Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:38])[CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[C:28]2[C:32]([NH:33][CH2:34][CH2:35][C:36]#[N:37])=[N:31][O:30][N:29]=2)=[CH:13][CH:12]=1)C1C=CC=CC=1.C(OCC)(=O)C.CO>C(OCC)(=O)C.CO.[Pd]>[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:38])[CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[C:28]2[C:32]([NH:33][CH2:34][CH2:35][C:36]#[N:37])=[N:31][O:30][N:29]=2)=[CH:15][CH:16]=1
Reactant: N#CCCNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CCCNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
To a suspension of 6.4 g of [4-(2-{2-[4-(2-cyano-ethylamino)-furazan-3-yl]-benzoimidazol-1-yl}-acetyl)-phenyl]-carbamic acid benzyl ester (12.3 mmol, 1 eq) in a mixture of 700 ml of ethyl acetate and 500 ml of methanol are added 1.3 g of 10% palladium on carbon. The reaction mixture is stirred for 3 h under hydrogen atmosphere (1 atm) at room temperature. Then it is filtered through celite and concentrated under reduced pressure to give the crude product as a light yellow solid, which is suspended in 60 ml of a 7/5 ethyl acetate/methanol mixture. Filtration provides 3.5 g of the desired product as off-white solid. The filtrate is concentrated and the residue is treated as above with 5 ml of the 7/5 ethyl acetate/methanol mixture. Filtration gives 0.45 g of a second crop of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[S:18]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19]1.C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][S:23]([C:20]4[CH:21]=[CH:22][S:18][CH:19]=4)(=[O:25])=[O:24])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reactant: O=S(=O)(Cl)c1ccsc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2-c1cccc(NS(=O)(=O)c2ccsc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.6 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (39 mg, 1.0 eq, 0.17 mmol), 3-thiophenesulphonylchloride (31 mg, 1.0 eq, 0.17 mmol) and diisopropylethylamine (30 μl, 1.0 eq, 0.17 mmol) were added to DMF (1 ml) and the mixture was stirred for 18 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant residue was absorbed onto silica and purified by column chromatography using DCM/MeOH (96:4) as eluent to yield the title compound as a white solid (13 mg, 0.03 mmol, 20%). LCMS: [M+H]+=373, Rt=1.60 min, 100% purity.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]CC)=O)=[CH:8][CH:7]=1>CO>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:2][NH2:3])=[O:15])=[CH:8][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(CC(=O)NN)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrazine hydrate (4.7 cm3) was added dropwise to ethyl (4-methoxyphenyl)acetate (3.73 g) and then methanol (20 cm3) was added to form a homogeneous reaction mixture. This mixture was stirred for 18 hours at ambient temperature during which time a white precipitate formed. The precipitate was isolated by filtration and washed with methanol and water, then air-dried to give (4-methoxyphenyl)acetic acid hydrazide (2 g). M+ =180; 1H NMR: δ 3.50(2H,s); 3.80(3H,s); 3.85(2H,br s); 6.70(1H,br s); 6.90(2H,d); 7.20(2H,d); (solid).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:10]([P:13](Cl)(Cl)=[O:14])([CH3:12])[CH3:11]>CC1CCCCC1>[CH:10]([P:13]1(=[O:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][N:2]1[CH3:1])([CH3:12])[CH3:11]
Reactant: CNCc1ccccc1
Reactant: CC(C)P(=O)(Cl)Cl
Solvent: CC1CCCCC1
Product: CC(C)P1(=O)c2ccccc2CN1C

Procedure:
The procedure of Example 30 was employed utilizing N-methyl-N-benzylamine and isopropyl phosphonic dichloride. The reaction of the dilithio compound and the isopropyl phosphonic dichloride was conducted at -72° C. The crude product produced as a result of the chromatographic separation was slurried in methylcyclohexane to yield a pale solid. The solid was recrystallized from diethyl ether and petroleum ether to yield 1-isopropyl-2-methyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as a crystalline precipitate. A second crop was obtained to give a total yield of 2.35 g (19% yield) of 1-isopropyl-2-methyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide having a melting point of 72°-74° C. and the following analysis:
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:20][C:18]1[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][CH3:30])[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:19]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Reactant: COc1ccccc1B(O)O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate E) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 7.13 min (HPLC 2); ESI-MS: tR=1.20 min, [M+H]+522/524/526 (LC-MS 1); TLC: Rf=0.35 (95:5 CH2Cl2/MeOH); 1H-NMR (d6-DMSO, 600 MHz): 7.91 (m, 1H), 7.88 (m, 1H), 7.44 (m, 1H), 7.43 (m, 2H), 7.33 (m, 2H), 7.25 (m, 1H), 7.11 (m, 1H), 7.02 (m, 1H), 6.34 (s, 1H), 6.21 (s, 1H), 3.92 (m, 1H), 3.74 (s, 3H), 3.44 (s, 3H), 1.33 (m, 3H), 0.39 (m, 3H).
