Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC)(=O)CC([O-])=O.[O-]CC.[Mg+2].[O-]CC.S(Cl)(Cl)=O.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>O.COC(C)(C)C.C(O)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31](=[O:33])[CH3:1])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CC[O-]
Agent: [Mg+2]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: COC(C)(C)C
Product: CC(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 72.5 °C
Reaction time: 0.75 h
Yield: 75 %

Procedure:
t-butyl methyl ether (290 ml), ethanol (40 ml) and ethyl malonate (70.04 g, 0.437 mol) were added to magnesium ethoxide (50.00 g, 0.437 mol), which was heated to reflux for 30 minutes and returned to room temperature (hereinafter, abbreviated as Solution A). Thionyl chloride (104.04 g, 0.875 mol) was added to 4-nitrophenylacetic acid (66.00 g, 0.364 mol), which was stirred at 70-75° C. for 45 minutes. Thionyl chloride was distilled off under reduced pressure, followed by azeotropy with toluene (66 ml) two times. t-butyl methyl ether (132 ml) was added to the azeotropic residue to dissolve it, which was added dropwise to Solution A. After stirred at 65° C. for 30 minutes, the mixture was cooled to room temperature, and 2N hydrochloric acid (264 ml) was added thereto dropwise under cooling. The organic layer was separated, the aqueous layer was reverse-extracted with t-butyl methyl ether (132 ml), the organic layers were combined, and the solvent was distilled off under reduced pressure. Acetic acid (111 ml), water (74 ml) and concentrated sulfuric acid (14 ml) were added to the concentrated residue, and the mixture was refluxed at an outer temperature of 125° C. for 5 hours while stirring vigorously. After completion of the reaction, the mixture was ice-cooled, returned to room temperature, and t-butyl methyl ether (264 ml) and water (264 ml) were added thereto, followed by extraction. An aqueous saturated sodium hydrogen carbonate solution (264 ml) and ethyl acetate (80 ml) were added to the organic layer to wash the layer, followed by further washing with an aqueous saturated sodium bicarbonate solution (264 ml). After washed with brine (264 ml) twice, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-nitrophenylacetone (48.96 g, 0.273 mol, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[Br:21][CH2:22][CH2:23]CBr>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:23][CH2:22][Br:21])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: BrCCCBr
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(SCCCBr)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
5.85 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. dimethylformamide is treated under nitrogen with 1.14 g. sodium borohydride at not greater than 30°. The mixture is stirred for one hour at 15°-20°, then treated with 12 g. of 1,3-dibromopropane at 20°-25°. After a further 3 hours, water is added and the crude product extracted with chloroform. The dried chloroform solution is passed through a column of silica gel to remove polar material. Pure 1-amino-2-nitro-4-(3-bromopropylthio)benzene is obtained from the eluate.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23](O)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([Cl:31])=[CH:33][CH:34]=4)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccn1
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)Nc2ccc(Cl)cc2)ccn1
Yield: 96.9 %

Procedure:
To solution of 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid (40 mg, 0.098 mmol), 4-chloroaniline (25.12 mg, 0.196 mmol) and DMAP (21.65 mg, 0.17 mmol) in DMF was added PyBOP (92.22 mg, 0.17 mmol), and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-(4-chloro-phenyl)-isonicotinamide as a colorless solid (49 mg, 98% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.O1CCOCC1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=3)[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(-c3cccc(F)c3)cnc2n1C
Temperature: 80 °C
Yield: 65.7 %

