Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC[O:5][CH:6]1[CH2:24][CH:23]2[N:8]([C:9](=[O:44])[N:10](CC3C=CC(OC)=CC=3)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH:18]3[C:20]([C:26]([NH:28][S:29]([CH:32]4[CH2:34][CH2:33]4)(=[O:31])=[O:30])=[O:27])([NH:21][C:22]2=[O:25])[CH2:19]3)[CH2:7]1)C.Cl.C(=O)([O-])O.[Na+]>C1COCC1.CO>[OH:5][CH:6]1[CH2:24][CH:23]2[N:8]([C:9](=[O:44])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH:18]3[C:20]([C:26]([NH:28][S:29]([CH:32]4[CH2:33][CH2:34]4)(=[O:31])=[O:30])=[O:27])([NH:21][C:22]2=[O:25])[CH2:19]3)[CH2:7]1
Reactant: CCOCOC1CC2C(=O)NC3(C(=O)NS(=O)(=O)C4CC4)CC3C=CCCCCCN(Cc3ccc(OC)cc3)C(=O)N2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NC2(C(=O)NS(=O)(=O)C3CC3)CC2C=CCCCCCNC(=O)N2CC(O)CC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A solution of the acetal 21j (0.038 g, 0.06 mmol) in 1:1:1 THF-methanol-2 M aq. hydrochloric acid (1.5 ml) was stirred at rt for 30 min, then additional conc. hydrochloric acid (0.1 ml) was added and then stirred at rt overnight. The reaction mixture was then neutralized using aq. saturated sodium hydrogen carbonate, then concentrated onto silica. Flash chromatography of the residue using 9:1 ethyl acetate methanol gave a colorless foam (0.020 g, 73%). LR-MS: Calcd for C20H29N4O6S: 453. Found: 453 [M−H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:20]=2)=[O:17])[CH:11]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:10][CH:9]1[S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:41])=[O:40].[OH-].[K+]>O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:30])[CH2:14][NH:15][C:16](=[O:17])[NH:18][C:19]2[CH:20]=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:11]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:10][CH:9]1[S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:41])=[O:40]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)N3CCOCC3)CC(S(=O)(=O)c3ccccc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)N3CCOCC3)CC(S(=O)(=O)c3ccccc3)C2c2ccccc2F)c1
Yield: 71.5 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 3.5 g of (2RS,4SR,5RS)-5-(2-fluorophenyl)-1-{2-[3-(3-(methoxycarbonylmethyl)phenyl)ureido]acetyl}-2-morpholinocarbonyl-4-(phenylsulphonyl)pyrrolidine and 0.3 g of potassium hydroxide in a mixture of 30 cm3 of distilled water and 50 cm3 of methanol. After treatment, there are obtained 2.45 g of (2RS,4SR,5RS)-3-{3-[2-(5-(2-fluorophenyl)-2-morpholinocarbonyl-4-phenylsulphonyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetic acid [Rf =0.64; eluent: methylene chloride/methanol (80/20)].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:12]([C:13]#[N:14])=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=2)=[CH:3][CH:2]=1.N1C=CC(NC2N(C[O:36]CC[Si](C)(C)C)N=CC=2C#N)=CC=1.[OH-].[Na+].OO.Cl>CS(C)=O.CCO.CO>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:12]([C:13]([NH2:14])=[O:36])=[CH:11][NH:10][N:9]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1ncc(C#N)c1Nc1ccncc1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(Nc2ccncc2)n1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: CO
Product: NC(=O)c1c[nH]nc1Nc1ccncc1
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
To a solution containing a mixture of 3-(pyridin-4-ylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile and 5-(pyridin-4-ylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (150 mg, 0.5 mmol) in DMSO (1.2 mL) and EtOH (1.2 mL) was added 5M aqueous NaOH (0.7 mL, 3.3 mmol). The mixture was heated to 55° C., followed by the dropwise addition of 30% H2O2 (0.7 mL, 7.1 mmol). After 10 minutes, additional 30% H2O2 (0.30 mL, 3.4 mmol) was added dropwise. The mixture was maintained for 30 minutes before it was allowed to cool to ambient temperature. To the crude reaction mixture was added MeOH (1 mL) and 6N aqueous HCl (2 mL). The resulting mixture was heated at 55° C. for 1.5 hours. Additional 6N aqueous HCl (1 mL) was added and the mixture continued stirring for another 1 hour. The mixture was cooled to ambient temperature and carefully neutralized with 5N aqueous NaOH until pH 6-7. The mixture was then concentrated in vacuo to remove most of the solvent. To the slurry-like residue was added MeOH (20 mL), and the resulting mixture was sonicated for 5 minutes. The mixture was filtered to remove insoluble precipitate and the filtrate was concentrated in vacuo to afford crude residue containing the title compound, Intermediate #34-1, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:33])=[CH:29][CH:30]=1)#[N:24]
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: N#Cc1ccc(N=C=O)cc1
Product: N#Cc1ccc(NC(=O)NCCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-cyanophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[CH:24]([Si:27]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[N:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1)([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:30]3[CH:31]=[CH:32][N:28]([Si:27]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:24]([CH3:25])[CH3:26])[CH:29]=3)=[CH:17][C:9]1=2
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Yield: 80 %

