Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C([O:13][C:14]([C:16]1[C:17](=[O:33])[O:18][C:19]([CH3:32])([CH3:31])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)=O)C.Cl>C(Cl)Cl>[CH3:31][C:19]1([CH3:32])[O:18][C:17](=[O:33])[C:16]([C:14]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:13])=[C:20]1[C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)N2CCCCC2)=C1c1ccc(S(C)(=O)=O)cc1
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
To a room temperature solution of piperidine (284 mg, 3.33 mmol) in CH2Cl2 (5 mL) was added trimethylaluminum (2M in hexane, 1.7 mL, 3.4 mmol). After 15 min, the product from Step 1 (310 mg, 0.92 mmol) was added in one portion and the mixture was heated to reflux for 20 h. The resulting solution was cooled and poured into 1M HCl (gas evolution). The organic layer was washed with brine, filtered through cotton and evaporated. Purification by flash chromatography (80% EtOAc/Hex) provided 175 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>C(Cl)Cl>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][NH:17][C:9]1[C:8]2[C:7](=[O:23])[C:6]3[C:15](=[C:2]([NH:27][CH2:26][CH2:24][OH:25])[CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)CCNc1cccc2c1C(=O)c1cccc(Cl)c1C2=O
Reactant: NCCO
Solvent: ClCCl
Product: CN(C)CCNc1cccc2c1C(=O)c1cccc(NCCO)c1C2=O
Temperature: -150 °C
Yield: 38.8 %

Procedure:
A mixture of Compound 17 (0.87 g, 2.7 mmol) and ethanolamine (0.8 mL, 13.23 mmol) was heated in an oil bath (−150° C.) for 18 hours. The mixture was cooled to room temperature, dissolved in 100 mL CH2Cl2 and extracted with water and brine. The organic layer was dried (Na2SO4) and evaporated to provide Compound 21 (370 mg). This product was used in the next step without any purification. Rf (9:1 CHCl3/MeOH) 0.19. The structure of Compound 21 is given below:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[O:11].[Cl:19]N1C(=O)CCC1=O>ClCCl.CCOCC>[Cl:19][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)=[O:11]
Reactant: CN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CN1CCN(C(=O)c2[nH]c3ccccc3c2Cl)CC1
Reaction time: 6 h
Yield: 63.1 %

Procedure:
(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 4, 0.5 g) in dichloromethane (3 mL) at ambient temperature was treated with N-chlorosuccinimide (0.301 g) and stirred for 6 h. The reaction mixture was diluted with ether, washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane, afforded the title compound (0.36 g). 1H NMR (400 MHz, CDCl3): δ 2.36 (3H), 2.52 (4H), 3.79 (4H), 7.21 (1H), 7.31 (1H), 7.38 (1H), 7.64 (1H), 9.05 (1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>CC(O)C>[CH3:9][S:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:11][NH2:12])[CH:7]=1
Reactant: CSc1cc(Cl)ncn1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CSc1cc(NN)ncn1
Temperature: 90 °C

Procedure:
A mixture of 4-Chloro-6-methylsulfanyl-pyrimidine (1.1 g, 6.85 mmol), hydrazine monohydrate (1.2 g, 23.5 mmol), and 2-propanol (10 mL) is heated to 90° C. for 4 hours. The reaction mixture is then cooled to room temperature, concentrated, triturated with water, and filtered. The undissolved solid is washed with water, air-dried to give (6-Methylsulfanyl-pyrimidin-4-yl)-hydrazine as light yellow solid: 1H NMR 400 MHz (d6-DMSO) δ 8.29 (s, 1H), 8.16 (s, 1H), 6.55 (s, 1H), 4.34 (s, 2H), 2.43 (s, 3H); MS m/z 157.05 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
Methyl 4-(methylamino)-3-nitrobenzoate (1.82 g, 8.66 mmol) was dissolved in a 1:1 ratio of tetrahydrofuran (THF) (41.4 mL) and water (41.4 mL). To this was added lithium hydroxide (1.817 g, 43.3 mmol) and the reaction stirred at r.t. for 16 h. The reaction mixture was cooled to 0° C. and acidified by the addition of 5M HCl (˜20 mL, until the pH reached ˜5)—a bright yellow precipitate formed, the slurry was filtered and the residue washed with distilled H2O (2×30 mL). The residue was collected and dried in vacuo at 50° C. to afford the product as a yellow solid (1.43 g, 7.29 mmol, 84% yield). This was used without further purification in the subsequent reactions.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9]>>[CH:1]1[CH:2]=[C:3]([CH2:4][C:6]2[C:1]([OH:7])=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:8]([OH:9])=[CH:5][CH:6]=1
Reactant: Oc1ccccc1
Reactant: C=O
Product: Oc1ccccc1Cc1ccccc1O