Reaction SMILES: [N:1]#[C:2]Br.Cl.[CH3:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:2]#[N:1])[CH2:25][CH2:24]3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)(=[O:8])=[O:7]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)cc1
Reactant: N#CBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C#N)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Cyanogen bromide (3.0M in CH2Cl2, 0.1 mL, 0.3 mmol) was added dropwise to a mixture of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (prepared as in Example 2, Step 1, 100 mg, 0.3 mmol) and triethylamine (0.083 mL, 0.6 mmol) in CH2Cl2 (5 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 h and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 5% MeOH/CH2Cl2 to give 60 mg (54%) of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarbonitrile as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H, J=8.4 Hz), 7.72 (d, 2H, J=8.6 Hz), 7.55 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.6 Hz), 3.87 (d, 2H, J=6.2 Hz), 3.58-3.47 (m, 2H), 3.08 (s, 3H), 1.96-1.86 (m, 2H), 1.53 (bs, 5H); LRMS (ESI), m/z 393 (M+Na).
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](Cl)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([Si](C)(C)[O:34][NH2:35])(C)(C)C.[CH2:38](N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:34][NH:35][C:26]([CH:25]([CH3:38])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:2]([CH3:1])[C:3](=[O:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:13]=2)=[CH:19][CH:20]=1)=[O:27]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: CCN(CC)CC
Reactant: CN(Cc1cccc(-c2ccc(CCC(=O)Cl)cc2)c1)C(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)NO

Procedure:
By reacting a solution of 669 mg (1.65 mmol) of 3-(3′-{[methyl-(1-phenylmethanoyl)amino]-methyl}biphenyl-4-yl)propionyl chloride in 6 ml of THF with 243 mg (1.65 mmol) of O-(tert-butyldimethyl-silyl) hydroxylamine in the presence of 250 μl (1.8 mmol) of triethylamine, followed by deprotection with 530 μl of tetrabutylammonium fluoride solution (1N in THF), and after purification by chromatography on a column of silica, 350 mg (42%) of N-[4′-(2-hydroxy-carbamoylpropyl)biphenyl-3-ylmethyl]-N-methylbenzamide, with a melting point of 65-66° C., are obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH:19]1([SH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:19]1([S:25][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: SC1CCCCC1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CSC3CCCCC3)c(C)o2)cc1
Yield: 57.5 %

Procedure:
A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (6.0 g, 22.64 mmol, 1.00 equiv), cyclohexanethiol (3.9 g, 33.62 mmol, 1.50 equiv) and cesium carbonate (11.1 g, 34.05 mmol, 1.50 equiv) in N,N-dimethylformamide (60 mL) was stirred under nitrogen overnight at 50° C. The reaction was then quenched by the addition of 30 mL of water. The precipitate was collected by filtration and washed with 3×10 mL of hexane to give 4.5 g (58%) of methyl 4-(4-(cyclohexylthiomethyl)-5-methyloxazol-2-yl)benzoate as a white solid after drying under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:11](=[O:42])[CH:12]([CH:15]([OH:41])[C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:6]1=[C:5]2[CH3:43]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:11](=[O:42])[CH:12]([CH:15]([OH:41])[C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:6]1=[C:5]2[CH3:43]
Reactant: Cc1c2n(c3ccc(Cl)cc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]cnc1C(O)C1CCc2c(C)c3cc(Cl)ccc3n2C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