Procedure:
To a mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (350 mg) and 1,4-dioxane (5 ml), 3-fluorophenylboronic acid (150 mg), sodium carbonate (320 mg), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (22 mg) were sequentially added. The mixture was heated to 80° C. and stirred with heating for 8 hours. Into the mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 240 mg of 2-(2-ethylsulfanylphenyl)-6-(3-fluorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 61).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([NH:10][C@H:11]([C@@H:28]([OH:30])[CH3:29])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([NH:10][C@@H:11]([C:12]2[O:13][C:16]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=3)=[N:15][N:14]=2)[C@@H:28]([OH:30])[CH3:29])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(S(C)(=O)=O)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(S(C)(=O)=O)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
To a 500 mL, round-bottomed flask equipped with a magnetic stir bar and septum was added N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenyl-amino)-3-hydroxybutanoyl)-4-(methylsulphonyl)benzohydrazide (1.12 mg, 2.4 mmol) followed by a addition of anhydrous THF (250 mL) under an atmosphere of nitrogen. To this was then added tosyl chloride (461 mg, 2.4 mmol) followed by addition of polystyrene bound (2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP) (2.2 mmol/g loading, 3.30 g, 7.3 mmol). This mixture was allowed to stir at room temperature for a period of 16 h. The solids were then filtered off and washed with additional THF (100 mL). The filtrate was then concentrated under reduced pressure to reveal a red solid. This was purified via silica gel chromatography eluted with 80% EtOAc/hexanes to yield product as a white solid (247 mg, 23%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.23 (AA′XX′, J=8.7 Hz, 2H), 8.12 (AA′XX′, J=8.6 Hz, 2H), 7.47 (d, J=8.7 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 5.70 (d, J=8.7 Hz, 1H), 5.17 (dd, J=3.6, 8.5 Hz, 1H), 4.86 (br s, 1H), 4.66 (m, 1H), 3.20 (s, 3H), 2.40 (s, 3H), 1.43 (d, J=6.3 Hz, 3H).
Reaction SMILES: [C:1]1([CH:7]([O:10][CH2:11][CH2:12][O:13][Si](C)(C)C)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>>[NH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:10][CH2:11][CH2:12][OH:13]
Reactant: C[Si](C)(C)OCCOC(C#N)c1ccccc1
Agent: Cl
Product: NCC(OCCO)c1ccccc1
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a 100 ml three-necked flask, 1.0 g (4.01 mmol) of Compound 2 was added and the atmosphere was changed to nitrogen after degassing. The flask was dipped in an ice bath and 30 ml of 1M BH3 solution in THF was slowly added. The resulting mixture was stirred for 30 minutes while cooling the mixture in ice and then at room temperature for 4 hours. After completion of the reaction, the reaction vessel was dipped in an ice bath and aqueous 1N HCl solution was added, thereby making the mixture acidic. After evaporating the solvent under reduced pressure, 20 ml of water was added and aqueous NaOH solution was added to adjust the pH to 10. The mixture was extracted with ethyl acetate and the organic phase was washed with water, followed by drying over anhydrous sodium sulfate to obtain a colorless oily compound (650 mg, Yield: 89.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([I:21])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]([O:34][C:35](=[O:38])[CH2:36]Br)([CH3:33])([CH3:32])[CH3:31].O>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([I:21])[CH:17]=3)[N:12]([CH2:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:38])[CH:11]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Reaction time: 8 h

Procedure:
To a flask containing N-(4-chlorobenzyl)-6-iodo-4-hydoxy-3-quinolinecarboxamide (0.22 g) obtained as described in Preparation No. 4 in DMF (5 mL) is added potassium carbonate (0.21 g) and tert-butylbromoacetate (0.11 mL). After stirring overnight, the reaction is diluted with dichloromethane and partioned against water. The organic phase is washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and dried in vacuo to give 0.26 g of the title compound as a white solid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:28]=[C:29]1[N:33]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:32](=[O:42])[CH2:31][S:30]1.N1CCCCC1>C(O)C>[O:28]=[C:29]1[N:33]([CH2:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C:32](=[O:42])[C:31](=[CH:26][C:24]2[N:25]=[C:21]([NH:20][C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:22][CH:23]=2)[S:30]1
Reactant: O=Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)CN1C(=O)CSC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C(=O)SC(=Cc2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O

Procedure:
Following a procedure similar to that described in Example 17, the desired compound was prepared from 2 g of 2-tritylaminothiazole-4-carbaldehyde, 1.2 g of t-butyl 2,4-dioxothiazolidine-3-acetate, 0.88 g of piperidine and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:9]([CH2:20][CH2:21][C@@H:22]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[F:36])[CH:23]([N+:26]([O-])=O)[CH2:24][OH:25])[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:9]([C:10]([OH:12])=[O:11])[CH2:20][CH2:21][C@@H:22]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[F:36])[CH:23]([CH2:24][OH:25])[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@@H](c1cccc(F)c1F)C(CO)[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@@H](c1cccc(F)c1F)C(N)CO)C(=O)O
Yield: 75.2 %

