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 400 (M+H). ES-HRMS m/z 400.1341 (M+H calcd for C22H19F2NO4 requires 400.1355).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].[CH:45](Br)([CH3:47])[CH3:46]>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:45]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:47])[CH3:46]
Reactant: CC(C)Br
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole trifluoroacetate (300 mg, 0.6 mmol, 1 eq) in anhydrous N,N-dimethylformamide (3 m) was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq). The resulting mixture was stirred for thirty minutes at room temperature. Isopropyl bromide (0.66 mmol, 1 eq) was added to the reaction and the resulting mixture was stirred for two hours at room temperature. The reaction was quenched with the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by flash column chromatography to yield the title product as a crystalline product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([C:21]([C@@H:23]2[CH2:25][C@H:24]2[C:26]([O:28]CC)=[O:27])=[O:22])[CH2:15]3)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([C:21]([C@@H:23]2[CH2:25][C@H:24]2[C:26]([OH:28])=[O:27])=[O:22])[CH2:15]3)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)N1Cc2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)CN(C(=O)[C@@H]2C[C@H]2C(=O)O)C3)nc1Cl
Yield: 67.8 %

Procedure:
Ethyl trans(±)-2-[(5-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1,3-dihydro-2H-isoindol-2-yl)carbonyl]cyclopropanecarboxylate obtained in Example (93a) (0.11 g, 0.26 mmol) was dissolved in methanol (5 mL) and dichloromethane (2 mL). The solution was subjected to the same operation as in Example (91d) using a 2 N aqueous lithium hydroxide solution (2 mL, 4 mmol), to obtain 71 mg of the title compound as a light brown solid (69%).
Reaction SMILES: [I-:1].[Na+].Cl[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1.C(Cl)(=O)C>C(#N)C>[I:1][C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: [I-]
Reactant: Clc1cc(C2=CCCC2)ccn1
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Ic1cc(C2=CCCC2)ccn1
Temperature: 25 °C

Procedure:
A flask was charged with sodium iodide (3.75 g, 25.0 mmol), 2-chloro-4-cyclopent-1-enyl-pyridine (450 mg, 2.5 mmol) and acetonitrile (8 mL). Acetyl chloride (0.27 mL, 3.76 mmol) was slowly added and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and quenched with water. Saturated Na2CO3 and 10% Na2S2O3 were added and the mixture was extracted with EtOAc (3×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by chromatography (0% to 10% EtOAc/hexanes) to afford 2-iodo-4-cyclopent-1-enyl-pyridine as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[NH2:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[N:20][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[NH2:15][C:16]1[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[N:18][CH:19]=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: Nc1cncnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ncncc2N)C1
Temperature: 150 °C
Yield: 39.3 %

Procedure:
tert-butyl ((3S)-1-(5-amino-4-pyrimidinyl)-3-piperidinyl) carbamate. A mixture of (S)-tert-butyl piperidin-3-ylcarbamate (486 mg, 2.42 mmol), 5-amino -4-chloropyrimidine (262 mg, 2.02 mmol, Magical Scientific, Atchison, Kans.) and Cs2CO3 (988 mg, 3.03 mmol) in 2 mL of DMF was heated in a microwave at 150° C. for 45 min. The mixture was diluted with 50 mL of EtOAc and filtered through a pad of Celite. The filtrate was washed with 5 mL saturated NH4Cl (aq.) followed by 5 mL of brine. The organic solution was concentrated and purified by silica gel chromatography (60-100% EtOAc in hexanes) to give tert-butyl ((3S)-1-(5-amino-4-pyrimidinyl)-3-piperidinyl)carbamate (233 mg, 39% yield, 90% purity). This material used without further purification. MS (ESI, pos. ion) m/z: 294.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:24][CH:25]([NH:33][C:34]([C:36]1[C:44]2[C:39](=[N:40][CH:41]=[C:42](Br)[N:43]=2)[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:37]=1)=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CN(C=O)C>CCOCC.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][CH:25]([NH:33][C:34]([C:36]1[C:44]2[C:39](=[N:40][CH:41]=[C:42]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:43]=2)[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:52])([CH3:51])[CH3:53])[CH:37]=1)=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Temperature: 90 °C
Reaction time: 15 h
Yield: 60.8 %