Procedure:
a preparation step comprising reacting phenol with formaldehyde in the presence of an acid catalyst and removing the acid catalyst, water and the unreacted phenol from the resulting reaction product to give a crude bisphenol F; and
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:20])/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>[OH-].[Na+]>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:20])/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCC/C=C/C=C/C(=O)Cl
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCC/C=C/C=C/C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
In the second method, trans , trans-2 ,4-tetradecadienoic acid (99.6 g) was dissolved in thionyl chloride (87 ml ), and the mixture was stirred at room temperature. The excessive thionyl chloride was removed by distillation to give trans,trans-2,4-tetradecadienoic acid chloride (102.0 g). To glycine (66.8 g) dissolved in an aqueous 2N sodium hydroxide solution (540 ml) were added at the same time trans,trans-2,4-tetradecadienoic acid chloride (102.0 g) and 2N sodium hydroxide (270 ml) with 1/10 portions at a 3 minute interval. After the addition was completed, the mixture was warmed to room temperature, stirred for 15 minutes and acidified with concentrated hydrochloric acid (140 ml) under ice-cooling. Precipitates thus produced were collected by filtration and desiccated to give trans,trans-2,4-tetradecadienoyl glycine (75.0 g). To the solution of trans,trans-2,4-tetradecadienoyl glycine (4.7 g) and 6-(6-(spicaminyl-amino)purine; (5.1 g) in N,N-dimethylformamide (DMF, 60 ml) was added N-hydroxysuccinimide (2.1 g), and the mixture was ice-cooled. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.4 g) dissolved in DMF (100 ml) was added dropwise to the mixture. After the addition was completed, the mixture was heated to room temperature and stirred for 12 hours. Water (500 ml) was added to the reaction mixture, and precipitates produced were collected by filtration and desiccated. Sodium methoxide (3.1 g) was added to a suspension of the precipitates in methanol (100 ml), and the mixture was stirred at room temperature, then ice-cooled and acidified by adding dropwise thereto a 10% methanolic hydrochloric acid solution. Precipitates produced were filtered, dried and subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK241 in the yield of 5.00 g.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([O:13][CH3:14])(=[O:12])[C:8]([O:10]C)=O.[C:15]([C:18]1[C:23](=[O:24])[C:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][N:20]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:19]=1)(=[O:17])[CH3:16]>C1COCC1>[CH2:32]([N:20]1[CH:21]=[C:22]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:23](=[O:24])[C:18]([C:15](=[O:17])[CH:16]=[C:8]([OH:10])[C:7]([O:13][CH3:14])=[O:12])=[CH:19]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1cn(Cc2ccccc2)cc(Cc2ccccc2)c1=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(O)=CC(=O)c1cn(Cc2ccccc2)cc(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of sodium t-butoxide (0.52 g, 5.23 mmol) in anhydrous THF (13 mL) at room temperature was added dropwise dimethyl oxalate (0.42 g, 3.48 mmol) in THF (6 mL) followed by 3-acetyl-1,5-dibenzyl-1H-pyridin-4-one 14 (0.55 g, 1.74 mmol) in THF (8 mL). The resulting mixture was stirred at room temperature for 4 h and then acidified (pH=6). The crude product was extracted with ethyl acetate (100 mL), washed with water (2×100 mL) and brine (2×100 mL), and dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by ion exchange chromatography (diethylamino sephadex anion exchange resin (CH3CN:H2O, 1:1) and then by flash chromatography on silica gel (chloroform, 100%). Yield 0.44 g (63%), mp 148-150° C. 1H NMR (CDCl3, 500 MHz): δ 8.34 (d, J=2.5, 1H), 8.12 (s, 1H), 7.40-7.12 (m, 10H), 6.91 (d, J=2.3, 1H), 4.94 (s, 2H), 3.88 (s, 3H), 3.82 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ 187.2, 175.2, 170.3, 162.7, 143.9, 138.4, 136.9, 136.1, 133.8, 129.4, 129.5, 129.3, 129.1, 129.1, 128.7, 128.6, 127.5, 127.4, 126.5, 120.2, 102.4, 61.2, 53.0, 33.5. HRMS (M+H)+ calcd for C24H22NO5 404.1498, found 404.1497.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Cl[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:18])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: O=C1CCCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1OC1CCCCC1=O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 5-bromo-2-methoxyphenol (120.0 g), 2-chloro-1-cyclohexanone (108.0 g), potassium carbonate (163.3 g), and DMF (1.2 l) was stirred at 70° C. for 3 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give Compound IId-a (138.5 g, 78.3%) as pale-yellow crystals.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([OH:30])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Br[CH:32]1[CH2:36][CH2:35][N:34]([CH3:37])[C:33]1=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30][C@@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: CN1CCC(Br)C1=O
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H]3CCN(C)C3=O)c2)cn1
Temperature: 25 °C
Reaction time: 21 h
Yield: 76 %