Procedure:
A solution of benzyl (2R,5S)-2-[bis(tert-butoxycarbonyl)amino]-5-(2,3-difluorophenyl)-7-hydroxy-6-nitroheptanoate (180 mg, 0.49 mmol) and 10% Pd/C (300 mg) in EtOH (5 mL, SureSeal from Aldrich), was hydrogenated at 55 psi for 7 d (200 mg more Pd/C was added after 3 d). The reaction was filtered through Celite with more EtOH and concentrated to afford the title compound (180 mg). MS 489.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[C@@H:9]([OH:13])[CH2:10][NH:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[C:24](Cl)(=[O:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[C@@H:9]([OH:13])[CH2:10][N:11]([C:24](=[O:26])[CH3:25])[CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC[C@H](O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Product: CC(=O)N(C)C[C@H](O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 5 with [(1R,2S)-1-(2,5-difluoro-benzyl)-2-hydroxy-3-methylamino-propyl]-carbamic acid tert-butyl ester (0.107 g, 0.32 mmol) and acetyl chloride (0.020 mL, 0.32 mmol) gives the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH2:14][CH2:15]O)=[CH:6][C:7]3[CH2:11][O:10][C:9](=[O:12])[C:8]=3[CH:13]=2)[CH2:3][CH2:2]1.CS(Cl)(=O)=O.[Cl-].[NH4+].C1CCN2C(=NCCC2)CC1>O.ClCCl>[CH:1]1([C:4]2[C:5]([CH:14]=[CH2:15])=[CH:6][C:7]3[CH2:11][O:10][C:9](=[O:12])[C:8]=3[CH:13]=2)[CH2:3][CH2:2]1
Reactant: O=C1OCc2cc(CCO)c(C3CC3)cc21
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: ClCCl
Product: C=Cc1cc2c(cc1C1CC1)C(=O)OC2
Reaction time: 0.33 h

Procedure:
To a 100 ml flask containing a stir bar was added compound 6-cyclopropyl-5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one, (0.5 g, 2.29 mmol), TEA (20 mL) followed by addition of dichloromethane (25 mL). The flask was placed in a cool bath of ° C., and slowly treated with methanesulfonyl chloride (6.5 mL, 83 mmol). The resulting mixture was then stirred for 20 min. TLC (hexanes/EtOAc=1/1) indicated completion of the reaction. The mixture was poured into saturated ammonium chloride and extracted with DCM. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried (Na2SO4) and concentrated in vacuo. The residue (LC/MS: [(M+1)]+=297; tR=1.01 min) was dissolved in dichloromethane (25 mL) and treated with DBU (0.7 mL, 4.72 mmol) and stirred for 2 h. TLC monitoring showed conversion to the olefin. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organics were washed with 1N HCl, saturated sodium bicarbonate solution, and brine, then dried (Na2SO4) and concentrated in vacuo. The material was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[C@@H:15]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:32][C:24]1[CH:23]=[C:22]([C@@H:15]([CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:14]([NH:13][C:10]2[CH:11]=[CH:12][NH:8][N:9]=2)=[O:33])[CH:27]=[CH:26][C:25]=1[S:28]([CH3:31])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cc[nH]n2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
3-[2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazole-1-carboxylic acid tert-butyl ester (1.72 g, 3.47 mmol) was dissolved in methylene chloride (12 mL) and trifluoroacetic acid (4 mL) was added. The solution was stirred at 25° C. for 4 h. The mixture was concentrated in vacuo and the resulting oil was dissolved in ethyl acetate (25 mL), washed with saturated aqueous sodium bicarbonate solution (2×15 mL), saturated aqueous brine solution (2×15 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to produce a yellow oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-pyrazol-3-yl)-propionamide as a white foam (802 mg, 58%) ESI-LRMS m/e calcd for C18H22ClN3O3S [M+] 395.1, found 396.0 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.00-1.19 (m, 2H, CH2), 1.34-1.91 (m, 8H, 4×CH2), 2.08-2.29 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.65 (t, J=7.6 Hz, 1 H, CH), 6.54 (d, 1H, J=1.7, Ar), 7.39 (m, 2H, Ar), 7.54 (d, Jm=1.3 Hz, 1H, Ar), 7.94 (d, Jo=8.2 Hz, 1H, Ar), 9.26 (s, 1H, NH).
Reaction SMILES: C([C@]1(C2C=CC(F)=CC=2)OC(=O)N([C@H](C(C)(C)C)C)CC1)C=C.[CH3:24][C:25]([CH3:46])([CH3:45])[C@@H:26]([N:28]1[CH2:33][CH2:32][C@:31]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)([CH2:34][CH2:35][OH:36])[O:30][C:29]1=[O:44])[CH3:27]>>[CH3:45][C:25]([CH3:24])([CH3:46])[C@@H:26]([N:28]1[CH2:33][CH2:32][C:31]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)([CH2:34][CH2:35][OH:36])[O:30][C:29]1=[O:44])[CH3:27]
Reactant: C[C@H](N1CC[C@@](CCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Agent: C=CC[C@@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Product: C[C@H](N1CCC(CCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C

