Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]([NH:12][C:13](=O)[CH2:14]Cl)([CH3:11])[CH2:9][OH:10])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@@:8]2([CH3:11])[NH:12][C:13](=[S:27])[CH2:14][O:10][CH2:9]2)[CH:7]=1
Reactant: C[C@@](CO)(NC(=O)CCl)c1cc(Br)ccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@]1(c2cc(Br)ccc2F)COCC(=S)N1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A pressure tube was charged with a solution of N—[(R)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (2.00 g, 6.9 mmol) in tetrahydrofuran (50 ml). The colorless solution was treated with Lawesson's reagent (2.81 g, 6.9 mmol) to give a yellow suspension. The tube was sealed and the mixture stirred at 70° C. overnight. For the workup, the reaction mixture was diluted with ethyl acetate (300 ml) and extracted with a saturated solution of sodium hydrogen carbonate (75 ml). The organic layer was washed with brine (2×80 ml). The combined aqueous layers were extracted with ethyl acetate (300 ml). The combined organic layers were dried over sodium sulphate and concentrated at reduced pressure. The (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholine-3-thione was obtained as a light yellow gum (1.93 g, 92% of theory) sufficiently pure to be engaged in the next step without further purification. MS (ISP): m/z=302.0 [M+H]+, 304.0 [M+2+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3]I.[C:5]1([S:11]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([SH:25])[N:22]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:29][CH:28]=4)[C:21]=3[CH:39]=2)=[O:16])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>CO.O>[C:5]1([S:11]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([S:25][CH3:3])[N:22]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:31][CH:32]=4)[C:21]=3[CH:39]=2)=[O:16])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CI
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1ccc2nc(S)n(Cc3ccc(-c4ccccc4)cc3)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A 20% potassium hydroxide aqueous solution (0.323 g), 2 ml of water and 0.123 g of methyl iodide were added to a solution of 0.310 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercaptobenzimidazole in 5 ml of methanol in this order, and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystals precipitated were separated through filtration, and were dried to give 0.281 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylthio-benzimidazole (237).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:28]=[N:29][CH:30]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:24][C:25]2[CH:26]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:28]=[N:29][CH:30]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(N(Cc2cncc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Preparation Example 9 to give pale yellow amorphous of the title compound.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:14]([CH3:24])=[N:15][CH:16]=[C:17]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[CH:18]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[C:14]([CH3:24])=[N+:15]([O-:9])[CH:16]=[C:17]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[CH:18]=1
Reactant: Cc1ncc(C2OCCO2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C2OCCO2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 21 h
Yield: 77.8 %

Procedure:
m-CPBA (626 mg, 2.72 mmol) was added to a suspension of 3-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyridine (271.4 mg, 1.359 mmol) and NaHCO3 (343 mg, 4.08 mmol) in DCM (3 ml) and stirred at room temperature. After 21 h, HPLC showed full conversion. DCM and 1M NaOH were added. It was extracted, dried (MgSO4), filtered, and concentrated yielding 3-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyridine 1-oxide (228 mg, 78%) as a pale yellow oil pure enough to be used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][C:20]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([OH:22])[CH2:19]1)=[O:17].ClC1C=C(C=CC=1)C(OO)=[O:41]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N+:12]([O-:41])[CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][C:20]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([OH:22])[CH2:19]1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2ccncc2Nc2ccc(I)cc2F)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2cc[n+]([O-])cc2Nc2ccc(I)cc2F)C1
Reaction time: 15 h
Yield: 69.4 %