Procedure:
3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (442 mg, 1.1 mmol) (Intermediate 1) and 3-bromo-1-methyl-pyrrolidin-2-one (385 mg, 2.2 mmol) (Intermediate 4) were dissolved in DMF and treated with potassium carbonate (377 mg, 2.7 mmol) and stirred at room temperature for 21 hours. The DMF was evaporated, the residue was partitioned between ethyl acetate (90 mL) and water (20 mL). The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give an oil which was purified by chromatography on silica eluting with 0-6% methanol in DCM to give the racemic product (420 mg). 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3R)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide was separated from its enantiomer by chiral HPLC using a Merck 50 mm 20 μm Chiralcel OJ No. CE001 column eluting with methanol at a flow rate of 50 mL/min; 420 mg of racemic material was separated in 3 injections of 15 mL at 11 mg/ml in 1:1:1 acetonitrile/ethanol/methanol to afford the product (187 mg, 33%) which eluted before its enantiomer. 1H NMR δ (400 MHz, CDCl3): 2.08-2.18 (m, 1H), 2.28 (quintet, 2H), 2.47-2.57 (m, 1H), 2.48 (s, 3H), 2.86 (s, 3H), 3.29-3.37 (m, 1H), 3.42-3.48 (m, 1H), 4.18 (t, 2H), 4.64 (t, 2H), 4.86 (t, 1H), 6.91 (s, 1H), 7.14 (s, 1H), 7.32 (d, 1H), 7.39 (s, 1H), 8.05 (d, 1H), 8.07 (s, 1H), 8.26 (s, 1H), 8.37 (s, 1H), 9.45 (s, 1H); m/z 503 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:14]=[N:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:14](=[N:15][OH:16])[C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C=NO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(Cl)=NO
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To the title compound of Example 3.1 (3.1 g, 13.7 mmol) in DMF (30 mL) at 40° C. was added N-chlorosuccinimide (2.0 g, 15.1 mmol) in 3 portions. After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate and then the organic layer washed with water (3 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product (3.1 g, 85%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Si]([O:27][CH2:28][CH:29]1[C:33]([CH2:34]Br)=[CH:32][CH2:31][CH2:30]1)(C(C)(C)C)(C)C>>[OH:27][CH2:28][CH:29]1[C:33]([CH2:34][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:32][CH2:31][CH2:30]1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC=C1CBr
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2=CCCC2CO)c(=O)[nH]c1=O
Yield: 21.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same method with example 6 to obtain the titled compound (52 mg).
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6].[OH-].[Na+]>CCOCC>[CH3:1][NH:2][CH2:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CNCC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methylamine (100 mL of 2M solution in THF) was charged into a 500 mL flask, to which was added 150 mL of Et2O. At −78° C., 15 g of 4-bromoacetyl benzonitrile was added, and the reaction was allowed to warm to rt. After stirring for 5 h, the reaction mixture was poured into a separatory funnel and shaken with 15% aq NaOH (20 mL). The precipitate was collected by filtration, and air-dried to give 4-(N-methylglycyl)benzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](N)=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].N([O-])=O.[Na+].[BrH:20]>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:20])=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)nc1C(F)(F)F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1sc(Br)nc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester (10 g) in 48% HBr (75 mL) at 0° C. is added a solution of sodium nitrite (4.25 g) in water (50 mL) dropwise over 1 h. The mixture is stirred at the same temperature for an additional 30 min, then a solution of CuBr (6 g) in 48% HBr (50 mL) is added dropwise over 30 min. The reaction mixture is stirred for additional 30 min at 0° C. and for 2 h at RT. The mixture is extracted three times with methylene chloride. The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography (silica gel, hexane to 3% EtOAc/Hexane) to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][C:13]([C:19]([OH:21])=O)([CH:14]=[CH:15]2)[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:23]1C2N=CC=CC=2N=N1.C(=O)([O-])O.[NH4+]>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][C:13]([C:19](=[O:21])[NH2:23])([CH:14]=[CH:15]2)[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1OC2(C(=O)O)C=CC1CC2
Reactant: On1nnc2cccnc21
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C12C=CC(CC1)N(C(=O)OCc1ccccc1)O2
Reaction time: 8 h
Yield: 82.7 %

