Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH3:15])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C=O)C>[Cl:19][C:9]([C:8]1[CH:12]=[C:13]([CH3:14])[C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([CH3:15])[CH:7]=1)=[O:10]
Reactant: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound 3,5-dimethyl-4-hydroxybenzoic acid (5.04 g, 30.33 mmol) was mixed with pyridine (20 mL). Acetic anhydride (3.72 g, 36.4 mmol) was added and the mixture was stirred at room temperature for 4 h. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid in quantitative yield (6.33 g). The compound 4-acetoxy-3,5-dimethyl-benzoic acid (0.36 g, 1.73 mmol)) was dissolved in dichloromethane (5 mL) and oxalyl chloride (0.3 mL, 3.46 mmol) was added dropwise, followed by 1 drop of DMF. The reaction mixture was stirred at room temperature under nitrogen for 2 h. The solvent was evaporated in vacuo to obtain acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester in quantitative yield (0.392 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH2:6])[CH3:5].[NH2:7][C:8]1[CH:15]=[C:14](F)[C:11]([C:12]#[N:13])=[CH:10][N:9]=1>CC(N(C)C)=O>[NH2:7][C:8]1[CH:15]=[C:14]([NH:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[C:11]([C:12]#[N:13])=[CH:10][N:9]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: COC[C@H](C)N
Solvent: CC(=O)N(C)C
Product: COC[C@H](C)Nc1cc(N)ncc1C#N
Temperature: 60 °C

Procedure:
A mixture of (S)-1-methoxy-2-propylamine (5.91 g, 65.6 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 3.0 g, 21.88 mmol) and diidopropylethylamine (11.52 ml, 65.6 mmol) in DMA (50 ml) was heated at 60° C. in a septum sealed reaction vessel for 48 h. The reaction mixture partitioned between DCM and aqueous NH4Cl, extracted with DCM (3×), the combined organic extracts were dried over Na2SO4 and evaporated to give the title compound as a pale yellow oil. (UPLC-MS 7) tR 0.40; ESI-MS 207.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29]Cl>CN(C=O)C.C1COCC1>[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29][N:9]1[C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:6]=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCc1nc(C(=O)OC)c(C(=O)OC)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106 %