A solution of the mixture of two diastereoisomers of 2-chloro-8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (0.50 g) in acetic acid-water (5:2, 7 ml) was stirred at 60° C. for 2 hours. After evaporation of the solvent, the residue was partitioned between water and chloroform and neutralized with an aqueous sodium hydroxide, to give precipitates. The organic layer and the precipitates were combined and chromatographed on silica gel eluted by chloroform-methanol (0-10% V/V), to give two isomers of 2-chloro-8,9-dihydro-10-methyl-7[(hydroxy)(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.037 g), respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([S:20]([NH2:23])(=[O:22])=[O:21])[C:16]([OH:19])([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]1([N:30]=[C:31]=S)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].BrN1C(=O)CCC1=O>CN1C(=O)CCC1.C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:16]([CH3:18])([CH3:17])[O:19][C:31]([NH:30][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:23][S:20]2(=[O:22])=[O:21])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(c1cccc(OCc2ccccc2)c1)S(N)(=O)=O
Reactant: S=C=NC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(OCc2ccccc2)c1
Reaction time: 0.75 h

Procedure:
At room temperature, a solution of 1.00 g of 1-(3-benzyloxyphenyl)-2-hydroxy-2-methylpropane-1-sulfonamide and 0.45 ml of cyclohexyl isothiocyanate in 6.5 ml of NMP was admixed with 1.49 ml of a 2 N solution of sodium bis(trimethylsilyl)amide in THF. After stirring for 45 minutes, the conversion was checked by means of LCMS. Since the reaction was still incomplete, an additional 0.22 ml cyclohexyl isothiocyanate and 0.74 ml of a 2 N solution of sodium bis(trimethylsilyl)amide in THF were added. After stirring for 20 minutes, 0.53 g of N-bromosuccinimide was added and the mixture was stirred at room temperature for a further hour. The reaction solution was admixed with 150 ml of water and extracted twice with 100 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC, and the product-containing fractions were freed of the organic solvent under reduced pressure. The aqueous residue was lyophilized. This gave the product (587 mg) with a molecular weight of 442.6 g/mol (C24H30N2O4S); MS (ESI): m/e=443 (M+H+).
Reaction SMILES: OC1CCNCC1.BrC1SC(C=O)=CC=1.[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[S:27][C:26]([CH:28]=O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:35][C:36]#[N:37]>>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[C:35](=[CH:28]/[C:26]2[S:27][C:23]([N:20]3[CH2:19][CH2:18][CH:17]([OH:16])[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)/[C:36]#[N:37])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(N2CCC(O)CC2)s1
Agent: O=Cc1ccc(Br)s1
Agent: OC1CCNCC1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)s2)cc1OC
Yield: 49.2 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from 4-hydroxypiperidine (3.03 g) was introduced into 5-bromothiophene-2-carboxaldehyde (1.91 g), to thereby yield 5-(4-hydroxypiperidin-1-yl)-thiophene-2-carbaldehyde (yield: 1.36 g, 64%). The produced 5-(4-hydroxypiperidin-1-yl)-thiophene-2-carbaldehyde (1.27 g) was condensed with 3,4-dimethoxybenzyl cyanide (1.06 g) through Method A (production step 2), to thereby yield the target product (yield: 1.09 g, 50%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])(=[O:13])=[O:12])=[C:6]([CH3:26])[CH:5]=1>C1COCC1>[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:12])=[O:13])=[C:6]([CH3:26])[CH:5]=1