Procedure:
1,1-Dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (80 mg, 0.134 mmol), prepared using procedures similar to those described in Example 38, was dissolved in dichloromethane (3 mL) and treated with 3-chloroperoxybenzoic acid (73% pure; 32 mg, 0.135 mmol) at ambient for 7 hours. 3-chloroperoxybenzoic acid (73% pure; 32 mg, 0.135 mmol) was added and the mixture was stirred for 15 hours. The mixture was purified by column chromatography (silica gel, 0-10% ethanol in ethyl acetate) to give 1,1-dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (57 mg, 0.093 mmol, 69% yield): 1H NMR (400 MHz, CDCl3): 9.38 (s, 1H), 8.00 (s, 1H), 7.68 (dd, 1H), 7.51 (dd, 1H), 7.46 (d, 1H), 7.19 (br d, 1H), 7.09 (t, 1H), 5.78 (br, 1H), 4.44-3.98 (m, 3H), 3.98-3.87 (m, 1H), 3.49-3.39 (m, 1H), 3.07-2.88 (m, 1H), 2.01-1.91 (m, 1H), 1.70-1.47 (m, 6H), 1.45 (s, 9H); MS (EI) for C2H30FIN4O5: 613 (MH+).
Reaction SMILES: Cl[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:10](=[O:19])[C:9]2[C:4](=[C:5]([I:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>CS(C)=O.O>[C:21]([NH:25][C:2]1[N:11]([CH2:12][CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:10](=[O:19])[C:9]2[C:4](=[C:5]([I:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CS(=O)(=O)CCCn1c(Cl)nc2c(I)cccc2c1=O
Reactant: CC(C)(C)N
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)Nc1nc2c(I)cccc2c(=O)n1CCCS(C)(=O)=O
Temperature: 100 °C
Yield: 199.2 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-8-iodo-3-(3-(methylsulfonyl)propyl)quinazolin-4(3H)-one (50 mg, 0.117 mmol) and tert-butylamine (0.123 mL, 1.172 mmol) in DMSO (0.5 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The reaction was repeated on 150 mg scale. The reaction mixture were combined and diluted with water (20 mL). The mixture was extracted with CHCl3/iPrOH (4:1, 40 mL×3) and the combined organic layers were washed with water, dried (MgSO4), filtered and concentrated. The residue was purified with silica gel chromatography (eluted with 10-70% EtOAc in Hexanes) to give 2-(tert-butylamino)-8-iodo-3-(3-(methylsulfonyl)propyl)quinazolin-4(3H)-one (108 mg, 50% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 464 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[C:3]=1[C:17]([NH2:19])=[O:18].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.N1CCCCC1>C(O)C>[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=3)[C:3]=2[C:17]([NH2:19])=[O:18])=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N=Cc1ccc(O)cc1
Yield: 47 %

Procedure:
5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 100 mL of ethanol and 4-hydroxybenzaldehyde (12.945 g, 2.00 eq.) and piperidine (0.25 eq.) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-hydroxybenzylidene)amino)-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (9.00 g, 47% yield).
Reaction SMILES: Cl.C(OC(OCC)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]#[N:16])=[C:7]1[CH:17]=[O:18])C.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH:17]([C:7]1[NH:6][C:14]2[C:9]([C:8]=1[C:15]#[N:16])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:18]
Reactant: CCOC(OCC)n1c(C=O)c(C#N)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1c(C=O)[nH]c2ccccc12
Temperature: 20 °C
Reaction time: 41 h
Yield: 84.4 %

Procedure:
Hydrochloric acid (4 mL, 20%) was added to a THF (100 mL) solution of 1-diethoxymethyl-2-formyl-1H-indole-3-carbonitrile (5.33 g, 19.57 mmol) at 0° C. The mixture was stirred at 20° C. for 41 h then treated with 5% aqueous K2CO3 (25 mL). The reaction mixture was concentrated to 50 mL and treated with methylene chloride (200 mL). The organic layer was washed with water, dried and evaporated to afford the title compound (2.81 g, 84%). 1H NMR (300 MHz, DMSO-d6, δ): 13.20 (s, br, 1H), 10.02 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.51 (t, J=7.1 Hz, 1H), 7.37 (t, J=7.5 Hz, 1H).
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:17]3[C:12](=[C:13](Cl)[CH:14]=[CH:15][CH:16]=3)[CH:11]([NH:19][C:20](=[O:22])[CH3:21])[N:10]([CH3:23])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O)(=O)/C=C\C(O)=O>CO>[C:2]1([CH:8]2[C:17]3[C:12](=[C:13]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:14]=[CH:15][CH:16]=3)[CH:11]([NH:19][C:20](=[O:22])[CH3:21])[N:10]([CH3:23])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(=O)NC1c2c(Cl)cccc2C(c2ccccc2)CN1C
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: CCO
Product: CC(=O)NC1c2c(cccc2N2CCOCC2)C(c2ccccc2)CN1C
Yield: 70 %