Procedure:
The diester 1 from Step (a) (23 g, MW 240, 0.096 mol) was dissolved in 300 ml DMF. Potassium t-butoxide (100 ml of a 1M solution in dry THF) was added through a syringe. The solution was stirred for 15 min at 25° C. [2-(trimethylsilyl)ethoxy]methyl chloride (SEM-chloride, 18.6 ml, 1.1 eq, MW 166, d 0.94) was added and a precipitate instantly formed. The reaction was stirred for 90 min at 25° C. The solvent was removed and the residue partitioned between ethyl acetate and water. The organic extract was dried over K2CO3 and concentrated. By TLC (SiO2, MeOH-CHCl3 /1-10) a single major spot was observed. This crude product (38 g, 106% yield) was used in subsequent steps without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][CH:15]=[CH:16][C:3]=12.[Br:17]Br>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:17])=[CH:16][C:3]=12
Reactant: BrBr
Reactant: CCOC(=O)c1c(C)nc2sccc2c1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc2sc(Br)cc2c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a stirred solution of ethyl 4-amino-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 65) (1 g, 4.23 mmol) in acetic acid (3 mL) was added bromine (0.65 mL, 12.70 mmol) and the resulting mixture stirred at RT overnight (ca. 18 h). The reaction was quenched by pouring the reaction mixture into water and the aqueous solution was basified with NaOH (5M) and diluted with ethyl acetate (30 mL). The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (20 mL×3). The combined organics were washed with saturated sodium thiosulphate solution, dried and concentrated. Purification by chromatography on silica, eluting with a gradient of 0-30% ethyl acetate in DCM afforded the title compound (1.16 g). LCMS (A) m/z: 315/317 [M+1]+, Rt 0.95 min (acidic).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:15][OH:16])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[Br:24][C:6]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][C:9]([O:11][CH2:12][O:13][CH3:14])=[CH:8][C:7]=1[CH2:15][OH:16]
Reactant: COCOc1cc(CO)cc(OCOC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(CO)c(Br)c(OCOC)c1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of (3,5-bis-methoxymethoxy-phenyl)-methanol (9.16 g, 40.2 mmol) in DMF (40 mL) was treated with NBS (7.51 g, 42.2 mmol) at room temperature and the mixture was stirred at same temperature for 30 min. The residue was diluted with ethyl acetate and washed with brine. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate=1:1) to afford the title compound (10.2 g, 83%). 1H NMR (300 MHz, CDCl3) δ 6.91 (s, 1H), 6.81 (s, 1H), 5.24 (s, 2H), 5.17 (s, 2H), 4.72 (d, J=6.3 Hz, 2H), 3.52 (s, 3H), 3.47 (s, 3H), 2.05 (t, 1H).
Reaction SMILES: C(O)(=O)C.N1C=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:11].Cl.[NH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25](=[O:26])[C:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][NH:22]2)=[N:19][CH:20]=1.COC1CCC(OC)O1>O>[ClH:11].[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:24]2[C:25](=[O:26])[N:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:13]4[CH:9]=[CH:8][CH:7]=[CH:6]4)=[CH:20][N:19]=3)[NH:22][CH:23]=2)[CH:28]=1
Reactant: NCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Reactant: c1ccncc1
Agent: COC1CCC(OC)O1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=c1c(-c2cccnc2)c[nH]n1-c1ccc(Cn2cccc2)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
565 mg (9.4 mmol) of acetic acid are initially charged in 0.3 ml of water. 744 mg (9.4 mmol) of pyridine are added slowly. 191 mg (0.6 mmol) of the compound from Example 13 and 74 mg (0.6 mmol) of 2,5-dimethoxytetrahydrofuran are then added, and the mixture is stirred at 100° C. for 16 h. The mixture is then concentrated on a rotary evaporator, 3 ml of acetonitrile and 3 ml of 1 N hydrochloric acid are added and the mixture is stirred at RT for 30 min. The solid formed is filtered off, washed once with water and dried under high vacuum.
Reaction SMILES: Cl.[F:2][C:3]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:27]([N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[C:12]([F:19])=[C:13]([F:18])[C:14]([F:17])=[C:15]([F:16])[C:3]=2[F:2])[CH2:7][CH2:8]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirring solution of 4.76 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride in 100 ml of dichloromethane was treated with 4.46 ml of triethyl amine followed by a solution of 1.413 g of acetyl chloride in 60 ml of dichloromethane (dropwise). After stirring at ambient temperature for 18 hours, the reaction mixture was washed with water followed by a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the solvents afforded an oil which was purified by means of high pressure liquid chromatography (silica gel; elution with 10% ethyl acetate/dichloromethane). The resultant oil solidified upon standing and this material was sublimed to 3.2 g (64.7%) of 1-acetyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 60°-65° C.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:15]O>>[CH3:15][O:9][C:8](=[O:10])[CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:13][CH:12]=1)[CH3:11]
Reactant: CO
Reactant: CC(Oc1ccc(N)cc1)C(=O)O
Agent: Cl
Product: COC(=O)C(C)Oc1ccc(N)cc1
Yield: 37.2 %

Procedure:
To a mixture of 2-(4-Amino-phenoxy)-propionic acid 17 (240 g, 1.103 mol), in methanol (4.8 liters) was passed dry HCl gas at 10° C. for 1 hour and refluxed for 48 hours. Methanol (2.5 liter) was distilled off, ice water (1 liter) was added and the pH was adjusted to 7.5 with K2CO3. Crude 18 was extracted into chloroform, washed with 5% NaHCO3 solution, water, dried over Na2SO4 and distilled to give 18 (80 g, 37.2%) as a brown syrup. The structure was confirmed with NMR.
Reaction SMILES: S(N=[N+]=[N-])([C:4]1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[CH:23]=O>C(#N)C.CO>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[C:23]#[CH:4]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: C#Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tosyl azide (2.70 g, 32 mmol) and K2CO3 (4.74 g, 34.3 mmol) in dry acetonitrile (20 mL) was added dropwise a solution of dimethyl 2-(oxopropyl)-phosphonate (1.89 mL, 2.27 g, 13.7 mmol) in acetonitrile (5 mL) then the mixture was stirred at ambient temperature for 3 h. To this mixture was added dropwise a solution of 2,6-dichlorobenzaldehyde (2.0 g, 11.4 mmol) in methanol (15 mL), and the resulting mixture stirred at ambient temperature for 18 h. The solvent was removed under reduced pressure, and the residue stirred with ethyl acetate and sat. ammonium chloride. This mixture was filtered to remove insolubles, and the filtrate separated. The aqueous phase was re-extracted with ethyl acetate, and the combined organic layers were dried, filtered, and the was solvent removed under reduced pressure. The residue was purified by chromatography using a gradient of 0-20% hexane/ethyl acetate to afford 2,6-dichlorophenylacetylene.
Reaction SMILES: [Br-].C([P+](CCCC)(CCCC)[CH:7]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[C:9](=[O:16])[O:8]1)CCC.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=O)[CH:29]=1.C(N(CC)CC)C>ClCCl>[O:16]=[C:9]1[C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:7](=[CH:34][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([O:26][CH3:25])=[O:36])[O:8]1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CCCC[P+](CCCC)(CCCC)C1OC(=O)C2=C1CCCC2
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C=C2OC(=O)C3=C2CCCC3)c1

