Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][CH3:13].[NH2:15][NH2:16]>CO>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([NH:15][NH2:16])=[O:2]
Reactant: COC(=O)c1ccc(OC)cc1OC
Reactant: NN
Solvent: CO
Product: COc1ccc(C(=O)NN)c(OC)c1
Yield: 78.1 %

Procedure:
Ex-109A: A solution of 2,4-dimethoxy-benzoic acid methyl ester (4.24 g, 21.6 mmol) and hydrazine (3.4 mL, 108.1 mmol) in methanol (50 mL) was refluxed overnight. Solvent was removed under reduced pressure. The residue was re-dissolved in ethyl acetate. The solution of ethyl acetate was washed with saturated solution of sodium bicarbonate and brine, dried over sodium carbonate and concentrated to afford 2,4-dimethoxy-benzoic acid hydrazide (3.31 g, 78%) as a white solid: 1H NMR (CDCl3) δ 8.77 (bs, 1H), 8.15 (d, J=8.8 Hz, 1H), 6.58 (dd, J=8.8, 2.2 Hz, 1H), 6.46 (d, J=2.2 Hz, 1H), 4.10 (bs, 2H), 3.91 (s, 3H), 3.83 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:34]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)N=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)NC(C)(C)C)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), tert-butyl isocyanate (0.0042 g, 0.043 mmol), DIPEA (33 μL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 15 min. Purification by HPLC afforded the title compound as a colorless solid. 1H NMR (400 MHz, CD3OD): δ=1.36 (s, 9H), 1.89 (d, J=6.8 Hz, 3H), 2.49 (br. s., 2H), 3.59 (t, J=5.7 Hz, 2H), 4.04 (d, J=2.5 Hz, 2H), 6.25 (br. s., 1H), 6.48-6.53 (m, 1H), 7.22 (t, J=8.7 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.65 (s, 1H), 8.20 (s, 1H). MS (ES+): m/z 521.07/523.09 (100/72) [MH+]. HPLC: tR=3.37 min (ZQ3, polar—5 min).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:18])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([Br:39])=[C:24]([NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CN(C)C1C=CN=CC=1>[Br:39][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([N:8]([CH3:7])[CH3:18])[CH:10]=2)=[CH:25][C:24]=1[NH:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1
Reactant: COc1ccc(C(=O)Nc2cc(N)ccc2Br)cc1OC
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N(C)C)c3)ccc2Br)cc1OC
Temperature: 7.5 °C
Reaction time: 4 h
Yield: 56.8 %