Procedure:
A mixture of 7 g (0.02 mole) of 4-phenyl-8-chloro-acetylamino-2-methyl-1,2,3,4-tetrahydro-isoquinoline-hydrochloride, 70 ml of ethanol and 20 ml (20.0 g, 0.23 mole) of morpholine is refluxed for 5 hours. The reaction mixture is evaporated in vacuo, the residue is dissolved in a mixture of 200 ml of water and 200 ml of ether, 30 ml of a 30% aqueous sodium hydroxide solution is added, the layers are separated and the aqueous phase is extracted four times with 200 ml of ether each. The united ether solutions are dried over anhydrous sodium sulfate and evaporated. The oily residue (6.7 g) is dissolved in 100 ml of ethanol and a solution of 6.6 g (0.057 mole) of maleic acid and 30 ml of methanol is added. The precipitated product is filtered in the cold. The beige coloured dimaleate (10.7 g) is dissolved in 100 ml of water, the solution is made alkaline by adding 60 ml of a 35% aqueous sodium hydroxide solution and extracted once with 200 ml and four times with 100 ml of ether each. The ether phases are united, dried over anhydrous sodium sulfate, clarified with activated charcoal and dried. The ether is evaporated and the residue is crystallized from a mixture of ether and petrolether. Thus 5.1 g of (0.014 mole) of white crystalline 4-phenyl-2-methyl-8-morpholino-acetylamino-1,2,3,4-tetrahydro-isoquinoline are obtained. Mp.: 120° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].ON1C2C=CC=CC=2N=N1.Cl.[CH2:23]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH2:29])[CH3:24].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:23]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH:29][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1)[CH3:24]
Reactant: CCOC(=O)CCN
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a solution of 4-formylbenzoic acid (27.4 g, 0.18 mol) in DMF (300 mL) was added N-ethyl-N′-3-dimethylaminopropylcarbodiimide (34.5 g, 0.18 mol) and N-hydroxybenzotriazole (29.9 g, 0.22 mol). The resulting mixture was stirred at room temperature for 1 hour, then β-alanine ethyl ester hydrochloride (65.4 g, 0.42 mol) and diisopropylethylamine (76 mL, 0.44 mol) was added. After 16 hours stirring at ambient temperature the reaction mixture was partitioned between water (600 mL) and ethyl acetate (600 mL). The organic phase was washed successively with hydrochloric acid (1N, 300 mL), saturated aqueous ammonium chloride (300 mL), water (2×300 mL) and brine (300 mL). The solvent was removed by rotary evaporation to leave an oil, which crystallised upon standing to afford 29.0 g (65%) of 3-(4-formylbenzoylamino)propionic acid ethyl ester.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]1[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:22]=2[F:21])[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(-c2ccccn2)c1F
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ccccn2)c1F

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 2-fluoro-3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.68 min.; [M+H]+: 421.11 g/mol.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([Cl:13])=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>CN(C)C=O>[Cl:13][C:5]1[C:4]([Cl:3])=[CH:9][N:8]=[C:7]2[N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[CH:11]=[CH:12][C:6]=12
Reactant: Clc1cnc2[nH]ccc2c1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) suspension of sodium hydride (60% dispersion in mineral oil, 0.556 g, 13.9 mmol) in N,N-dimethylformamide (20 mL) was added a solution of the 5-chloro-4-chloro-1H-pyrrolo[2,3-b]pyridine (2 g, 10.69 mmol) in N,N-dimethylformamide (10 mL) slowly over 5 minutes. The reaction was allowed to stir at ambient temperature for 0.5 hours, and was again cooled to 0° C. A solution of para-toluenesulfonyl chloride (2.14 g, 11.23 mmol) in N,N-dimethylformamide (5 mL) was added, and the reaction was stirred at ambient temperature for 1.5 hours. The reaction was poured into 60 mL water cooled in an ice bath. The suspension was filtered. The solid was collected and purified by flash chromatography on a silica gel, eluting with a gradient of 30% to 100% dichloromethane in hexane, to provide the title compound. MS ESI(+) m/z 340.8 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH:27]([C:29]1[N:36]2[C:32]([S:33][C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:35]2)=[C:31]([C:50]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[O:51])[N:30]=1)=[O:28]>>[CH:27]([C:29]1[N:36]2[C:32]([S:33][C:34]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[CH:35]2)=[C:31]([C:50]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[O:51])[N:30]=1)=[O:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(C=O)nc(C(=O)c3cccnc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4c(C=O)nc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Yield: 65.2 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[5-formyl-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (1.12 g) was prepared in the same manner as in step a) of Example 1, except that 1.04 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.56 g of 5-formyl-7(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].N1C=CC=CC=1.[S:17](Cl)([CH3:20])(=[O:19])=[O:18]>ClCCl>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 59.8 %