Procedure:
A solution of EXAMPLE 1B (25.8 g, 61.5 mmol), methyl-3-formylbenzoate (10.01 g, 61.0 mmol), and triethylamine (8.7 mL, 62.4 mmol) in dichloromethane (125 mL) was stirred at room temperature for 16 hours, and concentrated. The residue was stirred with a mixture of ethyl acetate and water. The precipitated solid was filtered, washed with water, and dried to provide the title compound. MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[N:5]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[N:4]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH3:33][S:34]([O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]([C:17]3[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[N:4]=[C:3]([CH:2]([F:1])[F:25])[CH:7]=2)=[CH:9][CH:10]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCO)cc2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCOS(C)(=O)=O)cc2)cn1
Reaction time: 1 h

Procedure:
To a solution of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethanol (7.4 g) and Et3N (4.5 ml) in CH2Cl2 (75 ml) was added MsCl (2.5 ml) under ice-cooling. After stirring for 1 hour, the reaction mixture was quenched with water, separated. The aqueous layer was extracted with CH2Cl2 and combined organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 10.5 g (quant) of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethyl methanesulfonate as an oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[N:24]([O-])=O.[Na+].[OH-].[Na+]>Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:24]=[N:15][C:14]=2[CH:16]=1
Reactant: O=N[O-]
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2oc(-c3ccc4c(c3)nnn4C3CCOCC3)nc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.35 g, 1.13 mmol) in concentrated hydrochloric acid (2 mL) was added dropwise an aqueous solution containing sodium nitrite (0.09 g, 1.24 mmol) with cooling to 0° C. After stirring for 2 hours at room temperature, this was cooled to 0° C. and was made alkaline with 1N aqueous sodium hydroxide solution, then extracted with ethyl acetate, washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to yield the title compound (0.17 g, 46.9% yield) as dark brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([NH:15][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CC(C)(C)NC(=O)c1ccc(Cl)cn1

Procedure:
The title compound was prepared by the same method as that described in Example 27, using 5-chloro-2-pyridinecarboxylic acid and t-butylamine.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19]>>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[C:17]3[S:13][C:14](=[O:19])[NH:15][C:16]3=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1noc2ccc(C=O)cc12
Product: Cc1noc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 3-Methyl-benzo[d]isoxazole-5-carbaldehyde (intermediate 6) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [NH2:1][NH2:2].Cl.[F:4][C:5]1[C:6]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[C:7]([C:11]([F:14])=[CH:12][CH:13]=1)[C:8](O)=[O:9]>C(O)C>[F:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:7]2[C:6]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[N:1][N:2]=[C:8]2[OH:9]
Reactant: O=C(O)c1c(F)ccc(F)c1C(=O)c1ccccn1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: Oc1nnc(-c2ccccn2)c2c(F)ccc(F)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 3M-solution of hydrazine (60 mmol) in ethanol is added to a solution of crude 3,6-difluoro-2-(2-pyridylcarbonyl)benzoic acid hydrochloride (20 mmol), and the mixture is stirred at room temperature for 5 hours. Precipitation yields 5,8-difluoro-4-(2-pyridyl)-1-phthalazinol.
Reaction SMILES: [CH2:1]1[CH2:30][O:29][C:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([OH:18])[C@H:7]2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[O:2]1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])(C)C.N1C=CN=C1>CN(C=O)C>[CH2:30]1[CH2:1][O:2][C:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:9][C@H:8]([O:18][SiH2:31][C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:7]2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[O:29]1
Reactant: CCCCCC1(CC[C@@H]2[C@H](CC(=O)OC)[C@@H](O)C[C@H]2OC2CCCCO2)OCCO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCC1(CC[C@@H]2[C@H](CC(=O)OC)[C@@H](O[SiH2]C(C)(C)C)C[C@H]2OC2CCCCO2)OCCO1