Reactant: COC(=O)CCC1CCCCN1S(=O)(=O)c1cc(C)c(Cl)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)N2CCCCC2CCC(=O)O)c(C)cc1Cl
Temperature: 0 °C

Procedure:
Aqueous NaOH solution (6 M, 100 ml) was added to a solution of methyl 3-(1-(4-chloro-2,5-dimethylphenylsulfonyl)piperidin-2-yl)propionate (12.82 g, 34.3 mmol) in THF (100 ml). After a reaction time of 1 h, the solvent was removed on a rotary evaporator and the residue was cooled to 0° C. HCl (6 M, 100 ml) was added and the mixture was extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated. Yield: 12.36 g, 100%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:36])[CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C@H:26]([CH2:30][C:31]([O:33]CC)=[O:32])[CH2:25][CH2:24]5)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.O.O[Li].O>C1COCC1.C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:36])[CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C@H:26]([CH2:30][C:31]([OH:33])=[O:32])[CH2:25][CH2:24]5)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nccc(-c4ccc5c(c4)OCO5)n3)ccc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)O)c1nccc(-c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[[4-(1,3-benzodioxol-5-yl)-2-pyrimidinyl](methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 292, 35 mg, 0.071 mmol) in THF (2 mL), ethanol (1 mL), and water (2 mL) was added LiOH.H2O (7 mg, 0.29 mmol), and the mixture was stirred at rt for 16 h. The reaction mixture was then extracted with Et2O (2×), organic layers discarded, and the remaining aqueous solution was acidified to pH ˜5 using HCl (1 M aqueous solution). The aqueous solution was then extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to give 9 mg (27%) of the product. 1H NMR (400 MHz, CDCl3): δ 1.70-1.80 (m, 1H), 2.15-2.20 (m, 2H), 2.32-2.50 (m, 2H), 2.71 (dd, 1H), 2.83-2.95 (m, 2H), 3.30 (s, 3H), 3.51-3.64 (m, 1H), 3.72 (q, 2H), 3.99 (t, 2H), 6.00 (s, 2H), 6.62 (d, 1H), 6.54 (s, 1H), 6.80 (d, 2H), 7.05 (d, 1H), 7.61 (s, 2H), 8.30 (d, 1H); LC-MS: RT=2.50 min, (M+H)+ 462.3.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][C:21](=O)[C:22]([F:25])([F:24])[F:23])C>C(O)C>[CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH:13][C:21](=[O:20])[C:22]([F:25])([F:24])[F:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Solvent: CCO
Product: O=C(CC[C@H](NC(=O)C(F)(F)F)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 g (421.5 mmol) of L-glutamic Acid-5-benzyl ester is dissolved in a mixture that consists of 1000 ml of trifluoroacetic acid ethyl ester/500 ml of ethanol, and it is stirred for 24 hours at room temperature. It is evaporated to the dry state, and the residue is crystallized from diisopropyl ether.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:43])([CH3:42])[CH2:6][N:7]([S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32])[CH2:8][C@@H:9]([OH:30])[C@@H:10]([NH:18][C:19](=[O:29])[O:20][C@@H:21]1[C@H:28]2[C@H:24]([O:25][CH2:26][CH2:27]2)[O:23][CH2:22]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.Cl[C:54]([O:56][CH3:57])=[O:55]>C1COCC1>[CH2:11]([C@H:10]([NH:18][C:19](=[O:29])[O:20][C@@H:21]1[C@H:28]2[C@H:24]([O:25][CH2:26][CH2:27]2)[O:23][CH2:22]1)[C@H:9]([OH:30])[CH2:8][N:7]([CH2:6][C:5]([CH3:43])([CH3:42])[CH2:4][CH2:3][CH2:2][NH:1][C:54]([O:56][CH3:57])=[O:55])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCN)c1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCNC(=O)OC)c1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 