Procedure:
Oxalyl chloride (0.24 ml) was added dropwise to a stirred suspension of 3-dimethylaminobenzoic acid (0.36 g) in methylene chloride (15 ml) at 20° C. DMF (2 drops) was added and the reaction mixture was stirred for 4 hours. The solvent was evaporated to give a yellow solid which was dissolved in methylene chloride (20 ml) and added dropwise over 5 minutes to a stirred mixture of N-(5-amino-2-bromophenyl)-3,4-dimethoxybenzamide (0.7 g), triethylamine (0.8 ml), 4-dimethylaminopyridine (0.005 g) and methylene chloride (20 ml) which had been cooled to 5-10° C. The reaction mixture was stirred at ambient temperature for 18 hours. The organic phase was washed with a saturated sodium bicarbonate solution, dried (MgSO4) and evaporated. The residual oil was purified by column chromatography on silica gel using a 49:1 mixture of methylene chloride and methanol as eluent. The solid so obtained was crystallised from a mixture of ethyl acetate and methyl tert-butyl ether to give the title compound (0.564 g), m.p. 184° C.;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([CH:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.C[O-].[Na+]>C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([CH:46]4[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:50][CH2:51]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 150 °C
Yield: 39.7 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (200 mg, 0.41 mmol), 5-methyl-2-(methyloxy)-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}aniline (120 mg, 0.37 mmol), and p-toluenesulfonic acid (186 mg, 0.98 mmol) were weighed into a 20 mL microwave vial. 7 mL of trifluoroethanol was added and the mixture was heated in the microwave to 150° C. for 2 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2.5 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 2 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (115 mg, 0.147 mmol, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.79 (s, 1H), 9.40 (d, J=6.97 Hz, 1H), 8.47 (s, 1H), 8.26 (d, J=5.13 Hz, 1H), 8.11 (d, J=2.57 Hz, 1H), 7.78 (dd, J=8.43, 2.20 Hz, 1H), 7.71 (d, J=8.80 Hz, 1H), 7.56 (s, 1H), 7.42-7.49 (m, 1H), 7.34-7.42 (m, 1H), 7.28 (d, J=8.80 Hz, 1H), 7.18 (t, J=8.07 Hz, 2H), 6.97 (t, J=6.97 Hz, 1H), 6.89 (s, 1H), 6.59 (d, J=5.13 Hz, 1H), 3.99 (s, 3H), 3.81 (s, 3H), 3.28-3.32 (m, 2H), 3.06 (s, 3H), 3.02 (d, J=11.36 Hz, 2H), 2.74 (t, J=6.97 Hz, 2H), 2.60-2.70 (m, 1H), 2.20 (s, 3H), 2.04-2.15 (m, 2H), 1.65-1.76 (m, 4H). MS (ESI): 782 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[C:24]([CH3:33])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:22]3[CH2:21][CH2:20][CH2:25][C:24]([CH3:33])([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CC1(c2ccccc2)CCCC(Br)C1=O
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc3c(s2)CCCC3(C)c2ccccc2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (0.45 g, 1.72 mmol) and 6-bromo-2-methyl-2-phenyl-cyclohexanone (0.69 g, 2.6 mmol) using in analogous manner the procedure described in example 1b). Obtained as an off-white solid (0.29 g, 39%). MS ISP (m/e): 431.4 [(M+H)+]. mp 123-126° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH:8]=O)[CH2:2][CH3:3].C[Si](C)(C)CCOCN1C=CN=C1C=O.Cl.[CH2:29]1[C:38]2[C:33](=[CH:34][C:35]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:37]=2)[CH2:32][CH2:31][NH:30]1>>[CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][N:30]1[CH2:31][CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[C:35]([C:39]([O:41][CH3:42])=[O:40])[CH:34]=2)[CH2:29]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)CCCC=O
Reactant: COC(=O)c1ccc2c(c1)CCNC2
Agent: C[Si](C)(C)CCOCn1ccnc1C=O
Agent: Cl
Product: CCCN(CCC)CCCCN1CCc2cc(C(=O)OC)ccc2C1

Procedure:
The same procedure as a series of reactions of Example 1 was carried out, except that 4-(dipropylamino)butanal was used in place of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde and methyl 1,2,3,4-tetrahydro-6-isoquinolinecarboxylate hydrochloride was used in place of {[4-(methyloxy)phenyl]methyl}amine, to obtain the title compound having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Br:13]Br.O>ClCCl>[Br:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)c(Br)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
KM03 Dissolve 1,3,5-trimethoxybenzene (10.0 g, 59.46 mmol) in anhydrous dichloromethane (100 mL), cool the reaction mixture to −78° C., add dropwise bromine (3.0 mL, 59.44 mmol) stir the mixture for 1 h between −70° C. and −40° C. Warm up the solution to 0° C. and add water. Separate layers and extract the aqu. layer with EtAOc (3 times). Wash combined organic layer with water and brine and dry it with Na2SO4. Remove solvent and purify the crude product by recrystallization from hot EtOAc and cyclohexane to obtain 2-Bromo-1,3,5-trimethoxy-benzene (48) as a white solid (8.84 g, 60%). 1H NMR (400 MHz, CDCl3): 3.80 (s, 3H); 3.86 (s, 6H); 6.15 (s, 2H).
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][C:7]1[C:15]2[C:10](=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.O.[OH-].[Na+]>CN(C=O)C>[Cl:5][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:9][CH:8]=[C:7]([CH3:6])[C:15]=12
Reactant: Cc1c[nH]c2c1ccc[n+]2[O-]
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c[nH]c2nccc(Cl)c12
Temperature: 59 °C
Reaction time: 4 h

