Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][O:9][CH:10]=[C:6]2[CH2:5]1)([OH:3])=[O:2].[CH3:12]OC(OC)(C)C.S(=O)(=O)(O)O>CO>[C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][O:9][CH:10]=[C:6]2[CH2:5]1)([O:3][CH3:12])=[O:2]
Reactant: COC(C)(C)OC
Reactant: O=C(O)C1Cc2cocc2C1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1Cc2cocc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve 5-(carboxy)-2,4,5,6-tetrahydro-cyclopenta[c]furan (3.6 g, 23.5 mmol) in methanol (60 mL) and treat with dimethoxypropane (5.8 mL, 47 mmol) and sulfuric acid (0.8 mL). Stir at room temperature for 1 day. Evaporate the solvent in vacuo, dilute with methylene chloride (75 mL) and wash with saturated sodium hydrogen carbonate (35 mL). Extract the aqueous phase with methylene chloride (30 mL), wash combined organics with brine (30 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and pass through a plug of silica gel to give 5-(carbomethoxy)-2,4,5,6-tetrahydrocyclopenta[c]furan.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1C=C[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[C:14]1([S:13][C:10]2[N:11]=[CH:12][C:4]([CH:5]=[O:1])=[CH:3][CH:2]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CCOC1
Reactant: Brc1ccc(Sc2ccccc2)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
To a tetrahydrofuran (40 mL) solution of 5-bromo-2-phenylsulfanyl-pyridine (2.24 g, 8.42 mmol) described in Manufacturing Example 97-1-1 was added n-butyl lithium (6.35 mL, 1.6 M hexane solution, 10.1 mmol) under nitrogen atmosphere at −78° C., which was stirred for 45 minutes at −78°. Next, N,N-dimethylformamide (848 μL, 10.9 mmol) was added to this reaction mixture, and stirred for 35 minutes as the temperature was gradually raised to room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (583 mg, 32%).
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O1CCOCC1>[O:1]([CH:8]([C:9]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Oc1ccccc1)C(=O)O
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(Oc1ccccc1)c1nnc(N)s1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
A 1,000 milliliter, 3-neck flask equipped with a Claisen adaptor, paddle stirrer, thermometer, addition funnel and condenser, was charged with 100 grams (0.602 moles) of 2-phenoxypropanoic acid, (54.8 grams, 0.602 mole) of thiosemicarbazide and 300 ml. of dioxane. The slurry was heated to 85° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 was slowly added (for 70 minutes) while maintaining the temperature within 90°-95° C., and then stirred for an additional 20 minutes. It was refluxed for 105 minutes and cooled. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), leaving a viscous residue to which 400 ml of water was added and the residue emulsified. A 50 percent solution of NaOH was added until the pH of the solution was 10, and a solid precipitate formed. The solid precipitate was filtered off, washed with water, air dried, then dried in a vacuum oven at 60° C. to a granular grey solid which was recrystallized from H2O/ethanol mixture, filtered and then dried in a vacuum oven at 60° C. to white needles of 5-(1-phenoxyethyl)-2-amino- 1,3,4-thiadiazole. (Melting point 157°-167° C.).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:20]([NH:24][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(F)c1
Solvent: C1CCOC1
Product: CCCCNc1cc(OCCCN(CC)CC)ccc1[N+](=O)[O-]

Procedure:
A solution of 2-fluoro-4-(3-diethylamino-1-propoxy)nitrobenzene (2 mmol; preparation described in Example 5) in THF (5 mL) is treated with n-butylamine (2.4 eq) at rt. After completion of the reaction, the reaction mixture is concentrated in vacuo. The residue is redissolved in EtOAc (10 mL), washed with saturated sodium bicarbonate solution, water, and brine. The organic phase is then dried over sodium sulfate and the solvent is removed in vacuo to afford the product, 2-n-butylamino-4-(3-diethylamino-1-propoxy)nitrobenzene (580 mg) which was used for further transformation without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:29]3[CH2:33][CH2:32][CH2:31][NH:30]3)=[N:9][C:10]=2[C:11]2[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:34][O:35][CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:29]3[CH2:33][CH2:32][CH2:31][N:30]3[C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][O:35][CH3:34])=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:27][CH:28]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4)n4ccnc(N)c34)cc2)c1
Reactant: COC/C=C/C(=O)O
Product: CCCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4C(=O)/C=C/COC)n4ccnc(N)c34)cc2)c1
Yield: 65.7 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-propylpyridin-2-yl)benzamide (intermediate 9) and (E)-4-methoxybut-2-enoic acid (Intermediate 3), to afford the title compound (30.9 mg, 65.7%). Data: UPLC (C) R: 2.73 min; m/z 566.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:11]=1[NH2:12].Cl>C(O)CCC>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:11]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:10]=2[Cl:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cc(Cl)ccc1Cl
Agent: Cl
Solvent: CCCCO
Product: Clc1ccc(Cl)c(Nc2ccnc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
2,4-Dichloropyrimidine (50 g, 0.34 mol), 2,5-dichloroaniline (54.38 g, 0.34 mol) and concentrated hydrochloric acid (cat. amount) were dissolved in n-butanol (250 ml). The reaction mixture was stirred at room temperature for 12 hours after which the solid that had formed was collected by filtration. The organics were allowed to stand for 48 hours and the solid that formed was collected by filtration, washed with EtOAc and dried to give the title product as a white solid (18.65 g). NMR (300 MHz): 6.82 (d, 1H), 7.31 (dd, 1H), 7.58 (d, 1H), 7.82 (s, 1H), 8.19 (d, 1H), 9.82 (s, 1H); m/z: (ES+) 273.9 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[Br:16]Br.O>CCCCCC>[Br:16][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Brc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,3-dihydrobenzofuran (11.06 g) and sodium carbonate (14.8 g) in hexane (100 ml) was added dropwise at 0° C. a solution of bromine (4.8 ml) in hexane (20 ml) for 1.5 hours, and the mixture was stirred at room temperature for 1 hour. To the mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give gray crystals of 5-bromo-2,3-dihydrobenzofuran (17.64 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH3:51]>>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][N:30]1[C:31]2[C:26](=[CH:25][CH:24]=[C:23]([CH2:22][O:21][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=5[CH3:51])=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10]3)[CH:32]=2)[CH2:27][CH2:28][C:29]1=[O:38]
Reactant: Cc1ccccc1OCCCCBr
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4ccccc4C)cc3)cc21