50 mg (0.081 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-((5-amino-2,2-dimethylpentyl)[3-(methylamino)phenyl]sulfonylamino)-1-benzyl-2-hydroxypropyl]carbamate and 17 μL (0.097 mmol) of N,N-diisopropylethylamine in 4 mL of anhydrous THF at 0° C. was treated with 6.9 μL (0.089 mmol) of methyl chloroformate. The solution was allowed to warm to RT with stirring. After 18 hours the solution was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 54 mg (98%) of the desired compound as a white foam. H1-NMR (CDCl3): 7.28 (m, 6H), 6.99 (d, 1H), 6.89 (s, 1H), 6.71 (dd, 1H), 5.54 (d, 1H), 5.30 (d, 1H), 4.93 (m, 2H), 4.17-3.50 (m, 11H), 3.25-2.60 (m, 12H), 1.60-1.12 (m, 6H), 0.89 (s, 3H), 0.81 (s, 3H). MS(ESI): 677 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.C1CCN2C(=NCCC2)CC1.CN(C)C=O.[F:39][C:40]1[CH:41]=[C:42]2[C@:49]3([C:53](=[O:54])[NH:52][C:51](=[O:55])[NH:50]3)[CH2:48][C@@H:47]([C:56](Cl)=[O:57])[O:46][C:43]2=[CH:44][CH:45]=1>>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]2[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][NH:1][C:56]([C@@H:47]3[CH2:48][C@@:49]4([C:53](=[O:54])[NH:52][C:51](=[O:55])[NH:50]4)[C:42]4[C:43](=[CH:44][CH:45]=[C:40]([F:39])[CH:41]=4)[O:46]3)=[O:57])[CH2:9][CH2:8]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)NCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)Oc3ccc(F)cc32)N1
Temperature: -30 °C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
A mixture of 1-(2-aminoethyl)-4-diphenylmethylpiperazine (10.0 g, 33.9 mmol), 1,8-diazabicyclo[5,4,0]-7-undecene (10.9 g, 71.7 mmol) and N,N-dimethylformamide (90.0 ml, 1.16 mol) was chilled to -30° C. To the mixture was added over 30 minutes a solution of (2S, 4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1, 10.0 g, 33.5 mmol) in N,N-dimethylformamide (90.0 ml, 1.16 mol) and the mixture was stirred for 15 hours at temperature of 15°-25° C. After distilling off the solvent, the reaction mixture was chromatographed on silica gel, eluted with CH2Cl2 /MeOH (9/1) and evaporated in vacuo to dryness to give the desired compound (12.2 g, 65.2%) as colorless amorphous substance.
Reaction SMILES: [CH3:1][NH2:2].O1CCCC1.C[Al](C)C.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]=1[OH:27]>C1(C)C=CC=CC=1>[OH:27][C:16]1[CH:17]=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:19]=[CH:20][C:15]=1[C:14]([NH:2][CH3:1])=[O:13]
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1O
Reactant: CN
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(N2CCOCC2)cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a cooled (0° C.), stirred solution of methylamine in dry tetrahydrofuran (1.27 mL of 2.0 M solution; 2.52 mmol) was slowly added a solution of trimethylaluminum in dry toluene (1.27 mL of 2.0 M solution; 2.52 mmol) via syringe under a nitrogen atmosphere. The resulting solution was allowed to warm to room temperature and stir for 2 hours. To the resulting solution, a solution of the 2-hydroxy-4-morpholin-4-yl-benzoic acid methyl ester (100 mg; 0.42 mmol) in dry toluene (4.0 mL) was added via cannula and the resulting solution was heated to reflux for 2 hours. After cooling to room temperature, the reaction was quenched with the careful addition of 1 N aqueous hydrochloric acid to pH 4. The mixture then was extracted with EtOAc (3×10 mL), and the combined organic layers washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was recrystallized from CH2Cl2— hexanes to provide the amide (93 mg; 93%).