Procedure:
At 50° C., 1.77 ml (22.81 mmol) of methanesulfonyl chloride are added dropwise to a solution of 1.30 g (8.77 mmol) of 3-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide in 7.5 ml of DMF such that the temperature increases to 59° C. The mixture is then stirred at 70° C. for 4 h. After cooling to room temperature, 30 ml of water are added slowly, at 5° C., the pH is adjusted to 10 by addition of 20% strength sodium hydroxide solution and the mixture is stirred for another hour. The precipitated solid is filtered off, washed with water and then dried under reduced pressure.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].[Br:11][C:12]1[CH:13]=[CH:14][C:15](F)=[C:16]([CH:19]=1)[C:17]#[N:18].O>CN(C)C=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:16]([CH:19]=1)[C:17]#[N:18]
Reactant: CCCCCCCO
Reactant: N#Cc1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOc1ccc(Br)cc1C#N
Reaction time: 1 h
Yield: 86.1 %

Procedure:
1-Heptanol (1.55 g) was dissolved in N,N-dimethylformamide (24 ml), and sodium hydride (0.321 g) was added at room temperature. The mixture was stirred for 1 hr, 5-bromo-2-fluorobenzonitrile (2.43 g) was added, and the mixture was further stirred for 50 min. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To consume the starting material, 5-bromo-2-fluorobenzonitrile, the reaction was performed again under the same conditions, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-5:1) to give the object product (3.10 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]=[CH:14][C:15]([OH:17])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]=[CH:14][C:15]([N:21]([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])=[O:17])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)C=Cc1nc(-c2ccc(F)cc2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)C=Cc1nc(-c2ccc(F)cc2)cs1)C(C)C

Procedure:
98 mg (0.39 mmol) of 3-[4-(4-fluoro-phenyl)-thiazol-2-yl]-acrylic acid, 79.6 mg (0.78 mmol) of diisopropylamine, 119.35 mg (1.17 mmol) of triethylamine and 164.5 mg (0.43 mmol) of HATU in 5 ml of DMF were stirred at room temperature for 2 h. The reaction mixture was concentrated, and water and ethyl acetate were added. The organic phase was separated, washed and evaporated. The residue was purified by chromatography (RP18). Yield: 39 mg.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (1.06 g, 3.00 mmol), 4-fluoro-benzylamine (0.457 mL, 4.0 mmol), and K2CO3 (0.967 g, 7.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-fluoro-benzyl)-2,3-dihydro-isoindol-1-one (0.21 g, 20%). GC-MS: m/z 355 (M)+. 1H NMR (300 MHz, CDCl3): δ (ppm) 4.20 (s, 2H), 4.73 (s, 2H), 7.02 (t, 2H), 7.29-7.31 (m, 2H), 7.44 (s, 1H), 7.58 (s, 1H).
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[N:4]=1.[CH:25]1([C:28](Cl)=O)[CH2:27][CH2:26]1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:19][C:18]([CH3:20])([CH3:21])[CH2:17][CH2:16][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:5]2[N:4]=[C:3]([C:2]3[N:1]=[C:28]([CH:25]4[CH2:27][CH2:26]4)[O:24][N:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:10][CH2:11]1)=[O:22]
Reactant: CC(C)(C)CCC(=O)N1CCN(c2nccc(C(N)=NO)n2)CC1
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)CCC(=O)N1CCN(c2nccc(-c3noc(C4CC4)n3)n2)CC1

Procedure:
1-{4-[Amino(hydroxyimino)methyl]pyrimidin-2-yl}-4-(4,4-dimethylpentanoyl)piperazine (59.5 mg) was dissolved in pyridine (1 mL), and cyclopropanecarbonyl chloride (0.020 mL) was added thereto and heated under reflux for 3 hours. The reaction liquid was diluted with ethyl acetate, washed with aqueous saturated ammonium chloride solution, aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=3/2) to obtain 31.9 mg of the entitled compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])=[C:6]([F:18])[C:5]=1[F:19])[CH3:2].C([Li])(CC)C.Cl.[C:26](OCC)(=[O:28])C>C1COCC1.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:26]=[O:28])=[C:12]([F:16])[C:11]=2[F:17])=[C:6]([F:18])[C:5]=1[F:19])[CH3:2]
Reactant: CCOc1ccc(-c2cccc(F)c2F)c(F)c1F
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2ccc(C=O)c(F)c2F)c(F)c1F
Reaction time: 2 h