Procedure:
Analogously to Method I, 0.160 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.099 g of 1-(4-bromobutoxy)-2-methylbenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.33 (2:1 EtOAc-heptane); Rt=6.34.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[O:5]=[C:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>ClCCl>[O:5]=[C:6]1[CH2:10][CH2:9][CH2:8][C@@:7]1([CH2:4][CH2:3][CH:1]=[O:2])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)C1CCCC1=O
Reactant: C=CC=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@]1(CCC=O)CCCC1=O

Procedure:
A solution of acrolein (4.19 g; 74.83 mmoles—2.5 eq.) in 10 mL of anhydrous dichloromethane is poured, over 30 minutes, at −25° C., under argon and with slow stirring, into a solution of tert-butyl 2-oxo-cyclopentanecarboxylate (5.51 g; 29.93 mmoles) and catalyst Q (1.46 g; 2.99 mmoles—0.1 eq.) in 60 mL of anhydrous dichloromethane
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1CC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperidine-1-carboxylate (0.0525 g, 0.107 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(piperidin-4-ylmethyl)benzofuran-3(2H)-one (0.0384 g, 92%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:10]=O>>[CH3:10][N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C=O
Reactant: CCCCNCCCC
Product: CCCCN(C)CCCC
Yield: 95.8 %

Procedure:
In a similar manner to Example 1, 258.5 g (2.0 mol) of di-n-butylamine and 330.2 g (3.2 mol) of formaldehyde (29.1%) are reacted in a 1 l autoclave; a maximum pressure of 3.2 MPa is established at a temperature of 120° C. After the crude amine (aqueous and organic phase) has been degassed at a maximum temperature of 80° C., the water is removed on a water separator. The remaining organic phase is subsequently fractionally distilled. 274.6 g of N-methyldi-n-butylamine having a purity of 99.6% are isolated, corresponding to a yield of 95.6% of theory.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9]C)[CH:5]=[CH:4][C:3]=1[CH:11]([NH:21][C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:33])[NH:27]2)[C:12]([OH:20])([CH2:17][O:18]C)[C:13]([F:16])([F:15])[F:14].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:21][C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:33])[NH:27]2)[C:12]([OH:20])([CH2:17][OH:18])[C:13]([F:16])([F:14])[F:15]
Reactant: COCC(O)(C(Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(OC)c(F)c1Cl)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1ccc2c(NC(c3ccc(O)c(F)c3Cl)C(O)(CO)C(F)(F)F)cc(F)cc2[nH]1
Reaction time: 16 h
Yield: 17.2 %

