Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](O)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl.C(OCC)C>N1C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:8][CH2:7][CH:5]2[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1(C)OCC(CO)O1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Temperature: 0 °C

Procedure:
5.29 g (40.0 mmol) of (2,2-dimethyl-[1,3]dioxolan-4-yl)methanol (Solketal®) and 10 ml of pyridine are introduced into a round-bottomed flask under an argon atmosphere. The mixture is cooled to 0° C., 8.39 g (44.0 mmol) of para-toluenesulphonic acid are added and the mixture is stirred for sixteen hours at room temperature. The reaction medium is poured into a 1N HCl/ethyl ether mixture, extracted with ethyl ether, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with dichloromethane. After evaporation of the solvents, 9.70 g (85%) of the expected product are collected in the form of yellow crystals with a melting point of 45–47° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH3:9])[C:6]([OH:8])=O)(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:25][C:26]1[CH:31]=[C:30]([O:32][C:33]2[C:38]([F:39])=[CH:37][C:36]([NH:40][C:41]([C:43]3([C:46]([NH:48][C:49]4[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=4)=[O:47])[CH2:45][CH2:44]3)=[O:42])=[C:35]([F:56])[CH:34]=2)[CH:29]=[CH:28][N:27]=1>C(Cl)Cl>[C:1]([O:4][C@@H:5]([CH3:9])[C:6]([NH:25][C:26]1[CH:31]=[C:30]([O:32][C:33]2[CH:34]=[C:35]([F:56])[C:36]([NH:40][C:41]([C:43]3([C:46](=[O:47])[NH:48][C:49]4[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=4)[CH2:45][CH2:44]3)=[O:42])=[CH:37][C:38]=2[F:39])[CH:29]=[CH:28][N:27]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)C(=O)O
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)O[C@@H](C)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of (S)-2-Acetoxy-propionic acid (300 mg, 2.278 mmol) and N-methylmorpholine (341 mg, 3.41 mmol) in anhydrous CH2Cl2 was added drop wise isobutyl chloroformate (457 mg, 3.41 mmol). The resultant mixture was stirred at 25° C. for 1 h. N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (250 mg, 0.578 mmol) was added and the resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give (S)-1-((4-(2,5-difluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl acetate (180 mg, 55.9% yield) which was without further purification.
Reaction SMILES: [CH:1]1([C:10](O)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>O1CCCC1>[CH:1]1([CH2:10][OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
150 mg (0.92 mmol) of indan-1-carboxylic acid compound was dissolved in 9 mL of tetrahydrofuran, and then 105 mg (2.77 mmol) of lithium aluminum hydride was added at 0° C. and stirred at room temperature for 2 hours. Water was slowly added to quench the reaction, and when a gel was formed by adding ethyl acetate, the celite was filtered. Then, the residue was dissolved again in 20 mL of ethyl acetate and the organic layer was washed with distilled water three times. The organic layer was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 124 mg of colorless oil (yield: 91%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:10]([CH3:21])[CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[CH3:21][C@H:10]1[C@H:11]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C[C@@H]1CN(Cc2ccccc2)CC[C@H]1OC(=O)C(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@@H]1CNCC[C@H]1OC(=O)C(C)(C)C

Procedure:
The trans-ester 18 (104 g, 359 mmol) is hydrogenated in methanol (1700 ml) with Pd/C in the presence of one equivalent of HCl (431 ml, 359 mmol, 1.25M in MeOH). The mixture is filtered and evaporated. The residue is redissolved in ether and extracted with 1N-NaOH and brine. Evaporation gives a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:30])[NH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.Br[CH2:32][CH2:33][O:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH2:32][CH2:33][O:34][CH3:35])=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: COCCBr
Reactant: O=c1[nH]n(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCOc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Yield: 84 %