Procedure:
The benzyl ester (d) (12.0 g, 41.5 mmol) and 1-hydroxy-7-azabenzotriazole (6.26 g, 46 mmol) were dissolved in DMF (100 ml) then I-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.79 g, 46 mmol) added. After stirring for 5 minutes ammonium hydrogen carbonate (8.22 g, 104 mmol) was added. Four further small portions of ammonium hydrogen carbonate were added over the next 7 hours. The mixture was then stirred overnight, diluted with water and extracted with ethyl acetate (×4). The combined organic extracts were washed with 5% aqueous citric acid then brine, dried and evaporated to give an off-white solid (9.9 g, 83%).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][NH:12][C:13](=[S:24])NC2C=CC([N+]([O-])=O)=CC=2)=[N:9][CH:10]=1)([CH3:4])[CH3:3]>COCCOC>[SH:24][C:13]1[N:9]2[CH:10]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[CH:6]=[CH:7][C:8]2=[N:11][N:12]=1
Reactant: CC(C)(O)c1ccc(NNC(=S)Nc2ccc([N+](=O)[O-])cc2)nc1
Solvent: COCCOC
Product: CC(C)(O)c1ccc2nnc(S)n2c1

Procedure:
A mixture of 2-(6-hydrazinylpyridin-3-yl)propan-2-ol (250 mg, 1.495 mmol) and 1-isothiocyanato-4-nitrobenzene (269 mg, 1.495 mmol) in ACN (Volume: 2.0 mL) was stirred at room temperature for 1 hr. The reaction was diluted with Et2O (Volume: 5.0 mL), and the resulting solid was filtered. Minimal product was present in the solid. On standing for 1 hr, the filtrate had formed a precipitate. This was filtered to provide 2-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-N-(4-nitrophenyl)hydrazinecarbothioamide (175 mg, 0.504 mmol, 33.7% yield) as an orange solid. A solution of 2-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-N-(4-nitrophenyl)hydrazinecarbothioamide (275 mg, 0.792 mmol) in DME (Volume: 2.0 mL) was heated in a microwave on high absorbance for 3 hr at 110° C. The reaction was stripped to dryness onto silica gel via rotary evaporation and purified compound by MPLC with DCM:MeOH (98:2) to provide 2-(3-mercapto-[1,2,4]triazolo[4,3-a]pyridin-6-yl)propan-2-ol.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:44]([C:60]([N:62]2[CH2:68][CH2:67][CH2:66][N:65]([C:69](=[NH:84])[NH:70]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:64][CH2:63]2)=[O:61])[CH2:43]1>>[C:69]([N:65]1[CH2:66][CH2:67][CH2:68][N:62]([C:60]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][NH:45]2)=[O:61])[CH2:63][CH2:64]1)(=[NH:70])[NH2:84]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCCN(C(=N)N)CC4)C3)[C@H](C)[C@H]12

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl -1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and (2S,4S)-4-mercapto-1-(4-nitrobenzyl -oxycarbonyl)-2-[4-(4-nitrobenzyloxycarbonylamidino)homopiperazin -1-ylcarbonyl]pyrrolidine (prepared as described in Preparation 94) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Reactant: OCc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(CO)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 35.5 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.2 g, 3.0 mmol), 3-(hydroxymethyl)benzeneboronic acid (0.555 g, 3.65 mmol), potassium carbonate (1.4 g, 10.0 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.021 g, 0.030 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere in a pressure vessel. The vessel was then sealed and heated at 110° C. for 16.5 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure. The residue was diluted with methanol, and silica gel was added. The mixture was concentrated under reduced pressure. The residue was purified by automated flash chromatography (FLASH 40+M silica cartridge, eluting with 5% to 20% methanol in ethyl acetate) followed by trituration with acetonitrile. The resulting solid was isolated by filtration, washed with acetonitrile, and dried in a vacuum oven at 65° C. to provide 449 mg of 1-{4-amino-2-(ethoxymethyl)-7-[3-(hydroxymethyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a white solid, mp 186-187° C.