Procedure:
Ex-100A: A solution of 4-aminoacetophenone (5.0 g, 37.0 mmol) and pyridine (3.0 mL) in anhydrous dichloromethane (300 mL) was treated with mesyl chloride (2.86 mL, 37.0 mmol). The reaction was stirred for 84 hours at room temperature under nitrogen, and then quenched with saturated NH4Cl solution (100 mL). The organic phase was collected, washed with water (100 mL) and brine, dried over sodium sulfate, and concentrated over silica. The material was purified by silica gel chromatography (50% ethyl acetate/hexanes) to give 4.72 g (60%) of N-(4-acetyl-phenyl)-methanesulfonamide as a yellowish oil. 1H-NMR (DMSO-d6) δ 10.28 (s, 1H), 7.90 (d, 1H), 7.24 (d, 1H), 3.06 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11]Br.[Mg]>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4](=[O:5])[CH3:11]
Reactant: CBr
Reactant: O=Cc1cc(F)ccc1F
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A solution (100 ml) of 2,5-difluorobenzaldehyde (24.6 g) in tetrahydrofuran was dropwise added to an ice-cooled solution (207 ml) of 0.92N magnesium methylbromide in tetrahydrofuran. The resulting solution was stirred at room temperature for 1.5 hours, and the organic phase was washed in a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to subsequently distill off the solvents under reduced pressure. To the residue were added anhydrous dichloromethane (500 ml), sodium acetate (14.2 g) and pyridinium chlorochromate (55.94 g), prior to stirring at room temperature for 10 hours. To the resulting mixture was added an aqueous saturated sodium hydrogen carbonate solution, prior to extraction in ethyl acetate three times. The organic phase was washed in water and in a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=85:15), to recover 2',5'-difluoroacetophenone (22.73 g; yield of 84%). By 1H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH2:25][OH:26]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:24][CH2:25][OH:26])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1oc2cccc(OCCO)c2c1C

Procedure:
4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (100 mg), potassium carbonate (500 mg) and 2-iodoethanol (195 μl) were suspended in acetonitrile (10 ml). The mixture was refluxed overnight. Inorganic salt was filtered out and the mother solution was evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography developed by ethyl acetate-hexane to give 4-(2-hydroxy-ethoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (77 mg) as a white powder. FAB-MS: m/z 265 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].Cl>O>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:12]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of glycine (100 mmol) and NaOH (100 mmol) in water (300 ml), at 5° C., o-chloro-benzoyl chloride (110 mmol) was added in small portions. The reaction mixture was stirred for 30 minutes at room temperature, then cooled again and acidified to pH=2 by addition of 6 M HCl. Extraction of the aqueous solution was performed with EtOAc. Then, the combined organic layers were dried over MgSO4 and the solvent was removed by reduced pressure. The residue was triturated in boiling chloroform, and the product was collected by filtration in 80% yield.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2>>[Br:6][C:7]1[CH:16]=[CH:15][C:14]([S:1]([OH:3])(=[O:5])=[O:2])=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2
Reactant: O=S(=O)(O)O
Reactant: Brc1cccc2cnccc12
Product: O=S(=O)(O)c1ccc(Br)c2ccncc12
Temperature: 25 °C
Yield: 90 %

Procedure:
To fuming sulfuric acid at 0° C. was added 5-bromoisoquinoline (20.0 g, 96 mmol), The resultant mixture was warmed to 200° C. for 4 h and was then cooled to rt and poured into 500 mL of ice water. The product was removed via filtration, washed with water and acetone, and dried to give 25 g (90%) of a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=O.[C:7]([NH:15][NH2:16])(=O)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>C(Cl)Cl>[N:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:1]3[CH2:5][CH2:4][CH2:3][C:2]3=[N:16][N:15]=2)=[CH:9][CH:10]=1
Reactant: NNC(=O)c1ccncc1
Reactant: O=C1CCCN1
Solvent: ClCCl
Product: c1cc(-c2nnc3n2CCC3)ccn1
Temperature: 120 °C
Reaction time: 24 h
Yield: 11 %

Procedure:
Me3OBF4 (2.66 g, 18 mmol) was added to a solution of 2-pyrollidinone in DCM (150 ml) and the reaction mixture was stirred for 24 h. The reaction mixture was washed with aq. sat. NaHCO3, dried and concentrated. The residue was dissolved in EtOH (4 ml) and isonicotinic hydrazide (1.37 g, 10 mmol) was added. The mixture was heated in a microwave reactor for 1 h at 120° C. The volatiles were removed and the crude product purified with column chromatography (DCM/MeOH 20:1) to give 319 mg (11%) of the title compound. 1H NMR: 2.87 (m, 2H), 3.05 (t, 2H), 4.28 (t, 2H), 7.72 (d,2H), 8.72 (d, 2H).