Procedure:
In a manner similar to that described in Example 1 (Step 1), 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (3B) was treated with 1-bromo-2-methoxyethane and potassium carbonate (DMF, room temperature, overnight) to provide 6-chloro-3-(2-methoxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (84% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1.I[CH2:28][CH:29]1[CH2:38][CH2:37][C:32]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)[CH2:28][CH:29]1[CH2:38][CH2:37][C:32]2([O:33][CH2:34][CH2:35][O:36]2)[CH2:31][CH2:30]1
Reactant: COC(=O)Cc1ccc(SC)c(Cl)c1
Reactant: ICC1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCC2(CC1)OCCO2)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
A solution of diisopropylamine (0.23 mL, 1.63 mmol) in dry tetrahydrofuran (5.0 mL) cooled to −78° C. under nitrogen was treated with a 2.5M solution of n-butyllithium in hexanes (0.65 mL, 1.63 mmol). The reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 340 mg, 1.48 mmol) in dry tetrahydrofuran (3.0 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.0 mL). The reaction mixture turned dark in color and was allowed to stir at −78° C. for 1 h, at which time, a solution of 8-iodomethyl-1,4-dioxa-spiro[4.5]decane (500 mg, 1.78 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C., where it was stirred for 24 h. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was acidified using a 10% aqueous hydrochloric acid solution. The resulting aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S Silica 8/2 hexanes/ethyl acetate) afforded the 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(1,4-dioxa-spiro[4.5]dec-8-yl)-propionic acid methyl ester (315 mg, 55%) as a yellow viscous oil: EI-HRMS m/e calcd for C19H25ClO4S (M+) 384.1162, found 384.1169.
Reaction SMILES: Cl.[N:2]1([C:7](=[NH:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:10][C:11]([SH:14])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:10][C:11]1[S:14][N:8]=[C:7]([N:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[N:9]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(N2CCCC2)ns1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
To a solution of pyrrolidine-1-carboximidamide hydrochloride (1.50 g, 10.0 mmol) and perchloromethyl mercaptan (1.08 ml, 10.0 mmol) in dichloromethane (20 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 590 mg (31.0%) of the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.99 min; [M+H]+=393.41.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([O:15]CC)[CH:3]=1.Cl.C(O)(=O)C>O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[NH:5][C:4](=[O:15])[CH:3]=1
Reactant: CCOc1cc(Cl)c2cc(F)c(F)c(F)c2n1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(Cl)c2cc(F)c(F)c(F)c2[nH]1
Temperature: 20 °C
Yield: 97.1 %

Procedure:
A suspension of 70.4 g of 4-chloro-2-ethoxy-6,7,8-trifluoroquinoline in 170 cm3 of a 35% aqueous solution of hydrochloric acid, 420 cm3 of acetic acid and 250 cm3 of water is heated, with stirring, at a temperature close to 100° C. for 2 hours and a half. After cooling to about 20° C., the reaction mixture is poured into 1,100 cm3 of water at about 5° C., the mixture is stirred for 15 minutes at this temperature and the insoluble matter is then drained and washed with 3 times 220 cm3 of water. 61 g of 4-chloro-6,7,8-trifluorocarbostyril are obtained in the form of a cream solid melting at 213° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Cl)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(O)CCC>[CH3:1][C:2]1[CH:3]=[C:4]([NH:17][NH:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(Cl)nnc1-c1ccccc1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Product: CCOC(=O)NNc1cc(C)c(-c2ccccc2)nn1

Procedure:
A 10.0 g. portion of 5-methyl-6-phenyl-3-chloropyridazine, 10.02 g. of ethyl carbazate and 150 ml. of butyl alcohol are stirred at reflux for 4 hours. The reaction mixture is concentrated free of butyl alcohol and the concentrate is placed in cold water containing a small amount of ethyl and scratched. The resulting solid is filtered, washed with water, recrystallized from a mixture of chloroform and petroleum ether and dried in vacuo giving a white solid, mp 143°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[CH2:14][OH:15])=[C:4](F)[CH:3]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[CH2:14][O:15][C:4]=2[CH:3]=1
Reactant: OCc1cnccc1-c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)OCc1cnccc1-2
Yield: 60.5 %