Procedure:
4-Ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl (s-7) (28.0 g) and THF (500 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00M; n-hexane and cyclohexane solution; 109 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. N,N-Dimethylformamide (8.0 g) in a THF (200 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for 8 hours while the mixture was allowed to return to 25° C. The resulting reaction mixture was poured into a vessel containing a 1N-HCl aqueous solution (300 ml) and ethyl acetate (300 ml) and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent and further purified by recrystallization from a mixed solvent of THF and heptane (THF:heptane=1:5 by volume) and dried to give 4′-ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl-4-carboxaldehyde (s-8) (28.0 g). The yield based on the compound (s-7) was 90.6%.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[NH2:8][C@@H:9]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11]
Reactant: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CNC(=O)[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-methyl 2-(2-((tert-butoxycarbonyl)amino)-4-methylpentanamido) acetate (3w) in 1,4-dioxane was added a 5M solution of HCl in 1,4-dioxane at room temperature. The reaction was stirred at room temperature for 16 h. The reaction mixture was filtered to afford (S)-methyl 2-(2-amino-4-methylpentanamido)acetate hydrochloride (4w) as the filtered solid.
Reaction SMILES: S(Cl)([Cl:3])=O.C(OC([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=O)(C)(C)C.[CH3:27]O>>[ClH:3].[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][S:15][CH2:14][C@@H:13]([C:24]([O:26][CH3:27])=[O:25])[NH2:12])=[CH:22][CH:21]=1
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)[C@@H](N)CSCc1ccc(C)cc1
Product: Cl
Temperature: 25 °C

Procedure:
At room temperature, add thionyl chloride (2.8 ml, 2.2 equiv.) dropwise to N-t-butyloxycarbonyl-S-(4-methylbenzyl)-L-cysteine (5.0g) in methanol (500 ml) and heat the resulting mixture under reflux for 90 minutes. Cool the reaction mixture to room temperature and concentrate in vacuo to give the title compound, a white solid (4.31g), m.p. 158°-160°, [α]D26 =-22.9° (MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][C@@H:9]1[C@@H:22]([OH:34])[C@@H:23]([NH2:33])[CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CC[O:39][CH2:38][CH2:37]1.ClCCl>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][C@@H:9]1[C@@H:22]([OH:34])[C@@H:23]([NH:33][C:38](=[O:39])[CH3:37])[CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(O[C@@H]2C[C@H]([C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)N(C(=O)OC(C)(C)C)C2)c1
Reactant: CN1CCOCC1
Solvent: ClCCl
Product: COc1cccc(O[C@@H]2C[C@H]([C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(C)=O)N(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
Add to an ice cold solution of (2R,4R)-2-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-4-(3-methoxy-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.24 g, 0.51 mmol) and 4-methylmorpholine (0.061 mL, 0.556 mmol) in dichloromethane (15 mL) 1-acetylimidazole (0.061 g, 0.556 mmol). Warm to room temperature and stir 18 h. Concentrate and dissolve in ethyl acetate and wash with 1N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate) and purify (silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures) to give the title compound as a foam (0.18 g, 69%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:10]=[C:9]1[C:22]([O:24]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I.O>CN(C)C=O>[CH2:1]([N:8]1[C:9]([CH:22]=[O:24])=[CH:10][C:11]([N:13]([CH3:29])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCOC(=O)c1cc(NS(=O)(=O)c2cccs2)cn1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cc(C=O)n(Cc2ccccc2)c1)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of ethyl 1-benzyl-4-[(2-thienylsulfonyl)amino]-1H-pyrrole-2-carboxylate (19.5 g) in N,N-dimethylformamide (100 mL) was slowly added sodium hydride (60%, oily, 2.2 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Methyl iodide (3.4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). To a solution of the yellow oil in tetrahydrofuran (150 mL) was slowly added lithium aluminum hydride (2.2 g) in small portions. The reaction mixture was stirred at room temperature for 1 hr, and water (2.2 mL), 15% aqueous sodium hydroxide solution (2.2 mL) and water (6.6 mL) were successively added to the reaction mixture under ice-cooling. The reaction mixture was stirred for 1 hr, and the insoluble material was filtered off. The filtrate was concentrated, manganese dioxide (30 g) was added to a solution of the residue in tetrahydrofuran (200 mL), and the mixture was stirred at room temperature overnight. The manganese dioxide was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give N-(1-benzyl-5-formyl-1H-pyrrol-3-yl)-N-methylthiophene-2-sulfonamide (10.3 g, yield 57%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).