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (111 mg) was reacted with 1-(triisopropylsilyl)-1H-pyrrole-3-boronic acid as in General Procedure 4B to give the title compound as an off-white solid (80% yield). LCMS: m/z=349.34 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.08 (18H, d, J=7.6 Hz), 1.41 (3H, m), 3.49 (2H, m), 3.65 (2H, m), 4.58 (2H, s), 4.92 (1H, bs), 6.37 (1H, m), 6.54 (1H, d, J=1.8 Hz), 6.72 (1H, m), 6.76 (1H, m), 7.32 (1H, d, J=8.6 Hz), 7.54 (1H, s), 7.61 (1H, d, J=8.6 Hz), 7.70 (1H, m).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])=[CH:12][CH:11]=1)=[O:8])C.Cl>CO.O>[F:23][C:18]([F:22])([CH:19]([F:20])[F:21])[CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([N:9]2[CH:4]=[CH:5][NH:6][C:7]2=[O:8])=[CH:15][CH:14]=1
Reactant: CCOC(CNC(=O)Nc1ccc(OCC(F)(F)C(F)F)cc1)OCC
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.1 %

Procedure:
N-(2,2-Diethoxyethyl)-N'-[4-(2,2,3,3-tetrafluoropropoxy)phenyl] urea (37.5 g) was dissolved in a mixture of 560 ml of methanol and 280 ml of water. To the solution was added 300 ml of an aqueous solution containing 0.48M of hydrochloric acid and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the precipitated crystals were washed with a mixture of water-methanol (5:1) to give 22.8 g of 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-(1H,3H)-imidazolone as colorless powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CC1C=CC(O)=CC=1>C(O)CCC>[NH2:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: NCC(O)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CCCCO
Product: NC[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 28 %

Procedure:
n-Butanol (20 ml) was added with the concentrate of the reaction products obtained in the same manner as in Example 296 which contained 1.67 g (7.50 mmol) of 2-amino-1-phenylethanol, and 2.11 g (7.50 mmol) of Boc-L-Tyr. The resultant mixture was heated for dissolution, cooled to room temperature and left over night to precipitate crystals. The crystals were isolated by filtration to afford 1.06 g (2.10 mmol) of (R)-2-amino-1-phenylethanol.Boc-L-Tyr salt. The yield of the compound based on (R)-2-amino-1-phenylethanol in the concentrate was 56.0%.
Reaction SMILES: CC1C(C2N3C4C=CN(COCC[Si](C)(C)C)C=4N=CC3=[N:9]C=2)CC(N)C1.Cl[S:29]([NH:32][C:33](=[O:38])[O:34][CH2:35][CH2:36]Cl)(=[O:31])=[O:30].CO>C(Cl)Cl>[O:38]=[C:33]1[N:32]([S:29]([NH2:9])(=[O:31])=[O:30])[CH2:36][CH2:35][O:34]1
Reactant: CC1CC(N)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Reactant: O=C(NS(=O)(=O)Cl)OCCCl
Solvent: CO
Solvent: ClCCl
Product: NS(=O)(=O)N1CCOC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.4 %