Procedure:
To 100 mg (0.20 mmol) of 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one of example 5 in 8.6 dichloromethane at −30° C. are added 1.6 ml of a 1M solution of boron tribromide in dichloromethane under argon. The reaction mixture is stirred for 16 hours in a temperature range of between 0° C. and 25° C. The reaction mixture is mixed at 0° C. with saturated sodium bicarbonate solution. After dilution with ethyl acetate the batch is allowed to come to room temperature, stirred for 10 minutes and phases are separated. The aqueous phase is acidified with 4 M HCl and extracted with 10% methanol in dichloromethane. After removal of the solvent preparative thin layer chromatography on silica gel (ethyl acetate/methanol 4:1) yields 16 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:23][Mg]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)([OH:12])[CH3:23])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Mg]I
Reactant: Cn1ncc2cc(C(=O)c3cnc4ccc(Cl)nn34)ccc21
Solvent: C1CCOC1
Product: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(1-methyl-1H-indazol-5-yl)methanone (410 mg, 1.32 mmol) in 10 mL THF was added methylmagnesium iodide (0.88 mL, 2.63 mmol) at 0° C. After stirring at 0° C. for 3 h, the reaction was quenched with saturated NH4Cl and concentrated under resdue pressure. The residue was extracted with DCM three times. The organic layers were combined, dried over Na2SO4 and concentrated to give the title compound as a white solid (430.0 mg, 95%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.17 (d, 1H), 7.99 (s, 1H), 7.50 (m, 1H), 7.40 (d, 1H), 7.25 (d, 1H), 5.98 (s, 1H), 3.99 (s, 3H), 2.05 (s, 3H). LCMS (method A): [MH]+=328, tR=4.55 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>N1C=CC=CC=1>[NH2:11][S:8]([C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([O:14][C:13]([F:12])([F:24])[F:25])=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:9])=[O:10]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cccc(NC(=O)c2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-amino-benzenesulfonamide (17 mg, 0.10 mmol) in pyridine (1 mL) was added 4-trifluoromethoxy benzoyl chloride (16 μL, 0.10 mmol). The reaction was stirred at room temperature for 15 h and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give N-(3-(aminosulfonyl)phenyl)-4-(trifluoromethoxy)benzamide. LC/MS: m/z 360.9 (M+H)+ at 3.02 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:26])[CH3:29]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(N)C1=O
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccco2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
Following the procedure described in Example 42(h), 0.40 g of t-butyl α-[6-amino-2-(2-furyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] was N-alkylated using 0.68 g of ethyl 2-bromo-4-phenylbutyrate. The resulting product was subjected to silica gel column chromatography eluted with a 1:20 by volume mixture of ethyl acetate and methylene chloride, to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH3:24][CH:25]([OH:27])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:27][CH:25]([CH3:26])[CH3:24])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CC(C)O
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Product: CCOC(=O)c1c(OC(C)C)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 11 step C from 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B) and propan-2-ol. Yellow solid (35 mg, 33%). LC-MS: 370 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]([OH:30])=O)=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:31])([CH3:3])[CH3:2].C(Cl)CCl.[CH3:36][NH:37][CH3:38]>CN(C1C=CN=CC=1)C>[CH3:36][N:37]([CH3:38])[C:28]([C:26]1[CH:25]=[CH:24][C:17]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]3=[O:31])=[N:15][C:16]=2[CH:27]=1)=[O:30]
Reactant: CNC
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=O)O)ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=O)N(C)C)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
A mixture of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5 carboxylic acid (42 mg, 0.1 mmol), EDC (23 mg, 0.12 mmol), DMAP (14 mg, 0.12 mmol) and dimethylamine (1M in THF, 0.12 mL) was stirred for 12 h at ambient temperature. The solvent was evaporated and the residue purified by prep-HPLC (gradient 10%-100% B) to give 22 mg (49%) of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid dimethylamide as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][CH:21]=O)[CH:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C@H:26]([C@@H:32]([OH:54])[C@H:33]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@H:35]([N:46]2[CH:51]=[CH:50][C:49](=[O:52])[NH:48][C:47]2=[O:53])[O:34]1)[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:39]([O:38][C@H:37]1[C@@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@H:35]([N:46]2[CH:51]=[CH:50][C:49](=[O:52])[NH:48][C:47]2=[O:53])[O:34][C@@H:33]1[C@H:32]([OH:54])[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:25][CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:23])[C@H:11]([C@@H:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[NH:10][C:9](=[O:24])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: CCOC(=O)[C@H](N)[C@@H](O)[C@@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)C(O)C(NC(=O)OCc1ccccc1)C(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(NCCCNC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](O)C(C)C)[C@@H](O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
A solution of [2-hydroxy-3-methyl-1-(3-oxo-propylcarbamoyl)-butyl]-carbamic acid benzyl ester (313 mg, 0.93 mmol, obtained from Reference Example 14) and ethyl (2R,3R)-2-amino-3-hydroxy-3-[(2S,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoate [400 mg, 0.93 mmol, obtained by hydrogenation of ethyl (2R,3R)-2-{[(benzyloxy)carbonyl]amino}-3-{[(benzyloxy)carbonyl]oxy}-3-[(2S,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoate (from Reference Example 41)] in anhydrous tetrahydrofuran (7 ml) was stirred at room temperature under a nitrogen atmosphere for 15 minutes. Acetic acid (53 μl) and sodium triacetoxyborohydride (395 mg, 1.86 mmol) were added, and the resulting solution was stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution and the aqueous layer was separated and extracted with ethyl acetate (2×75 ml). The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (250×21 mm Phenomenex Prodigy ODS3 column eluted with 10-90% acetonitrile in water containing 0.02% trifluoroacetic acid over 72 minutes) to provide ethyl (5S)-12-[(R)-[(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxy-2-methylpropyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate as white amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 110.9 %

Procedure:
(RS) 2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.21 g) and 2-chlorobenzoxazole (0.153 g) and triethylamine (0.1 g) were combined in tetrahydrofuran (10 ml) and stirred at room temperature for 4 hours. The mixture was partitioned between ethyl acetate and water, the organic phase dried and solvent removed at reduced pressure to give the title compound (0.36 g) as an oil that solidified on standing.