Procedure:
6-Fluoro-3-tributylstannyl-1H-indazole (0.20 g, 0.47 mmol), copper(I) iodide (12 mg, 0.06 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide (200 mg, 0.41 mmol) were combined with DMF (6 mL) to give a yellow solution. The mixture was degassed with nitrogen for 10 min then tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) was added. The reaction was stirred at 90° C. under nitrogen for 15 h. The reaction mixture was cooled, diluted with ether (60 mL) and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-3% methanol in dichloromethane with 0.5% ammonium hydroxide) to give 136 mg (61%) of 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide as a foaming solid. MS: (M+H)+=546.
Reaction SMILES: [Br:1]C1C(C#N)=NC=CC=1.C(O/N=C(\C1C=CC=CN=1)/[C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=1[OH:24])(C)(C)C.[C:31]([O:35]/[N:36]=[C:37](\[C:46]1[C:51]([Br:52])=[CH:50][CH:49]=[CH:48][N:47]=1)/[C:38]1[CH:43]=[C:42]([Br:44])[CH:41]=[CH:40][C:39]=1[OH:45])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35]/[N:36]=[C:37](\[C:46]1[C:51]([Br:52])=[CH:50][CH:49]=[CH:48][N:47]=1)/[C:38]1[CH:43]=[C:42]([Br:44])[CH:41]=[CH:40][C:39]=1[OH:45])([CH3:34])([CH3:32])[CH3:33].[Br:1][C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=1[OH:24]
Reactant: N#Cc1ncccc1Br
Reactant: CC(C)(C)O/N=C(\c1ccccn1)c1cc(Br)ccc1O
Agent: CC(C)(C)O/N=C(/c1cc(Br)ccc1O)c1ncccc1Br
Product: Oc1ccc(Br)cc1Br

Procedure:
Employing 3-bromo-2-cyanopyridine (5.88 g) in place of 2-cyanopyridine in the production of Compound 75 in Example 9, substantially the same reaction as in Example 9 was conducted to give (Z)-2-(5-bromo-2-hydroxybenzoyl)-3-bromopyridine O-t-butyloxime (3.74 g) (Compound 81) from 2,4-dibromophenol (8.01 g).
Reaction SMILES: [OH:1][CH:2]([N:15]1[C@H:18]([SH:19])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].Br[CH2:32][C:33]([CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:34].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O>[OH:1][CH:2]([N:15]1[C@H:18]([S:19][CH2:32][C:33]([CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:34])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(CBr)C1CCOCC1
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SCC(=O)C2CCOCC2)cc1
Reaction time: 0.33 h
Yield: 76 %

Procedure:
Crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl]acetate (prepared from 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-on-6-yl]acetate (8.35 g, 20 mmol)) was dissolved in acetone (25 ml) and treated with a solution of 4-bromoacetyltetrahydropyran (G. H. Harnest and A. Burger, J. Amer. Chem. Soc., 1943, 65, 370) (4.4 g, 20 mmol). After 20 min., potassium carbonate (1.38 g, 10 mmol) was added and the mixture stirred again for a further 45 min. Excess ethyl acetate was then added and the organic solution washed with water, brine and dried over anhydrous MGSO4. Evaporation of solvent and chromatography of the residue on silica gel using 50% hexane in ethyl acetate to 100% ethyl acetate gave the title compound as a pale yellow foam (8.5 g; 76%); νmax (CHCl3) 3420, 1780, 1750, 1680 and 1615 cm-1. [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (579)].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:7]=[C:6]([O:23][CH3:24])[N:5]=1.I[CH3:26]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[N:16]([CH3:26])[C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:7]=[C:6]([O:23][CH3:24])[N:5]=1
Reactant: CI
Reactant: COc1cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 0.13 g (2.9 mmol) sodium hydride (55%, suspension in mineral oil) were added 0.90 g (2.8 mmol) 6-(2-chloro-6-methoxy-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10 mL DMF at RT. The reaction mixture was stirred for 30 min at RT. Then 0.18 mL (5.0 mmol) iodomethane in 1 mL DMF were added dropwise and the mixture was stirred overnight at RT. The reaction mixture was poured onto water and the precipitate formed was suction filtered and washed with water. The residue was extracted with diethyl ether, suction filtered and dried.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cc1cccc(CN2C(=O)CN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CC(=O)N(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 46E (0.020 g, 0.046 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.172 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.023 g, 73% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.82 (s, 9 H), 0.87 (s, 9 H), 1.32 (m, 1 H), 1.53 (t, J=11.40 Hz, 1 H), 2.41 (s, 3 H), 2.63 (m, 3 H), 2.85 (m, 1 H), 3.16 (d, J=18.02 Hz, 1 H), 3.60 (m, 5 H), 3.90 (m, 3 H), 4.19 (m, 1 H), 4.35 (s, 1 H), 4.68 (m, 2 H), 6.90 (d, J=9.93 Hz, 1 H), 7.03 (m, 6 H), 7.16 (d, J=7.72 Hz, 1 H), 7.25 (d, J=8.09 Hz, 2 H), 7.34 (m, 1 H), 7.69 (t, J=7.72 Hz, 1 H), 7.93 (m, 6 H), 8.65 (d, J=4.78 Hz, 1 H).