Procedure:
To a solution of 3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (0.50 g, 1.3 mmol) and 2-chloroethyl chlorosulfonylcarbamate (0.288 g, 1.297 mmol, prepared as detailed in Biorg. Med. Chem. Lett, 2006 16, 3367-3370) in DCM (16 mL) was added TEA (0.542 mL, 3.89 mmol) drop-wise. The mixture was stirred at ambient temperature for about 2 h. The solvent was removed under reduced pressure and the residue was partitioned between water and EtOAc (30 mL each). The organic layer was washed with brine (20 mL), dried over anhydrous MgSO4, filtered and concd under reduced pressure. The residue was purified by silica gel chromatography (0% DCM for 5 min, then to 6% MeOH in DCM over the next 30 min.) to yield N-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide (0.24 g, 35% yield) as an off-white solid. LC/MS (Table 1, Method a) Rt=2.42 min; MS m/z 535 (M+H)+.
Reaction SMILES: CC1C=CC(N2CCN(CCC=C[C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]4)CC2)=CC=1>O1CCOCC1.[Pd]>[NH:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:27][CH:26]=2)[CH2:21][CH2:22][C:23]1=[O:28]
Reactant: Cc1ccc(N2CCN(CCC=Cc3ccc4c(c3)CCC(=O)N4)CC2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1CCc2ccccc2N1

Procedure:
1.0 Gram of 6-{4-[4-(4-Methylphenyl)-1-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyril and 0.2 g of palladium black were suspended in 100 ml of dioxane and the mixture was catalytically hydrogenated under an ordinary pressure at an ordinary temperature. The catalyst was removed by filtration and the filtrate was dried under a reduced pressure. The residue was recrystallized from isopropanol-diisopropyl ether to obtain 6-{4-[4-methylphenyl)piperazinyl]-butyl}-3,4-dihydrocarbostyril in colorless prism-like crystals. Yield: 0.7 g. Melting point: 160°-161° C.
Reaction SMILES: Cl.C1(NCC2CCCCC2N)CC1.[CH:14]1([N:17]2[CH2:26][CH:25]3[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]3)[N:19]3[C:27](=[O:56])[C:28]4[N:29]([CH:31]=[C:32]([C:44]([NH:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=5[F:55])=[O:45])[C:33](=[O:43])[C:34]=4[O:35]CC4C=CC=CC=4)[CH2:30][CH:18]23)[CH2:16][CH2:15]1>>[CH:14]1([N:17]2[CH2:26][CH:25]3[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]3)[N:19]3[C:27](=[O:56])[C:28]4[N:29]([CH:31]=[C:32]([C:44]([NH:46][CH2:47][C:48]5[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=5[F:55])=[O:45])[C:33](=[O:43])[C:34]=4[OH:35])[CH2:30][CH:18]23)[CH2:16][CH2:15]1
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C3CCCCC3CN(C3CC3)C1C2
Agent: Cl
Agent: NC1CCCCC1CNC1CC1
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C3CCCCC3CN(C3CC3)C1C2

Procedure:
In a manner similar to that described in example Z-35, from 16a (45 mg, 0.0957 mmol) and racemic-(1S,2S)-2-[(cyclopropylamino)methyl]cyclohexanamine hydrochloride (102 mg, 0.425 mmol) was prepared racemic-(4aS,6aS,14aS)-6-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide as a white solid after silica gel chromatography (1-12% methanol/dichloromethane gradient elution). This material was deprotected in a second step similar to the procedure described in example Z-37. Thus, from racemic-(4aS,6aS,14aS)-6-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (56 mg, 0.0949 mmol) the title compound was prepared as a white solid (41 mg, 81%). 1H NMR (CDCl3) 12.10 (br s, <1H), 10.45 (m, 1H), 8.27 (s, 1H), 7.33 (m, 1H), 6.88 (m, 2H), 4.77 (m, 1H), 4.61-4.49 (m, 4H), 4.33 (m, 1H), 2.94 (m, 1H), 2.79 (m, 1H), 2.17 (m, 1H), 1.86-0.86 (m, 10H), 0.658 (m, 1H), 0.499-0.32 (m, 2H); ES+ MS: 499 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[F:12])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1ccccc1CBr
Reactant: Fc1cnc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.1 g (about 39.65 mmol) of the compound from Example 6A were initially charged in DMF (217 ml), and 8.25 g (43.62 mmol) of 2-fluorobenzyl bromide and 14.21 g (43.62 mmol) of caesium carbonate were then added. The mixture was stirred at RT for two hours. The reaction mixture was then added to water (1.17 l) and extracted twice with ethyl acetate (502 ml). The collected organic phases were washed with saturated aqueous sodium chloride solution (335 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (mobile phase:petroleum ether/ethyl acetate 97:3) and the product fractions were concentrated. This gave 9.0 g (61% of theory) of the title compound as a solid. The solid was taken up in ethyl acetate and washed with 10% strength aqueous sodium thiosulphate solution and then with saturated aqueous sodium chloride solution, dried and concentrated.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].OCCCCCCCCCC(O)=O.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[CH2:10]([OH:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: OCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)CCCCCCCCCO
Agent: O=C1CCC(=O)N1O
Product: CCCCCCCCCCO