Procedure:
(S)-6-allyl-3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one [Isomer 2] (500 mg, 1.57 mmol) was converted to (R)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one [Isomer 2] (300 mg, 59%) following a procedure analogous to that described immediately above. LC-MS Method 1 tR=1.112, min, m/z=324.2; 1H NMR (CDCl3): 0.85-0.99 (m, 12H), 2.09-2.18 (m, 1H), 2.19-2.34 (m, 3H), 2.73-2.84 (m, 1H), 3.12-3.28 (m, 1H), 3.48-3.57 (m, 1H), 3.69-3.76 (m, 1H), 4.26-4.35 (m, 1H), 7.02-7.08 (m, 2H), 7.24-7.32 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH:7]=[C:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:17]([O:16][C:14]([CH:11]1[CH2:12][CH2:13][C:8](=[CH:7][C:6]([OH:19])=[O:5])[CH2:9][CH2:10]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCC(=CC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCC(=CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.6 %

Procedure:
To a solution of ethyl 4-(2-tert-butoxy-2-oxoethylidene)cyclohexanecarboxylate (5.3 g, 21 mmol) in CH2Cl2 (30 ml) was added TFA (30 ml). The solution was stirred at room temperature overnight. The solution was concentrated in vacuo to afford 6 g of product as colorless oil, which was used directly for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32]>ClCCl>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([NH:1][C:2]2[CH:23]=[CH:22][C:5]3[N:6]([CH:9]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=3[CH:3]=2)=[O:39])=[CH:41][CH:42]=1)([O-:33])=[O:32]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(N)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (100 mg, 324 μmol) in dichloromethane (6 mL) was added triethylamine (100 μL, 710 μmol) and 4-nitrobenzoyl chloride (132 mg, 712 μmol). The solution was stirred at room temperature for 96 hours, and was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=4.92 min, MH+ 459].
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].S(Cl)(Cl)=O.[NH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1>>[NH:19]1[C:18]([NH:17][C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:9]=2)=[O:12])=[N:22][N:21]=[N:20]1
Reactant: Nc1nnn[nH]1
Reactant: CCCc1cccc(C(=O)O)n1
Solvent: O=S(Cl)Cl
Product: CCCc1cccc(C(=O)Nc2nnn[nH]2)n1
Yield: 9.9 %

Procedure:
1.9 g of 6-n-propyl-2-pyridinecarboxylic acid, 12 ml of thionyl chloride and 0.96 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and water, whereby 0.26 g of N-(5-tetrazolyl)-6-n-propyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26].O1CCOCC1>CC(O)C.Cl.O1CCOCC1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Temperature: 80 °C
Yield: 94.8 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (407.5 g, 1.251 mol) was dissolved in 2-propanol (5.7 L). 3-Chloro-4-fluoroaniline (191.2 g, 1.313 mol) and a 4 M solution of gaseous hydrogen chloride in dioxane (17.4 mL, 63 mmol) were added. The mixture was heated to 80° C. for 3 days. The thick suspension was then diluted with additional 2-propanol (1 L), and further 4 M hydrogen chloride in dioxane (695 mL, 2.5 mol) was added. The mixture was again heated to 80° C. for 3 h. The solvent was then removed in vacuo, and the residue was treated with 1 M aqueous sodium hydroxide solution (12 L). The precipitate was collected by suction filtration and washed with water. The product was dried for 2 days at 50° C., then triturated with tert-butyl methyl ether and collected by suction filtration to yield 397 g (95%) of the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][N:16]1[C:20]2=[N:21][CH:22]=[C:23]([CH2:25][NH2:26])[CH:24]=[C:19]2[CH:18]=[CH:17]1>>[CH3:15][N:16]1[C:20]2=[N:21][CH:22]=[C:23]([CH2:25][NH:26][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[CH:24]=[C:19]2[CH:18]=[CH:17]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1ccc2cc(CN)cnc21
Product: COC(=O)c1ccc(S(=O)(=O)NCc2cnc3c(ccn3C)c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanamine (step-1 of Example 35).