Procedure:
To a solution of methyl 2-[(1S,2R,3R,5S)-2-(3,3-ethylenedioxyoctyl)-3-(tetrahydropyranyloxy)-5-hydroxycyclopentyl]acetate (61) in DMF (80 ml) were added t-butyldimethylsilyl chloride (2.11 g) and imidazol (0.95 g), and the resultant mixture was stirred. The crude product obtained by treating in the conventional manner was subjected to silica gel column chromatography to give the title compound (62). Yield: 5.41 g((71.2 g)
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:34])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[NH:16][C:15]1=[O:33])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br.Br[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([C@@H:10]([CH3:34])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][CH:39]=2)[C:15]1=[O:33])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: BrCc1ccnc2ccccc12
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2ccnc3ccccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
To a rt solution of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (147 mg, 296 μmol) in DMF (740 μl) was added 4-(bromomethyl)quinoline hydrobromide (135 mg, 444 μmol) and cesium carbonate (289 mg, 888 μmol). The reaction was stirred at rt for 18 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-5-(quinolin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (57 mg, 30%) as a white solid. MS m/z 638 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]2)O)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:22])CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([F:22])[CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: CN1CCC(C(O)c2ccc(Br)cc2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CN1CCC(C(F)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Cool a solution of (4-bromo-phenyl)-(1-methyl-pyrrolidin-3-yl)-methanol in CH2Cl2 (6.5 mL) to 0° C. Add slowly a solution of DAST (0.1 mL, 0.78 mmol) in CH2Cl2. Stir the mixture at RT overnight. Cool the mixture to 0° C., then carefully quench with saturated NaHCO3 (exothermic and gas evolution). Extract the aqueous layer with CH2Cl2. Dry the combined organic phases with Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography, collecting all the fractions as the product does not show by UV. Elute with 5-10% MeOH (2 N NH3)/CH2Cl2 to give 0.049 g (35%) of the title compound. LC-MS/ES m/z (79Br) 272.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23][SH:24])[CH3:20].O>CN(C=O)C>[CH2:19]([O:21][C:22]([C:23]1[S:24][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[CH:4]=1)=[O:25])[CH3:20]
Reactant: CCOC(=O)CS
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-chloro-5-nitro-benzaldehyde (31.01 g, 167.1 mmol) in 330 mL of anhydrous DMF at 0° C. was added K2CO3 (27.80 g, 201.1 mmol), followed by slow addition of mercapto-acetic acid ethyl ester (18.5 mL, 168.7 mmol). After stirring at 0° C. for 20 min, the resulting mixture was allowed to warm to rt and stir at rt overnight. The reaction mixture was then poured into 1.5 L of water. The solid formed was filtered and washed with 600 mL of water. After drying, 5-nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester was obtained as pale solid. MS (EI): cal'd 252.0 (MH+), exp 252.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.CN(C)[CH:26]=[O:27].P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH:26]=[O:27])=[C:9]2[CH3:23])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Example 1) (1.55 g, 4.71 mmol) in dimethylformamide (3.65 ml, 47 mmol) and toluene (20 ml), phosphorous oxychloride (3.5 ml, 37.7 mmol) was added. After stirring for 20 minutes, the reaction mixture was heated at 70° C. for 5 hours. The reaction mixture was cooled, poured into aqueous sodium acetate solution and extracted with ethyl acetate. The organic fractions were washed with 10% aqueous potassium carbonate and water. After drying (Na2SO4), filtration and concentration, the crude yellowish liquid (2.06 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carboxaldehyde (1.2 g, 71%): mp (DSC) 155° C. Anal Calc'd. for C19H16NSFO3 : C, 63.85; H, 4.51; N, 3.92. Found: C, 63.50; H, 4.66; N, 3.85.