Procedure:
Coupling of glycylserylglycylaspartylyaline with 1,10-decanediol. The protected peptide is reacted with 10-hydroxydecanoic acid (Aldrich) in the presence of dicyclohexylcarbodiimide (DCC) (Aldrich) and N-hydroxysuccinimide (Aldrich) according to Bergeron et al. (1981) J. Org. Chem. 46:4524, until the complete consumption of the peptide starting material is confirmed by thin layer chromatography. Flash column purification gives 10-(peptidyloxy) decanol as product, through formation of an amide linkage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:27](I)[CH3:28]>C1COCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:13]([CH2:27][CH3:28])[C:14]([OH:16])=[O:15])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C(=O)O)c1cc(OC)c(OC)c(OC)c1
Temperature: -25 °C
Reaction time: 8 h

Procedure:
A 20 L reactor was purged with nitrogen and 3,4,5-trimethoxyphenylacetic acid (1000 g, 4.42 moles) added followed by THF (4000 mL). The suspension was stirred until all acid was dissolved. The resulting solution was then cooled to −25° C. and a 1.0 M THF solution of sodium bis(trimethylsilyl)amide added via cannula over a period of 1 hour in 2 batches of 500 mL each (10.0 moles total) and the mixture stirred for a further 30 minutes. The temperature of the reaction mixture was not allowed to rise above −15° C. during the course of addition. The resulting cream colored colloidal solution was treated at −25° C. with ethyl iodide (424 mL, 5.30 moles) via cannula over a 1 hour period. (A heat kick of 5° C. may be observed for the initial addition of 50 mL of ethyl iodide. If this occurs, the temperature was adjusted to −25° C. and ethyl iodide addition continued.) The solution was allowed to stir at −25° C. for 2 hours as the colloidal solution slowly changes to a homogeneous brown solution. The brown solution was then allowed to warm to room temperature and stirred overnight. After this time the reaction mixture was quenched, with constant stirring, with water (1500 mL) and allowed to stir for a further 1.5 hours. The organic and aqueous layers were allowed to then separate and the organic layer removed and extracted with water (2×1000 mL). All aqueous solutions were combined and acidified to pH 2 by the addition of a 2N HCl solution (3500 mL) and the solution extracted in batches of ˜400 mL with an roughly equivalent volume of EtOAc (6000 mL total). The combined organic extracts were washed with brine (2×1500 mL) and reduced to a volume of 2000 mL on a rotary evaporator at which time a brown crystalline solid began to precipitate. The solution was allowed to cool and the solid material was filtered, washed with a 1:1 EtOAc:hexanes solution, and the cream colored solids left in a vacuum oven at 40° C. overnight for a first crop of product, AP14900, (582.8 g). The filtrate was further evaporated and two additional crops (166.2 and 158.1 g) were obtained (907.05 g total, 80.6%).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
2-Chloro-3-methyl-5-nitropyridine (67.0 g, 0.389 mol) was dissolved in anhydrous methanol (600 ml) and 0.5 M NaOMe in MeOH (800 mL) was added slowly to the mixture (temperature rises to ca. 30° C.). The reaction mixture was stirred at room temperature overnight. The solution was concentrated and the residue was transferred to a separatory funnel containing water (2 L). The aqueous layer was extracted with CH2Cl2 (2×2 L). The combined organic layers were dried over MgSO4, filtered and concentrated to give 2-methoxy-3-methyl-5-nitropyridine (63.0 g, 97% yield) as a white solid which was dried under vacuum: 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J=2.0 Hz, 1H), 8.16 (s, 1H), 4.06 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.83, 141.91, 139.37, 132.92, 121.77, 54.83, 15.84; An analytical sample was recrystallized from hexane to give white needles, mp 95-96. 5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:18]1CCOCC1.C(#N)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=[O:18])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1COCCO1