Procedure:
To a cooled solution of (4-(4-chloro-2-fluorophenyl)pyridin-3-yl)methanol (2.89 g, 12.14 mmol) in THF (10 mL) at 0° C. was added a sodium hydride (1.94 g, 48.6 mmol) suspension in THF (10 mL) and the resultant mixture was stirred at 0° C. for 40 min. The reaction was quenched by addition of cold water (15 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried with sodium sulfate and concentrated under reduced pressure. The residue so obtained was purified by column chromatography (50% ethyl acetate in pet ether) to afford 8-chloro-5H-chromeno[3,4-c]pyridine (1.6 g, 7.35 mmol, 61% yield) as a white solid. 1H NMR (400 MHz, MeOD) δ 8.54 (d, J=5.60 Hz, 1H), 8.43 (s, 1H), 7.89 (d, J=8.40 Hz, 1H), 7.76 (d, J=5.60 Hz, 1H), 7.14 (dd, J=2.40, 8.40 Hz, 1H), 7.07 (d, J=2.00 Hz, 1H), 5.24 (s, 2H); LCMS (ESI) m/e 218 [(M+H)+, calcd for C12H9ClNO 218.0].
Reaction SMILES: C(=[N:14][C:15]1[N:16]=[C:17]2[C:23]([Cl:24])=[CH:22][N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]2=[N:19][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])=O.[Na+].NO.Cl>CO>[Cl:24][C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([NH2:14])[N:16]=2)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:22]=1
Reactant: C[Si](C)(C)CCOCn1cc(Cl)c2nc(N=C(c3ccccc3)c3ccccc3)cnc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(Cl)c2nc(N)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
Benzhydrylidene-[7-chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-amine (992 mg, 2.14 mmol), NaOAc (421 mg, 5.14 mmol) and NH2OH HCl (268 mg, 3.85 mmol) were dissolved in MeOH (21 mL) and stirred at RT overnight, and partitioned between EtOAc and H2O. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (150 g SiO2, hexanes/EtOAc 0 to 50% EtOAc) to give 202 mg of 7-chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine as a white solid (32% yield).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]([OH:30])=O)=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.CN.C[CH2:34][N:35](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O.CN(C=O)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]([NH:35][CH3:34])=[O:30])=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: O=C(O)c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.9 %