Reactant: Clc1ccc(C2CCCc3sccc32)cc1Cl
Agent: [Cu+2]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccsc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
4-(3,4-Dichlorophenyl)-4,5,6,7-tetrahydro-1-benzothiophene (3.25 g, 11.5 mmol), 1,4-dioxane (93 mL), acetonitrile (93 mL), water (100 mL), copper(II) sulfate pentahydrate (11.46 g, 45.90 mmol), and potassium persulfate (12.41 g, 45.90 mmol) were combined in a round bottomed flask equipped with a stirbar. The mixture was stirred overnight at 90° C. under an atmosphere of nitrogen during which time the blue color of the reaction disappeared to leave a light brown solution with some light greenish solid. The reaction was cooled to rt then additional copper(II) sulfate pentahydrate (11.46 g, 45.90 mmol) and potassium persulfate (12.41 g, 45.91 mmol) were added and the reaction was stirred at 90° C. under an atmosphere of nitrogen for an additional 5 hours. The reaction was cooled to rt and quenched with a solution of saturated sodium bisulfite. Saturated NaHCO3 solution was added until the mixture was basic, then ethyl acetate was added, the biphasic mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was extracted with additional ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to leave crude product as darkish orange oil. The residue was purified using column chromatography on silica gel (330 g RediSep column, gradient 0% EA in hexane to 25% EA in hexane over 30 minutes) give the product 1.29 g (38% yield) product as a light tan solid. LCMS: (FA) ES+ 297, 299. 1H NMR (400 MHz, DMSO) δ 8.00-7.93 (d, J=5.0 Hz, 1H), 7.64-7.57 (d, J=8.3 Hz, 1H), 7.55-7.49 (d, J=2.1 Hz, 1H), 7.22-7.14 (dd, J=8.3, 2.1 Hz, 1H), 6.72-6.65 (d, J=5.0 Hz, 1H), 4.41-4.32 (dd, J=9.2, 4.8 Hz, 1H), 2.72-2.59 (m, 1H), 2.57-2.51 (m, 1H), 2.39-2.19 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[C:33]([CH2:39][NH:40]C(OC(C)(C)C)=O)[CH:32]=2)[C:17]2[CH:22]=[C:21]([CH2:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH2:27][OH:28])[C:18]=2[F:29])=[N:11]1)=[O:4].CO.C1COCC1.[OH-].[Na+]>C(O)(=O)C>[CH2:23]([C:21]1[CH:20]=[C:19]([O:25][CH2:26][CH2:27][OH:28])[C:18]([F:29])=[C:17]([CH:16]([NH:30][C:31]2[CH:32]=[C:33]3[C:34](=[CH:35][CH:36]=2)[C:37](=[NH:38])[NH:40][CH2:39]3)[C:12]2[NH:13][C:14](=[O:15])[N:10]([C:9]3[CH:8]=[CH:7][S:6][C:5]=3[C:3]([OH:2])=[O:4])[N:11]=2)[CH:22]=1)[CH3:24]
Reactant: CCc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ccsc3C(=O)OC)c(=O)[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(OCCO)c(F)c(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)c1
Yield: 35 %

Procedure:
A mixture of 3-(3-{[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylamino]-[5-ethyl-2-fluoro-3-(2-hydroxyethoxy)phenyl]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid methyl ester (31 mg), a methanol:THF (2:1) mixed solvent (1.5 mL) and a 5N sodium hydroxide aqueous solution (0.1 mL) was heated for 14 hours at 65° C. under a nitrogen atmosphere. Acetic acid was added to the mixture, which was then purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (9.0 mg).