Procedure:
A mixture of 1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid (100 mg, 0.24 mmol) from the previous step, methylamine (1 mL, 22.5 mmol), DIEA (91 mg, 0.35 mmol) and DMF (5 mL) was stirred at rt for 15 min. HATU (180 mg, 0.23 mmol) was added and the mixture was stirred at rt for 15 h. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with water (10 mL) and brine (10 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified directly by reverse-phase preparative HPLC to afford 1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-1H-benzo[d]imidazole-5-carboxamide (26 mg, 25%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.37 (br s, 1H), 8.16 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.58-7.75 (m, 3H), 7.29 (m, 1H), 7.20 (m, 1H), 5.49 (s, 2H), 4.72 (d, J=5.1 Hz, 1H), 3.50 (m, 1H), 3.35 (m, 1H), 2.50 (s, 3H), 2.04 (m, 1H), 1.88 (m, 1H), 1.60-1.62 (m, 2H), 1.18-1.21 (m, 4H). LCMS (ESI) m/z 436 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 ml single neck round bottom flask, under a nitrogen atmosphere, 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (300 mg, 0.572 mmol) was added to anhydrous methylene chloride (20 ml). To this was added trifluoroacetic acid (0.44 ml, 652 mg, 5.72 mmol). The resulting mixture is stirred overnight at room temperature. The progress of the reaction was monitored by thin layer chromatography. The solvents were removed in vacuo.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Mg]Cl)(C)C.[Li+].[Cl-].[CH:28]1([CH:34]=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[Si:6]([O:5][CH2:4][C:3]1[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:2]=1[CH:34]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[OH:35])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: O=CC1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)benzyloxy)(tert-butyl)dimethylsilane (1.3 g, 3.5 mmol) in THF at 0° C. was added i-PrMgCl/LiCl in THF (3.5 mL, 4.5 mmol). The mixture was stirred at 0° C. for 4 hours and cyclohexanecarboxaldehyde (0.61 g, 0.65 mL, 5.4 mmol) was added. The mixture was stirred at 0° C.-room temperature for 1 hour, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+M Biotage silica column (eluted with 0-20% ethyl acetate in heptane) to afford the title compound (1.27 g, 90%). 1H NMR (400 MHz, CDCl13) δ ppm 0.13 (s, 6H) 0.94 (s, 9H) 0.96-1.38 (m, 7H) 1.63-1.73 (m, 2H) 1.77-1.83 (m, 1H) 2.06(d, J=13.28 Hz, 1H) 2.28 (d, J=3.73 Hz, 1H) 4.58 (dd, J=7.68, 3.94 Hz, 1H) 4.75 (d, J=13.28 Hz, 1H) 4.85 (d, J=13.28 Hz, 1H) 7.53 (s, 2H) 7.68 (s, 1H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[S:15][CH:16]=[C:17]([CH2:19][C:20]([OH:22])=O)[N:18]=1.FC(F)(F)C([O-])=O.[NH2:30][C@@H:31]1[C:38](=[O:39])[N:37]2[C@@H:32]1[S:33][CH2:34][C:35](/[CH:43]=[C:44]1/[C:45](=[O:67])[N:46]([CH2:49][C:50]3[CH:55]=[CH:54][N+:53]([CH2:56][C:57](=[O:66])[NH:58][C:59]4[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=4)=[CH:52][CH:51]=3)[CH2:47][CH2:48]/1)=[C:36]2[C:40]([OH:42])=[O:41]>CN(C)C=O>[NH2:13][C:14]1[S:15][CH:16]=[C:17]([CH2:19][C:20]([NH:30][C@@H:31]2[C:38](=[O:39])[N:37]3[C@@H:32]2[S:33][CH2:34][C:35](/[CH:43]=[C:44]2/[C:45](=[O:67])[N:46]([CH2:49][C:50]4[CH:51]=[CH:52][N+:53]([CH2:56][C:57](=[O:66])[NH:58][C:59]5[CH:60]=[CH:61][C:62]([OH:65])=[CH:63][CH:64]=5)=[CH:54][CH:55]=4)[CH2:47][CH2:48]/2)=[C:36]3[C:40]([O-:42])=[O:41])=[O:22])[N:18]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)cc5)cc4)C3=O)CS[C@H]12
Reactant: Nc1nc(CC(=O)O)cs1
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Nc1nc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C4\CCN(Cc5cc[n+](CC(=O)Nc6ccc(O)cc6)cc5)C4=O)CS[C@H]23)cs1

Procedure:
With 54.5 mg (0.34 mmol) 1,1′-carbonyldiimidazole, 53.0 mg (0.34 mmol) (2-aminothiazole-4-yl)-acetic acid and 182.0 mg (0.28 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml N,N-dimethylformamide. The resulting solid was purified by reversed phase chromatography (RP-18 LiChroPrep gel, water:acetonitrile=9:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18][C:5]2=[N:6][C:7]=1[CH2:8][N:9](C)[C:10](=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[CH:19]=[CH:18][C:5]2=[N:6][C:7]=1[CH2:8][NH:9][CH3:10]
Reactant: CN(Cc1nc2ccn(COCC[Si](C)(C)C)c2cc1F)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1nc2ccn(COCC[Si](C)(C)C)c2cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A mixture of tert-butyl (6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-Pyrrolo[3,2-b]pyridin-5-yl)methyl(methyl)carbamate (200 mg, 0.5 mmol) in CH2Cl2 (5 mL) and TFA (0.5 mL) was stirred at RT for 2 h. The reaction mixture was cooled to 0° C. and then quenched by adding a sat'd. aq. NaHCO3 until the pH was about 8. The mixture was extracted with EtOAc (20 mL×2), and the combined extracts dried (MgSO4), filtered and concentrated under reduced pressure to afford 120 mg (70%) of (6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-methylmethanamine as a brown oil. MS (ESI): m/z=310.3 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1([C:25]([NH:27][NH2:28])=[O:26])[CH2:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:28][NH:27][C:25]([CH:21]1[CH2:24][CH2:23][CH2:22]1)=[O:26])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)C1CCC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added cyclobutanecarbohydrazide 199 (0.155 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography to give 200 (0.34 g, quant. yield) as a white foam.